Enediyne to Polyyne: Spontaneity in the Biosynthesis of Uncialamycin and
Intermolecular Trapping of Benzynes Generated from the
Hexadehydro-Diels–Alder Reaction
A DISSERTATION
SUBMITTED TO THE FACULTY OF THE GRADUATE SCHOOL
OF THE UNIVERSITY OF MINNESOTA
Junhua Chen
IN PARTIAL FULFILMENT OF THE REQUIREMENTS
FOR THE DEGREE OF
DOCTOR OF PHILOSOPHY
Thomas R. Hoye, Advisor
August 2016
© Junhua Chen 2016
i Acknowledgements
As my time as a graduate student is coming to an end, I start to reflect on this wonderful journey that is only made possible by the love, tutelage, and support of so many people. First and foremost, I would like to thank my parent, Yongming Chen and Xiaomei Zhou. They were my first teachers, my role models, and the ones to shape who I am now. When I was little, my father would place me on his lap and started to sketch out a three- dimensional perspective of a random object on a piece of paper. In the hindsight, that could have been the initial driving force that ultimately led me to the ubiquitous tetrahedron skeletons in organic chemistry. As a role model, there were countless nights when my father would study coding language to materials for becoming a registered cost engineer. He would always advise me to solve problems independently and understand the underlining logic behind the theories I learned from school. He instilled me with an image of being responsible to his family, his parents, and to his job. I would like to thank my mother for her tremendous dedication to family, her love and support for me to travel across the ocean to pursue my goal, and for taking care of my father and I day by day. I would also thank my extended family of my uncle Yongju, my aunt Shuping, and my cousin Tingliang. They make sure I know they are here in this foreign country when I need them. In addition, I would thank my two roommates during different times in Minnesota and my good friends, Xu Zou and Shengbo Hu, for the laughs and dinner we had together. I would like to thank my advisor, Prof. Thomas R. Hoye, for showing me the art of teaching and his contagious passion for guiding young students. Tom demonstrates what a true scholar is. He always pays great attention to detail, from “How to balance that equation” to frowning at a mechanism that involves a plausible hydrolysis step in an anhydrous solvent, from the thirty-minute analysis of a GC-MS trace at a subgroup meeting to the absolute level of precision for NMR interpretation. He is an extraordinary advisor. Patient and approachable does not suffice to describe him at all. He provides sufficient space for each individual to develop their own professional character, and yet offers enlightening advice to make us better chemists, from registering for the computational chemistry class during my first year, to being less obsessive in a tunnel vision. I cannot say how much Tom has influenced me on teaching and mentoring, as I was surprised to hear myself saying the ii same phrases and the same kind of advice to the undergraduate student I was working with and other new graduate students in the Hoye group. Additionally, I thank Tom for his commitment and advice on my career plan during my later stage in the graduate school. I would also like to thank my committee members, Prof. Joseph Topczewski, William Pomarantz, and Daniel Harki for their patience and suggestion for the final thesis submission, as well as Prof. Wayland Noland and George Barany for their constructive advice throughout my written and oral preliminary examinations. I would like to thank Prof. Jane Wissinger. The experience of working as a lab TA is highly valuable. I appreciate and admire her passion with course innovation. To the faculty members who had taught their courses to me, I thank Prof. Valerie Pierre, Christopher Douglas, Andrew Harned, Christopher Cramer, Steven Kass, and one more time, Tom. Throughout the two additional semesters when I was the course TA for Tom, I was able to reinforce what I learned by creating problems for problem sets, mid-term and final examinations and the useful advice he gave me not as my research advisor, but as an instructor. I would also like to thank Dr. Letitia Yao and all the NMR TAs for maintaining the NMR facilities and their knowledge for data collection. I have the great honor to mentor a highly motivated and talented undergraduate student, Vignesh Palani, for three years, and to witness his growth from an eager freshman to become a mature and insightful chemist with a bright future ahead. Our relationship has evolved from one-way instillation of knowledge and experience to a mutually instructive team. I greatly appreciate his work under all circumstances and it had been a joy to work with him. His contribution to benzyne chemistry has been immensely inspiring and constitutes an important portion of this Thesis and beyond. The development of the HDDA chemistry would have been possible without the endeavor by the original “team benzyne”: Dr. Beeru Baire, Dawen Niu, Patrick, and Brian woods. Their work has paved the foundation on which more elaborated and exotic precursors as well as trapping reactions were designed and implemented. I would also like to thank the senior graduate students of the Hoye group during my time as an immature new graduate student. I thank Dr. Dawen Niu and Patrick Willoughby once again, who were with me on the same subgroup at the beginning, for introducing me the way to conduct iii research in the Hoye group. I thank Dr. Cagui Izgu for showing me how a senior graduate student is focused and productive with research, and his friendship as well. I thank Dr. Matthew Jansma for being a role model not only to me, but many other Hoye group members. His bench skills and hard working have defined an outstanding experimentalist. I also thank other previous Hoye group members Dr. Susan Brown, Mandy Schmit, Susie Emond, and Adam Wohl for creating a positive environment overall within the Hoye group. And for the cordial relationship with the current Hoye group member, I have been having fruitful and pleasant conversations with Sean Ross on our research projects on a daily basis. I would like to thank Severin Thompson for some suggestions on my computational work, and Jutian Zhang for maintaining the essential GC-MS instrument, as well as their friendship to make Smith 415 a great place to stay. I would also like to thank Dr. Andrew Michel for his extraordinary work with the LC-MS, and later Xiao Xiao and Dr. Bryce Sunsdale for their continuing effort under compromised conditions.
iv Abstract
The enediyne natural products are potent antitumor antibiotics. According to the presence of a bicyclo[7.3.0]-dodecadienediyne or a bicyclo[7.3.1]-tridecadiynene unit, they are further divided into nine-membered or ten-membered sumfamilies. Enediynes are capable of causing single or double DNA strand lesion due to their propensity to undergo cycloaromatization reactions to generate 1,4-benzenoid diradical species under biological conditions. We envision that the establishment of the enediyne skeleton of uncialamycin, a ten-membered enediyne, is biosynthetically derived from a linear precursor via an hetero- intramolecular Diels–Alder reaction without enzymatic catalysis. Hence, we aim to synthesize a key intermediate in order to examine this proposal. Meanwhile, a related study on the generic biosynthesis of the nine-membered enediynes had resulted in the serendipitous discovery of the underutilized hexadehydro- Diels–Alder (HDDA) reaction. During such an event, a 1,3-diyne moiety engages an intramolecularly placed alkyne moiety in a formal [4+2]-cycloaddition reaction to produce a fused bicyclic benzyne intermediate, which is subsequently trapped in situ to yield highly substituted benzenoid products. We are dedicated to the investigation of mode of reactivity between the HDDA-generated benzynes and sulfur-based nucleophiles. Thus, consistent with the prior reports, sulfides react with benzyne to form the S-arylsulfonium ylides, which we further utilize in the development of a highly versatile three-component process. We describe the first examples of the reactions between aromatic thioamides and the HDDA-generated benzynes to form dihydrobenzothiazines through an unusual thiolate- relayed 1,3-proton migration of the pivotal ortho-mercaptoaryliminium betaine intermediate. The trapping reaction manifold with thioamide is found to be altered by tuning the electronic property to give rise to 2,2-disubstituted benzothiazoline derivatives. On the other hand, vinyl sulfoxides are shown to participate a tandem three-component reaction the produce ortho-sulfanylaryl ethers and benzooxathiine derivatives. These new trapping reactions are not only rich in mechanistic content, but also show potential in drug discovery industry.
v Table of Contents
Acknowledgement i Abstract iv Table of Contents v List of Figures viii List of Tables xi List of Abbreviations xii Structures are numbered according to the following format: Chapter 1, 1xxx; Chapter 2, 2xxx; … Chapter 7, 7xxx. Part I: Spontaneity in the Biosynthesis of Uncialamycin Chapter 1. Enediyne Natural Products and Their Biosyntheses 2 1.1 The enediyne Natural Products 2 1.2 Mode of Action 4 1.3 Previous Chemical Syntheses of the Ten-Membered Enediyne Core 7 1.4 Previous Studies toward the Biosynthesis of Enediynes in the Pre-genomic Era 12 1.5 Enediyne Gene Clusters 14 1.6 Isolation of Possible Biosynthetic Intermediates 17 1.7 Divergence between Nine-Membered and Ten-Membered Enediyne Warheads 19 Chapter 2. Spontaneity in the Biosynthesis of Uncialamycin 22 2.1 Biosynthetic Hypothesis 22 2.2 Progress toward the Synthesis of the Proposed Biosynthetic Precursor 23 Part II: Intermolecular Trapping of the Benzynes Generated from the Hexadehydro- Diels–Alder Reaction Chapter 3. The Hexadehydro-Diels-Alder Reaction 29 3.1 Early History of Benzyne Chemistry 29 3.2 Synthetic Applications of Benzyne 30 3.3 Discoveries of the Hexadehydro-Diels–Alder Reaction 32 3.4 Resurfacing of the HDDA Reaction 36 3.5 Uncovering New Modes of Reactivity of the HDDA-Generated Benzynes 38 3.6 Mechanistic Insights into the HDDA Reaction 44 Chapter 4. Cycloaddition Reactions of the HDDA-Generated Benzynes 49 4.1 Trapping Reactions of the HDDA-Generated Benzynes with Furans and Pyrroles vi 49 4.2 Additional Types of Cycloaddition Reactions of the HDDA-Generated Benzynes 54 Chapter 5. Trapping Reactions between the HDDA-Generated Benzynes and Sulfides 56 5.1 Sulfonium Ylide Formation 56 5.2 Mechanistic Investigation toward the Ylide Formation 60 5.3 Application of the Ylide Chemistry to Three-Component Reactions 65 5.4 Limitations of Reactant Scope for the Three-Component Reaction 72 Chapter 6. Trapping Reactions between the HDDA-Generated Benzynes and Thioamides 75 6.1 Reactions between Benzyne and Thiocarbonyl Compounds 75 6.2 Discovery of the Reactions between the HDDA-Generated Benzynes and Thioamides 78 6.3 Mechanistic Studies toward the Dihydrothiazine Synthesis 83 6.4 [3+2]-Mode of Reactivity of Benzynes toward Sulfur-Based Nucleophiles 89 6.5 Summary and Prospect 93 Chapter 7. Ongoing and Future Work 97 7.1 Trapping Reactions between the HDDA-Generated Benzynes and Sulfoxides 97 7.1.1 Mode of Reactivity between Benzyne and Sulfoxide 97 7.1.2 Use of Vinyl Sulfoxide in Three-Component Reaction 100 7.2 Dearomatization Strategy 104 7.2.1 Ubiquitous [2+2]-Mode of Addition 104 7.2.2 Computational Consideration Regarding the Possibility of Dearomatization Processes 106 7.3 Review and Prospect on the Development of the HDDA Reaction Precursors 109 7.3.1 Evolution of HDDA Precursors 109 7.3.2 Heteroatom-rich HDDA Precursors 111 7.3.3 Four-Atom-Linked Precursors and Intermolecuar HDDA Reaction 115 7.3.4 Templated HDDA Reaction 117 Part III. Experimental Procedures and Computational Details Chapter 8. Experimental Procedures and Compound Characterization Data 120 General Experimental for Chapters 2, and 4-7 120 8.1 Procedures and Data for Chapter 2 122 vii 8.2 Procedures and Data for Chapter 4 129 8.3 Procedures and Data for Chapter 5 153 8.4 Procedures and Data for Chapter 6 185 8.5 Procedures and Data for Chapter 7 223 Chapter 9. Computational Data 229 Bibliography 278
viii List of Figures
Figure 1 | Representative members of the enediyne natural products. 3 Figure 2 | Mode of action for the NCS chromophore. 4 Figure 3 | Mode of action for the calicheamicins. 5 Figure 4 | Mode of action for uncialamycin. 6 Figure 5 | Incorporation and folding pattern of the 13C-labeled precursors for NCS chromopore, esperamicin aglycon, and dynemicin A. 15 Figure 6 | Architecture and domain organization of enediyne PKSE (adapted from reference 36a). 16 Figure 7 | Production of the heptaene catalyzed by SgcE/SgcE10 in E. coli (adapted from reference 39). 18 Figure 8 | Proposed construction of the ten-membered enediyne core during the biosynthesis of uncialamycin. 23 Figure 9 | Retrosynthetic analysis of the proposed biosynthetic precursor. 24 Figure 10 | Resonance contributors of ortho-benzyne. 29 Figure 11 | Representative traditional methods of benzyne generation. 31 Figure 12 | Prototypical Diels-Alder reactions at various oxidation states: A) a Diels–Alder reaction, B) a didehydro-Diels–Alder reaction, C) a tetradehydro-Diels–Alder reaction, D) a hexadehydro-Diels–Alder reaction. 33
Figure 13 | Intermolecular trapping of the HDDA-generated benzyne: A) the generic mode of trapping reaction in the presence of a non-participating tether, B) examples of intermolecular trapping products derived from the HDDA-generated benzyne. 39 Figure 14 | Concentration dependent competing reactions between ether formation and dihydrogen transfer reaction with cyclohexanol. 41 Figure 15 | Qualitative analysis for the origin of the distortion of unsymmetrically substituted benzynes: A) a generic picture of the molecular orbitals, B) examples of benzynes exhibiting different level of regioselectivity toward intermolecular trapping events. 43 ix Figure 16 | Computed plausible mechanisms for the HDDA reaction (adapted from reference 82). DFT calculation were performed at the B3LYP-D3BJ level of theory. All values are of the enthalpies in kcal/mol. 46 Figure 17 | Computed bimolecular and trimolecular processes between benzyne and methanol (adapted from reference 74). DFT calculations were performed using M062X/6- 311+G(d,p) and the SMD solvation model (methanol). All values are of the free energies in kcal/mol. 56 Figure 18 | Computed intermediates and transition state structures for the ylide formation. DFT calculations were performed using M062X/6-31+G(d,p) and the SMD solvation model (benzene). All values are of the free energies in kcal/mol. 65
Figure 19 | Examples of some compromised three-component reactions: A) ambidence of isatin, B) ambidence of sulfinate, C) complication arising from the reactivity of nitronate and trifluoromethyl ketone, D) ring contraction reaction of the thietane-derived sulfonium ylide. 73 Figure 20 | Fragmentation pathways of some cyclic sulfonium ylides. 74 Figure 21 | Mode of reactivity of benzyne with sulfanyl group and thiocarbonyl group 75 Figure 22 | Computed reaction pathway for the dihydrobenzothiazine formation. DFT calculations were performed using M062X/6-31+G(d,p) and the SMD solvation model (benzene). All values are of the free energies in kcal/mol. 87 Figure 23 | Origin of diastereoselectivity with the dihydrobenzothiazine synthesis. 88 Figure 24 | Computed intermediates and transition state structures to rationalize the regioselectivity with respect to the azomethine ylide formation. DFT calculations were performed using M062X/6-31+G(d,p) and the SMD solvation model (benzene). All values are of the free energies in kcal/mol. 89 Figure 25 | Computed pathways for the reaction between benzyne and N,N- dimethyltrifluorothioacetamide. DFT calculations were performed using M062X/6- 31+G(d,p) and the SMD solvation model (benzene). All values are of the free energies in kcal/mol. 93 Figure 26 | Reaction of benzyne with thiadiazoles: A) regioselective synthesis of benzoisothiazoles, B) computed reaction pathway. DFT calculations were performed using x M062X/6-31+G(d,p) and the SMD solvation model (benzene). All values are of the free energies in kcal/mol. 96 Figure 27 | Computed intermediates for the modes of reaction between benzyne and DMSO. DFT calculations were performed using M062X/6-31+G(d,p) and the SMD solvation model (benzene). All values are of the free energies in kcal/mol. 98 Figure 28 | Computed reaction pathways: A) electrophilic aromatic substitution, B) Wittig rearrangement, C) secondary addition reaction with benzyne, D) a proposed reaction cascade. DFT calculations were performed using M062X/6-31+G(d,p) and the SMD solvation model (benzene). All values are of the free energies in kcal/mol. 108
Figure 29 | Rates of cycloaromatization for different HDDA substrates. In each series except for column D, the precursors are ranked according to the experimental rate of reaction from the highest at the top of the column to the lowest at the bottom. 110 Figure 30 | Debated anthraquinone formation and conformation analysis for the viability of such transformation. 115
xi List of Tables
Table 1 | Substrate scope with respect to various types of linkers (adapted from reference 71). 37 Table 2 | Relative rates of the HDDA reactions for a series of triyne substrates and their comparisons with Hammett constant (sp) and radical-stabilizing energy values. 47 Table 3 | Trapping reactions of the HDDA-generated benzynes with furan. 50 Table 4 | Trapping reactions of the HDDA-generated benzynes with symmetrically substituted. 52 Table 5 | Reactant scope for the three-component reaction. 69 Table 6 | Computed degree of distortion of different benzynes. DFT calculations were performed using M062X/6-31+G(d,p) and the SMD solvation model (benzene). 71 Table 7 | Substrate scope for the aromatic thioamides trapping reaction. 82 Table 8 | Effect of electronic properties of thioamides. 84 Table 9 | Substrate scope with more exotic aromatic thioamides. 90 Table 10 | Degree of aromaticity in the 1,2-bifunctional intermediates. 107 Table 11| Computed overall thermodynamic profile of the dearomatizational Diels–Alder pathways. DFT calculations were performed using M062X/6- 31+G(d,p) and the SMD solvation model (benzene). All values are of the free energies in kcal/mol. 107
xii List of Abbreviations
Ac Acetyl
ACP Acyl transfer protein
Alloc Allyloxycarbonyl
Ar Aryl
AT Acyltransferase
Bn Benzyl
Boc Tert-Butoxycarbonyl
Bu Butyl calE7 Calicheamicin thioesterase gene
CalE7 Calicheamicin thioesterase calE8 Calicheamicin polyketide synthase gene
CalE8 Calicheamicin polyketide synthase
CAN Ceric ammonium nitrate cod Cyclooctadiene
DBU 1,8-Diazabicycloundec-7-ene
DCC N, N’-Dicyclohexylcarbodiimide
DCE 1,2-Dichloroethane
DCM Dichloromethane
DFT Density Functional Theory
DH Dehydrogenase
DIBAL Diisobutylaluminum hydride
DME Dimethoxyethane xiii DMF N,N-Dimethylformamide
DMSO Dimethyl sulfoxide
DNA Deoxyribonucleic acid
DynE8 Dynemicin A polyketide synthase
EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
Et Ethyl
GC-MS Gass phase chromatography mass spectrometry
HDDA Hexadehydro-Diels–Alder reaction
HOBt 1-Hydroxybenzotriazole
HRMS High resolution mass spectrometry
Im Imidazole
IR Infrared spectroscopy iAm Isopentyl
KHMDS Potassium bis(trimethylsilyl)amide or Potassium hexamethyldisilazide
KR Ketoreductase
KS Ketosynthase
LC-MS Liquid phase chromatography mass spectrometry
LiHMDS Lithium bis(trimethylsilyl)amide or Lithium hexamethyldisilazide
LovB Lovastatin nonaketide synthase
LovC Lovastatin enoyl reductase
Me Methyl
MIC Minimal inhibitory concentration
MPLC Medium-pressure liquid chromatrography xiv Ms Methanesulfonyl
NCS Neocarzinostatin ncsE Neocarzinostatin polyketide synthase gene
NcsE Neocarzinostatin polyketide synthase ncsE10 Neocarzinostatin thioesterase gene o-DCB ortho-dichlorobenzene
NMR Nuclear magnetic resonance
NMTD N-Methyltriazolinedione
Nu Nucleophile
Ph Phenyl
Phth Phthaloyl
PKS Polyketide synthase pksE Enediyne polyketide synthase gene
PKSE Enediyne-specific polyketide synthase
PPTase Phosphopantetheinyl transferase
PyBroP Bromotripyrrolidinophosphonium hexafluorophosphate sgcE C-1027 polyketide synthase gene sgcE10 C-1027 thioesterase gene
TBAF Tetrabutylammonium fluoride
TBDPS tert-Butyldiphenylsilyl
TBS tert-Butyldimethylsilyl tBu tert-Butyl
TDDA Tetrahydro-Diels–Alder reaction xv TE Thioesterase
TES Triethylsilyl
Tf Trifluoromethylsulfonyl
TFA Triflroroacetic acid
TIPS Triisopropylsilyl
TLC Thin-layer chromatography
TMEDA Tetramethylethylenediamine
TMS Trimethylsilyl
Tol Toluene
Ts 4-Methylbenzenesulfonyl (Para-toluenesulfonyl) Part I: Spontaneity in the Biosynthesis of Uncialamycin 1
◊ Part I ◊
Spontaneity in the Biosynthesis of
Uncialamycin
Part I: Spontaneity in the Biosynthesis of Uncialamycin 2
Chapter 1. Enediyne Natural Products and Their Biosyntheses
1.1 The Enediyne Natural Products The enediyne natural products are a family of structurally distinctive antibiotics that are produced mainly by soil and marine microorganisms. They are characterized by their unprecedented highly unsaturated enediyne core, remarkable biological activities, and unique mode of action.1,2,3 All of the members in this family structurally fall into one of two categories based on the molecular constitution of their enediyne-containing portion in their chromophores (Figure 1). The nine-membered enediyne chromophores possess a bicyclo[7.3.0]-dodecadienediyne core. Neocarzinostatin (1001) has an epoxide-masked (Z)-1,5-diyn-3-ene moiety and is the first reported enediyne natural product.4 Most nine- membered enediynes require a specific associated protein as a stabilizer and carrier for the chemically unstable chromophore to interact with the target DNA. On the other hand, ten- membered enediynes share a bicyclo[7.3.1]-tridecadiynene core and are isolated in the absence of an apoprotein. Enediyne natural products are some of the most cytotoxic substances ever discovered. For example, C-1027 （1002） shows potent in vitro cytotoxicity against KB
5 carcinoma cells with IC50 of 0.1 ng/mL. The calicheamicins （1003） are extremely active against both Gram-positive and Gram-negative bacteria. 6 , 7 They also exhibit
1 Thorson, J. S.; Shen, B.; Whitwam, R. E.; Liu, W.; Li, Y.; Ahlert, J. Enediyne biosynthesis and self- resistance: a progress report. Bioorg. Chem. 1999, 27, 172-188.. 2 Nicolaou, K. C.; Chen, J. S.; Dalby, S. M. From nature to the laboratory and into the clinic. Bioorg. Med. Chem. 2009, 17, 2290-2303. 3 Shen, B.; Hindra; Yan, X.; Huang, T.; Ge, H.; Yang, D.; Teng, Q.; Rudolf, J. D.; Lohman, J. R. Enediynes: exploration of microbial genomics to discover new anticancer drug leads. Bioorg. Med. Chem. Lett. 2015, 25, 9-15. 4 Ishida, N.; Miyazaki, K.; Kumagai, M.; Rikimaru, M. Neocarzinostatin, an antitumor antibioticum of high molecular weight. J. Antibiot. 1965, 18, 68-76. 5 Sugimoto, Y.; Otani, T.; Oie, S.; Wierzba, K.; Yamada, Y. J. Antibiot. 1990, 43, 417. 6 Lee, M. D.; Manning, J. K.; Williams, D. R.; Kuck, N.; Testa, R. T.; Borders, D. B. Calicheamicins, a Br novel family of antitumor antibiotics. 3. Isolation, purification and characterization of calicheamicins b1 , Br I I I I g1 , a2 , a3 , b1 , and d1 . J. Antibiot. 1989, 42, 1070-1087. 7 Maiese, W. M.; Lechevalier, M. P.; Lechevalier, H. A.; Korshalla, J.; Kuck, N. A.; Fantini, A.; Wildey, M. J.; Thomas, J.; Greenstein, M. Calicheamicins, a novel family of antitumor antibiotics: taxonomy, fermentation and biological properties. J. Antibiot. 1989, 42, 558-563. Part I: Spontaneity in the Biosynthesis of Uncialamycin 3 exceptional potency against murine tumors such as P338 and L1210 leukemias, and solid neoplasms such as colon 26 and B-16 melanoma.8 Dynemicin A （1004） was first reported in 1989. It is structurally reminiscent of the anthracycline antibiotics.9 Dynemicin A and its derivatives also demonstrate promising in vivo antibacterial activities with low toxicity.
Figure 1 | Representative members of the enediyne natural products.
MeO O O O O O N O H OMe O O
O O O Me O Me O Me O O O HO OH Me O Me OH NH MeHN Me2N Cl 2 O HN OH Me O OH HO 1001 1002 OH MeSSS Neocarzinostatin C-1027 chromophore chromophore OH Me O O O OH 1005 Me O O Me O N O Me Uncialamycin H NH O I OH OH O HN CO H S CO2Me O 2 OH O O OMe OMe HO OH OMe O NHEt OH O OH MeO Me 1003 1004 I Me Calicheamicin γ1 Dynemicin A
Uncialamycin (1005) is the most recently discovered member of the enediyne natural products. It was isolated in 2005 from the surface of a lichen Cladonia uncialis in British Columbia. 10 The producing strain is related but not identical to Streptomyces cyanogenus. Like other enediynes, initial investigation revealed that uncialamycin showed extraordinary in vitro activity against Staphylooccus aureus (MIC 0.0000064 µg/mL), E. coli (MIC 0.002 µg/mL), and Burkholderia cepacia (MIC 0.001µg/mL). Uncialamycin
8 Zhao, B.; Konno, S.; Wu, J. M.; Oronsky, A. L. Modulation of nicotinamide adenine dinucleotide and poly(adenosine diphosphoribose) metabolism by calicheamicin ç1 in human HL-60 cells. Cancer Lett. 1990, 50, 141-147. 9 Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki, T.; VanDuyne, G. D.; Clardy, J. Crystal and molecular structure of dynemicin A: A novel 1,5-diyn-3-ene antitumor antibiotic. J. Am. Chem. Soc. 1990, 112, 3715-3716. 10 Davies, J.; Wang, H.; Taylor, T.; Warabi, K.; Huang, X.-H.; Andersen, R. Uncialamycin, a new enediyne antibiotic. Org. Lett. 2005, 7, 5233-5236. Part I: Spontaneity in the Biosynthesis of Uncialamycin 4 bears obvious structural resemblance to dynemicin A (1004), and is the scarcest enediyne isolated so far. 1.2 Mode of Action The consensual mode of action for all enediyne natural products, which include both nine-membered and ten-membered subfamilies, is their ability to induce single- stranded or double-stranded DNA lesions.11 In such a process, the chromophore binds to the minor groove of the target DNA and triggers a series of events to generate a benzenoid diradical species, which then abstracts hydrogen atoms from the deoxyribose phosphate backbone of DNA. Molecular oxygen can quench the resulting radicals to form peroxides, which in turn will decrease DNA replication significantly and ultimately lead to cell death.
Figure 2 | Mode of acition for the NCS chromophore.
O O O O O O O O O O MeO C 2 O OH SH O O MeO2C MeO C OH MeO C OH Myers–Saito 2 DNA 2 H ● ● O S ● S S O cyclization O ● O Ar O Me H O O Ar O Ar O Ar O OH O Sugar O Sugar O Sugar MeHN OH 1001 1006 1007 1008 NCS chromophore
The DNA damaging activity of the free neocarzinostatin chromophore (1001)4 primarily leads to single strand cleavage (Figure 2). The NCS apoprotein binds specifically to the NCS chromophore and delivers the active chromophore to the target DNA by controlled release. 12 The reaction is oxygen dependent 13 and is shown to be greatly
11 Totsuka, R.; Aizawa, Y.; Uesugi, M.; Okuno, Y.; Matsumoto, T.; Sugiura, Y. Biochem. Biophys. Res. Commun. 1995, 208, 168. 12 Jung, G.; Ko¨hnlein, W. Neocarzinostatin: controlled release of chromophore and its interaction with DNA. Biochem. Biophys. Res. Commun. 1981, 98, 176-183. 13 Povirk, L. F.; Goldberg, I. H. Competition between anaerobic covalent linkage of neocarzinostatin chromophore to deoxyribose in DNA and oxygen dependent strand breakage and base release. Biochemistry 1984, 23, 6304-6311. Part I: Spontaneity in the Biosynthesis of Uncialamycin 5 enhanced by thiols14 and UV radiation.15 Myers et al. first suggested the mechanism by which the neocarzinostatin chromophore exerts its biological activity.16 In an in vitro experiment, the vinylogous epoxide opening reaction by methyl thioglycolate17 gave rise to the cumulene 1006. This highly strained intermediate undergoes rapid cycloaromatization via the Myers–Saito reaction to generate the a-dehydrotoluene diradical species 1007, which proceeds with hydrogen atom abstraction from the DNA strand to produce the indene derivative 1008. This thiol triggered pathway was supported by the observation of the cumulene 1006 by NMR spectroscopy at low temperature and the isolation and full characterization of 1008.17b
Figure 3 | Mode of action for the calicheamicins.
O O NHCO2Me O O O NHCO2Me NHCO2Me NHCO Me NHCO2Me HO 2 H HO Bergman ● DNA HO HO HO ● O cyclization H Sugar O Sugar SO S O S O S Sugar Sugar Sugar HS S2Me Nu 1003 1009 1010 1011 1012 I Calicheamicin γ1
The calicheamicins are the most well studied ten-membered enediyne natural 6 I products. The calicheamicin g1 (1003) aglycon (termed calicheamicinone) features a highly functionalized bicyclic carbocycle that contains the signature bicyclo[7.3.1]- tridecadiynene moiety (Figure 3). The aryltetrasaccharide portion of calicheamicin serves to transport and bind in the minor groove of the double helical DNA.18 The reactivity of
14 Kappen, L. S.; Goldberg, I. H. Activation and inactivation of neocarzinostatin-induced cleavage of DNA. Nucleic Acids Res. 1978, 5, 2959-2967. 15 Uesawa, Y.; Kuwahara, J.; Sugiura, Y. Light-induced DNA cleavage by esperamicin and neocarzinostatin. Biochem. Biophys. Res. Commun. 1989, 164, 903-911. 16 Myers, A. G. Proposed structure of the neocarzinostatin chromophore- methyl thioglycolate adduct; a mechanism for the nucleophilic activation of neocarzinostatin. Tetrahedron Lett. 1987, 28, 4493-4496. 17 (a) Myers, A. G.; Proteau, P. J.; Handel, T. M. Stereochemical assignment of neocarzinostatin chromophore - methyl thioglycolate adducts. J. Am. Chem. Soc. 1988, 110, 7212-7214. (b) Myers, A. G.; Proteau, P. J. Evidence for spontaneous, low temperature biradical formation from a highly reactive neocarzinostatin chromophore - thiol conjugate. J. Am. Chem. Soc. 1989, 111, 1146-1147. (c) Hensens, O. D.; Goldberg, I. H. Mechanism of activation of the antitumor antibiotic neocarzinostatin by mercaptan and sodium borohydride. J. Antibiot. 1989, 42, 761-768. 18 Smith, A. L.; Nicolaou, K. C. The enediyne Antibiotics. J. Med. Chem. 1996, 39, 2103-2117. And the references therein. Part I: Spontaneity in the Biosynthesis of Uncialamycin 6 the enediyne motif is locked by the conformational restraint of the bridged bicycle, which is unleashed by the nucleophilic cleavage of the trisulfide trigger. The intramolecular conjugate addition of the resulting thiol within 1009 to the adjacent cyclohexanone causes
Figure 4 | Mode of action for uncialamycin.
Me Me
O HN OH OH HN OH O bioreduction O OH OH
O OH OH OH 1005 1013 epoxide opening Me Me Me
OH HN OH O HN OH + O HN OH HO H2O HO H3O HO
OH OH OH H OH
OH OH OH OH O OH 1015 1014 1016 Bergman Bergman cyclization • cyclization • • • H Me H Me OH HN O HN HO OH HO OH OH OH OH H
OH OH O OH 1017 1018
DNA DNA
H Me H Me H Me OH HN oxidation O HN O HN HO OH HO OH HO OH OH OH OH OH OH H
OH OH O OH O OH 1019 1021 1020 structural reorientation that brings the distal alkynyl carbon atoms of 1010 in proximity for the Bergman cyclization19 to generate the 1,4-benzenoid diradical intermediate 1011. Uncialamycin (1005) is suggested to follow an analogous mode of action to dynemicin A (1004),9 in which the anthraquinone undergoes bioreduction after its
19 Bergman, R. G. Reactive 1,4-dehydroaromatics. Acc. Chem. Res. 1973, 6, 25-31. Part I: Spontaneity in the Biosynthesis of Uncialamycin 7 intercalation into the DNA to produce the anthraquinol 1013 (Figure 4).20 Promoted by the electron-rich aromatic system, the benzylic epoxide is now prone to ring opening. Therefore, the electron-withdrawing anthraquinone portion of uncialamycin serves as a locking device for the ortho-oxiranylaniline moiety that is responsible for triggering its bioactivity. The quinone methide 1014 arising from the ring cleavage can be trapped by a nucleophile such as H2O to form the tetraol 1015 or an electrophile such as hydronium ion to form the triol 1016. Each of these two pathways leads to a less rigid ten-membered carbocycle bearing the (Z)-1,5-diyn-3-ene “warhead” unit, which facilitates the Bergman cycloaromatization reaction to generate the 1,4-benzenoid diradical intermediates 1017 and 1018 requisite for subsequent DNA damage. The cyclized product 1019 resulting from the hydrogen atom abstraction from the DNA along the nucleophilic pathway is likely to undergo re-oxidation.21 Indeed, the experimental observation of both analogs of 1020 and 1021 in the dynemicin series supports the involvement of this proposed mechanism by which uncialamycin exerts its biological properties. 1.3 Previous Chemical Syntheses of the Ten-Membered Enediyne Core Danishefsky et al. reported the first synthesis of the racemic calicheamicinone, in which the key ten-membered carbocycle formation was accomplished by consecutive nucleophilic acetylide addition reactions (Scheme 1).22 With the aldehyde protected in situ as the N-methyl-N-phenyl hemiaminal 1024, the dithio enediyne 1023 selectively added to the elaborated cyclohexadienone 1022 to afford the aldehyde 1025. Following the masking of the nascent tertiary alcohol, the tertiary potassium alkoxide effected the ring closure to forge 1026 with the complete calicheamicinone skeleton.
20 Sugiura, Y.; Shiraki, T.; Konishi, M.; Oki, T. DNA intercalation and cleavage of an antitumor antibiotic dynemicin that contains anthracycline and enediyne cores. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 3831-3835. 21 (a) Semmelhack, M. F.; Gallagher, J.; Cohen, D. Bioreductive alkylations as a trigger for toxic effects of dynemicin. Tetrahedron Lett. 1990, 31, 1521-1522. (b) Nicolaou, K. C.; Dai, W.-M.; Wendeborn, S. V.; Smith, A. L.; Torisawa, Y.; Maligres, P.; Hwang, C.-K. Enediyne compounds equipped with acid-, base-, and photo-sensitive triggering devices. Chemical simulation of the dynemicin A reaction cascade. Angew. Chem., Int. Ed. Engl. 1991, 30, 1032-1036. (c) Nicolaou, K. C.; Dai, W.-M. Molecular design and chemical synthesis of potent enediynes. 2. Dynemicin model systems equipped with C-3 triggering devices and evidence for quinone methide formation in the mechanism of action of dynemicin A. J. Am. Chem. Soc. 1992, 114, 8908-8921. 22 Cabal, M. P.; Coleman, R. S.; Danishefsky, S. J. Total synthesis of calicheamicinone: a solution to the problem of the elusive urethane. J. Am. Chem. Soc. 1990, 112, 3253-3255. Part I: Spontaneity in the Biosynthesis of Uncialamycin 8
Scheme 1 | Ten-membered enediyne core formation in the synthesis of calicheamicinone by Danishefsky et al.
Li Li
OMe OMe O O Br Br O 1023 O Me 1) silylation HO TMSO N LiN(Me)Ph 2) KOCEt MeO MeO Ph CHO 3 Br O Br OLi O O OH 1022 1024 1025 1026
Nicolaou et al. opted to employ a similar ring closure strategy in their total synthesis I 23 of (–)-calicheamicin g1 (1003) (Scheme 2). The enediyne arm was assembled via a Sonogashira coupling reaction between the propargylic acetate 1027 and the cis- chloroenyne 1028. In their case, however, the intramolecular acetylide addition within the aldehyde 1030 gave rise to the undesired diastereomer 1031. Hence, mesylation of the
Scheme 2 | Enediyne core formation in the total synthesis of (–)-calicheamicin.
Cl
TMS O O O O O O O O N NPhth NPhth N 1028 O KHMDS O AcO TESO TESO AcO OH Sonogashira CO Me 2 O CO2Me TMS CO2Me CO2Me MsCl 1027 1029 1030 1031 DMAP, Py
O O O O O O NPhth NPhth NPhth TESO 1) DIBAL TESO TESO OMs 2) NaBH 4 O OH O
HO O MeO 1034 1033 1032
23 (a) Groneberg, R. D.; Miyazaki, T.; Stylianides, N. A.; Schulze, T. J.; Stahl, W.; Schreiner, E. P.; Suzuki, I T.; Iwabuchi, Y.; Smith, A. L.; Nicolaou, K. C. Total synthesis of calicheamicin g1 . 1. Synthesis of the oligosaccharide fragment. J. Am. Chem. Soc. 1993, 115, 7593-7611. (b) Smith. A. L.; Pitsinos, E. N.; Hwang, C.-K.; Mizuno, Y.; Saimoto, H.; Scarlato, G. R.; Suzuki, T.; Nicolaou, K. C. Total synthesis of calicheamicin I g1 . 2. Development of enantioselective route to (–)-calicheamicinone. J. Am. Chem. Soc. 1993, 115, 7612- 7624. (c) Nicolaou, K. C.; C. W. Hummel, Nakada, M.; Shibayama, K.; Pitsinos, E. N.; Saimoto, H.; Mizuno, I Y.; Baldenius, K.-U.; Smith, A. L. Total synthesis of calicheamicin g1 . 3. The final state. J. Am. Chem. Soc. 1993, 115, 7525-7635. Part I: Spontaneity in the Biosynthesis of Uncialamycin 9 incipient secondary alcohol induced the inversion of the stereogenic center by virtue of an intramolecular displacement by the ester motif within 1032. The resulting lactone 1033 was reduced in a two-step sequence to reveal the calicheamicinone framework as the diol 1034. Schreiber et al. reported the synthesis of the truncated analog of dynemicin A 1041 (Scheme 3).24 The enediyne-containing bridged bicycle of dynemicin A was constructed via the macrolactionization reaction of 1035 followed by an transannular Diels–Alder reaction to form the epimeric lactones 1036 and 1037. Allylic oxidation of the thermodynamically more favorable cis-lactone 1037 and the subsequent intramolecular diimide reduction of the tertially alcohol 1038 through the intermediacy of 1039 simultaneously achieved the transposition of the C3-C4 olefin and the C4 stereochemistry.
Scheme 3 | Enediyne core formation via the intramolecular Diels–Alder reaction.
Me Me Me MeO C PyBroP MeO C MeO C 3 CAN MeO C 2 N 2 N Me 2 N 4 2 N + O O OH Et3N H H H H H O H O OH O CO2H H H O OH OMe OMe OMe 1035 1036 1037 1038 DBU 1) MeAlCl2 2) ArSO2NHNH2
Me Me Me MeO C MeO C MeO C 2 N 2 N H 2 N O CO2H O O H N N OMe O O
OMe OMe OMe 1041 1040 1039
Danishefsky et al. utilized the Sonogashira variant of the Castro-Stevens reaction to forge the ten-membered enediyne portion in their first total synthesis of racemic
24 Wood, J. L.; Porco, J. A.; Tauton, J.; Lee, A. L.; Clardy, J.; Schreiber, S. L. Application of the allylic diazene rearrangement: synthesis of the enediyne-bridged tricyclic core of dynemicin A. J. Am. Chem. Soc. 1992, 114, 5898-5900. Part I: Spontaneity in the Biosynthesis of Uncialamycin 10 dynemicin A (Scheme 4). 25 The diphenyl ketal directed diastereoselective acetylide addition to the quinoline 1042 with the activation of methyl chloroformate produced the 2- ethynyl dihydroquinoline 1043. The epoxy bis-iodoalkyne 1044 underwent the desired coupling reaction with the cis-bis-stannylethylene 1045 to complete the A-C ring system of dynemicin A. On the other hand, only the bis-stannyl enyne 1048 arose from the reaction of the bis-iodoalkyne 1047 under the same condition. The contrasting behavior between the bis-iodoalkynes 1044 and 1047 reflects the subtle difference between the acetylenic termini that alters the reactivity of the otherwise analogous substrates.
Scheme 4 | Enediyne core formation in the total synthesis of dynemicin A.
TIPS I
Me Me3Sn SnMe3 OTBS Me Me Me MeO C OAc N TIPSC≡CH MeO C 2 1045 MeO2C O 2 N O Ph N N O O O Ph Ph EtMgBr O OAc Pd(PPh3)4 AcO ClCO2Me AcO OTBS OTBS OTBS OTBS I 1042 1043 1044 1046
I Me3Sn
Me3Sn SnMe3 Me Me MeO C OAc MeO C OAc 2 N 1045 2 N
OAc Pd(PPh3)4 OAc
OTBS OTBS I SnMe3 1047 1048
Myers et al. integrated the key bond forming events from the synthetic efforts by Danishefsky et al. and Nicolaou et al (Scheme 5). in their total synthesis of (+)-dynemicin A. 26 The diastereoselectivity acetylide addition of the enediyne 1050 to the AllocCl
25 Yoon, T.; Shair, M. D.; Danishefsky, S. J.; Shulte, G. K. Experiments directed toward a total synthesis of dynemicin A: a solution to the stereochemical problem. J. Org. Chem. 1994, 59, 3752-3754. (b) Shair, M. D.; Yoon, T.; Danishefsky, S. J. A remarkable cross coupling reaction to construct the endyne linkage relevant to dynemicin A: synthesis of the deprotected ABC system. J. Org. Chem. 1994, 59, 3755-3757. (c) Shair, M. D.; Yoon, T.; Danishefsky, S. J. Total synthesis of (±)-dynemicin A. Angew. Chem. Int. Ed. Engl. 1995, 34, 1721-1723. 26 Myers, A. G.; Tom, N. J.; Fraley, M. E.; Cohen, S. B.; Madar, D. J. A convergent synthetic route to (+)- dynemicin A and analogs of wide structural variability. J. Am. Chem. Soc. 1997, 119, 6072-6094. Part I: Spontaneity in the Biosynthesis of Uncialamycin 11 activated quinoline 1049 was controlled by the chelate 1051. The resulting dihydroquinoline was converted to the ketone 1053 through functional group manipulations to reveal the ketone 1053, which readily cyclized via the cerium acetylide to furnish the advanced intermediate 1054. Nicolaou et al. accomplished the total syntheses of both the racemic and naturally occurring enantiomer of uncialamycin (Scheme 6).27 Analogous to the synthesis of (+)-
Scheme 5 | Enediyne core formation in the total synthesis of (+)-dynemicin A.
TBS H
Me Me TBS Alloc Me Me N N 1050 Alloc Alloc OMe OMe N N O OMe OMe OMe OMe OH EtMgBr, AllocCl O Mg OMe OMe OH O OTBS OTBS X OTBS OTBS 1049 1051 1052 1053 KHMDS CeCl3
Me Alloc N O OMe HO MeO
OTBS 1054 dynemicin A, the strategic bond forming steps in the construction of the uncialamycin skeleton included an intermolecular nucleophilic addition of an acetylide to the AllocCl activated quinoline 1055 and the anthraquinone portion was assembled via a Hauser annulation reaction. The dihydroquinoline 1057 was carried forward to produce the epoxy aldehyde 1058, which then proceeded via an intramolecular diastereoselective acetylide addition by exposure to KHMDS to form the epoxy alcohol 1059 with a fully functionalized enediyne motif. Oxidative dearomatization of 1059 and removal of the
27 (a) Nicolaou, K. C.; Zhang, H.; Chen, J. S.; Crawford, J. J.; Pasurooni, L. Total synthesis and stereochemistry of uncialamycin. Angew. Chem. Int. Ed. 2007, 46, 4704-4707. (b) Nicolaou, K. C.; Chen, J. S.; Zhang, H.; Montero, A. Asymmetric synthesis and biological properties of uncialamycin and 26-epi- uncialamycin. Angew. Chem. Int. Ed. 2008, 47, 185-189. (c) Nicolaou, K. C.; Wang, Y.; Lu, M.; Mandal, D.; Pattanayak, M. R.; Yu, R.; Shah, A. A.; Chen, J. S.; Zhang, H.; Crawford, J. J.; Pasurooni, L.; Poudel, Y. B.; Chowdari, N. S.; Pan, C.; Nazeer, A.; Gangwar, S.; Vite, G.; Pitsinos, E. N. J. Am. Chem. Soc. 2016, 138, 8235-8246. Part I: Spontaneity in the Biosynthesis of Uncialamycin 12 Alloc group from the resulting methyl hemiaminal afforded the labile iminoquinone 1060, which was in turn submitted to the Hauser annulation condition with the cyanophthalide 1061 in the presence of LiHMDS. In this event, the enolate of 1061 proceeded with a conjugate addition to the enone moiety in 1060 and the resulting ketone enolate 1062 underwent a Dieckman condensation to give rise to the anthraquinone 1064 via the bicylic intermediate 1063. Deprotection of the TES ether would then lead to uncialamycin. The convergent nature of this synthetic route is amenable to preparation of novel analogues of uncialamycin for further biological tests and drug development.
Scheme 6 | Total synthesis of (+)-uncialamycin.
Me TMS H Me Me N Me O H 1056 TMS KHMDS AllocN AllocN OTES AllocN OTES O O O OTES EtMgBr, AllocCl CeCl CHO 3 OH OTES ODMB DMBO OH OH 1055 1057 1058 1059
CN
O
Me Me O Me 1061 CN HN OTES CN N OTES N OTES O O O OH LiHMDS O O OH OH O
O O O O 1063 1062 1060
Me Me 3HF•Et N O HN OTES 3 O HN O O OH OH OH
O OH O OH 1064 1005 Uncialamycin
1.4 Previous Studies toward the Biosynthesis of Enediynes in the Pre-genomic Era The biosynthetic origin of the enediyne natural products, and in particular, of the enediyne warheads, has aroused great amount of interest due to their highly unusul molecular structure and phenomenal biological activity. Schreiber et al. postulated that a highly unsaturated branched species like 1065 might be a plausible biosynthetic precursor Part I: Spontaneity in the Biosynthesis of Uncialamycin 13 for the ten-member enediynes (Scheme 7).28 They further achieved an intramolecular Diels-Alder reaction of the acyclic diyntetraene 1066 to produce the cycloadduct 1067 that bears the calicheamicin/esperamicin enediyne core skeleton (cf. 1035). An initial foray into the biosynthesis of NCS chromophore (1001) by Hensen et al. revealed the origin of its all carbon atoms on the basis of the incorporation of 13C-labeled acetate in the feeding experiments (Figure 5).29 Culturing with doubly and mixed labeled acetate established the pattern of assembly of these acetate groups in a head-to-tail fashion (1068), which was indicative of a linear precursor like 1069.
Scheme 7 | Chemical synthesis of the ten-membered enediyne core via an intramolecular DielsAlder reaction.
OMe OMe CO2Me CO2Me TBSO ArSSAr TBSO ● H H H H H PhH, 80 ºC
OR 1065 1066 1067
A similar series of isotopic labeling experiments with the esperamicin-producing Actinomadura verrusospora indicated that the enediyne portion of the esperamicin aglycon 1070, which conincidentally is identical to calicheamicinone, is also assembled from seven acetate units in a head-to-tail fashion from a linear progenitor like 1072.30 In this instance, the two carbon atoms constituting each acetylene motif originate from different acetate units whereas the two carbon atoms constituting each acetylene motif in NCS chromophore originate from the same acetate unit. The yield of esperamicin A1 was significantly reduced by the presence of cerulenin as an inhibitor for the b-ketosynthase (KS) domain of both fatty acid synthase (FAS) and polyketide synthase (PKS). However, supplementing the
28 Schreiber, S. L.; Kiessling, L. L.; Synthesis of the bicyclic core of the esperamicin/calichemicin class of antitumor agents. J. Am. Chem. Soc. 1988, 110, 631-633. 29 Hensens, O. D.; Giner, J. L.; Goldberg, I. H. Biosynthesis of NCS Chrom A, the chromophore of the antitumor antibiotic neocarzinostatin J. Am. Chem. Soc. 1989, 111, 3295-3299. 30 Lam, K. S.; Veitch, J. A.; Golik, J.; Krishnan, B.; Klohr, S. E.; Volk, K. J.; Forenza S.; Doyle, T. W. Biosynthesis of esperamicin A1, an enediyne antitumor antibiotic. J. Am. Chem. Soc. 1993, 115, 12340- 12345. Part I: Spontaneity in the Biosynthesis of Uncialamycin 14 culture with oleate did not restore the esperamicin A1 production. These observations provided early insights that the enediynes are of polyketide origin. Tokiwa et al. reported the results of 13C labeling experiments with the dynemicin A (1004) producing Micromonospora chersina M956-1. 31 The C5 carboxylic acid is unexpectedly derived from the methyl group of a separate acetate. The O-methyl group is most likely transferred from methionine via a late stage methylation event. However, the origin of the nitrogen atom remained unknown. The head-to-head connectivity between C8 and C9 revealed by the doubly labeled experiment indicated that the enediyne and the anthraquinone portions are biosynthesized as two separate heptaketides like 1074 and assembled at a later stage. There has been no reported biogenetic studies on uncialamycin presumably due to its low natural abundance. An analogous schematic analysis to that of dynemicin A would lead to the head-to-head assembly of a heptaketide and a hexaketide like 1076, in which the two carbon atoms of each acetylenic group would be derived from the same acetate unit. This pattern of connectivity, however, is contradictory to what isotopic labeling experiments had established with esperamicin and dynemicin A with respect to the origin of the acetylenic units of the enediyne core.10 1.5 Enediyne Gene Clusters Isolation of C-1027 chromoprotein complex by Shen et al. led to the localization of the C-1027 gene cluster.32 Meanwhile, Thorson et al. identified the gene locus for chalicheamicin biosynthesis by screening the clones that are capable of conferring calicheamicin resistance to M. echinospora.33 In 2002, Shen et al. and Thorson et al.
31 Tokiwa, Y.; Miyoshi-Saitoh, M.; Koyabashi, H.; Sunaga, R.; Konishi, M.; Oki, T.; Iwasaki, S. Biosynthesis of dynemicin A, a 3-ene- 1,5-diyne antitumor antibiotic. J. Am. Chem. Soc. 1992, 114, 4107- 4110. 32 Liu, W.; Shen, B. Antimicrob. Agents Chemother. 2000, 44, 382-392. 33 (a) Thorson, J. S.; Sievers, E. L.; Ahlert, J.; Shepard, E.; Whitwam, R. E.; Onwueme K. C.; Ruppen, M. Curr. Pharm. Des. 2000, 6, 1841-1879. (b) Thorson, J. S.; Shen, B.; Whitwam, R. E.; Liu, W.; Li, Y.; Ahlert, J. Enediyne biosynthesis and self-resistance: a progress report. Bioorg. Chem. 1999, 27, 172-188. (c) Whitwam, R. E.; Ahlert, J.; Holman, T. R.; Ruppen. M.; Thorson, J. S. The gene calC encodes for a non- heme iron metalloprotein responsible for calicheamicin self-resistance in Micromonospora. J. Am. Chem. Soc. 2000, 122, 1556-1557. Part I: Spontaneity in the Biosynthesis of Uncialamycin 15
Figure 5 | Incorporation and folding patterns of the 13C-labeled precursors for NCS chromophore, esperamicin aglycon, and dynemicin A.
O O O O ■ ■
● ● ■ ■ ● ● O ● ● ■ ■ ■ ■ ● ● ● ● Ar O Me ■ ■ O ● ■ ● ■ O ● ● ■ ■ OH MeHN OH 1001 1068 1069 NCS chromophore
O ● ● NHCO2Me ■ ■ ■ ■ HO ● ■ ● ■ ● ■ ● ■ ● ● ● ● ■ ■ ● ● ■ ■ ■ ■ ● ● OH ■ ■ MeSSS 1070 1071 1072 Esperamicin aglycon (calicheamicinone)
■ ■ ● ● ● ● ■ ■ Me ■ ■ ● ■ ● ■ OH O HN ● ● 5 CO H ● ● 2 ■ ■ O HN ■ ■ ■ ■ 8 9 ■ ■ ■ ● ■ ■ ■ ■ ● ■ OMe ● ● ● ● ● ● ● ● ● ● ▲ ■ ■ ■ ■ O ■ ■ ■ ■ ● ● ● ● ● ● OH O OH 1004 1073 1074 Dynemicin A
■ ■ ● ● ● ● ■ ■ Me ■ ■ ● ■ ● ■ ● ● O HN ● ● O OH HN ■ ■ OH ■ ■ ■ ● ■ ■ ■ ■ ● ■ ● ● ● ● ● ● ● ●
■ ■ ■ ■ ■ ■ ■ ■ ● ● ● ● ● ● O OH 1005 1075 1076 Uncialamycin O 13 ● = [1,2- C]-CH3CO2Na NaO ■ Part I: Spontaneity in the Biosynthesis of Uncialamycin 16 completed the sequencing and partial annotation of gene clusters for C-1027 and calicheamicin respectively.34,35 Although C-1027 and the calicheamicins do not share any common peripheral motif, these two gene clusters contain a pair of PKS genes (calE8 and sgcE) that encode two single-module PKSs with high sequence homology and identical domain organization (Figure 6). On the basis of this conserved architecture of the enediyne biosynthetic gene clusters featuring the enediyne-specific PKS, sequencing of the gene clusters for NCS, maduropeptin, and dynemicin was accomplished over the following years.36,37 These gene clusters all share one common PKS gene in spite of the diversity of the enediyne peripheral structures, which implicates its involvement in the biosynthesis of the enediyne warhead.
Figure 6 | Architecture and domain organization of enediyne PKSE (adapted from reference 36a).
No. aa: 461 329 72 250 143 344
NsE (1977 aa) KS AT (ACP) KR DH PPTase
% Identify/% Homology: 80/89 66/74 73/84 69/79 82/86 67/78
No. aa: 460 329 71 250 143 344
SgcE (1939 aa) KS AT (ACP) KR DH PPTase
% Identify/% Homology: 79/86 54/64 63/81 62/72 57/70 47/58
No. aa: 460 331 71 251 145 344 CalE8 (1919 aa) KS AT (ACP) KR DH PPTase
34 Liu, W.; Christenson, S. D.; Standage, S.; Shen, B. Biosynthesis of the enediyne antitumor antibiotic C- 1027. Science 2002, 297, 1170-1173. 35 Ahlert, J.; Shepard, E.; Lomovskaya, N.; Zazopoulos, E.; Staffa, A.; Bachmann, B. O.; Huang, K.; Fonstein, L.; Czisny, A.; Whitwam, R. E.; Farnet, C. M.; Thorson, J. S. The calicheamicin gene cluster and its iterative type I enediyne PKS. Science 2002, 297, 1173-1176. 36 (a) Van Lanen, S. G.; Shen, B. Biosynthesis of enediyne antitumor antibiotics. Curr. Top. Med. Chem. 2008, 8, 448-459. (b) Liang, Z.-X. Complexity and simplicity in the biosynthesis of enediyne natural products. Nat. Prod. Rep. 2010, 27, 499-528. 37 (a) Liu, W.; Nonaka, K.; Nie, L. P.; Zhang, J.; Christenson, S. D.; Bae, J.; Van Lanen, S. G.; Zazopoulos, E.; Farnet, C. M.; Yang C. F.; Shen, B. The neocarzinostatin biosynthetic gene cluster from Streptomyces carzinostaticus ATCC 15944 involving two iterative type I polyketide synthases. Chem. Biol. 2005, 12, 293- 302. (b) Gao, Q.; Thorson, J. S. FEMS Microbiol. Lett. 2008, 282, 105-114. (c) Van Lanen, S. G.; Oh, T. J.; Liu, W.; Wendt-Pienkowski, E.; Shen, B. Characterization of the maduropeptin biosynthetic gene cluster from Actinomadura madurae ATCC 39144 supporting a unifying paradigm for enediyne biosynthesis J. Am. Chem. Soc. 2007, 129, 13082-13094. Part I: Spontaneity in the Biosynthesis of Uncialamycin 17 Bacterial polyketide biosynthesis typically follows one of the three paradigms: a noniterative modular PKS (type I), a multienzyme complex of iterative PKSs (type II), or an iterative acyl transfer protein (ACP) independent PKS (type III). 38 However, the enediyne PKS family (PKSE) represents an alternative pathway of polyketide biosynthesis that uses a single set of catalytic domains in resemblance to a family of fungal iterative type I PKS. Disruption of the C-1027 PKS SgcE in the C-1027 producer abolished the production of C-1027, which was restored by supplementing sgcE containing plasmid.34 The homologous NCS PKS NcsE exhibited identical results. The PKSE consists of four domains in the order of N-terminus to C-terminus: a ketosynthase (KS), an acyltransferase (AT), a ketoreductase (KS), and a dehydrogenase (DH). An internal region between the AT and the KR was assigned as an ACP domain and the C-terminal domain was proposed to be a phosphopantetheinyl transferase (PPTase) responsible for initiating the polyketide biosynthesis. The identities of these two domains were later confirmed by Shen et al.39 and Liang et al.40 1.6 Isolation of Possible Biosynthetic Intermediates Shen et al. were able to isolate the conjugated pentadecaheptaene 1078 when the C-1027 PKS gene sgcE was coexpressed with its cognate thioesterase (TE) gene sgcE10 in E. coli as a heterologous host.39 Coexpression of the NCS PKS gene ncsE with its corresponding TE gene ncsE10 produced the same product. The heptaene 1078 was postulated to arise from the decarboxylative dehydration of the hexaen-b- hydroxycarboxylate 1077, which in turn would be offloaded from the ACP-anchored hydroxythioester by the thioesterase (Figure 7).
38 (a) Wenzel, S. C.; Müller, R. Formation of novel secondary metabolites by bacterial multimodular assembly lines: deviations from textbook synthetic logic. Curr. Opin. Chem. Biol. 2005, 9, 447-458. (b) Shen, B. Polyketide biosynthesis beyond the type I, II, and III polyketide synthase paradigms. Curr. Opin. Chem. Biol. 2003, 7, 285-295. 39 Zhang, J.; Van Lanen, S. G.; , Ju, J.; Liu, W.; Dorrestein, P. C.; Li, W.; Kelleher, N. L.; Shen, B. A phosphopantetheinylating polyketide synthase producing a linear polyene to initiate enediyne antitumor antibiotic biosynthesis. Proc. Natl. Acad. Sci. USA 2008, 105, 1460-1465. 40 (a) Murugan, E.; Liang, Z.-X. FEBS Lett. 2008, 582, 1097-1103. (b) Quadri, L. E. N.; Weinreb, P. H.; Lei, M.; Nakano, M. M.; Zuber, P.; Walsh, C. T. Characterization of Sfp, a bacillus subtilis phosphopantetheinyl transferase for peptidyl carrier protein domains in peptide synthetases Biochemistry, 1998, 37, 1585-1595. Part I: Spontaneity in the Biosynthesis of Uncialamycin 18
Figure 7 | Production of the heptaene catalyzed by SgcE/SgcE10 in E. coli (adapted from reference 39).
O ● + KS AT ACP KR DH PPT + TE NaO ■ SH
O ■ ■ ■ ■ ■ ■ ■ ■ ● ● ● ● ● ● ● ● O OH 1077
– CO2 – H2O
■ ■ ■ ■ ■ ■ ■ ■ ● ● ● ● ● ● ● 1078
Meanwhile, Liang et al. reported the isolation of the pentadecenone 1083 when the calicheamicin PKS gene calE8 was coexpressed with the TE gene calE7 in E. coli.41 Incubation of purified CalE8 and CalE7 with acetyl CoA, malonyl CoA and NADPH in an in vitro experiment further identified three pyrone derivatives 1086-1088. The formation of these products can be rationalized with the expected functions of CalE8 and CalE7. Seven rounds of PKS-catalyzed Claisen condensation in an iterative manner with concomitant ketoreduction and dehydration would produce the ACP-bound hexaen-b- ketothioester 1080. The b-ketocarboxylate 1081 would be released by CalE7 and give rise to the methyl ketone 1083 via decarboxylation of the b-ketoacid 1082. The pyrone products would result from premature offloading of the ACP-bound intermediate b-ketothioesters 1079 and subsequent cyclization. Townsend et al. further observed the heptaene 1078 (Scheme 7, cf. Figure 8), the labile b-ketoacid 1082, and triacetic acid lactone (1085) in addition to the hexaenyl ketone 1083 during their in vitro experiment with CalE8 and CalE7 in E coli.42 In a unifying scheme, the PKS-tethered b-ketothioester would proceed via one more round of
41 Kong, R.; Goh, L. P.; Liew, C. W.; Ho, Q. S.; Murugan, E.; Li, B.; Tang, K.; Liang, Z.-X. Characterization of a Carbonyl-Conjugated Polyene Precursor in 10-Membered Enediyne Biosynthesis. J. Am. Chem. Soc. 2008, 130, 8142-8143. 42 Belecki, K.; Crawford, J. M.; Townsend, C. A. Production of octaketide polyenes by the calicheamicin polyketide synthase calE8: implications for the biosynthesis of enediyne core structures. J. Am. Chem. Soc. 2009, 131, 12555-12556. Part I: Spontaneity in the Biosynthesis of Uncialamycin 19 ketoreduction and dehydration to generate the corresponding b-hydroxythioester 1084, which upon CalE7-catalyzed hydrolysis and decarboxylative dehydration would lead to 1078. Townsend et al. speculated the lack of detection of 1078 and 1082 was most likely due to the TFA quench by Liang et al. 1.7 Divergence between Nine-Membered and Ten-Membered Enediyne Warheads. The variety of products observed in the in vitro experiments by Liang et al. and Townsend et al. indicated that the apparent catalytic difference between nine-membered and ten-membered PKSE may be an artifact of assay conditions and that CalE8 may be missing some required accessory enzymes. In a strikingly similar instance of lovastatin biosynthesis, the lovastatin nonaketide synthase (LovB) releases conjugated hexa- and heptaketide derived pyrone aberrant products in the absence of LovC, a trans-acting enoyl reductase.43 With optimized in vitro reaction conditions, Liang et al. further observed both 1078 and 1083 as major products in nine-membered and ten-membered PKSE/TE systems,44 which juxtaposed the consistent in vivo production of 1078 reported by Shen et al (Scheme 8).39 The advantage of in vivo methods may therefore represent the difficulties with reconstructing the large multifunctional PKSE megaenzymes under in vitro conditions. In a more systematic study, Shen et al. identified the heptaene 1078 as the only major product by coexpressing the pair of pksE gene with its cognate TE gene from each of the five sequenced enediyne gene clusters in E. coli.45 They continued to show that 1078 was also produced by PKSE/TE coexpression in Streptomyces lividans K4-114, a host more closely related to the enediyne native producers, and finally, in all of the native producers tested. They further demonstrated that all five TEs were interchangeable with all five PKSEs to yield 1078 from all twenty possible mismatched PKSE/TE combinations in
43 (a) Ma, S. M.; Li, J. W. H.; Choi, J. W.; Zhou, H.; Lee, K. K. M.; Moorthie, V. A.; Xie, X.; Kealey, J. T.; Da Silva, N. A.; Vederas, J. C.; Tang, Y. Competing reconstitution of a highly reducing iterative polyketide synthase. Science, 2009, 326, 589-592. (b) Kennedy, J.; Auclair, K.; Kendrew, S. G.; Park, C.; Vederas, J. C.; Hutchinson, C. R. Modulation of polyketide synthase activity by accessory proteins during lovastatin biosynthesis. Science, 1999, 284, 1368-1372. 44 Sun, H.; Kong, R.; Zhu, D.; Lu, M.; Ji, Q.; Liew, C. W.; Lescar, J.; Zhong, G.; Liang, Z.-X. Products of the iterative polyketide synthases in 9- and 10-membered enediyne biosynthesis. Chem. Comm. 2009, 7399-7401. 45 Horsman, G. P.; Chen, Y.; Thorson, J. S.; Shen. B. Polyketide synthase chemistry does not direct biosynthetic divergence between 9- and 10-membered enediynes. Proc. Natl. Acad. Sci. USA 2010, 107, 11331-11335. Part I: Spontaneity in the Biosynthesis of Uncialamycin 20 E. coli and S. lividans K4-114. Therefore, it became clear that nine-membered and ten- membered systems do not bifurcate under the PKS machinery.
Scheme 8 | Production of various biosynthetic intermediates in the in vitro experiment with CalE8/CalE7 in E. coli (adapted from reference 42).
Cal SH E8
Mal–CoA NADPH HO O Mal–CoA ) Me ) Me n Cal n ( S ( E8 O O O 1079 1085-1088 n = 0-3 Mal–CoA NADPH O O ) Me NADPH ) Me Cal 6 Cal 6 S ( S ( E8 E8 O KR domain HO 1080 1084 Cal Cal E7 E7 O O O )6Me )6Me )6Me O ( HO ( O ( O O HO 1081 1082 1077
– CO2 – CO2 – H2O Me Me )6 ) Me ( ( 6 O 1083 1078
Townsend et al. further argued that the free heptaene 1078 might not be a true precursor of the enediyne cores based on an earlier observation that only the nine- membered pksE genes, but not calE8, were able to restore C-1027 and NCS production in pksE null mutants. More recently, they reported that expression of CalE8 alone in E. coli in dark followed by nonenzymatic release of the intermediates with cysteamine led to the isolation of the b-hydroxyacid 1077 as the major product.46 The in vivo production of 1077 provided evidence of programmed control of polyketide processing by CalE8 during the last round of chain extension. Selective preservation of the b-hydroxy group terminates the polyene conjugation at the carbinol position, which is the single common carbon atom
46 Belecki, K.; Townsend, C. A. Angew. Chem. Int. Ed. 2012, 51, 11316-11319. Part I: Spontaneity in the Biosynthesis of Uncialamycin 21 involved in the cyclization manifold for all enediyne members. Collectively, they believed that the PKS-bound b-hydroxythioester 1084 is a native intermediate in the biosynthesis of calicheamicin, and that it represents the last common intermediate in enediyne biosynthesis and serves as the branching point for downstream divergence.47
47 Belecki, K.; Townsend, C. A. J. Am. Chem. Soc. 2013, 135, 14339-14348. Part I: Spontaneity in the Biosynthesis of Uncialamycin 22
Chapter 2. Spontaneity in the Biosynthesis of Uncialamycin
2.1. Biosynthetic Hypothesis Although the 13C labeling experiments established the polyketide origin of the anthraquinone portion of dynemicin A,31 the gene cluster of dynemicin does not contain a second pksE that encodes a separate PKS for anthraquinone biosynthesis.37b With the recent report of an iterative PKS by Tkacz et al. that generates 6-methylsalicylic acid as well as benzophenone,48 it is interesting to probe the possibility that the dynemicin PKS DynE8 may be regulated to generate different products. With the advance in the understanding of enediyne biosynthesis in the genomic era, little has been uncovered regarding the late-stage modification to arrive at the fully elaborated enediyne core. Some of the pivotal questions and speculations include the identification of the putative acetylases,49 the phase at which cyclization events occur, the determining factors that direct the divergence between nine-membered versus ten- membered warhead, and the mechanism of chain truncation for nine-membered enediynes. In light of the collective progress in the investigation of the biosynthesis of enediynes, we envision a spontaneous event in the biosynthesis of uncialamycin (1005) (Figure 8). With the lack of report on genes that encode any specific enzymes in the involvement of the post-PKS transformations so far, we propose that the formation of the strained bicyclo[7.3.1]-tridecadiynene moiety in uncialamycin does not require enzyme catalysis. Specifically, we envision a late stage converged biosynthetic intermediate like 2001, in which the ortho-aminostyrene oxide moiety could undergo an acid-catalyzed ring opening reaction to produce the iminoquinone methide 2002. This reactive intermediate,
48 Lu, P.; Zhang, A.; Dennis, L. M.; Dahl-Roshak, A. M.; Xia, Y. Q.; Arison, B.; An, Z.; Tkacz, J. S. Mol. Genet. Genomics 2005, 273, 207-216. 49 Fox, B. G.; Lyle, K. S.; Rogge, C. E. Reactions of the diiron Enzyme stearoyl-acyl carrier protein desaturase. Acc. Chem. Res. 2004, 37, 421-429. (b) A. S. Carlsson, S. Thomaeus, M. Hamberg and S. Stymne, Eur. J. Biochem. 2004, 271, 2991-2997. (c) Fox, B. G.; Shanklin, J.; Somerville, C.; Munck, E. Stearoyl-acyl carrier protein delta 9 desaturase from Ricinus communis is a diiron-oxo protein. Proc. Natl. Acad. Sci. USA. 1993, 90, 2486–2490. (d) Reed, D. W.; Polichuk, D. R.; Buist, P, H.; Ambrose, S. J.; Sasata, R. J.; Savile, C. K.; Ross, A. R. S.; Covello, P. S. Mechanistic study of an improbable reaction: alkene dehydrogenation by the Δ12 acetylenase of Crepis alpine. J. Am. Chem. Soc. 2003, 125, 10635-10640. Part I: Spontaneity in the Biosynthesis of Uncialamycin 23
once formed, would proceed via an intramolecular hetero-Diels–Alder reaction as a key event in our biosynthetic hypothesis. The viability of this step would be driven by the thermodynamically favorable rearomatization of the iminoquinone methide. Schreiber’s intramolecular Diels-Alder reaction (cf. 1035 to 1036 and 1037, Scheme 3; 1066 to 1067, Figure 5) lends support in terms of the geometric accessibility of such a process as well.24,28 The configuration of the disubstituted epoxide in 2001 would in turn dictate the diastereoselectivity for the transition state structure 2002* by virtue of the A-1,3-strain argument during the cycloaddition reaction. The resulting cycloadduct 2003 bears the essential framework of uncialamycin only lacking the tetrasubstituted epoxide functionality. Subsequent enzyme-catalyzed oxidation reactions would furnish uncialamycin.
Figure 8 | Proposed construction of the ten-membered enediyne core during the biosynthesis of uncialamycin.
HO HO OH HO Me Me Me O H H O NH2 NH HN IMDA HN oxidation O HN O H R Me O OH OH OH H
O OH OH OH OH O OH 2001 2002 2002* 2003 1005 Uncialamycin
2.2 Progress toward the Synthesis of the Proposed Biosynthetic Precursor In order to maintain the acid sensitive ortho-aminostyrene oxide functionality over the course of the chemical synthesis of 2001, we envision the synthesis of the aryl azide 2004, the Staudinger reduction50 of which would reveal the aniline motif under mildly basic condition. The unsaturated arm of 2004 would in turn be forged via a Sonogashira reaction between the propargylic epoxide 2005 and the cis-vinyl chloride 2006. Although only one of the enantiomers of each coupling partner are needed for the synthesis of 2004, we aimed for their racemic mixtures 2007 and 2008 at the early stage of the development
50 (a) Staudinger, H.; Meyer, J. Über neue organische Phosphorverbindungen III. Phosphinmethylenderivate und Phosphinimine. Helv. Chim. Acta. 1919, 2, 635. (b) Gololobov, Y. G. Sixty years of Staudinger reaction. Tetrahedron 1981, 37, 437-472. Part I: Spontaneity in the Biosynthesis of Uncialamycin 24
Figure 9 | Retrosynthetic analysis for the proposed biosynthetic precursor.
O N 3 O HO HO HO HO Cl Me 2006 Me Me O OH Me Cl O NH2 O N3 O N3 2007 2008 O O O O
O N O NH 3 O 2 O OH O OH O OH Br 2001 2004 2005
O OH O OH 2009 2010 toward their viable syntheses. The acetylenic motif of 2007 would be forged via an Ohira- Bestmann reaction51 of the epoxy aldehyde 2009, the three-carbon unit of which would be installed by a cross coupling reaction with the anthraquinonyl bromide 2010 (Figure 9).
Scheme 9 | Synthesis of the racemic cis-vinyl chloride.
TMS TMS Cl 1) TBSCl. Im Cl Cl HO CuI, TMEDA LiAlH4 DMF Pd(PPh3)4, CuI + TMS Me acetone, air Et2O 2) K2CO3 BuNH2, THF MeOH TBSO Me HO Me HO Me TBSO Me 2011 2012 2013 2014 54% quant. 69%
Preparation of the vinyl chloride 2008 was straightforward (Scheme 9). Glaser coupling between 3-butyn-2-ol and ethylyltrimethylsilane afforded the diyne 2011, which was stereospecifically reduced with LiAlH4 to give the enyne 2012. Silyl protection of the allylic alcohol followed by removal of the trimethylsilyl group revealed the terminal enyne 2013. Sonogashira reaction of 2011 with cis-dichloroethylene smoothly produced the TBS protected 2014 in 69% yield.
51 (a) Seyferth D.; Marmor, R. S.; Hilbert, P. Reactions of dimethylphosphono-substituted diazoalkanes. (MeO)2P(O)CR transfer to olefins and 1,3-dipolar additions of (MeO)2P(O)C(N2)R. J. Org. Chem. 1971, 36, 1379-1386. (b) Gilbert, J. C.; Weerasoriya, U. Diazoethenes: their attempted synthesis from aldehydes and aromatic ketones by way of the Horner-Emmons modification of the Wittig reaction. A facile synthesis of alkynes. J. Org. Chem. 1982, 47, 1837-1845. Part I: Spontaneity in the Biosynthesis of Uncialamycin 25
Preparation of the anthraquinone-incorporating propargyl epoxide, on the other hand, was met with challenges. The synthesis commenced with the preparation of 2010 via a boric acid-mediated hydrolysis of the commercially available dibromoanthraquinone 2015 in quantitative yield. The Sandmeyer reaction of the highly insoluble aminophenol 2010 smoothly afforded the aryl azide 2016 under the non-aqueous condition. As expected, the azide motif exhibited heat sensitivity in the facile transformation to the isoxazole 2017, which precluded its viability in the ensuing cross coupling reaction (Scheme 10).
Scheme 10 | Heat sensitivity of the anthraquinonyl azide.
O NH O NH i O N O N 2 1) conc. H2SO4 2 1) AmONO 3 Br B(OH)3, 140 ºC Br AcOH-EtCO2H, 0 ºC Br > 60 ºC Br
2) aq. NaOH 2) NaN3, 0 ºC - rt – N2 O Br O OH O OH O OH 2015 2010 2016 2017 quant. 63%
Indeed, the Stille reaction52 between 2010 and the stannylallyl alcohol 2018 at elevated temperature gave rise to the cinnamyl alcohol derivative 2019 in moderate yield. However, the subsequent Sandmeyer reaction of 2019 and the allylic oxidation of the resulting azide 2020 with MnO2 did not cleanly provide the cinnamaldehyde derivative 2021 (Scheme 11).
Scheme 11 | Protecting group free synthesis of a key intermediate.
OH OH O CH2OH Bu3Sn O NH2 2018 O NH2 1) iAmONO O N3 O N3 Br PdCl2(PPh3)2, LiCl AcOH-EtCO2H, 0 ºC MnO2
DMF, 90 ºC 2) NaN3, 0 ºC - rt CH2Cl2 O OH O OH O OH O OH 2010 2019 2020 2021 42%
We speculated that protection of the acidic phenol functionality would improve the outcome of these transformations. In order to selectively mask the less nucleophilic oxygen atom, we elected to prepare the tert-butyldiphenylsilyl ether 2022, which was found to undergo the cross coupling reaction smoothly to deliver the cinnamyl alcohol 2023.
52 Stille, J. K. The palladium-catalyzed corss-coupling reactions of organotin reagents with organic electrophiles. Angew. Chem. Int. Ed. Engl. 1986, 25, 508-524. Part I: Spontaneity in the Biosynthesis of Uncialamycin 26
However, the aryl silyl ether did not survive the non-aqueous-mediated Sandmeyer reaction condition (Scheme 12).
Scheme 12 | Protecting group strategy for the synthesis of advanced intermediates.
OH OH CH2OH Bu3Sn O NH2 2018 O NH2 1) iAmONO O N3 Br TBDPSCl, Im Pd(PPh3)4 AcOH-EtCO2H, 0 ºC
DMF toluene, 90 ºC 2) NaN3, 0 ºC - rt O OTBDPS O OTBDPS O OTBDPS O NH 2 2022 2023 2024 Br 72% 95%
O OH OH CH OH 2010 NH Bu Sn 2 2 O NH 3 O NH Br 2 2018 2 Br BnBr, Cs2CO3 Pd(PPh3)4
DMF, 60 ºC toluene, 90 ºC O O O OBn O OBn M 2025 2026 2027 73% 95%
CO2Me reduction CH2=CHCO2Me O NH2 Pd(PPh3)4
Et3N, DMF 90 ºC, 72 h O OBn 2028 90%
Alternatively, we aimed for the benzyl ether 2026, even though cleavage of a benzyl group only takes place under harsh conditions. However, the seemingly trivial benzylation reaction was only effectively promoted by Cs2CO3 or the combination of K2CO3 and a full equivalent of 18-crown-6. Use of a stronger base such as NaH resulted in partial conversion even though complete deprotonation of 2010 was evident by the characteristic dark blue color of the corresponding phenolate. These observations were consistent with the formation of the chelate 2025. The analogous coupling reaction produced the benzyl protected cinnamyl alcohol 2027. The poorly atom economical Stille reaction could be cirvumvented with a Heck reaction with methyl acrylate to forge the side arm. However, we were unable to reduce the resulting cinnamate ester 2028 without afflicting the anthraquinone moiety.
Part I: Spontaneity in the Biosynthesis of Uncialamycin 27
2.3 Furture Direction for the Assembly of the Biosynthetic Precursor With the properly functionalized anthraquinone derivative 2027 in place, the Sandmeyer reaction would afford the azide 2029 (cf. 2024). The epoxy aldehyde 2031 (cf. 2009) would arise from a Sharpless epoxidation of the cinnamyl alcohol motif and subsequent oxidation of the corresponding epoxy alcohol 2030. In addition, we were able to verify the feasibility of the Ohira-Bestmann reaction on a model compound 2032 under unoptimized condition (Scheme 13).
Scheme 13 | Future plan for the completion of synthesis of the biosynthetic precursor.
OH OH OH O
O NH O N O N O N 2 Sandmeyer 3 Sharpless 3 O oxidation 3 O
O OBn O OBn O OBn O OBn 2027 2029 2030 2031
Br O O P(OEt) CHO Br Br I Me 2 N N 3 O N 3 O CBr Pd(PPh ) MeHN NHMe CHO 2 4 3 4
K2CO3, MeOH PPh3 Bu3SnH CuI, NaI 2032 2033 TBSO Me TBSO Me TBSO Me TBSO Me 47% 2034 2035 2036 2037
Meanwhile, the projected Sonogashira reaction between the vinyl chloride 2014 and the mimic terminal alkyne 2033 was unproductive. This is likely due to the lower reactivity of chlorides during the oxidative addition step so that the unhindered azido motif was shunted to a number of possible undesired pathways. Therefore, we envision the synthesis of the more reactive cis-vinyl bromide, which would be prepared by the olefination of the aldehyde 2034 followed by selective reduction of the resulting vinyl dibromide 2035. A copper-catalyzed Finkelstein reaction would further provide the yet more reactive, corresponding iodide 2037.53
53 Martin, R.; Revero, M. R.; Buchwald, S. L. Domino Cu-catalyzed C–N coupling /hydroamidation: a highly efficient synthesis of nitrogen heterocycles. Angew. Chem. Int. Ed. 2006, 45, 7079-7082. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 28
◊ Part II ◊
Intermolecular Trapping of
Benzynes Generated from the
Hexadehydro-Diels–Alder Reaction
Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 29
Chapter 3. The Hexadehydro-Diels–Alder Reaction
3.1 Early History of Benzyne Chemistry ortho-Benzyne, or 1,2-dehydrobenzene, is one of the bifunctional reactive intermediates that form two new bonds upon reaction. Among the resonance structures one could lay out, the strained cyclic alkyne 3001 can be related to acetylenedicarboxylates 3003 with regard to their respective reactivities of the alkyne functionality, although benzyne displays greater reactivity due to its ring strain (Figure 10). Another resonance contributor of dehydrobenzene, in the form of the cyclic cumulene 3002, is rarely mentioned. The predominant use of 3001 over 3002 to represent dehydrobenzene has provided an incomplete portrait of the bonding nature of dehydrobenzene and the degree of aromaticity. Nevertheless, the terms “benzyne” and “aryne” are widely used.
Figure 10 | Resonance contributors of ortho-benzyne.
O OR
RO O 3001 3002 3003
Historically benzyne chemistry did not develop in the wake of the community’s interest in its nature of a 1,2-bifunctional intermediate or it being a strained cyclic species. Instead, benzyne was invoked merely to rationalize puzzling experimental outcomes. For example, it was postulated to arise from the pyrolysis of diphenylmercury in order to account for the formation of biphenyl54 and in the Wurtz reaction of chlorobenzene with sodium metal for the formation of polyphenyls.55 The independent entity of benzyne was not taken up and further pursued until Wittig envisioned the intermediacy of benzyne to interpret the biphenyl generation in the reaction of phenyl lithium with fluorobenzene
54 Dreher, E.; Otto, R. Liebigs Ann. Chem. 1870, 154, 93. 55 (a) Bachmann, W. E.; Clarke, H. T. The mechanism of the Wurtz-Fittig reaction. J. Am. Chem. Soc. 1927, 49, 2089-2098. (b) Morton, A. A.; Davidson, J. B.; Hakan, B. L. Condensations by sodium. XXIII. The general theory of the Wurtz reaction. Part II. The second phase. J. Am. Chem. Soc. 1942, 64, 2242-2247. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 30 (3004).56 This rational was supported by the observation of 2-biphenylyl lithium (3006) that arose from trapping benzyne with phenyllithium as the primary product of this reaction. Benzyne was later confirmed in 1953 by Roberts et al. by virtue of the isotopic labeling 57 14 experiments. The amination reaction of [1- C]-PhCl (3007) with KNH2 in liquid 14 14 ammonia gave rise to equal amounts of [1- C]-PhNH2 (3010) and [2- C]-PhNH2 (3011) through the 14C-labeled symmetrical benzyne 3009. In both instances, benzyne formation was formulated to arise from the elimination process of the ortho-metalated halobenzenes 3005 and 3008 respectively (Scheme 14).
Scheme 14 | Early experimental evidence in favor of the intermediacy of benzyne.
Li Li
F F
Li Li 3004 3005 3001 3006
K H KNH2 KNH2 NH2 + 14 14C 14C 14 14C C liq. NH liq. NH C Cl 3 Cl 3 H NH2 3007 3008 3009 3010 3011
3.2 Synthetic Applications of Benzyne Extensive studies of benzyne following the experimental disclosure of its existence were detailed in a monograph by Hoffman in 1967. 58 One important aspect of such development is the advance of the methods for benzyne generation beyond the use of ortho- metalated halobenzenes such as 3005, 3008, and 3012 as precursors (Figure 11).59 Notable examples include thermolysis of benzenediazonium60 and diphenyliodonium carboxylates
3013 and 3014 and oxidation of 1-aminobenzotriazole (3015) with Pb(OAc)4. Most notably,
56 Wittig, G. Naturwiss 1942, 30, 696. 57 Robers, J. D.; Simmons, H. E. Jr.; Carlsmith, L. A.; Vaughan, C. W. Rearrangement in the reaction of chlorobenzene-1-C14 with potassium amide. J. Am. Chem. Soc. 1953, 75, 3290-3291. 58 Hoffmann, R.W. Dehydrobenzone and Cycloalkynes. Organic Chemistry, a Series of Monographs , 11; Academic Press, 1967. 59 Kitamura, T. Synthetic methods for the generation and preparative application of benzyne. Aust. J. Chem. 2010, 63, 987-1001. 60 Stiles, M.; Miller, R. G.; Burckhardt, U. Reactions of benzyne intermediates in non-basic media. J. Am. Chem. Soc. 1963, 85, 1792-1797. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 31 Kobayashi in 1983 pioneered the use of ortho-trimethylsilylphenyl triflate 3016 as the precursor and a fluoride reagent such as TBAF to produce benzyne under mild conditions.61 Benzyne chemistry garnered much research interests for a second period with the advent of this evolution in benzyne/aryne formation, unlimited by the harsh conditions under which benzynes were initially observed. Use of benzynes in organic synthesis has also allowed for the strategic advantage of making multiple bonds in one operation enabled by their nature as 1,2-bifunctional intermediates. The popularity of the Kobayshi method for the benzyne generation hallmarked the resurgence of the versatile aryne chemistry.62 In particular, the collective synthetic utilities of benzynes, and in a broader sense arynes, have culminated in a number of syntheses of complex natural products.63
Figure 11 | Representative traditional methods of benzyne generation.
F F
Li MgBr 3005 3012
–20 ºC 0 ºC
heat Bu NF TMS N2 4
OTf CO2 3013 3001 3016 heat Pb(OAc)4 Ph N I N N
CO2 NH2 3014 3015
61 Himeshima, Y.; Sonoda, T.; Kobayashi, H. Fluoride-induced 1, 2-elimination of o -trimethylsilylphenyl triflate to benzyne under mild conditions. Chem. Lett. 1983, 12, 1211-1214. 62 (a) Dubrovskiy, A. V.; Markina, N. A.; Larock, R. C. Use of benzynes for the synthesis of heterocycles. Org. Biomol. Chem. 2013, 11, 191-218. (b) Wu, C.; Shi, F. A Closer look at aryne chemistry: details that remain mysterious. Asian J. Org. Chem. 2013, 2, 116-125.(c) Peréz, D.; Peña, D.; Guitian, ́E. Aryne cycloaddition reactions in the synthesis of polycyclic aromatic compounds. Eur. J. Org. Chem. 2013, 27, 5981-6013. (d) Bhunia, A.; Yetra, S. R.; Biju, A. T. Recent advances in transition-metal-free carbon-carbon and carbon-heteroatom bond-forming reactions using arynes. Chem. Soc. Rev. 2012, 41, 3140-3152. (e) Okuma, K. Reaction of arynes with carbon-heteroatom double bonds. Heterocycles 2012, 85, 515-544. (f) Yoshida, H.; Ohshita, J.; Kunai, A. Aryne, ortho-quinone methide, and ortho-quinodimethane: synthesis of multisubstituted arenes using the aromatic reactive intermediates. Bull. Chem. Soc. Jpn. 2010, 83, 199-219. 63 (a) Tadross, P. M.; Stoltz, B. M. A comprehensive history of arynes in natural product total synthesis. Chem. Rev. 2012, 112, 3550-3577. (b) Gampe, C. M.; Carreira, E. M. Aryne and cyclohexyne in natural product synthesis. Angew. Chem. Int. Ed. 2012, 51, 3766-3778. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 32 3.3 Discoveries of the Hexadehydro-Diels–Alder Reaction In light of the pivotal roles the Bergman cyclization and Myers–Saito cyclization play in the enediyne chemistry, considerable research activities devoted to other types of cycloaromatization reaction and their synthetic values. In 1997 Johnson et al. proposed the logical plausibility of benzyne formation from 1,3-butadiyne and acetylene in a cycloaromatization assembly as a new mode of Diels–Alder reaction (Scheme 15A).64 It should be noted that the cumulene resonance structure 3002 of dehydrobenzene is the more cognizable depiction for this cycloaddition from a retrosynthetic point of view. The recognition of benzyne as a hybrid of the cyclic alkyne 3001 and the cumulene 3002 should also reinforce the understanding of its structure on a more fundamental level. They further demonstrated the viability of such a process in an intramolecular fashion during the flash vacuum pyrolysis of 1,3,8-nonatriyne (3017) to produce indan (3019) and indene (3020), the latter being a secondary product of indan dehydrogenation (Scheme 15B). The intermediacy of benzyne 3018 was supported by the deuterium isotopic labeling experiment and the precedented reduction of benzynes under similar conditions.65
Scheme 15 | An cycloaromatization approach to form ortho-benzyne: A) a schematic cycloaddition reaction, B) the thermal intramolecular cycloaromatization reaction. A +
3002 3001 B 580 ºC + 0.01 Torr H H H H 3017 3018 3019 3020
64 Bradley, A.; Johnson, R. Thermolysis of 1,3,8-nonatriyne: Evidence for intramolecular [2+4] cycloaromatization to a benzyne intermediate. J. Am. Chem. Soc. 1997, 119, 9917-9918. 65 (a) Berry, S. R.; Spokes, G. N.; Stiles, M. The absorption spectrum of gaseous benzyne. J. Am. Chem. Soc. 1962, 84, 3570-3577. b) Corbett, T. G.; Porter, Q. N. Reactions of benzyne and 1,2-naphthyne with some dienes. Aust. J. Chem. 1965, 18, 1781-1785. (c) Bove, J. L.; Arrigo, J. R. Chem. Ind. 1984, 803. (d) Brown, R. F.; Coulston, K. J.; Eastwood, F. W. Formation of biphenylene by elimination of C2 from 9, 10- didehydrophenanthrene at 1100 ºC. Tetrahedron Lett. 1996, 37, 6819-6820. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 33 The discovery of this novel cycloaromatization process supplemented the scope of the well-known Diels–Alder reaction (Figure 12). In a representation of the prototypical Diels–Alder reaction, 1,3-butadiene reacts as the 4p-component and ethylene as the 2p- component in a [4+2]-cycloaddition. 66 When ethylene is replaced by acetylene, the analogous transformation to form 1,4-cyclohexadiene can be viewed as a didehydro-Diels– Alder reaction due to the formal two-electron oxidation of the 2p-component. Accordingly, the well-studied tetradehydro-Diels-Alder (TDDA) reaction involves the essential pair of 3-buten-1-yn and acetylene that produces benzene following a [1,5]-H-sigmatropic rearrangement of the initially formed cylic allene.67 Along this line, the paradigmatic engagement of 1,3-butadiyne and acetylene in a formal [4+2] cycloaddition fashion constitutes a hexadehydro-Diels–Alder (HDDA) reaction in relation to the existing classes of Diels–Alder reaction.
Figure 12 | Prototypical Diels–Alder reactions at various oxidation states: A) a Diels–Alder reaction, B) a didehydro-Diels–Alder reaction, C) a tetradehydro-Diels–Alder reaction, D) a hexadehydro-Diels–Alder reaction.
A B + +
C D 1,5-H + + shift H H
On a more synthetically practical front, Ueda et al. independently reported the synthesis of the fluorenol derivatives 3025 and 3026 from the elaborated tetrayne 3021 under mild conditions (Scheme 16). 68 Following the cycloaromatization reaction, the
66 Diels, O.; Alder, K. Syntheses in the hydroaromatic series. Justus Liebigs Ann. Chem. 1928, 460, 98-122. 67 Michael, A.; Bucher, J. E. Über die Einwirkung von Eissigsäureanhydrid auf Phenylpropiolsäure. Chem. Zentrblt. 1898, 731-733. 68 Miyawaki, K.; Suzuki, R.; Kawano, T.; Ueda, I. Cycloaromatization of a non-conjugated polyenyne system: Synthesis of 5H-benzo[d]fluoreno[3,2-b]pyrans via diradicals generated from 1-[2-{4-(2- alkoxymethylphenyl)butan-1,3-diynyl}]phenylpentan-2,4-diyn-1-ols and trapping evidence for the 1,2- didehydrobenzene diradical. Tetrahedron Lett. 1997, 38, 3943-3946. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 34 projected fluorenolyl benzyne 3022 was trapped by the oxygen atom of the methyl ether in an intramolecular fashion. In our interpretation, the resulting 1,3-zwitterion 3023 would then give rise to the pentacyclic fluorenol 3025 in a net disproportionation process that involved the pronation by the alcohol 3021 (AlkO–H) and the intramolecular displacement of the O-methyldibenzofuranium alkoxide ion pair 3024. The corresponding methyl ether 3027 would also lead to the formation of fluorenol methyl ether 3026 as a secondary product through the analogous reaction cascade. It is conceivable that the extended conjugation offered by the extra alkynyl unit along with the locked cis-geometry within the benzenoid linker attributed to the drastic decrease of the temperature used for the benzyne generation vis-à-vis Johnson’s initial example.
Scheme 16 | A thermal cycloaromatization reaction reported by Ueda et al. and our interpretation of the mechanism.
OMe TMS
R OMe R OMe R O R O R O rt Me + 72 h HO HO HO H O HO MeO H Alk O HO Alk
3021 3022 3023 3024 3025 3026 Me O Alk 3027
However, Ueda et al. did not opt to further explore the viability of the HDDA reaction beyond the synthesis of polycyclic benzenoids in their ensuing publications over the next decade. Although their envisioned radical-initiated mechanism by which the HDDA reaction occurs is not invalid, they deemed the dehydrobenzenoid intermediate like 3022 a diradical species and accounted for the formation of the products downstream of the initial cycloaromatization reaction in an entirely radical-centered manner. 69 This
69 (a) Miyawaki, K.; Kawano, T.; Ueda, I. Multiple cycloaromatization of novel aromatic enediynes bearing a triggering device on the terminal acetylene carbon. Tetrahedron Lett. 1998, 39, 6923-6926. (b) Ueda, I.; Sakurai, Y.; Kawano, T.; Wada, Y.; Futai, M. An unprecedented arylcarbene formation in thermal reaction of non-conjugated aromatic enetetraynes and DNA strand cleavage. Tetrahedron Lett. 1999, 40, 319-322.( c) Miyawaki, K.; Kawano, T.; Ueda, I. Domino thermal radical cycloaromatization of non-conjugated aromatic hexa- and heptaynes: Synthesis of fluoranthene and benzo[a ]rubicene skeletons. Tetrahedron Lett. 2000, 41, Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 35 mechanistic bias had probably limited their perspective of the merit of the HDDA reaction in a broader synthetic setting. Thus, the cycloaromatization approach to generate benzyne had lain fallow ever since. The most only example of the sporadically encountered HDDA reaction was a metal-templated cycloaromatization reaction described by Sterenberg et al (Scheme 17).70 The hetero-dinuclear tetraynyl bisphosphine complex 3028 undergoes a facile regioselective HDDA reaction. The resulting benzyne 3029 was trapped by furan in a standard Diels–Alder reaction or reduced by THF via an atypical dihydrogen transfer reaction.
Scheme 17 | A metal-templated HDDA reaction.
Ph2 O P Ph2 (OC) W P 4 PtCl2 PPh Ph2P 2
Ph Ph Ph2 O Ph Ph P P P Ph2 (OC)4W PtCl2 (OC) W P 3030 4 PtCl2 P P Ph Ph P PPh2 Ph Ph Ph 2 Ph2 3028 3029 P Ph2 (OC) W P 4 PtCl2 O PPh Ph2P 2
H H 3031
1447-1451. (d) Kawano, T.; Inai, H.; Miyawaki, K.; Ueda, I. Synthesis of indenothiophenone derivatives by cycloaromatization of non-conjugated thienyl tetraynes. Tetrahedron Lett. 2005, 46, 1233-1236. (e) Kawano, T.; Inai, H.; Miyawaki, K.; Ueda, I. Effect of water molecules on the cycloaromatization of non-conjugated aromatic tetraynes. Bull. Chem. Soc. Jpn. 2006, 79, 944-949. (f) Kawano, T.; Suehiro, M.; Ueda, I. Synthesis and inclusion properties of 6,6′ -Bi(benzo[b ]fluoren-5-ol) derivative by cycloaromatization. Chem. Lett. 2006, 35, 58-59. (g) Kimura, H.; Torikai, K.; Miyawaki, K.; Ueda, I. Scope of the thermal cyclization of nonconjugated ene–yne–nitrile system: A facile synthesis of cyanofluorenol derivatives. Chem. Lett. 2008, 37, 662-663. (h) Torikai, K.; Otsuka, Y.; Nishimura, M.; Sumida, M.; Kawai, T.; Sekiguchi, K.; Ueda, I. Synthesis and DNA cleaving activity of water-soluble non-conjugated thienyl tetraynes. Bioorg. Med. Chem. 2008, 16, 5441-5451. 70 Tsui, J. A.; Sterenberg, B. T. A metal-templated 4+2 cycloaddition reaction of an alkyne and a diyne to form a 1,2-Aryne. Organometallics 2009, 28, 4906-4908. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 36 3.4 Resurfacing of the HDDA Reaction71 In the course of the investigation of the biosynthetic origin of the nin-membered enediyne natural products within the Hoye group, an attempted oxidation of tetrayne 3032 with MnO2 was found to deliver the tricyclic indenone derivative 3036 in 53% yield instead of the desired ketone 3033 (Scheme 18A). The identification of the product and the sequence of events incurred extensive studies at the time of this discovery due to the unawareness of the prior body of work on HDDA chemistry. In retrospect, the pathway by which 3036 was produced paralleled what Ueda et al. postulated in their account. Once the secondary alcohol within 3032 was converted to the corresponding ketone, the highly conjugate tetrayne 3033 proceeded via an HDDA reaction using the ynone moiety as the 2p-component. The indenonyl benzyne 3034 was trapped by the oxygen atom in the pendant siloxy ethyl group in a formal retro-Brook reaction to give the hexa-substituted benzenoid 3036 via the intermediacy of the betaine 3035.
Scheme 18 | Initial uncovery of the HDDA reaction cascade by Hoye et al.: A) the serendipitous finding by Dr. Baire, B) a second, analgous reaction, now with a designed triyne substrate. A OH O
O MnO2, CH2Cl2 O TBS O
R rt, 5 h TBS O R O TBSO OTBS OTBS OTBS OTBS OTBS 3032 3033 3034 3035 3036 53% B O O TMS O TMS TMS CHCl3 OTBS rt, 2 d O TBS TBSO 3037 3038 3039 93%
71 Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P. The hexadehydro-Diels-Alder reaction. Nature 2012, 490, 208-212. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 37 An analogous cycloaromatization reaction of the cyclohexene-tethered ketotriyne 3037 smoothly produced the tetracyclic ketone 3039 via the benzyne 3038 (Scheme 18B). Therefore, it was evident that a triyne endowed with the proper functional groups may also serve as a feasible substrate for the HDDA reaction.
Table 1 | Substrate scope with respect to various types of linkers (adapted from reference 71).
product product entry HDDA temp. isolated yield entry HDDA temp. isolated yield
O O TMS TMS O CO2Et CO2Et 1 85 ºC O Me O 6 110 ºC O O Me Me Me TBSO TBS 3040 3041 3050 3051 85% 86% O O CO2Et CO2Et O 2 120 ºC O O 7 N 120 ºC TBS Ts N O TBSO TBSO Ts 3042 3043 TBS 86% 3052 3053 80% O O HO OH PhN 3 120 ºC PhN O 8 TsN 65 ºC TBSO TBS 3044 3045 TsN 92% O HO O O 3054 3055 95% 4 O 195 ºC HO O O OH
TBS MeO2C 3046 TBSO 3047 9 95 ºC MeO2C 75% MeO2C AcO MeO C AcO TMS HO 2 O TMS 3056 3057 5 120 ºC 87% O
TBSO TBS 3048 3049 86%
Researchers in our group quickly recognized the HDDA reaction as a fundamentally new method for benzyne formation. The de novo generation of benzyne from an acyclic polyyne precursor is distinct from all the prior techniques where an aromatic substrate undergoes a 1,2-elimination reaction. The HDDA reaction manifests a Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 38 completely atom economical process that avoids the synthesis of the substituted benzenoid precursors, especially of those with high structural complexity. It also creates a pristine environment for the benzyne production in the absence of any reagents and byproducts, which facilitates the studies of the inherent reactivity of benzynes. In addition to the ketones 3033 and 3037, the HDDA reaction is compatible with a variety of classes of polyyne precursor (Table 1). The aromatic ketotriyne 3040 gives rise to the fluorenone derivative 3041 via a tandem HDDA-(didehydro)-Diels–Alder reaction sequence with the tethered benzyl ether moiety (entry 1). Other carbonyl group-containing triynes such as the ester 3042 and the amide 3044 participate to afford the lactone 3043 and the lactam 3045, respectively (entries 2 and 3). Seven-membered ring formation is also feasible (entry 4). The slow cycloaromatization of the ketotriyne 3046 to the dibenzoxepinone 3047 is due to the entropic penalty caused by the five-atom linker and the use of a terminal alkyne as the diynophile. On the other hand, it is not necessary to incorporate a carbonyl group within the linker. The acetate triyne 3048 derived from the ketone 3047 cyclizes at a comparable rate with those of the carboxylic acid derivatives 3042 and 3044 to produce the fluorenol acetate 3049 (entry 5, cf. the cycloaromatization of 3021). The smooth transformations of the ether 3050 and the ynamide 3052 lead to the dihydroisobenzofuran 3051 and the indoline 3053 (entries 6 and 7). The additional conjugation within the symmetrical tosylamide-linked tetrayne 3054 significantly reduces the temperature at which the HDDA reaction occurs with an appreciable rate (entry 8). The resulting tosylisoindoline 3055 arises from the subsequent intramolecular trapping of the hydroxyl group. Finally, the malonate 3056 represents the viability of a linker with exclusive sp3-hybridized carbon atoms. The indane 3057 is formed with similar efficiency due to the Thorp-Ingold effect (entry 9, cf. the cycloaromatization of 3017). 3.5 Uncovering New Modes of Reactivity of the HDDA-Generated Benzyne Intermolecular capture of the HDDA-generated benzynes provides more convergent, and therefore more versatile, access to highly substituted benzenoid compounds (Figure 13A). Equipped with a non-participating acetate protected tail, the fluorenonyl benzyne 3059 is trapped by benzene or norbornene following the Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 39 cycloaromatization of the ketotriyne 3058 in the synthesis of the benzobarrelene 3061 and the benzocyclobutene 3062. The neutral condition for the benzyne formation also allows for the direct engagement of acidic species (as opposed to their conjugate bases) as the trapping agents, as evident by the hydrobromination reaction of 3059 with bromoethylammonium bromide in aqueous THF. The resulting isomeric aryl bromides 3063 and 3063’ can be exploited in a plethora of cross coupling reactions (Figure 13B).
Figure 13 | Intermolecular trapping of the HDDA-generated benzyne: A) the generic mode of trapping reaction in the presence of a non-participating tether, B) examples of intermolecular trapping products derived from the HDDA-generated benzyne. A O TMS O TMS TMS O 85 ºC T1–T2
1 14 h OAc T OAc AcO T2 3058 3059 3060
B O TMS O TMS O TMS
H OAc OAc Br(H)OAc H H(Br) 3061 3062 3063/3063' 70% 63% 72% (6:1)
Benzynes produced via the HDDA reaction do not always behave in parallel with those under the popular fluoride induced Kobayashi conditions (Scheme 19). The reaction of 3058 in the presence of phenol gives the biaryl phenol 3065 whereas the ortho- silylphenyl triflate was reported to afford diphenyl ether 3064 with cesium fluoride.72 The fluoride ion increases the electron density on the oxygen atom of phenol for its nucleophilic attack on benzyne. Under the fluoride-free thermal condition, an oxa-ene reaction can account for the carbon-carbon bond formation in a concerted fashion.
72 Liu, Z.; Larock, R. C. Facile O-arylation of phenols and carboxylic acids. Org. Lett. 2004, 6, 99-102. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 40
Scheme 19 | Divergent reactivity of the thermally produced benzyne with phenol: A) diaryl ether synthesis under the fluoride based condition, B) biaryl synthesis with the HDDA- generated benzyne.
A B O O TMS TMS O O TMS H CsF PhOH OAc +
OTf MeCN, rt H CHCl3, 85 ºC H AcO HO 3016 3064 3058 3065 92% 85%
The divergent reaction pathways of benzynes with phenols heralded the discoveries of other complementary and unique reactivities enabled by this thermal generation of benzynes. A number of cyclic alkanes and THF were found to effect the reduction of benzynes in this pristine environment (cf. 3029 to 3031) (Scheme 20).73 The experimental results were suggestive of a bimolecular concerted event for this dihydrogen transfer process. The fluorenonyl benzyne 3059 engages a pair of eclipsed vicinal C-H of cyclooctane in a six-membered transition state structure to produce the 1,2-disubstituted fluorenone 3066 in excellent yield.
Scheme 20 | Reduction of benzyne via a dihydrogen transfer reaction with cyclooctane.
‡ TMS O TMS O TMS TMS O cyclooctane
85 ºC H H OAc OAc H AcO H
3058 3059 3059* 3066 89%
Primary and secondary alcohols exhibit concentration-dependent reactivities toward the HDDA-generated benzynes (Figure 14).74 For example, the thermal reaction of the ketotriyne 3058 in the presence of a small excess (1.6 equiv) of cyclohexanol (3068)
73 Niu, D.; Willoughby, P. H.; Woods, B. P.; Baire, B.; Hoye, T. R. Alkane desaturation by concerted double hydrogen atom transfer to benzyne. Nature 2013, 501, 531-534. 74 Willoughby, P. H.; Niu, D.; Wang, T.; Haj. M. K.; Cramer, C. J.; Hoye, T. R. Mechanism of the reactions of alcohols with o-benzynes. J. Am. Chem. Soc. 2014, 136, 13657-13665. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 41 leads to the predominant formation of the disubstituted fluorenone 3070 (80%) and a minor amount of the cyclohexylaryl ether 3071. On the contrary, the same reaction carried out in cyclohexanol as the solvent displays the reversed chemoselectivity where 3071 is isolated as the major product (60%). The reduction product 3070 arises from a concerted but asynchronous removal of the two hydrogen atoms of the carbinol motif with the fluorenonyl benzyne 3069. On the other hand, extensive kinetic studies and DFT calculations have indicated that the alcohol dimer is most likely responsible for the concentration dependent formation of the alcohol adduct 3071. This phenomenon is absent in the fluoride based benzyne chemistry due to the perturbed hydrogen bonding of alcohols with fluoride ion.
Figure 14 | Concentration dependent competing reactions between ether formation and dihydrogen transfer reaction with cyclohexanol.
OH
TMS TMS O O TMS O O n n TMS 3068 nPr Pr Pr + nPr 85 ºC H O H 3067 3069 3070 3071
‡ equiv of 68 70 : 71 yield O TMS nPr 1.6 17 : 1 80%, 3070 neat 1 : 12 60%, 3071 H H O 3069*
An intramolecular reduction of the HDDA-produced benzyne was also observed during the reaction of the TIPS-capped symmetrical tetrayne 3072 (Scheme 21). 75 In addition to the expected silyl transferred tricyclic product 3074, the isopropenyldiisopropylsilyl-containing bicyclic isoindoline 3073 is formed via a concerted pathway, explained by the transition state structure 3072*. Lee et al. described a series of silver cation-mediated C-H insertion reactions of the
75 Hoye, T. R.; Baire, B.; Wang, T. Tactics for probing aryne reactivity: mechanistic studies of silicon– oxygen bond cleavage during the trapping of (HDDA-generated) benzynes by silyl ethers. Chem. Sci. 2014, 5, 545-550. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 42
Scheme 21 | Intramolecular dihydrogen transfer reaction with the tethered isopropyl group.
‡ OTIPS OTIPS TIPSO OTIPS
CHCl3 TsN + 65 ºC, 30 h TsN TsN TsN O O i i Si Pr H Si Pr2 O TIPSO H i H Pr H TIPS Me 3072 3072* 3073 3074 19% 78%
HDDA-generated benzynes (Scheme 22).76 The ynamide-linked tetrayne 3075 gives rise to the tricyclic tosylindoline 3076, in which the secondary C-H bond is selectively activated. The analogous reaction of the silylated tetraynes 3077 and 3089 to yield the cyclic silanes 3078 and 3080 allows for the silicon-templated C-H insertion of alkanes and arenes. They further demonstrated the feasibility of the intermolecular hydroarylation of benzynes when benzene was used as the solvent for the reaction of ynamide 3081 to form the tosylindolinylbiaryl 3082 in moderate yield. The regioselectivity of these intermolecular trapping reactions and the tentative relative orientation in the transition state strucutures for the dihydrogen transfer reactions can be rationalized by the distortion of the fused bicyclic benzynes (Figure 15).77 In a generic [4.3.0]-bicyclic benzyne 3083, the ring restraint imposed by the bridgehead carbons causes the stretching of the aromatic motif. The proximal carbon atom adopts more s character for the benzyne p bond to accommodate the more acute internal bond angle whereas the distal carbon atom adopts more p character for the benzyne p bond to accommodate its more obtuse bond angel. This effectively induces a polarization of the benzyne p bond toward the proximal carbon due to the higher electronegativity of the s
76 (a) Yun, S. Y.; Wang, K.-P., Lee, N.-K.; Mamidipalli, P.; Lee, D. alkane C–H insertion by aryne intermediates with a silver catalyst. J. Am. Chem. Soc. 2013, 135, 4668-4671. (b) Lee, N.-K.; Yun, S. Y.; Mamidipalli, P.; Salzman, R. M.; Lee, D.; Zhou, T.; Xia, Y. Hydroarylation of arynes catalyzed by silver for biaryl synthesis. J. Am Chem. Soc. 2014, 136, 4363-4368. (c) Mamidipalli, P.; Yun, S. Y.; Wang, K.-P.; Zhou, T.; Xia, Y. Chem. Sci. 2014, 5, 2362-2367. 77 (a) Hamura, T.; Ibusuki, Y.; Sato, K.; Matsumoto, T.; Osamura, Y.; Suzuki, K. Strain-Induced Regioselectivities in Reactions of Benzyne Possessing a Fused Four-Membered Ring. Org. Lett. 2003, 5, 3551-3554. (b) Finnegan, R. A. Organometallic Chemistry. IX. The Metalation of Benzocyclobutene with Sodium and Potassium Alkyls. J. Org. Chem. 1965, 30, 1333-1335. (c) Streitwieser, A., Jr; Ziegler, G. R.; Mowery, P. C.; Lewis, A.; Lawler, R. G. Some generalizations concerning the reactivity of aryl positions adjacent to fused strained rings. J. Am. Chem. Soc. 1968, 90, 1357-1358. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 43
Scheme 22 | Silver-catalyzed C–H insertion reactions with the HDDA-generated benzynes reported by Lee et al.
Ar Ar =
Cl AgOTf (10 mol%) N toluene, 90 ºC, 5 h Ts N H Ts H Me 3075 Me 3076 75% TBS
TBS AgOTf (10 mol%) Si TsN TsN Si toluene, 90 ºC, 5 h
H H 3077 3078 92% SiBnMe2
SiBnMe2 TsN AgOTf (10 mol%) Me2 Si Si H toluene, 90 ºC, 5 h TsN
H
3079 3080 92% nBu
nBu AgOTf (10 mol%)
N Ph–H, 90 ºC, 5 h Ts N Ts H 3081 3082 60% orbital. Accordingly, nucleophilic attacks will preferentially occur on the more electrophilic distal carbon. The additional polarization imposed by the carbonyl group at 1 position reinforces this tendency (3059 to 3063/3063’), which is further enhanced by the placement of a heteroatom at 3 position because of its stronger inductive effect (3084 to 3082). Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 44 Results of the independent computational studies by Cramer/Buszek 78 and Garg/Houk 79 agree with the qualitative analysis as to the regioselectivity of unsymmetrically substituted benzynes. This difference of the computed internal bond angles is correlated with the degree of preference for the site of nucleophilic attack. This computational protocol thus provides a more quantitative basis on which one can assess and predict the level of selectivity with the HDDA-based strategy for the synthesis of structurally diverse benzenoids.
Figure 15 | Qualitative analysis for the origin of the distortion of unsymmetrically substituted benzynes: A) a generic picture of the molecular orbitals, B) examples of benzynes exhibiting different level of regioselectivity toward intermolecular trapping events.
A B O TMS O TMS TMS O 85 ºC
14 h OAc Br(H)OAc X AcO H(Br) Y 3058 3059 3063/3063' Z 6:1 R = R R 3083 nBu AgOTf (10 mol%)
N Ph–H, 90 ºC, 5 h N N Ts Ts Ts H 3081 3084 3082 single product
3.6 Mechanistic Insights into the HDDA Reaction With much progress made on the downstream trapping reactions of the HDDA- generated benzynes, researchers attempted to elucidate the mechanistic aspects of the initial cycloaromatization event as well. The question centered around the concerted versus stepwise nature of the HDDA reaction. Prior to the serendipity from the Hoye group, Johnson et al. reported in 2011 their computational results of the hypothetical reaction
78 Garr, A. N.; Luo, D.; Brown, N.; Cramer, C. J.; Buszek, K. R.; VanderVelde, D. Experimental and Theoretical Investigations into the Unusual Regioselectivity of 4,5-, 5,6-, and 6,7-Indole Aryne Cycloadditions. Org. Lett. 2010, 12, 96-99. 79 Im, G.-Y. J.; Bronner, S. M.; Goetz, A. E.; Paton, R. S.; Cheong, P. H.-Y.; Houk, K. N.; Garg, N. K. Indolyne Experimental and Computational Studies: Synthetic Applications and Origins of Selectivities of Nucleophilic Additions. J. Am. Chem. Soc. 2010, 132, 17933-17944. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 45 between butadiyne and acetylene for the benzyne formation. 80 They found that the concerted pathway is only marginally more favorable than the stepwise pathway. However, the concertedness of the HDDA reaction was challenged by the extraordinary effectiveness of the alkyne activation observed in numerous instances. In order to gain more insight into the mechanism and substituent effect of the HDDA reaction, Houk et al. conducted computational studies on a handful of intermolecular model reactions.81 They surmised that the HDDA reaction occurs via a stepwise mechanism through a diradical intermediate, and they further attributed the origin of the alkyne activation to the significant decrease of the distortion and repulsion energies in a stepwise transition state structure relative to those in a concerted transition state structure.
Scheme 23 | Influence of substitution at the acetylenic termini of the triyne precursors on the rates of reactions.
O O HOAc H O O o-DCB, 130 ºC H OAc 3085 3086
O O TMS HOAc TMS TMS O O o-DCB, 130 ºC TMS OAc 3087 3088
O O HOAc H SiPh3 O O o-DCB, 130 ºC SiPh3 OAc 3089 3090
Nevertheless, tolerance of the HDDA reaction to light, triplet oxygen, or good hydrogen atom donors may implicate a concerted process. On the other hand, we noted the insensitivity of the rate of reaction to the steric hindrance on the diyne and the diynophile (Scheme 23). For example, the minimally substituted ester triyne 3085 cycloaromatizes at essentially the rate as its doubly silylated analog 3087 in the presence of acetic acid to form
80 Ajaz, A.; Bradley, A. Z.; Burrell, R. C.; Li, W. H. H.; Daoust, K. J.; Bovee, L. B.; DiRico, K. J.; Johnson, R. P. Concerted vs stepwise mechanisms in dehydro-Diels–Alder reactions. J. Org. Chem. 2011, 76, 9320. 81 Liang, Y.; Hong, X.; Yu, P.; Houk, K. N. Why alkynyl substituents dramatically accelerate hexadehydro- Diels–Alder reactions: stepwise mechanism of HDDA cycloadditions. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 46 the phthalides 3086 and 3087.82 This observation is in line with the involvement of a rate- limiting transition state structure where bonding is not significant between the remote alkyne termini. Computed activation enthalpies of the concerted transition state structures for the series of differentially substituted ester triynes are all substantially higher (5–7 kcal/mol) than those deduced from the Eyring equation with kinetic data (i.e., 3085**), whereas the transition state structure for the reaction of 3087 could not be located due to the instability of the restricted determinant. Instead, optimization using the broken-symmetry unrestricted Kohn-Sham formalism led to new transition state structures for all the substrates examined (i.e., 3085), in which bond formation is evident between the proximal alkyne termini and the distal alkyne termini, which remain far apart (i.e., 3085*). These transition state structures all bear significant diradical character, and their computed activation enthalpies are less than 3 kcal/mol different from those derived from experiment. The resulting
Figure 16 | Computed plausible mechanisms for the HDDA reaction (adapted from reference 82). DFT calculations were performed at the B3LYP-D3BJ level of theory. All values are of the enthalpies in kcal/mol.
‡ ‡ O O H O O ‡ O H 3085** 3085* 31.5 O H 25.5 3091* 18.8 18.1 O H H 0.00 O O H O 3091 H O
3085 O
3092 –56.9
82 Marell, D. J.; Furan, L. R.; Woods, B. P.; Lei, X.; Bendelsmith, A. J.; Cramer, C. J.; Hoye, T. R.; Kuwata, K. T. Mechanism of the intramolecular hexadehydro-Diels–Alder reaction. J. Org. Chem. 2015, 80, 11744- 11754. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 47 diradical intermediates (i.e., 3091) and the subsequent transition state structures (i.e., 3091*) for the benzyne generation (i.e., 3092) were also located, with the exception for the reaction of the mono-triphenylsilylated triyne 3089 to give rise to 3090, in which case the reaction is indeed concerted, albeit extremely asynchronous. In several instances, the activation enthalpies for the second bond formation event became negative (i.e., 3091 to 3092). Taken as a whole, it is reasonable to assign the intramolecular HDDA reaction as a stepwise-like process, in which the diradical intermediate either fails to be a minimum for the case of 3091, or fails to have sufficient lifetime to interact with exogenous species prior to completing the cycloaromatization.
Table 2 | Relative rates of the HDDA reactions for a series of triyne substrates and their comparisons with Hammett constant (sp) and radical-stabilizing energy values.
R R toluene N Ts 110 ºC N O TBSO Ts TBS 3093a-g 3094a-g
radical-stabilizing polyyne R half-life k rel σp energy
3093a C≡CMe 0.26 320 0.03 –12.1
3093b CHO 0.82 100 0.42 –7.7
3093c COMe 5.1 16 0.34 –6.7
3093d CO2Me 9.2 9.1 0.34 –4.9
3093e CONEt2 84 1 0.26 –4.9
3093f H > 400 – 0 0
3093g CF3 > 600 – 0.54 +1.9
It is possible to experimentally distinguish between a concerted and a stepwise mechanism for the intramolecular HDDA reaction (Table 2).83 The rates of reaction for the ynamide-linked polyynes 3093a-g that differ only at the substituent on the diynophile to produce the corresponding tosylindolines 3094a-g correlate well with the radical stabilizing character of these functional groups, whereas the same trend do not hold for the
83 Wang, T.; Niu, D.; Hoye, T. R. The hexadehydro-Diels–Alder cycloisomerization reaction proceeds by a stepwise mechanism. J. Am. Chem. Soc. 2016, 138, 7832-7835. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 48 concerted Diel-Alder reaction where the rate of reaction is dictated by the electron- withdraw effect and the steric bulk of the substituent on the dienophile.
Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 49
Chapter 4. Cycloaddition Reactions of the HDDA-Generated Benzynes
4.1 Trapping Reactions of the HDDA-Generated Benzynes with Furans and Pyrroles Perhaps one of the most straightforward trapping reactions to leverage the 1,2- bifunctional character of benzyne is the cycloaddition reaction, in which one can achieve two bond formations simultaneously. The first example was a Diels–Alder reaction between furan and benzyne (3001) that was generated from ortho-bromofluorobenzene (4001) and lithium amalgam (Scheme 25A).84 The resulting oxabenzonorbornadiene like 4002 is susceptible to further transformations as demonstrated in the total synthesis of gilvocarcin M (4007) by Suzuki et al., in which the 2-methoxyfuran cycloadduct 4005 of benzyne 4004 aromatized to give the a-naphthol derivative 4006 (Scheme 25B).85
Scheme 25 | Diels–Alder reaction of benzyne with furan: A) the first example, B) application in the total synthesis of gilvocarcin M.
A O F Li/Hg O Br 4001 3001 4002
OMe B OMe OBn OBn OBn OMe OBn OMe OBn I O OMe O Me TfO nBuLi, THF OH OH BnO –78 ºC BnO BnO O O O O O BnO O Me HO O OH BnO Me BnO Me BnO Me BnO Me BnO BnO BnO BnO 4003 4004 4005 4006 4007 (gilvocarcin M) 88%
The HDDA reaction has provided a reagent-free approach to produce structurally elaborated benzynes, whose functionality may not be compatible with some of the conditions for benzyne generation (i.e., nBuLi promoted elimination of the ortho-iodo
84 Wittig, G.; Pohmer, L. Intermediäre bildung von dehydrobenzol (cyclohexa-dienin). Angew. Chem. 1955, 67, 348. 85 Hosoya, T.; Takashira, E.; Matsumoto, T.; Suzuki, K. Total synthesis of the Gilvocarcins. J. Am. Chem. Soc. 1994, 116, 1004-1015. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 50 triflate 4003). Indeed, the structural diversity of the polyynes 4008 through 4013 demonstrate such advantage of the HDDA reaction. The reactions between these HDDA precursors and furan efficiently construct the heteroatom-rich polycyclic benzenoids 4014- 4019 (Table 3).
Table 3 | Trapping reactions of the HDDA-generated benzynes with furan.
product entry HDDA precrusor temp. isolated yield
Me
Me 1 O 75 ºC Me Me O O
4008 4013 72% TMS O O Me TMS 2 90 ºC Me O
4009 4014 78% Me
Me
3 90 ºC Me N Me Ts N O Ts 4010 4015 98% Me
Me BocN 4 95 ºC Me N Me Boc N Boc N O Boc 4011 4016 68%
O TMS O Me TMS 5 95 ºC BnN BnN Me O
4012 4017 quant.
Each distinctive type of benzyne precursor speaks to the mechanistic characteristics of the cycloaromatization process and the unique structural space it affords for further functionalization of the product. The ether-linked tetrayne 4008 undergoes the HDDA Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 51 reaction at an appreciable rate at 60 ºC (the preparative HDDA reaction cascades are carried out at 75 ºC to achieve shorter reaction time) due to the shorter C–O bond and the smaller bond angle at the oxygen atom that synergistically bring the proximal alkyne termini closer to one another in its reactive conformer (entry 1). On the other hand, the facile cycloaromatization of 4008 presents some challenge for its long term storage. The intramolecular HDDA reaction of the ynone precursor 4009 to furnish the fluorenone derivative 4014 outcompetes possible premature intermolecular engagement of furan (entry 2). Regioselective cycloaromatization reaction of ynamide-linked tetraynes like 4010 and 4011 would provide access to indole and indazole derivatives following removal of protecting groups and subsequent oxidation of the products like 4015 and 4016 (entries 3 and 4). The harsher condition under which the hydrazide tetrayne 4011 undergoes the HDDA reaction implicates the unfavorable alignment of the dipoles and steric interaction in its reacting conformer (entry 4). The aliphatic amine-derived amide 4012 cycloaromatizes more rapidly than its aromatic analog due to the greater degree of rotational restriction around the amide bond (entry 5). The presence of two rotamers in its NMR spectroscopy reinforces such argument. We proceeded to demonstrate that electron rich (4021) and electron deficient (4020 and 4022) furans are equally competent dienes toward benzyne (entries 2-5). Likewise, pyrroles of distinct electronic properties (4023 and 4024) readily participate (entries 6 and 7). Intermolecular Diels–Alder reactions between the propiolic ester 4018 and the furans or pyrroles were not observed at elevated temperature (4018 undergoes the HDDA reaction with a practical rate at 130 ºC).86 The unsymmetically substituted furans add to the HDDA- generated benzynes according to their mutual direction of polarization (Scheme 26). For example, use of 2-methyl furan (4032) resulted in a 1:1 ratio of the cycloadducts 4033 and 4033’. Electron deficient furan like 4034 exhibits opposite regioselective to electron rich furan like 4038 toward polarized benzyne in the cycloaddition reaction. The more electrophilic distal benzyne carbon matches the ipso-carbon atom of 2-acetylfuran in a transition state structure like 4036 to produce the fluorenone derivative 4037 as the
86 Luu Nguyen, Q.; Baire, B.; Hoye T. R. Competition between classical and hexadehydrl-Diels–Alder (HDDA) reactions of HDDA triynes with furan. Tetrahedron Lett. 2015, 56, 3265-3267. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 52 predominant product. On the other hand, use of the 2-siloxyfuran 4038 gave rise to the hydroxynaphthofuranone 4040 as the only isolated product via hydrolysis of the primary Diels–Alder adduct 4039 (cf. Scheme 25B).
Table 4 | Trapping reactions of the HDDA-generated benzynes with symmetrically substituted furans and pyrroles.87
HDDA product HDDA product entry precursor diene isolated yield entry precursor diene isolated yield
Me OMe O Me Me OAc 4 4020 O O Br Me O OMe 1 O O OMe MeO Br O 4022 4028 O Br 44% O Br 4019 4025 OAc 4008 EtO2C O 52% 5 O 4020 O Me EtO2C CO2Et CO2Et EtO2C Me 4020 4029 2 4008 O O 60% O EtO C 2 O Me OAc O O CO2Et Me 6 4020 N CO Et 2 Ph N 4020 4026 Me Me Ph 54% O OAc 4023 4030 O 67% Me O OAc O Me OAc 3 O Me O O Me Me N Me 7 4020 N Me O O Me Br 4018 4021 4027 Br 50% 4024 4031 56%
Products of the cycloaddition reaction between benzyne and furan are characterized by the oxabenzonorbornadiene moiety, which in turn are valuable intermediates in a variety of syntheses. In addition to the well-established alkene chemistry, we showcase the rhodium-catalyzed ring opening reaction of 4014 with methanol to afford the
87 Chen, J.; Baire, B.; Hoye, T. R. Cycloaddition reactions of azide, furan, and pyrrole units with benzynes generated by the hexadehydro-Diels–Alder (HDDA) reaction. Heterocycles 2014, 88, 1191-1200. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 53
Scheme 26 | Trapping reactions of the HDDA-generated benzynes with unsymmetrically substituted furans.
Me
O TMS O TMS O O Me Me TMS 4032 + Me Me PhH, 90 ºC O O Me 4009 4033 1:1 4033' Me O ‡ TMS Me TMS MeO TMS Me O O O Me O Me O O TMS δ+ 4035 O O O + MeO Me PhH, 90 ºC δ+ O MeO MeO MeO MeO Me OMe OMe OMe
4034 4036 4037 10:1 4037'
OTMS
O O O O 4038 OAc OAc O O O OH o-DCB, 130 ºC O OAc TMSO HO 4018 4039 4040
dihydronaphthanols 4041 and 4042 in 82% overall yield (Scheme 27).88 A number of common nucleophiles have been shown to undergo such transformation to provide architecturally and stereochemically defined dihydronaphthalene derivatives under similar catalytic systems. The pyrrole derived azabenzonorbornadiene unit is susceptible to analogous ring opening processes as well.89
88 Lautens, M.; Schmid, G. A.; Chau, A. Remote electronic effects in the rhodium-catalyzed nucleophilic ring opening of oxabenzonorbornadienes. J. Org. Chem. 2002, 67, 8043-8053. 89 Cho, Y.; Tseng, N.; Senboku, H.; Lautens, M. Rhodium-catalyzed ring-opening reactions of N-Boc azabenzonorbornadiene with chiral amine nucleophiles derived from amino acids. Synthesis 2008, 64, 6002- 6014. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 54 4.2 Additional Types of Cycloaddition Reactions of with the HDDA-Generated Benzynes The less readily available a-pyrones are four-carbon Diels–Alder synthons for the de novo synthesis of benzenoids.90 Heating of 4034 in the presence of two equivalents of a-pyrone cleanly gave rise to the angular fluorenone derivative 4044. The arrangement of the lactone moiety in 4043 is predicated on the addition pattern of electronically biased furans to benzyne even though the regioselectivity is inconsequential for this transformation (cf. Scheme 26). On the other hand, ejection of isocyanate from the analogous 2-pyridone (4045) adduct 4046 would be thermaldynamically unfavorable.91 This methodology would therefore constitute an alternative to capitalize on the simultaneous establishment of the incipient stereogenic centers through the Diels–Alder reaction.
Scheme 27 | Rodium-catalyzed ring opening reaction of oxabenzonorbornadiene.
TMS TMS O O TMS O Me Me Me [Rh(cod)Cl]2 OH + O THF-MeOH, 80 ºC HO OMe OMe 4014 4041 4042 48% 34%
Many 1,3-dipoles are reactive intermediates in that they are produced in situ in solution at lower temperature. Nominal examples include ozone and nitrone that readily engage alkene and alkyne motifs. Nevertheless, we obtained promising results with [3+2]- cycloaddition reactions between the HDDA-generated benzyne and a few stable 1,3- dipoles. In particular, Heating the ether-linked tetrayne 4008 with a stabilized diazo compound like ethyl diazoacetate yielded the isomeric indazoles 4047 and 4047’, and use
90 Wittig, G.; Hoffman, R. W. Dehyrobenzol aus 1.2.3-benzothiadiazol-1.1-dioxyd. Chem. Ber. 1962, 95, 2718. 91 (a) Hoshino, M.; Matsuzaki, H.; Fujita, R. Cycloaddition of 2-pyridones having an electron-withdrawing group. Heterocycles 2008, 76, 267-273. (b) Tomisawa, H.; Nakano, H.; Hongo, H. High pressure Diels– Alder reaction of 1-methyl-2(1H)-pyridones having a phenyl group with N-phenylmaleimide. Heterocycles 1990, 30, 359-362. (c) Nakano. H.; Kato, T.; Tomisawa, H.; Hongo. H. Diels–Alder cycloaddition using phenyl-2(1H)-pyridones as dienes. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 55 of and the thermally stable cyclic azomethine imine 4048 led to dihydroindazoles 4049 and 4049’.
Scheme 28 | Preliminary results of additional cycloaddition reactions between the HDDA- generated benzynes and dienes and 1,3-dipoles.
O O O TMS O TMS TMS Me Me O O
MeO Me PhH, 90 ºC MeO O MeO MeO 4034 MeO 4043 MeO 4044
O O RN
4045 R N
3001 4046
Me Me O N N Me OEt Me O Me + Me PhH, 75 ºC O O
CO2Et NH HN N N EtO2C 4008 4047 4047' O
N Me N Me MeO Me 4048 O Me + 4008 O O PhH, 75 ºC N OMe N N N O MeO 4049 4049'
Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 56
Chapter 5. Trapping Reactions between the HDDA-Generated Benzynes and Sulfides
Majority of the work presented in this Chapter is included in a recent publication.92
5.1 Sulfonium Ylide Formation
Figure 17 | Computed bimolecular and trimolecular processes between benzyne and methanol (adapted from reference 74). DFT calculations were performed using M06-2X/6- 311+G(d,p) and the SMD solvation model (MeOH). All values are of the free energies in kcal/mol.
Me ‡ ‡ Oδ+ Me H δ+ + MeOH O δ– Me H O 5001* δ– H 8.3 5002* 7.3
1.0 0.8 G 0.0 Me –3.7 O H + MeOH 3001 Me 3001 O 5001 2 x MeOH Me H Me O O H H 5002
O H Me
In the course of the mechanistic studies toward the reaction between the HDDA- generated benzyne and nontertiary alcohols,74 DFT calculations indicated that the pathway that is second-order in alcohol is more favorable than the seemingly more obvious bimolecular process toward the aryl ether synthesis. Furthermore, it is intuitively not obvious to many that the formation of the zwitterionic adduct 5001 is endogonic with respect to benzyne and methanol and it is only slightly exogonic for the instance of the
92 Chen, J.; Palani, V.; Hoye, T. R. Reactions of HDDA-derived benzynes with sulfides: mechanism, modes, and three-component reactions. J. Am. Chem. Soc. 2016, 138, 4318-4321. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 57 hydrogen-bonded adduct 5002. The equilibria among these species allow for the interference of the irreversible hydrogen transfer process (Figure 17). On the other hand, the reactions of benzyne with phenols occur exclusively via the hetero-ene pathway under neutral condition (i.e., 3058 to 3065). One could attribute the diverse modes of reactivity between benzyne and oxygen nucleophiles to the mismatch between the tight lone pair molecular orbital on the oxygen atom and the defused benzyne p-bond antibonding orbital.
Scheme 29 | Nucleophile induced allyl transfer reactions with benzyne: A) Proposed mode of reactivity with diallyl sulfide, B) intramolecular SN2 reaction to produce dihydrocarbazole reported by Wittit et al., C) benzyne promoted aza-Claisen rearrangement reported by Greaney et al. A S S SN2' + S
3001 5003 5004 5005
B Me N Me F Me S 2' N N N H
Br Mg, THF H 4001 5006 5007 22%
C O O N O O O TMS MeCN [3.3] N N N N OTf CsF, Tol/MeCN 110 ºC H H 3016 5008 5009 5010 5011 62%
We envisioned that the nucleophilic attack would be preferred with sulfides (i.e., diallyl sulfide 5003) based on the enhanced stability of the zwitterionic adduct like 5004, which in turn would undergo an intramolecular SN2’ reaction to produce the ortho- allylphenyl sulfide like 5005 (Scheme 29A). Wittig et al. reported a related process in which the addition of the Diels–Alder adduct of benzyne and N-methyl pyrrole to excess benzyne gave rise to the dihydrocarbozole 5007 through the ammonium betaine 5006 Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 58 (Scheme 29B).93 More recently, Greaney et al. demonstrated a more efficient ortho-allyl amination process of benzyne with tertiary allylic amines through a charge-accelerated aza- Claisen rearrangement (Scheme 29C).94 Protonation of the incipient zwitterion 5008 by acetonitrile gave N-allyl-N-phenylmorpholinium ion 5009, which then proceeded via the [3.3]-sigmatropic reaarangement and ensuing rearomatization to form 2-allylphenyl morpholine 5011.
Scheme 30 | Wittig rearrangement of the sulfonium ylide.
Me Me Me Me Me Me Me
(CH2=CHCH2)2S 5003 Me [2.3]- Me Me Me + Me O O O PhH, 75 ºC O Wittig O S H S S S NOE O H H
4008 5012 5013 5014 5015 5015' 52% 17%
Me Me
Me Me [2.3]-Wittig O O H S H S
5013' 5014'
We set out with the projected ortho-allyl sulfanylation 95 reaction of the dihydroisobenzofuranyl benzyne 5012, in which the ether-linked tetrayne 4008 was heated in benzene in the presence of 2.5 equiv of diallyl sulfide 5003 (Scheme 30). To our surprise, the NMR spectrum of the crude reaction mixture showed a pair of aromatic C–H resonances upon the complete consumption of the tetrayne, which attested against the formation of the expected fully substituted products. Indeed, we isolated 3:1 ratio of the pentasubstituted benzenoid adducts 5015 and 5015’ in 72% overall yield favoring the
93 (a) Wittig, G.; Behnisch, W. Dehydrobenzol und N-methyl-pyrrol. Chem. Ber. 1958, 91, 2358-2365; (b) Wittig, G.; Behnisch, W. Über das Verhalten von Dehydrobenzol gegenüber Pyrrol, N-benzyl- und N-phenyl- pyrrol. Chem. Ber. 1963, 96, 2851-2858. 94 Cant, A. A.; Bertrand, G. H. V.; Henderson, J. L.; Roberts, L.; Greaney, M. F. The benzyne aza-Claisen reaction. Angew. Chem. Int. Ed. 2009, 48, 5199-5202. 95 IUPAC now recommends the use of sulfane instead of sulfide and sulfanyl instead of sulfenyl. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 59 addition of the sulfur atom at the benzyne carbon distal to the ring fusion. The identity of the minor isomer as 5015’ was assigned on the basis of the finite coupling between the aromatic proton and protons on the benzylic methyl group as well as their NOE interaction, neither of which were observed in the major isomer 5015. The deviation of the outcome of this reaction from the expected allyl group migration process is explained by the intramolecular proton transfer within the 1,3-zwitterion 5013 (cf. 5004) followed by a [2.3]-Wittig rearrangement of the resulting sulfonium ylide 5014 to deliver the desymmetrized aryl sulfanyl diene 5015. The isomeric diene 5015’ arose from a parallel pathway involving the alternative betaine 5013’ and its incurring sulfnoium ylide 5014’. The productive reaction between the HDDA-generated benzyne 5012 and diallyl sulfide encouraged us to explore additional modes of reactivity associated with the sulfonium ylide intermediate. The thermal reaction between 4008 and dibenzyl sulfide (5016) produced the pair of isolable isomers 5019 and 5019’ in moderate overall yield, in which a Stevens rearrangement of the ylide 5018 is responsible for the skeletal desymmetrization of the alkyl sulfide moiety (Scheme 31).
Scheme 31 | Stevens rearrangement of the sulfonium ylide.
Me Me Me Me Me Me
(PhCH2)2S 5016 Stevens Me Me Me Me PhH, 75 ºC O O O O rearrange Ph S Ph S Ph -ment S O H H Ph Ph Ph 4008 5012 5017 5018 5019/5019' 25%/5%
The viability of the Stevens rearrangement prompted us to question the exact mechanism by which the allyl group transfer occurred during the reaction between 4008 and diallyl sulfide, as a Stevens rearrangement of the ylides 5014 and 5014’ would account for the formation of the same products, although one could intuitively argue for the operation of the sigmatropic rearrangement. Subjecting dipropargyl sulfide (5020) to the same reaction condition cleanly led to the skipped allenynes 5023 and 5023’ in support of the Wittig rearrangement pathway (i.e., 5022 to 5023, Scheme 32A). The reaction with the thioglycolate 5024 demonstrated the selective formation of the more stablilized ylides (i.e., Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 60 5026) to afford the allenyl esters 5027 and 5027’ in good overall yield (Scheme 32B). The analogous ylides like 5030 that is derived from the mesylamide-linked tetrayne 5028 and the S-butylthioglycolate 5029 are capable of an intramolecular elimination in the efficient synthesis of the S-aryl thioglycolate 5031 and 5031’ (Scheme 32C).
Scheme 31 | Additional modes of reactivity of the sulfonium ylide: A) Wittig rearrangement on the propargyl group to form the allene, B) selective formation of the more stablilized ylide, C) intramolecular 1,2-elimination.
A Me Me Me Me Me Me
(HC≡CCH2)2S 5020 [2.3]- Me Me Me Me O + O O O PhH, 75 ºC Wittig S S S S O H H ● ● 4008 5021 5022 5023 5023' 39% 10%
B Me Me CO2Me Me Me Me Me S 5024 [2.3]- Me Me Me Me O + O O O PhH, 75 ºC Wittig S S S S CO2Me O H MeO2C H CO Me 2 MeO2C ● ● 4008 5025 5026 5027 5027' 63% 12%
C Me Me Me Me Me BuS CO2Me 5029 – Me + Me Me PhH, 75 ºC MsN MsN S Et MsN N H S CO2Me H S CO2Me Ms MeO2C 5028 5030 5031 5031' 63% 19%
5.2 Mechanistic Investigation toward the Ylide Formation Ollis et al. first reported the reaction of benzyne (generated from ortho- fluorophenylmagnesium bromide) with an allylic sulfide (digeranyl sulfide 5032) to give mixture of the sigmatropically rearranged sulfide 5034 (following arrow set a) and the Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 61 isomeric [1.3]-shifted sulfide 5035 (following arrow set b) in 3:7 ratio (Scheme 3).96,97 The diminished chemoselectivity for the rearrangement of the ylide 5033 compared to that of the thermally generated ylides (i.e., 5014 and 5014’) once again echoes the benefit of the reagent and byproduct free condition of the HDDA reaction.
Scheme 33 | First example of benzyne promoted sulfonium ylide formation to give the Wittig rearranged product as well as the Stevens rearranged product.
C5H9 C5H9 Me Me
S C5H9 C5H9 C5H9 C5H9 Me F 5032 Me C5H9 Me Me Me b a + Br Mg, THF S SPh Ph Me C5H9 SPh 4001 5033 5034 5035 minor major
Extensive survey of the literature showed that the majority of the early studies toward the mode of reactivity between benzyne and sulfides came from the Nakayama laboratory.98 The involvement of sulfonium ylide was consistently used to account for a variety of experimental results. To probe the reactivity profile of ylide, we used thioanisole (5036, 2 equiv) as the sulfide, the ylide of which is not susceptible to intramolecular charge annihilation, in conjuction with 1.5 equiv of p-chlorobenzaldehyde (5037) to capitalize on the nucleophilicity of the ylide 5038. The progression of this HDDA cascade was monitored by NMR spectroscopy in d6-benzene. GC-MS analysis agreed with the generation of the isomeric diaryl sulfides 5040 and 5040’. The presence of the epoxide 5041, generated from the oxido sulfonium betaine 5039, was confirmed by NMR and
96 Blackburn, G. M.; Ollis, W. D. Chem. Commun. 1968, 1261-1262. 97 Baldwin, J. E.; Hackler, R. E.; The relationship between 1,3- and 1,5-sigmatropic rearrangements of sulfonium ylides. J. Am. Chem. Soc. 1969, 91, 3646-3647. 98 (a) Summarized (pp 400−406) in Nakayama, J. J. Sulfur Chem. 2009, 30, 393-468. (b) Nakayama, J.; Fujita, T.; Hoshino, M. Reactions of benzyne with sulfides having a carboxyl group: a novel synthesis of ester and lactone. Chem. Lett. 1982, 1777-1780. (c) Nakayama, J.; Hoshino, K.; Hoshino, M. Benzyne- induced fragmentation of 1,3-oxathiolanes: a novel method for deprotection of carbonyl groups, preparation of phenyl vinyl sulfides, and 1,2-carbonyl transposition. Chem. Lett. 1985, 677-678. (d) Iwamura, H.; Iwamura, M.; Nishida, T.; Yoshida, M.; Nakayama, J. Tetrahedron Lett. 1971, 12, 63-66. (e) Nakayama, J.; Takeue, S.; Hoshino, M. Benzyne-induced ring opening reaction of thiiranes: efficient synthesis of phenyl vinyl sulfides. Tetrahedron Lett. 1984, 25, 2679-2682. (f) Nakayama, J.; Ozasa, H.; Hoshino, M. Benzyne- induced fragmentation reactions of 1,3-dithiolanes. Heterocycles 1984, 22, 1053-1056. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 62 further found to form in approximately 60% yield based on the relative integral in the in situ NMR spectrum (Scheme 34A). More recently Xu et al. described a benzyne-mediated Corey-Chaykovsky reaction for the synthesis of epoxyoxindoles 5045 and 5045’ with almost 1:1 diastereomeric ratio from cinnamyl p-tolyl sulfide (5032) and N-methylisatin (5033) through the betaine 5044 (Scheme 34B).99
Scheme 34 | Intermolecular trapping reactions of the sulfonium ylide by the Corey– Chaykovsky epoxidation.
Me Me Me Me Me Me
PhSCH3 p-ClPhCHO 5036 5037 Me Me O O Me + Me + C D , 60 ºC O Ph p-ClPh 6 6 Ph S O O S H O SPh O H H H SPh Ar 4008 5038 5039 5040 5040' 5041
Ph Me O Ph S O N H Tol O O H TMS CsF Ph S + + O + O O O N MeCN OTf N N Me Me 87% Ph Me Me 3016 5042 5043 5044 5045 5045'
A control experiment in which 4008 was heated in the presence of thioanisole alone in d6-benzene delivered the same products without compromising the cleanliness of the reaction. The in situ NMR analysis did not reveal the fate the methylene unit of the ylide 5038. Repeating the reaction on a larger scale afforded 5:1 ratio of 5040 and 5040’ in 61% overall yield. However, use of ethyl phenyl sulfide (PhSEt) in place of thioanisole substantially deteriorated the yields of the products. The analogous reaction between 4008 and benzyl phenyl sulfide (5046) led to minor amount of the sulfanyl bibenzyl 5050, a formal C–H insertion product of phenyl carbene to the sulfide 5046 (Scheme 35). In the process, one could invoke an experimentally unjustified tetravalent sulfur zwitterion 5048 that would arise from the addition of a second molecule of 5046 to the primarily formed
99 Xu, H.-D.; Cai, M.-Q.; He, W.-J.; Hu, W.-H.; Shen, M.-H. RSC Adv. 2014, 4, 7623-7626. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 63 ylide 5047, which is followed by an intramolecular benzyl migration and a subsequent formal reductive elimination of the sulfide 5050 off the resulting thiosulfurane 5049.
Scheme 35 | Attempt to trace the formal carbene moiety by use of benzyl phenyl sulfide.
Me Me Me Me Me Me
PhSCH2Ph 5046 PhSCH2Ph PhS Me Me Me Me Ph PhH, 75 ºC O O Ph Ph O Ph Ph + Ph O S S S S S Ph O H Ph Ph SPh Ph Ph Ph 4008 5047 5048 5049 5040/5040' 5050
The yields of the net benzenethiol adducts 5040/5040’ were most improved (79% overall yield) with 2 equiv of thioanisole and 1.5 equiv of acetic acid added as the ylide scavenger (Scheme 36). The use of a moderately acidic species in the synthesis of aryl sulfides from the HDDA-generated benzynes and sulfides is probably the most practical approach. Protonation of the basic sulfonium ylide 5038 by acetic acid would generate the S-methyldiarylsulfonium acetate ion pair 5051, which would collapse to produce 5040/5040’ and volatile methyl acetate (5052).
Scheme 36 | Use of acetic acid to improve the yields of the diaryl sulfides.
Me Me Me Me Me
PhSCH3 5036 HOAc Me Me Me + CH3–OAc PhH, 75 ºC O Ph O O S Ph S SPh O H OAc H H CH3 4008 5038 5051 5040/5040' 5052 67%/12%
The participation of a carboxylic acid in the context of reaction between benzyne with sulfide is not unique to HDDA chemistry. Nakayama et al. invoked the intermdiacy of the ylide 5051 during the synthesis methyl 2-phenylthiobenzoate (5057) in a net S- arylation and concomitant methyl migration reaction of 2-methylthiobenzoic acid (5053) effected by benzenediazonium -2-carboxylate-generated benzyne (Scheme 37).98b In their rational, the methyl transfer process took place through the protonation of the ylide with Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 64 the intramolecularly poised carboxylate and the nucleophilic displacement within the resulting S-methylsulfonium diaryl-2-carboxylate 5056.
Scheme 37 | Benzyne promoted intramolecular S-arylated methyl transfer reaction.
CH 3 CO CH SCH CH3 CO2 2 3 N2 3 S O + S S CO H CO2 2 O H H 3013 5053 5054 5056 5057 56% CH2 CO2H S
H 5055
The alternative pathway to arrive at the inner salt 5056, which was not discussed in Nakayama’s report, is a direct protonation of the initial adduct 5054 in either intramolecular or intermolecular fashion. As for the case of the HDDA-generated benzyne, isotopic labeling experiment stands as the most straightforward means to address the ambiguity regarding the stage at which the protonation occurs (Scheme 38). Thus, the tetrayne 4008 was heated with d3-thioanisole (PhSCD3, 5036-d3) and acetic acid in d6- benzene. The in situ NMR spectroscopy of the reaction showed the presence of d2-methyl acetate (5052-d2) in greater than 80% of how much h3-methyl acetate (5052) would have been produced in an otherwise identical experiment where h3-thioanisole (5036) was used. GC-MS analysis confirmed the production of the deuterated diaryl sulfides 5040-d and 5040’-d. Therefore, the result of this experiment clearly established the viability of the
Scheme 38 | Deuterium labeling experiment to differentiate between ylide formation and direct protonation of the initial betaine.
Me Me Me Me Me
PhSCD3 5036-d3 HOAc Me Me Me + CD2H–OAc C6D6, 75 ºC O O O Ph Ph S S SPh(D) O D OAc D D D CD2H D(SPh) 4008 5038-d3 5051-d3 5040-d/5040'-d 5052-d2
Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 65 ylide formation as the dominant pathway even under acidic condition. This is in stark contrast to the behavior of the zwitterionic adduct derived from benzyne and amines (cf. 5008 to 5009), in which an external proton source is crucial to carry the reaction forward. We attempted simple DFT calculation for a simplified model system of the reaction between benzyne and dimethyl sulfide in complement to the experimental observations (Figure 18). Against our initial judgement on the trapping reaction of benzyne by sulfides (cf. 5004), formation of the betaine 5053 is endogonic with respect to benzyne and the sulfide. We were not able to locate a transition state structure for such a process that takes place on a flat potential surface. On the other hand, the intramolecular proton transfer was found to be a rapid process to proceed to the much more stable methylene ylide 5054.
Figure 18 | Computed intermediates and transition state structures for the ylide formation. DFT calculations were performed using M06-2X/6-31+G(d,p) and the SMD solvent model (benzene). All values are of the free energies in kcal/mol.
CH ‡ ‡ 3 CH3 S S δ+ CH3 CH2 δ– δ– δ– H 5053* 5054* ? 5.1
3.3
CH3 G 0.0 S CH3
CH3 + S 5053 CH3 –20.6 3001 CH3 S CH2
H 5054
5.3 Application of the Ylide Chemistry to Three-Component Reactions The longer life time and the milder basicity of sulfonium ylides compared to its 1,3- zwitterionic betaine precursor should afford more diverse modes of reactivity as well as enhanced functional group compatibility when one designs novel sulfide-effected HDDA cascade. In particular, it is not far-fetching to construct a three-component reaction if a cyclic sulfide is in place (Scheme 39). Following the mechanism established earlier, the Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 66 thermally generated benzyne 5056 (from the generic HDDA precursor 5055) would lead to the cyclic ylide 5057 with the cyclic sulfide, whose protonation by the protic nucleophile (H–Nu) would furnish the w-functionalized alkyl aryl sulfide 5059 through the ion pair 5058. The overall process constitutes a net electrophilic ring opening reaction of the cyclic sulfide by the electrophilic benzyne and the nucleophile of choice.
Scheme 39 | A generic pattern of the sulfide-mediated three-component reaction.
S H H–Nu H–Nu ( )n Nu S S heat S ( )n Nu H ( )n ( )n 5055 5056 5057 5058 5059
We were pleased to see that heating an acetonitrile solution of the mesylamide-linked tetrayne 5028 (0.1 mol/L) in the presence of 2 equiv of tetrahydrothiophene (THT) and 1.5 equiv of acetic acid produced 2:1 ratio of the isomeric mesylisoindolinyl 4-acetoxybutyl sulfides 5060 and 5060’ in 91% combined yield. Encouraged by this result, we advanced to examine the feasibility of other Brønsted acids under the same set of condition using the ether-linked tetrayne 4008 for the ease of quick qualification of the reaction by GC-MS analysis due to the lower molecular weight of the products 5061/5061’. To our delight, species with higher pKa value than carboxylic acids participated in the three-component reaction as well according to the GC-MS spectra of the respective trial runs. Notably, the sulfide outpaces phenol for its interaction with benzyne due to the low activation free energies required for the ylide formation whereas the hetero-ene reaction between benzyne and phenol (cf. 3058 to 3065) entails greater amount of entropic penalty for the higher degree of bimolecular orientation therein. In addition, b-dicarbonyl compounds including acetoacetate, malonate, and cyanoacetate only exhibited their acid character over the course of the reaction. There was one single set of examples of such process by Nakayama et al. prior to our independent development of the sulfide-mediated three-component reaction (Scheme 41A).98c Protic diazotization of anthranilic acid followed by thermolysis of the resulting benzenediazonium carboxylic acid chloride 5062 (cf. 3013) in the presence of a cyclic sulfide gave rise to the cyclic ylide 5063 (cf. 5057), which was converted to the Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 67
Scheme 40 | Preliminary results of the three-component reaction.
Me Me Me Me
CH3CN + S + H–OAc Me + Me 90 ºC, 12 h MsN MsN OAc S OAc N Ms S 5028 5060 5060' 61% 30%
Me Me Me Me
CH3CN + S + H–Nu Me + Me 75 ºC, 12 h O O Nu S Nu O S H–Nu = H–OPh MeO2C CO2Me
4008 O H 5061 5061' CO Et NC CO Me Me 2 2 H H corresponding w-chloroakyl sulfides by the fortuitously liberated HCl in good yields. The limitation of the protic nucleophiles to the counterions of a handful of mineral acids clearly speaks to the advantage of pristine environment the HDDA-generated benzynes reside. On a side note, their attempted phenyldeprenylation reaction of diprenyl sulfide (5065) led to the smooth formation of the branched sulfide 5068 (Scheme 41B, cf. Scheme 33), which
Scheme 41 | Examples pertinent to the feasibility of the three-component reaction: A) the only precedented three-component reaction, B) proclivity of the sulfonium ylide toward facile Wittig rearrangement. A ( ) ( ) S n n HCl N2 Cl S
DCE, heating S ( )n Cl CO2H H 5062 5063 5064 65-70%
B Me Me Me Me Me Me HCl N2 Cl DCE S Me S Me S + S heating Me Me Me CO H H 2 Me Me Me Me Me 5062 5065 5066 5067 5068 50% Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 68 clearly demonstrated the overriding predisposition toward ylide formation and Wittig rearrangement even in the presence of aggressive Brønsted acid. Extension of this chemistry to a larger pool of substrates brought immense success in terms of the reaction scope for the synthesis of compounds that are characteristic of sulfide-linked chromophores (Table 5). Benzene was found to be the optimal solvent for all instances whereas acetonitrile is only compatible with the less polarized benzynes (i.e., 4008 and 5028). Indolinyl and indazolinyl benzynes (5073-5075) typically exhibits complete regioselectivity as expected of the strong inductive effect exerted by the amide functionality (entries 4-9). Derivatization of the secondary amide 5070 to the N-phenyl tertiary anilide 5071 decreases the rate of cycloaromatization. The isoindolinonyl benzyne 5076 is readily generated at 90 ºC whereas its N-arylated analog 5077 is produced with appreciable rate at 110 ºC (cf. entry 3, Table 1 and entry 6, Table 2). The efficiency of the three-component reaction is insensitive to the ring size of the cyclic sulfide. The ring opening of 2-vinylthiolane occurs selectively at the allylic center by acetate anion (entry 6). A wide variety of weak Brønsted acids participate. Besides phenol and cyanoacetate that had shown promise at the outset (entries 1, 4, and 12), the vinylogously activated p- nitrobenzyl cyanide serves as a viable proton donor (entry 11). The more electrophilic acetylacetone, maleimide, nitro compound, p-hydroxybenzaldehyde, and dimethyl 2- chloromalonate all cleanly afford the corresponding three-component coupling products (entry 2, 7, and 11-13). The reaction is tolerant of a certain degree of steric bulk born with the sulfide and the protic nucleophile (entries 5 and 6). Carbon- nitrogen bonds are formed effectively with amides, carbamates, and N-heterocycles provided that the pKa value of these species are sufficiently low to promote their proton transfers with the ylide partner (entries 3, 7, 9, and 10). The regioselectivity with respect to the site of nucleophilic addition to the HDDA- generated benzyne is consistent with the qualitative prediction offered by the computational protocol (Table 6). Symmetrical tetrayne derived benzynes 5012 and 5078 that display lesser degree of distortion typically result in greater proportion of the isomeric products (entries 1 and 8, cf. Scheme 40 and entry 13, Table 5). The ynamide-derived benzynes 5073-5075 represent the highest level of selectivity toward intermolecular Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 69
Table 5 | Reactant scope for the three-component reaction.
cyclic protic benzyne product, isolated yield of entry HDDA precursor sulfide nucleophile intermediate major (minor) constitutional isomer
O O TMS O TMS TMS Me Me CN S 1 NCCH2CO2Me CO Me Me S 2 4009 5072 5079(5079') 67%(10%)
O TMS Me O O Me S 2 4009 5072 O Me Me S Me OH 5080(5080') 60%(6%)
O TMS O Me N CF3 S 3 4009 p-IPhNHCOCF3 5072 S 5081 48% I Me Me
Me Me S 4 p-HOPhCO Me O N Me 2 Me Ts N S N Ts Ts 4010 5073 5082 CO Me 65% 2 Me
O CO Et 5 4010 S Me 2 5073 Me Me COMe N S Me CO2Et Ts 5083 55% Me Me
Me 6 HOAc N Me Me Me S Ms N N S OAc 5069 Ms 5074 Ms 5084 55% Me Me O Me Boc N 7 S NH Me O N Me Me BocN Boc Boc N N O N N S Boc Boc O 4011 5075 5085 54% Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 70 (continued)
cyclic protic benzyne product, isolated yield of entry HDDA precursor sulfide nucleophile intermediate major (minor) constitutional isomer
Me
OMe Me 8 4011 HOAc 5075 OAc BocN S N S Boc OMe 5086 80% Me
Me CHO BocN S N 4011 Me 5075 S 9 N Boc H N
Me CHO 5087 50% Me O O TMS TMS Me S O HN BocNH–OBoc HN Me Boc Me N 10 HN Me Me OBoc Me Me S Me Me 5070 5076 5088 quant. Me NO2
O 5070 S p-O NPhCH CN 5076 Me 11 2 2 HN S CN
5089 69% CHO
O O TMS O TMS TMS S p-HOPhCHO 12 PhN PhN PhN O S
5071 5077 5090(5090') 43%(16%) Me Me
Me Cl S 13 MsN CO Me Me Me Cl 2 Me MeO2C CO2Me CO2Me MsN MsN S 5028 5078 5091(5091') 53%(21%) Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 71 trapping reactions (entries 3-5, cf. entries 4-9, Table 5), even though the fluorenonyl benzyne 5072 is calculated to bear the same level of polarization (entry 2, cf. entries 1-3, Table 5). N-arylation of the triyne 5070 attenuates the conjugation of the amide functionality. As a result, the increased C–N bond length and the liberated rotation around it in the triyne 5071 not only causes higher entropy of activation for the HDDA event, but also leads to a less rigid bicyclic benzyne 5077, which in turn is able to accommodate less significant degree of distortion (entries 6 and 7, cf. entries 10-12, Table 5).
Table 6 | Computed degree of distortion of different benzynes. DFT calculations were performed using M062X/6-31+G(d,p) and the SMD solvation model (benzene).
b b a a
entry 5056 ∠a ∠b Δ(∠a, ∠b) entry 5056 ∠a ∠b Δ(∠a, ∠b) Me Me
1 124º 131º 7º 5 Me 119º 134º 15º Me BocN O N Boc 5012 5075 TMS O TMS O Me Me 2 119º 136º 17º 6 HN 117º 137º 20º
Me Me 5072 5076 Me
O TMS 3 Me 119º 135º 16º 7 119º 133º 14º PhN N Ts 5073 5077 Me Me
4 Me 118º 136º 18º 8 123º 132º 9º Me N MsN Ms 5074 5078
N-methylbenzothiazoline (5092) was shown to trap benzyne selectively with its sulfide motif (Scheme 42). In the presence of acetic acid, ring cleavage within the ion pair 5093 and subsequent in situ acidolysis of the acetyl hemiaminal 5094 leads to the ortho- aminophenylsulfanyl indazoline 5095, which shares some key structural elements to the tyrosine kinase inhibitor Axitinib (5096). On the outlook, the possible functional groups Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 72 that can be installed by virtue of this three-component process and further chemical elaboration thereof will possess relevance and potential in drug discovery industry. 5.4 Limitation of Reactant Scope for the Three-component Reaction Throughout our expansion of the reaction scope for the versatile three-component process described earlier, we had encountered numerous occasions where the acidic species H–Nu of choice gave rise to less than ideal result. For other instances, they completely failed to deliver the desired product. Use of isatin (5097) typically resulted in multiple
Scheme 42 | Three-component reaction shows promise in drug discovery industry.
Me N Me Me Me Me Me HOAc OAc Me N S + S BocN N PhH, 95 ºC NMe S N N S N S NHMe H N OAc Me Boc MeHN N Boc O Boc
4011 5092 5093 5094 5095 5096 35% Axitinib products, presumably due to the resonance contributors represented by 5099a-5099c (Figure 19A). The use of p-toluenesulfinate for the synthesis of w-sulfonylalkyl aryl sulfides like 5100/5100’ was complicated by the ambident nature of the sulfinate anion. The 4-arylsulfanylbutyl sulfinic ester 5101 was isolated as a minor product along with the aryl acetate 5102 (Figure 19B). On the other hand, the a-nitrotoluene 5103 and the 3- phenylsulfanyl trifluoroacetone 5104 had not been productive under all circumstances, most likely as a result of the alternative modes of reaction of the nitronate and the electrophilicity of the trifluoromethylketone moiety respectively (Figure 19C). Perhaps the biggest unresolved question arose from the futile capture of the ylide 5106 with ortho- nitrophenylacetate 5105 (cf. p-nitrobenzyl cyanide in entry 11, Table 3) in the context of the three-component reaction with the tetrayne 5028 and thietane. Instead, the aryl cyclopropyl sulfide 5107 was formed via a ring contracting Stevens rearrangement as the only detectable product, which is in contrast to the regioselectivity typical of the mesylamide-linked benzyne 5078 (Figure 19D, cf. Scheme 40 and entry 13, Table 5). However, repeating the experiment without the seemingly irrelevant ester 5105 resulted in Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 73 the isolation of only trace amount of 5107 along with polymerized material, and the isomeric sulfide deriving from the initial addition of thietane to the proximal benzyne carbon was still not observed. On the other hand, attempts to incorporate thiirane into the three-component process had all led to the exclusive formation of vinyl sulfides (Figure 20). Thus, heating the tosylynamide-linked tetrayne 4011 with excess thiirane produced the tosylindolinyl vinyl sulfide 5110 in 90% yield. It is not unreasonable to speculate that this rearrangement proceeded directly through the betaine 5108 in a highly asynchronous but concerted
Figure 19 | Examples of some compromised three-component reactions: A) ambidence of isatin, B) ambidence of sulfinate, C) complication arising from the reactivity of nitronate and trifluoromethyl ketone, D) ring contraction reaction of the thietane-derived sulfonium ylide. A
O O O O
S + O O S O O ( )n N N H ( )n N N H 5057 5097 5098 5099a 5099b 5099c
B Me Me Me S Me , TolSO2Na, HOAc O + + Me Me Me Me CH3CN-H2O, 75 ºC SO2Tol O O O O Tol S S S OAc 4008 5100/5100' 5101 O 5102
C D Me Me Me Me
H NO2 CO2Me O PhH S NO Me Me PhS + + 2 CF3 90 ºC MsN MsN H S S N Br Ms H 5103 5104 5028 5105 5106 5107 40% Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 74 manner that effectively circumvented the desired proton transfer event. A less efficient formation of 5110 was also effected by tetrahydrothiophene via a fragmentation pathway of the ylide 5109.98e,f,100 We close the discussion of this chapter by noting the degree of aromaticity and the high reactivity of ortho-benzyne as its two seemingly contradictory and yet unified facets. Along this line, it is not difficult to comprehend that the initial zwitterionic adduct formation between benzyne and a monovalent nucleophile (i.e., ether, alcohol, amine, sulfide) is in facile equilibrium and that benzyne is not a promiscuous reactive intermediate. This reversibility reflects the innate reactivity of benzyne and is directly consequent to the absence of metal counterion that serves to further stabilize any charge separated intermediates. Indeed, the successful story of the sulfide-templated three-component reaction not only upholds the well-acknowledged advantage of the HDDA reaction for the generation of structurally elaborated benzynes, but also reiterates the hierarchy with which functional groups may engage benzyne, even though the exact nature of the trapping event may well depend on the reaction condition.
Figure 20 | Fragmentation pathways of some cyclic sulfonium ylides.
H
S H Me
S NTs Me Me 5108 Me Me
N Me N S Ts Ts 4011 5110 90% via 5108 Me 40% via 5109 S
Me
N S Ts 5109
100 Brewer, J. P. N.; Heaney, H.; Jablonski, J. M. Aryne chemistry part XV. The cleavage of ethers and thioethers by arynes. Tetrahedron Lett. 1968, 42, 4455-4456. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 75
Chapter 6. Trapping Reactions between the HDDA-Generated Benzynes and Thioamides
The studies presented in this chapter are the collaborative results from Mr. Vignesh Palani and the author of this Thesis, in which the author of this Thesis contributed to the intellectual development of the chemistry as well as all the computational studies. The collective experimental details are included in the experimental section to serve as the comprehensiive support of this unpublished body of work, where the syntheses and characterization data collected by Mr. Palani are explicitly indicated by [VP].
6.1 Reactions between Benzyne and Thiocarbonyl Compounds The superb reactivity of sulfide toward benzyne is a dynamic phenomenon. In a prototypical reaction, an equilibrium is quickly established for the formation of the betaine 5053, which is siphoned to the much more stable sulfonium ylide 5054 with an extremely low barrier (Figure 21, cf. Figure 18).101 Similarly, we envisioned that the initial addition of a thiocarbonyl compound (6001) to benzyne would be a facile process. At the outset, we anticipated that the nature of the substituents R1 and R2 would dictate both the relative energetics of the betaine 6002/6003 and the downstream reactivity thereof.
Figure 21 | Mode of reactivity of benzyne with sulfanyl group and thiocarbonyl group.
CH CH3 CH 3 3 S + S S CH CH3 2 CH3 H 3001 5053 5054
R1 S R2 S R2 + S 1 1 R2 R R 3001 6001 6002 6003
To the best of our knowledge, Nakayama et al. reported the first reaction of benzyne with a thiocarbonyl compound (Scheme 43).102 The dithiolylium betaine adduct 6005
101 (a) Hellmann, H.; Eberle, D. Liebigs Ann. Chem. 1963, 662, 188-201. (b) Franzen, V.; Joschek, H.-I.; Mertz, C. Liebigs Ann. Chem. 1962, 654, 82-91. 102 (a) Nakayama, J.; Kimata, A.; Taniguchi, H.; Takahashi, F. Reactions of benzyne with 1,3-benzodithiole- 2-thione and related compounds: formation of novel tetracyclic sulfonium salts and their reactions leading to dibenzo-1,3,6-trithiocin derivatives. Bull. Chem. Soc. Jpn. 1996, 69, 2349-2354. (b) Nakyama, J.; Kimata, A.; Taniguchi. H.; Takahashi, F. Reactions of 1,3-benzodithiole-2-thione and ethylene trithiocarbonate with Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 76 deriving from benzyne and ethylene trithiocarbonate (6004) collapsed to form the dithiathionium ylide 6006 (cf. 6002), which expelled ethylene to produce benzodithiole-2- thione (6007). The trithiocarbonate 6007 further underwent an analogous transformation in the presence of excess benzyne, and the resulting ylide 6008 was sequestered as its stable hydrochloride salt 6009. The same pattern of transformation applied to the reactions between benzyne and thiozolidine-2-thiones. Benzyne effected the stereospecific olefination of amino alcohols from which the cyclic dithiocarbamates were prepared.103 Thus, threo-a-methylprolinol (6010) was converted to the corresponding bicyclic erythro- dithiocarbamate 6011, and its addition to benzyne, which was generated from the ortho- silylphenyl triflate 3016 promoted by CsF, gave rise to the cis-alkene in the iminobenzodithiole 6013 through the presumably concerted fragmentation reaction of the adduct azathiasulfonium ylide 6012.
Scheme 43 | Reaction of benzyne with trithiocarbonate and thiozolidine-2-thione.
S
S S S S S – S S N2 Cl 6004 S S S S 3001 HCl S S S S Cl propylene oxide CO H S S 2 DCE, heating
5062 6005 6006 6007 6008 6009 62%
TMS
S TfO S S H DBU, CS N Me 2 3016 N S N S N S OH MeCN CsF, MeCN Me Me Me 6010 6011 6012 6013 60%
Although the nature of the addition of the dithiocarboxylic acid derivatives to benzyne awaits mechanistic elucidation, this net [3+2]-cycloaddition process is thermodynamically driven by the stability of the thiasulfonium ylides (cf. 6006 and 6008).
benzyne generated from 2-carboxybenzenediazonium chloride: preparation of novel bicyclic sulfonium salts by trapping 1,3-dipolar cycloaddition intermediates. Chem. Comm. 1996, 205-206. 103 Hwu, J. R.; Hsu, Y. C.; Stereospecific benzyne-induced olefination from b-amino alcohols and its application to the total synthesis of (–)-1-deoxy-D-fructose. Chem. Eur. J. 2011, 17, 4727-4731. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 77 Okuma et al. described the reactions of benzyne with dithiolactone that formally proceeded via the same mechanistic pathway (Scheme 44).104 In particular, ring contraction of the S- sulphanyl thiasulfonium ylide 6015 that derived from the dithiolane thione 6014 gave the spirobenzodithiol thietane 6019 in good yield via the benzodithiolylium thioenolate 6016. Use of the isomeric thiolane dithione 6017 led to the same zwitterionic intermediate 6016 through the thiasulfonium ylide 6018.
Scheme 44 | Reaction between benzyne and dithioland thione.
Me Me Me S Me Me S S S S Me TMS Me 6014 S S S S Me Me Me Me Me OTf TBAF, CH2Cl2 S S Me S Me Me Me 3016 6015 6016 6019 Me Me 85% with 6014 S S 78% with 6017
Me Me Me Me S S 6017 S Me Me TBAF, CHCl3 S 6018
Greaney et al. observed an alternative mode of reactivity between benzyne and trisubstituted thioureas (Scheme 45).105 When the thiourea 6020 was heated with 3016 under fluoride-mediated conditions, the initial thiouronium betaine adduct 6021 (cf. 6002 and 6003) bifurcated to form the arylated amidine 6025 along with the simple S-aryl isothiourea 6022 as a minor product. The net 2:1 adduct 6025 would arise from a C=S metathesis process via the benzothietane 6023 followed by the S-arylation of the resulting ortho-mercaptobenamidinium zwitterion 6024. Most recently, Li et al. described the reactions between the domino benzyne precursor 6026 and monothioimides like 6027 in the synthesis of 2,4-disubstituted
104 Shigetomi, T.; Nojima, A.; Shioji, K.; Okuma, K.; Yokomori, Y. Novel formation of 1,2-dithiolane-3- thione from b-dithiolactone. Heterocycles 2006, 68, 2243-2246. 105 Biswas, K.; Greaney, M. F. Insertion of arynes into thioureas: a new amidine synthesis. Org. Lett. 2011, 13, 4946-4949. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 78 benzothiazoles (Scheme 46).106 The thioimidate 6029 was believed to serve as a more potent nucleophile toward 3-trifloxybenzyne (6028) due to its enhanced acidity of the
Scheme 45 | Reaction between benzyne and trisubstituted thiourea.
S
PhHN NEt2 H TMS S SPh 6020 S N S H 3001 Ph NHPh N NPh OTf CsF, Tol/MeCN NEt2 Ph NEt2 90 ºC NEt2 NEt2 3016 6021 6023 6024 6025 66%
S N Ph NEt H 2 6022 25% thioimide. The nascent anionic adduct 6030 eliminated triflate to generate the secondary benzyne 6031 in a tandem fashion, which ultimately gave rise to 2-phenyl-4- pivaloylbenzothiazole (6033) via a precedented acyl migration within the N-acyl thiazoliminium betaine 6032.
Scheme 46 | Synthesis of benzothiazole from domino benzyne precursor and secondary thioimide.
S O S O
Ph N tBu t t Ph N tBu Bu O Bu OTf H OTf O OTf Piv TMS 6027 6029 Piv N N N N Ph Ph CsF, dioxane S Ph S S OTf 80 ºC S Ph 6026 6028 6030 6031 6032 6033 82%
6.2 Discovery of the Reactions between the HDDA-Generated Benzynes and Thioamides We were most attracted to Greaney’s formal [2+2] process between benzyne and thiourea that led to C–arylation. However, in our hands, heating the tetrayne 4008 with N, N’-dibutylthiourea (6034) only produced the thiols 6038/6038’ along the S-arylation
106 Shi, J.; Qiu, D.; Wang, J.; Xu, H.; Li, Y. Domino aryne precursor: efficient construction of 2,4- disubstituted benzothiazoles. J. Am. Chem. Soc. 2015, 137, 5670-5673. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 79 pathway (cf. 6021 to 6022, Scheme 47). The primary adduct S-arylisothiourea 6036 further dissociates through the ion pair 6037 to release N, N’-dibutylcarbodiimide in an overall
H2S transfer reaction.
Scheme 47 | Reaction of the HDDA-generated benzyne with disubstituted thiourea.
Me Me S Me Me Me Me BuHN NHBu Bu 6034 Me Me N – BuN=C=NBu O O Me ● Me MeCN, 75 ºC O N O S S H Bu H H S SH O N NHBu N NHBu H Bu Bu 4008 6035 6036 6037 6038/6038'
In the hope of minimizing the S-arylation process, we shifted our attention to N,N- diethylthiophenylacetamide (6039) that only differs with the thiourea 6020 at the secondary amide functionality (Scheme 48). Indeed, submitting 6039 to the same HDDA reaction resulted in a 2:1 ratio of partially separable isomeric 3-aminobenzothiophenes 6046/6046’ in moderate overall yield. The lack of the kinetically readily deprotonated N–H bond (cf. 6021) in the thioamide allows for the formation of the benzothietane 6040, whose ring opened product 6041 has a sufficient life time for an intramolecular imine-enamine tautomerization. The resulting stilbene-2-thiol derivative 6042 undergoes an intramolecular thiol-ene reaction and subsequent autoxidation to give the benzothiophene 6046 via the diradical 6043. On the other hand, the radical recombination within the alternative diradical species 6044 would lead to 6040 in a nonproductive pathway. In spite of our initial success in orienting benzyne to the desired 1,2- bifunctionalization with aliphatic thioamide, this benzothiophene synthesis is plagued by numerous drawbacks. The choice of substrate is limited to the symmetrical tetraynes 4008 and 5028, whose corresponding benzynes typically exhibit mediocre regioselectivity with intermolecular trapping agents (cf. 6046 and 6046’). The reaction is also sensitive to the nature of the thioamide. Neither thiopropionamide or thioisobutyramide is effective to promote benzothiophene synthesis. On the other hand, attempt to preserve the dihydrobenzothiophene products by the use of cyanothioacetamide was further complicated by the formation of diastereomers. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 80
Scheme 48 | Reaction of the HDDA-generated benzyne with thiophenylacetamide to form the benzothiophenes.
Ph Me Me Me Me Me Me Me S Et2N
6039 Me Me Me Me Me O O O O O MeCN, 75 ºC S S S 40% S S Ph H H O Et2N Et2N Et2N NEt2 H Et N Ph Ph Ph 2 Ph 4008 6040 6041 6042 6043 6045
Me Me Me
Me Me Me + O O O S NEt2 S H S Et2N Ph Et2N Ph Ph 6046' 1:2 6046 6044
Meanwhile, heating the ketotriyne 4009 with N,N-dimethylthiobenzamide in benzene led to the isolation of a single product 6053 in moderate yield, whose molecular connectivity was only confirmed after extensive 2-D NMR analysis (Scheme 49). The lack of additional aromatic resonance in the 1H NMR spectroscopy implicated the intermediacy of the N,N-dimethylaminobenzothietane 6048, the fragmentation of which would be poised for an unusual thiolate-relayed iminium tautomerization. An intramolecular proton transfer from one of the available C–H bonds within the ortho-mercaptoaryliminium 6049 produced the azomethine ylide 6050/6051, which underwent an alternative protonation to give the isomeric methylene iminium zwitterion 6052 to furnish the dihydrobenzothiazine 6053. As a prelude to the discussion of the mechanistic details for the dihydrobenzothiazine synthesis in the following section (see Section 6.3), a few features in this proposed mechanism are worth mentioning. The geminal methyl groups attached to the nitrogen atom are necessarily chemically nonequivalent. Furthermore, we suggestively portrayed a trans-relationship between the methyl group where the initial deprotonation occurs and the proton receiving arylthiolate motif, even though this arrangement appears counter-intuitive. One corollary of this mechanistic perspective is the establishment of an Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 81 equilibrium between the benzothietane 6048 and the ring opened zwitterion 6049. The analogous equilibrium between 6040 and 6041, on the other hand, would be inconsequential. Nonetheless, we assign the generation of azomethine ylide as the rate limiting step for the trapping process based on the difference of the pKa values between benzenthiol and iminium ion, notwithstanding that this assessment is complicated by the proximity of these functional groups.
Scheme 49 | Reaction of the HDDA-generated benzyne with thiobenzamide to form the dihydrobenzothiazine.
Ph Me S O TMS Me2N Me Me Me Me Me Me Me 6047 S S S S S H H H S PhH, 90 ºC Me Me Me CH2 Ph Ph N Ph N Ph N Ph N NMe2 Ph N O CH CH Me H 2 2 Me 4009 6048 6049 6050 6051 6052 6053 46%
In spite of the lack of a clear picture of the mechanism, we were delighted to find that the reaction between benzyne and aromatic thioamide enjoyed a more substantial reactant scope than with aliphatic thioamide (Table 7). The more highly branched groups on the nitrogen atom promoted the progression of the reaction (entries 1 and 2). This trend argues against the representation of the diarylazomethine ylide like 6050 for which the bulkier aromatic substituents would cause reduced degree of resonance stabilization, but it favors the representation of the dialkylazomethine ylide 6051 for which the branched substituents would stabilize the alternative carbocation character by virtue of hyperconjugation. Most notably, the reactions typically resulted in the isolation of only one of the two possible diastereomers (entries 1, 3, 4, 6, and 7). The skeletal connectivity and relative configuration of the stereogenic centers of 6062 was unambiguously established by X-ray crystallographic analysis. The yield of the reaction was boosted by the use of N,N-diallylthiobenzamide (6056) due to the extended conjugation of the allylic carbocation (entries 3 and 6). Nucleophilic heterocycle (i.e., 6057) was tolerated during the reaction (entry 4). The thioanilide 6058 participated with equal efficiency. The dihydrobenzothiazine formation was equally efficient with benzynes of different degree of Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 82
Table 7 | Substrate scope for the aromatic thioamides trapping reaction.
benzyne product entry HDDA precursor intermediate thioamide isolated yield
O TMS TMS Me O O S H TMS Me 1 Ph N Me S Me Et H Ph N Me Et 4009 5072 6054 6060 58% O TMS Me S H
2 4009 5072 Ph N Me Me S iPr H Me Ph N Me iPr 6055 6061 60% O TMS Me S H
3 4009 5072 Ph N S H N H Ph 6056 6062 79% O TMS Me S H 4 4009 5072 N S H N N
N 6057 6063 50% O TMS Me S H
5 4009 5072 Ph N S Ph Ph N 6058 6064 Ph 50% R = R R Me Me S H Me 6 N N Me Ph N S N Ts Ts H Ts Ph N
4010 5073 6056 6065 R 66% R R Me Me Me S H Me O O H 7 O Ph N S Ph Me O H S N Ph N
6066 6066' 4008 5012 6059 60% 16% Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 83 polarization (entries 5 and 6). The less polarized benzyne (i.e. 5012) gives rise to a separable mixture of isomers as anticipated (entry 7). The site of the preferential attack by the sulfur atom is confirmed by the NOE correlation for the N,N-diisopropylthiobenzamide derived dihydrobenzothiazine 6061 (entry 2). 6.3 Mechanistic Studies of the Dihydrothiazine Formation Reaction
Scheme 50 | Isopic labeling experiment with d3-thiobenzamide.
TMS O O TMS Me Me
S SH S CD3 CD Ph N Ph N 3 CD3 Me Ph N CH H 2 TMS TMS CH 6067 6069 O O 3 Me Me Me 6047-d3 S + S C D , 90 ºC 6 6 D D H H N N O Ph D Ph H CH3 CD3 TMS O O TMS 6071 1:4 6072 4009 Me Me
S SD CH3 CH Ph N Ph N 3 D C 2 D CD2 6068 6070
We opted to use the isotopic labeling experiment to probe the mechanism of the dihydrobenzothiazine synthesis reaction in more detail (Scheme 50). The d3-thiobenzamide
6047-d3 exists as a mixture of two rotamers in approximately 1:1 ratio. Subjecting 6047- d3 to the HDDA reaction of 4010 in d6-benzene led to a 1:4 ratio of isotopic isomers 6071 and 6072 as indicated by in situ NMR spectroscopy of the reaction mixture. Under the premise that only one transition state is responsible for the azomethine ylide formation, one of the (essentially) energetically equivalent and yet geometrically isomeric ortho- mercaptoaryliminium zwitterions (6067 vs. 6068) would proceed to produce its corresponding dipole and the other would produce the alternative (6069 vs. 6070). Therefore, the observation of both 6071 and 6072 advocates the sampling between 6067 and 6068 through the common benzothietane (cf. 6048), and that the barrier for their interconversion is much lower than that for the proton transfer to generate the azomethine Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 84
Table 8 | Effect of electronic properties of thiobenzamides.
azomethine ylide product entry HDDA precursor thioamide intermediate isolated yield
Me Me
Me S Me Me 1 Ph N Me Ph N N Ts Me SH N S Ts Ts Ph N Ph N Ph Ph 4010 6058 6075 6085 79% Me
Me
Me OMe S Me 2 4010 N S Ph N Ts Me N SH Ph N Ts Ph N OMe
OMe 6067 6076 6086 74% Me
Me
Me CF S 3 Me N 3 4010 S Ph N Ts Me N SH Ph N Ts Ph N CF3
CF3 6068 6077 6087 64% TMS O O TMS Me Me O S Me i SH 4 N Pr2 S iPr Me Me N O2N N Me iPr Me Me O2N O N 4009 6069 6078 2 6088 70% O TMS O TMS Me Me S
i SH S 5 4009 N Pr2 iPr Me MeO N N Me iPr Me Me MeO MeO 6070 6079 6089 20% Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 85 (continued)
azomethine ylide product entry HDDA precursor thioamide intermediate isolate yield
Me Me Me
S O Me Me Me Me O 6 Ph N OMe O O O Me nPr Ph S S S N Ph N Ph N Et CO2Me n CO2Me Pr CO2Me Et 4008 6071 6080 6090 6090' 10% 10% Me Me Me
S Me Me Me 7 4008 O O O Ph N CO2Me Me SH SH S
Ph N CO2Me Ph N Ph N Me CO2Me CO2Me 6072 6081 6082 6091 Me
S Me 8 4008 – Ph N CO2Et O Ph SH
Ph N CO2Et Ph 6073 6083
Me
OTBS S Me O 9 4008 Ph N – SH F3C Ph N OTBS
CF3 6074 6084 ylide in agreement with the observed primary kinetic isotope effect. Changing of substituents in the thioamide are shown to influence the outcome of the reaction (Table 8). Anilides with both electron donating and electron withdraw substituents participate. The less nucleophilic trifluoromethylated analog 6068 leads to marginally lower yield (entries 1-3). The presence of an even stronger electron withdrawing group as in the thioimide 6071, however, undermines the reaction by retarding the ionization event of the benzothietane 6080, to afford the isomeric dihydrobenzothiazine Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 86 derivatives 6090/6090’ in a 1:1 ratio (entry 6). The use of 4-nitrothiobenzamide 6069 increases the yield of reaction (entry 4, cf. entry 2, Table 7) whereas the use of the 4- methoxythiobenzamide 6070 is detrimental (entry 5, cf. entry 2, Table 7). This substantiates our interpretation that the azomethine ylide carries more cabanion character at the benzylic center (cf. 6078 and 6079). On the other hand, thioamides bearing a- electron deficient groups prove unproductive (entries 7-9) as a result of the destabilization effect on the carbocation character for the ylides 6081, 6083 and 6084. The sarcosine- derived thioamide 6072 gives rise to a number of products that possess the molecular weight of the expected product 6091 according to GC-MS analysis, while the presence of ester and trifluoromethyl groups leads to unproductive reactions (entries 8 and 9). A more comprehensive picture of the mechanism for the dihydrobenzothiazine synthesis emerged from DFT calculations of the reaction between benzyne and N,N- dimethylthiobenzamide (6047, Figure 22). Most of our proposed intermediates can be mapped onto the landscape. Notable exceptions are the thioiminium betaine 6092 that consequently leads to the benzothietane 6093 in a tremendously exergonic fashion, and the preceding zwitterion 6096 to furnish the dihydrobenzothiazine 6097. An equilibrium is very likely in place between 6093 and 6094, given the marginal difference in their free energies. We were able to locate a reasonable transition state structure 6094* for the rate determining proton transfer event, in which the benzyne derived aryl thiolate resides trans to the participating methyl group. This remarkable geometric arrangement is accommodated by the distortion of the diaryliminium ion and the longer C–S bond length. It is clear from this energy diagram that the combination of an electron deficient aryl group and the presence of an carbocation stabilizing a-substituent on the thioamide is optimal to facilitate the overall transformation by stabilizing the azomethine ylide (like 6099a) and the ensuing iminium zwitterion while destabilizing its preceding iminium zwitterion (like 6098a, cf. entry 4, Table 8). An electron donating aryl group raises the free energy of activation for the azomethine ylide formation by stabilizing the incipient diaryliminium ion (like 6098b) while destabilizing the carbanion character of the corresponding ylide (6099b, cf. entry 5, Table 8). On the other hand, an electron withdrawing substituent at the a- position of the amido group (like 6073, entry 8, Table 8) elevates the barrier for the Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 87 generation of dihydrobenzothiazine by virtue of the destabilized glyoximinium zwitterion (like 6101).
Figure 22 | Computed reaction pathway for the dihydrobenzothiazine formation. DFT calculations were performed using M06-2X/6-31+G(d,p) and the SMD solvation model (benzene). All values are of free energies in kcal/mol.
S NMe2
Ph ‡ H 6092 Me δ– ‡ Ph ? N 0.0 S S H δ– Me δ– N Ph N Ph S 6094* H δ– CO2Et Ph 6101 –24.9 6095* 3001 –30.0 + H –33.4 Ph S S N Me Ph NMe2 Me N 6096 6047 –54.2 H S –55.8 ? G Ph S 6095 S Me iPr NMe2 N Ph Me N –68.2 Me H S 6093 Ph 6094 Me Ph
S H S iPr R N N 6099a R = NO2 Me i Pr 6099b R = OMe 6097
Ph N EtO2C H S R Ph 6098a R = NO 2 6100 6098b R = OMe
The diastereoselectivity of the dihydrobenzothiazine formation can be rationalized based on conformational analysis of the intermediates and relevant transition state structures (Figure 23). For the case of the fluorenone derivative 6060 (cf. entry 1, Table 4), the unique geometric constraint of the fluorenone moiety would impose the pseudoaxial orientation of the phenyl group and pseudoequatorial orientation of the methyl group on the rate determining transition state structure 6102. The facile proton delivery within the resulting azomethine ylide 6103 via the early transition state structure 6103* (cf. 6095*) would lead to the re-oriented iminium zwitterion 6104, in which the phenyl group points perpendicular to the plane of the fluorenone and the ethyl group avoids eclipsing Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 88 interactions. Ring closure with the exposed Re-face of the iminium ion would give rise to the sterically accommodated diastereomer 6060.
Figure 23 | Origin of diastereoselectivity with the dihydrobenzothiazine synthesis.
O O O O O TMS TMS TMS H TMS TMS H H H Ph H Ph Et δ– Et Et δ– H Me N Me N Me N Me Me δ+ S Me S Me S Me S H S H δ– H H δ– N N Ph Ph Ph Et Me H H H Me Et 6102 6103 6103* 6104 6060
The mechanistic scheme is complicated when a thioamide derived from a differentially substituted dialkylamine is used (Figure 24). With N-methyl-N-allyl thiobenzamide, one could envision two geometrically isomeric ortho-mercaptoiminium zwitterions 6107 and 6108, as well as three distinct isomeric rate limiting transition state structures, two of which are constitutional isomers (6107* vs. 6108*), in addition to the diastereomeric transition state structure 6107**. The iminium zwitterions 6107 and 6108 are arise from the rotamers 6105 and 6106, respectively The results of DFT calculations implicate a Curtin-Hammett scenario in which all the involved intermediates (6105 to 6108) are rapidly interconverting (6107* vs. 6108*). On the other hand, this model system does not fully reflect the origin of the observed diastereoselectivity as evident by the marginal difference in free energies between the diastereomeric transition state structures 6107* and 6107**. It is conceivable that the more extensive mechanistic understanding of the individual events over the course of the dihydrobenzothiazine formation would be instructive to the synthetic application of such transformation. Guided by these principles, we were able to expand the scope of this reaction to incorporate more exotic functional groups (Table 9). The cyclopropylmethyl group is equally effective to stabilize the carbocation character of the azomethine ylide intermediate (entry 1). The ortho-substituted arylthioamide 6110 participates (entry 2), although the diastereoselectivity of the transformation deteriorates with the isoindolinonyl benzyne 5076 (cf. entries 10 and 11, Table 5 and entry 6, Table 6). The thionaphthamide 6112 (entry 4) and the heterocyclic Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 89
Figure 24 | Computed intermediates and transition state structures to rationalize the regioselectivity with respect to the azomethine ylide formation. DFT calculations were performed using M06-2X/6-31+G(d,p) and the SMD solvation model (benzene). All values are of the free energies in kcal/mol.
‡ δ– N H S δ– ‡ ‡ Ph Me Me δ– δ– 6108* N N H H S H S δ– δ– 31.2 Ph Ph H 6107* 6107** 26.6 26.2 Me N
G S Ph 3.1 6106 1.9 1.4 0.0 Me N Me Me N S Ph N S Ph 6108 S Ph 6107 6105 aromatic thioamides 6111 and 6113 (entry 3 and 5) are efficient trapping agents. In particular, the electron rich nature of the indole or pyrrole motif can be altered by virtue of an electron withdrawing group (entry 3, cf. entry 5, Table 8) or the site of substitution (entry 5) respectively. The N-methylbenzylamine derived thiourea 6113 displays reasonable regioselective azomethine ylide formation to produce the pyrrole-N- methylaminal 6120 as the major product (entry 5). This trend is magnified for the instance of the N-allylglycine thiobenzamide 6114 in which the glycine unit is shown to be non- participating (entry 8, Table 8). Disappointingly, the reaction with the thiozole-4-thioamide 6115 is unproductive, for which a fragmentation pathway of the azomethine ylide 6122 might be responsible. 6.4 [3+2]-Mode of Reactivity of Benzynes toward Sulfur-Based Nucleophiles In order to further extend the dihydrobenzothiazine synthesis beyond the use of aromatic thioamides, we recognized that a stronger electron withdrawing group substituted thioamide like 6124 would further amplify the effect of an electron deficient aryl group to Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 90
Table 9 | Substrate scope with more exotic aromatic thioamides.
product entry HDDA precursor thioamide isolated yield R = R Me Me S 1 N Me Ph N N S Ms Ph Ms Ph N Ph 5069 6109 6116 94% O TMS O Me I S TMS HN 2 HN NEt2 S Me Me Me Me Me N Me I Et 5070 6110 6117/6117' 59%, dr=2.2:1 R S Me Me NEt2 Boc N Boc N N 3 S N Me Boc Boc N N Me Ts Et N 4011 6111 Ts 6118 69% R Me Me S N 4 N S N Me Ts Ts O N O 4010 6112 6119 R 52% R Me Me S N 5 4010 N N Ph N S S Ts Me Ts N N Ph N N Me Ph 6113 6120 6120' 80% 13% R R Me S Me Me O O Ph 6 O Ph N S Me S N CO2Et CO2Et Ph N
CO2Et 4008 6114 6121 6121' 57% 5% R R Me Me S O – CH3CN O 7 N 4008 Me N SH SH S NBoc N Me N S ● N S NBoc NBoc 6115 6122 6123 Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 91 promote the overall transformation by destabilizing the iminium zwitterion 6127 and stabilizaing the azomethine ylide 6128 to a greater extent. Conversely, the initial thioiminium betaine 6125 formation and the fragmentation of the supposedly resulting benzothietane 6126 would be disfavored by destabilization imposed by the electron withdrawing group in the iminium ion of these intermediates (Scheme 51).
Scheme 51 | Reaction of the thioamide bearing an electron withdrawing group.
S NMe2
EWG ‡ 6124 S NMe2 S SH S S Me Me δ– N EWG NMe N N N 2 Me H S δ– Me Me EWG EWG EWG EWG EWG 3001 6125 6126 6127 6127* 6128 6129
We started this portion of the study by preparing the thiotrifluoroacetamides 6130 and 6131 as well as the thiooxalamide 6132. The projected dihydrobenzothiazine products 6133 and 6134 would encompass an a-trifluoromethylbenzylamine motif and the chiral a- aminoester motif in 6135 would be valuable for a plethora of derivatization methods (Scheme 52A). In order to examine the reactivity of the thioamides 6130-6132, each of them was heated in benzene with a selected HDDA precursor. Molecular sieves were also added to prevent hydrolysis of these highly electrophilic reagents (Scheme 52B). The reaction of the tetrayne 5028 with N-allyltrifluorothioacetanilide (6130) cleanly yielded a pair of isolable isomeric adducts. However, the NMR spectra of these two products are inconsistent with the dihydrobenzothiazines like 6133 with respect to the chemical shifts of the two characteristic methine protons. The reaction of 5028 with the morpholine derived thiooxalamide 6132 gave rise to one single product, the NMR analysis of which shows the absence of a substructure like 6135. On other hand, the reaction between the amide linked triyne 5070 and the N-methylbenzylamine derived thioamide 6131 led to a number of products, among which we were able to identify the benzothiazoline derivatives 6137 and 6138 based on the presence of the diastereotopic methylene protons of 6139 in the NMR spectroscopy. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 92
Scheme 52 | Reactions of HDDA-generated benzynes with strongelectron-withdrawing group substituted thioamides: A) unexpected dihydrobenzothiazine formation, B) observed dihydrobenzothiazoline formation.
S A B Me Me Ms N F3C N Ph S S 6130 F C N + 3 MsN MsN F C N PhH, 4 Å MS, 90 ºC Ph 3 H H Ph S NPh N S 6130 6133 Me Me Ph CF3 CF3 5028 6136 6136' S S 49% 20% S H TMS Me F C N Ph O F3C N Ph N O 3 O TMS Me Me Me Me F3C N Ph Me H H HN Me 6131 HN S + 6131 6134 Me PhH, 4 Å MS, 90 ºC Me S TMS N Me Me Me CF3 N H Me S Ph CF3 Me H EtO S N 5070 6137 6138 O O EtO2C N 20% 10% H H O S Me 6132 6135 EtO2C N O Me 6132 MsN MsN Me PhH, 4 Å MS, 90 ºC S N CO2Et
O 5028 6139 53%
The 2,2-benzothiazoline formation speaks for the enhanced stability of a benzothiazolinium ylide like 6141 (Scheme 53), which would formally arise from an alternative mode of cyclization of the betaine 6140 (cf. 6125 to 6126). This net [3+2]- cycloaddition pathway is reminiscent of the reaction between benzyne and dithiocarboxylic acid derivatives (cf. reactions with 6004, 6011, 6014, and 6017). For the instance of the reaction with 6131, the ylide 6141 would undergo a Stevens rearrangement through the inner sphere radical pair 6142 to produce 6137 whereas the monosubstituted benzothiazoline 6138 would result from 6143 via the diffusion controlled pathway. Accordingly, we were able to infer the identities of the benzothiazolines 6136/6136’. The ylide 6144 would proceed via a Wittig rearrangement to transpose the allyl group. The Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 93 unusual ring expansion reaction of the ylide 6145 would account for the formation of 6139, whose structural assignment was endorsed by extensive 2D-NMR spectroscopy.
Scheme 53 | Mechanisms of the benzothiazoline synthesis.
Me TMS TMS O TMS O O O TMS Me Me Me Me Me HN HN HN HN Me S S S Me Me Me Me Me Me S S MsN Me N N Me N Me Me ● N S Me N CF3 CF CF Me CF3 Ph 3 3 Bn CF Bn Ph H ● H 3 N Ph CF3 Ph 6144 6136 6140 6141 6142 6137
O TMS O TMS Me Me CO2Et CO2Et S S HN HN H N N ● ● 6139 S S Me Me Me Me H N ● N O O Me Me CF3 CF3 H 6145 6146 6143 6138
Computation of the reaction of benzyne with N,N-dimethylthiotrifluoroacetamide (6147, Figure 25) revealed a different mechanistic perspective. In this instance, the betaine 6148 was located as a local minimum although its formation is not favorable. The intermediacy of 6148 is rendered questionable as the dominant preference for the generation of the benzothietane 6149 along this hypothetical potential energy surface contradicts experimental observation. The intermediacy of the trifluoromethyliminium zwitterion 6151 also becomes elusive, and the transition state structure 6151* for the hypothetical dihydrobenzothiazine manifold is not effectively stabilized by the CF3 group. Instead, we envisioned a low barrier [3+2]-cycloaddition pathway that directly gives rise to the ylide 6150 via a concerted and yet highly asynchronous transition state structure like 6150*. 6.5 Summary and Prospect From a unified perspective, we recognize that it is possible to define the subtle balance of the electronic effect dependent divergence between the formal [2+2] and [3+2] pathways by screening thioamides with a continuum of electronic properties. On the other hand, with the dual modes of reactivity associated with thioamide, functional group Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 94
Figure 25 | Computed pathways for the reaction between benzyne and N,N- dimethyltrifluorothioacetamide. DFT calculations were performed using M06-2X/6- 31+G(d,p) and the SMD solvation model (benzene). All values are of free energies in kcal/mol.
‡ S NMe S 2 δ– CF3 CF3 Nδ+ Me Me 6148 16.8 6150* ‡ ? Me δ– N H S δ– 0.0 CF3 6151* –24.3 –25.9 G 3001 S + CF3 S N Me Me F3C NMe2 6150 ? 6147 –59.2 S Me S N Me NMe2 CF3 CF3 6149 6151
interconversion would further achieve complementary reaction manifolds (Scheme 54). For example, the sulfonylthioformamide 6152 and the cyanothioformamide 6153 are expected to afford the corresponding allyl group migrated benzothiazoline products 6156 and 6157. Dissociation of benzenesulfinate from 6155 would produce the ion pair 6156. The nitrile 6159, which would have been assembled from benzyne and 6153, could be synthesized from the tetrazole-2-thioamide 6154 and a subsequent nucleophilic displacement of the labile tetrazole motif. Incidentally, Willis et al. described a synthesis of benzoisothiazoles from benzynes and thidiazoles with regioselective ejection of isocyanic acid (Figure 26A). 107 Our computational modeling with thiadiazole (6164) suggested a concerted [3+2]- cycloaddition reaction via the transition state structure 6164* followed by a nearly
107 Chen, Y.; Willis, M. C. An aryne-based route to substituted benzoisothiazoles. Org. Lett. 2015, 17, 4786- 4789. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 95 barrierless [3+2]-cycloreversion event through 6165* (Figure 26B). As expected, heating of the ether-linked tetrayne 4008 with two equivalents of 3,4-dichlorothiadiazole 6162 likewise gave the 3-chlorobenzoisothiazole 6163 as the single product.
Scheme 54 | Use of novel thioamides in complementary syntheses of dihydrobenzothiazine and benzothiazoline derivatives.
S [benzyne] S S PhSO PhO2S N 2 Me N N Me Me SO2Ph 6152 6155 6156
S [benzyne] S NC N Me N Me CN 6153 6157
S [benzyne] TMSCN N S S N N Me N N N N NC N N Me N N Me 6154 6158 6159
Reaction between benzyne and thioamide is rich in mechanistic diversity and synthetic versatility with which structure modification of the products may be achieved via functional group interconversion. The development of this body of work is by no means limited to what we have alluded to in this Chapter, as we begin to perceive a more integrated and intertwined view of the chemistry of benzyne with thiocarbonyl compounds through successful and failed experiment results. As such, we have laid out a systemtic investigation into the reactions of benzyne with thioamides that was largely born out of one single exploratory reaction (cf. Scheme 48). The modes of reactivity between benzyne and thioamide epitomize the utility of ortho- benzyne as a 1,2-bifunctional reactive intermediate. The skeletal rearrangements during these transformations represent a higher level of mechanistic sophistication. Most importantly, a more comprehensive picture only emerged as a result of the combined forces of experimental design as well as our enhanced appreciation of the value in the computational approach. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 96
Figure 26 | Reaction of benzyne with thiadiazoles: A) regioselective synthesis of benzoisothiazoles, B) computed reaction pathway. DFT calculations were performed using M06-2X/6-31+G(d,p) and the SMD solvation model (benzene). All values are of free energies in kcal/mol. A B ‡ N S S N N N S N TMS CsF O 6164* + + ● HO N N 12.2 OTf THF, 60 ºC NH O O 0.0 S ‡ N 3016 6160 6161 N 96% 6165* Me G Me Me 3001 –16.3 –16.3 S + PhH Cl S N N Me N + + S N O N N Cl Cl 75 ºC N S S 6165 N O N 6164 Cl 4008 6162 6163 6166 + H N
Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 97
Chapter 7. Ongoing and Future Work
This chapter is dedicated to the proposed future direction pertaining to the HDDA chemistry and some preliminary results thereof that the author of this Thesis deems promising for the incoming researchers of the Hoye group. Therefore, computational studies are presented for the ease of discussion of the furture directions where laboratory experimentation has yet to be implemented.
7.1 Trapping Reactions between the HDDA-Generated Benzynes and Sulfoxides 7.1.1 Mode of Reactivity between Benzyne and Sulfoxide Sulfoxide loosely falls into the category of ambident nucleophile (Scheme 55). Studies on alkylation reactions of DMSO have revealed some of the kinetic and thermodynamic features of product formation. Specifically, the kinetically favored O- alkylated products (generically shown as 7001) tend to isomerize in solution to the thermodynamically favored S-alkylated products (generically shown as 7002) mediated by the couterions (X-) of the corresponding alkylating agents. In this regard, sulfoxide is distinct from classical ambident nucleophiles such as enolates, nitrites, and cyanides with respect to the reversibility for the formation of the kinetically controlled dialkyl alkoxysulfonium salts 7001.108
Scheme 55 | Alkylation of DMSO.
O R–X O O R–X OR S X X H C CH S S S 3 3 H3C CH3 H3C CH3 R H3C CH3 7002 7001
In the context of the reaction of DMSO with benzyne, the kinetically controlled O- arylation process to produce the benzooxathietane 7004 would be in analogy with arylation of thioamide, aldehyde, and formamide (Figure 27). DFT calculation suggests that 7004 would undergo spontaneous ring opening reaction with remarkable exogonicity to give rise to the ortho-oxidophenylsulfonium zwitterion 7005 that is characterized by the highly delocalized sulfonium ylide 7006. However, we were unable to locate either 7004 or the incipient betaine 7003 on the potential energy surface. This implies that 7005 may be
108 Smith, S. G.; Winstein, S. Sulfoxides as nucleophiles. Tetrahedron 1958, 317-321. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 98 formed via a concerted, but highly asynchronous pathway. Computational results further revealed that the S-arylation process to produce the S-phenyl oxosulfonium ylide 7008 would be a thermodynamically less favorable intermediate.
Figure 27 | Computed intermediates for the modes of reaction between benzyne and DMSO. DFT calculations were performed using M06-2X/6-31+G(d,p) and the SMD solvation model (benzene). All values are of free energies in kcal/mol.
O S Me O Me H S 7007 Me 16.7 7003 O ? 0.0 S Me Me CH3 7004 + O S G ? –25.0 CH3
O 3001 S Me –78.5 CH2
O O 7008 = Me Me S S Me Me 7005 7006
This mechanistic interpretation is consistent with the first reported reaction between benzyne and DMSO. In an otherwise unrelated study, the solvent DMSO was found to competitively engage paracyclophyne that was generated from the base-induced elimination reaction of bromoparacyclophane (7009, Scheme 56A). The resulting ortho- oxidoarylsulfonium intermediate 7010 would afford the ortho-methylthioparacyclophenol 7012 in addition to the intended displacement products 7013a/b.109 Fast forwarding, The betaine 7005 was shown to undergo S-demethylative O-alkylation in the presence of various activated alkyl bromides to deliver the ortho-methylthiophenyl ether 7015 via the S-aryldimethylsulfonium bromide 7014 in a three-component fashion (Scheme 56B).110
109 (a) Kise, M.; Asari, T.; Furukawa, N.; Oae, S.; Chem. Ind. 1967, 276. (b) Cram, D. J.; Day, A. C. Macro rings. XXXI. Quinone derived from [2.2]paracyclophane, an intramolecular –molecular complex. J. Org. Chem. 1966, 31, 1227-1232. 110 Liu, F.-L.; Chen, J.-R.; Zou, Y.-Q.; Wei, Q.; Xiao, W.-J. Three-component coupling reaction triggered by insertion of arynes into the S=O bond of DMSO. Org. Lett. 2014, 16, 3768-3771. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 99 Wang et al. demonstrated the prolonged life time of 7005 in the arylation reaction of 7005 with excess benzyne precursor 3016 to form the diaryl ether 7018 via the sulfonium ylide 7017 (Scheme 56C).111
Scheme 56 | Reactivity of the 2-oxidophenyl sulfonium intermediate: A) a serendipitous discovery, B) O-alkylative S-demethylation in a three-component fashion, C) O-arylation and subsequent ylide formation. A
Br t O t O + OH OR KO Bu KO Bu H3O + Me DMSO S SMe SMe Me 7009 7010 7011 7012 7013a 10% R = H, 14% 7013b R = tBu, 4%
B TMS KF, 18-crown-6 O RCH2Br O R - CH3Br O R + R Br
OTf DMSO, 50 ºC SMe2 SMe2 Br SMe 3016 7005 7014 7015 31–79%
C
H TMS CsF, DMSO O 3001 O O O OTf DME, 50 ºC H SMe2 CH S 2 S SMe Me Me 3016 7005 7016 7017 7018 80%
The integrated nucleophilicity and electrophilicity of 7005 shows potential for the development of additional synthetic utility based on the reaction of benzyne with sulfoxide. At the outset, we envisioned that the moderately basic phenolate like 7019 would be susceptible to protonation by an appropriate Brønsted acid (H–A, Scheme 57). The displacement of the methyl group within the resulting ion pair 70120 would afford an ortho-methylsulfanylphenol like 7016. In order to benchmark the basicity of 7019, we heated the tetrayne 4008 in d6-benzene in the presence of excess DMSO with one of the three Brønsted acids of choice whose pKa values spread across a wide range. Benzoic acid
111 Li, H. Y.; Xing, L.-J.; Lou, M.-M.; Wang, H.; Liu, R.-H.; Wang, B. Reaction of arynes with sulfoxides. Org. Lett. 2015, 17, 1098-1101. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 100 was found to cleanly promote the desired transformation whereas phenol and dimethyl malonate are not effective. Calibration with phthalate as the internal standard indicated that the phenol 7021 was formed in approximately 50% yield as a single isomer. The fluorenonyl phenol 7022 was isolated in 49% yield when TFA was used as the protic nucleophile. The constitution of 7022 with respect to the placement of the hydroxy and methylthio groups is assigned based on the presence of the NOE correlation between the
C5–H atom and the S-CH2–H atom. The regioselectivity with the reaction between DMSO and the polarized fluorenonyl benzyne 5072 (cf. Table 5) further supports the operation of the O-arylation pathway. The ortho-4-acetoxybutylsulfanylphenol 7024 was isolated in 26% yield from heating 4009 with a cyclic sulfoxide (tetrahydrothiophene 1-oxide) and acetic acid. Xiao et al. also noted that the use of cyclic sulfoxide in their alkylative three- component reaction had resulted in impractical yield.110 Incidentally, it is conceivable that the carbonyl group of the fluorenone moiety further stabilizes the corresponding ortho- oxidoarylsulfonium betaine in the case of species like 7023.
Scheme 57 | Synthesis of ortho-sulfanylphenols.
Me Me Me Me Me H–A = H OBz DMSO (3 equiv) H–A (2 equiv) H–A – CH –A 3 H OPh Me Me Me C6D6, 75 ºC O O O CO2Me O OH OH H O A SMe2 SMe2 SMe CO2Me 4008 7019 7020 7021
Me Me O O TMS O TMS S O TMS TMS TMS Me DMSO, TFA Me , HOAc Me O MeCN, 90 ºC OH PhH, 90 ºC OH OAc S S H S O H O H NOE H 4009 7022 4009 7023 7024 49% 26%
7.1.2 Use of Vinyl Sulfoxide in Three-Component Reaction Wang et al. had established that the secondary reaction of ortho-oxidosulfnoium intermediate with benzyne is a competitive pathway against otherwise intended transformation (Scheme 54). Along this line, we envisioned that the use of a vinyl sulfoxide Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 101 like 7025 would incur a tandem electrocyclic cyclization reaction of the betaine 7026/7027 to effectively prevent possible shunt reactions (Scheme 58). DFT calculations suggested that an equilibrium between 7026/7027 and the dihydrobenzooxathiinium ylide 7028 favors the ring opening reaction to a marginal extent, which causes the selective conversion of 7028 under dynamic control. The S-allylsulfonium ylide 7029 would give rise to 3- allyldihydrobenzooxathiine (7030) via a facile Wittig rearrangement. Disappointingly this route is thwarteded by the reported predisposition of allyl vinyl sulfoxide (7029) toward thio-Claisen rearrangement to afford pententhial-S-oxide (7032).112
Scheme 58 | Tandem electrocyclic ring closure reaction of ortho-oxidophenyl-S- vinylsulfonium intermediate.
O O O O + S R S S S R R R 3001 7025 7026 7027 7028
O O O + S S S 3001 7029 7030 7031
–7 ºC
O S
7032
Alternatively, we expected a Brønsted acid to protonate the more basic sulfonium ylide 7028 (Scheme 59). When the R group is not susceptible to displacement, the resulting ion pair 7033 would undergo ring opening reaction to afford the ortho-sulfanylphenyl ether 7034, reminiscent of the sulfoxide-mediated three-component reaction. The O-alkylation approach to arrive at 7034 would not be feasible due to the reduced reactivity of the b- substituted ethyl bromide 7036 (cf. Scheme 56B). On the other hand, the undesired protonation of 7026 would ultimately result in the formation of the ortho-sulfanylphenol 7040 through iterative proton transfer events (cf. Scheme 57).
112 Block, E.; Ahmad, S. Unusually facile thio-Claisen rearrangement of 1-alkenyl 2-alkenyl sulfoxides: a new sulfine synthesis. J. Am. Chem. Soc. 1985, 107, 6731-6732. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 102 Consistent with our proposed reaction pathway, heating the ether-linked tetrayne 4008 in benzene with two equivalents of phenyl vinyl sulfoxide (7041) and acetic acid produced the 2-acetoxyethyl ether 7043 in moderate yield as a single isomer (Scheme 60). The assignment of constitution of 7043 was confirmed by 2D-NMR analysis. The reactivity of dimethyl malonate was altered by virtue of the ylide formation. The ion pair 7044 underwent elimination reaction to afford the aryl vinyl ether 7045 in 92% yield. We had anticipated the interference of such elimination pathway on the basis of the increased steric congestion within 7044 as well as the greater basicity of malonato anion. Use of malononitrile in conjuction with the mesylynamide-linked tetrayne 5069 resulted in the isolation of the phenol 7047, which apparently arose from the S-vinylsulfonium ion 7046 (cf. Scheme 59). This complementary mode of reactivity was achieved with allenyl phenyl sulfoxide (7047) under otherwise identical conditions to form the allylic molononitrile 7051. It is conceivable that the presence of an allenyl group had favored the generation of the ylide 7050 in this instance. The reaction of 4008 with 2- methylidenetetrahydrothiophene oxide and acetic acid delivered the aryl vinyl sulfide 7056 instead of the desired hydrobenzooxathiine product derived from the bicyclic sulfonium
Scheme 59 | Competivie protonation pathways of ortho-oxidophenyl-S-vinylsulfonium betaine under dynamic control.
O O
S S R R 7026 7028
H–A H–A Br O A OH O O O S 7036 R Me Me S S S A S A A R R R R 7037 7033 7034 7035 3001
O OH A OH A A OH O S – A H–A R Me Me S S R S A S R R R 7038 7039 7040 7035 3001
Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 103 ylide 7054. As such, this dual reactivity associated with the ortho-oxido-S-vinylsulfonium intermediate reiterates the presence of a geometry dependent equilibrium.
Scheme 60 | Vinyl sulfoxide-mediated three-component reactions.
O Me Me S Ph Me 7041, HOAc HOAc Me O Me O Me PhH, 75 ºC O O O S Ph SPh OAc 4008 7042 7043 58% CH2(CO2Me)2
Me Me 7041 CH2(CO2Me)2 Me 4008 CO2Me Me PhH, 75 ºC O O CO Me O 2 O S Ph SPh 7044 7045 92%
Me Me
Me 7041, CH2(CN)2 CH2(CN)2 Me Me N Me PhH, 90 ºC Ms N OH N OH Ms S Ms Ph SPh 5069 7046 7047 60%
O Me Me Me S ● Ph 7048, CH (CN) CH (CN) 2 2 Me 2 2 5069 Me Me PhH, 90 ºC N N O O N O CN Ms Ms S ● S Ms PhS Ph Ph CN 7049 7050 7051 40% O Me Me Me S Me
Me 7052, HOAc Me Me HOAc Me Me O O O O O Me PhH, 75 ºC O O OH OH S S S S OAc AcO 4008 7053 7054 7055 7056 46% Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 104 7.2 Dearomatization Strategy 7.2.1 Ubiquitous [2+2]-Mode of Addition
Scheme 61 | Reactions between benzynes and compounds with A=B unsaturated functionality: A) a prototypical [2+2]-retro-[2+2] cascade, B) formal [2+2] reactions with electron rich olefins, C) tandem reactions with aldehydes to form chromene derivatives.
A A A A A + B B B B 3001 7057 7058 7059
B OAc O OAc O o-DCB Me Me H + N 175 ºC Me O Ph N Ph Me O O O 4018 4025 7060 75% O O OAc O OAc Me OAc O o-DCB O O Me Me 4018 + + H + N NR 130 ºC H NR R Me RN
7061 R = H or Me 7062 7063 7064
C CHO O OAc O OAc O OAc OEt O OEt O O OMe O 4018 O O o-DCB, 130 ºC OEt
MeO MeO MeO 7065 7066 7067 40% O O OAc O OAc Me Me O 6-π electrocyclic O 4018 O O o-DCB, 130 ºC ring closure Me Me Me Me 7068 7069 73%
We have encountered numerous instances where benzyne engages an unsaturated functionality (A=B) in a formal [2+2] fashion (cf. 3062). A tandem formal retro-[2+2] reaction of the initial adduct 7057 may follow to generate a secondary 1,2-bifunctional Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 105 intermediate 7058/7059, for which the true resonance representation of such species highly depends on the nature of the substitutents A and B. Indeed, the Diels-Alder reactivity of 1-benzoylpyrrole 4025 was altered at elevated temperature to afford the [2+2] adduct 7060. The [2+2] process became the only mode of cycloaddition for the electron rich indoles 7061 in addition to the Alder-ene reaction to produce the 3-arylated indole 7062. Aromatic aldehydes were reported to react with benzyne using the carbonyl group in a [2+2] manner.113 The incipient benzoxete 7065 proceeded via a strain-induced ring opening reaction to generate the ortho-quinone methide 7066, which was trapped by ethyl vinyl ether to form the chromanylacetal 7067 in a three- component process. Enals are equally effective participants, as is shown for the reaction of tiglic acid to furnish the isochromene derivative 7069 via a 6p-electrocyclic ring closure reaction.114 It is noteworthy that enals do not react with benzyne in a hetero-Diels–Alder reaction pathway. In addition, Dr. Brian Woods from the Hoye group demonstrated the viability of the formal [2+2] reaction between formamide and an HDDA-generated benzyne (Scheme 62A).115 Heating the alkyl chloride-tether ketotriyne 7070 in the presence of DMF gave rise to the chromane derivative 7073 through an intramolecular nuleophilic displacement of the chloride by the ortho-quinone methide 7071 and subsequent in situ hydrolysis of the formiminium intermediate 7072. More recently, we found that formamidines participate in the [2+2] manifold as well. Studer et al. reported a nitrosoarene-mediated carbazole synthesis, in which the proposed ortho-iminoquinone methide 7074 underwent cyclization reaction (Scheme 62B).116 However, it is unclear as to the detail regarding the formal reduction of the resulting carbazolol 7075 to account for the formation of 7076.
113 Yoshida, H.; Watanabe, M.; Fukushima, H. Ohshita, J.; Kunai, A. A 2:1 coupling reaction of arynes with aldehydes via o-quinone methides: straightforward synthesis of 9-arylxanthenes. Org. Lett. 2004, 6, 4049- 4051. 114 Zhang, T.; Huang, X.; Wu, L. A facile synthesis of 2H-chromenes and 9-functionalized phenanthrenes through reactions between a,b-unsaturated compounds and arynes. Eur. J. Org. Chem. 2012, 3507-3519. 115 (a) Yaroslavsky, S. Reaction of aryldiazonium salts with dimethylformamide. Tetrahedron Lett. 1965, 6, 1503-1507. (b) Yoshioka, E.; Kohtani, S.; Miyabe, H. A multicomponent coupling reaction induced by insertion of arynes into the C=O bond of formamide. 116 Chakrabarty, S.; Chatterjee, I.; Tebben, L.; Studer, A. Reactions of arynes with nitroarenes–an approach to substituted carbazoles. Angew. Chem. Int. Ed. 2013, 52, 2968-2971. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 106
Scheme 62 | Additional reactions between benzynes and trapping agents in a [2+2] fashion: A) ortho-hydroxyformylation with DMF, B) carbazole synthesis with nitrosobenzene. A O TMS O TMS O O TMS TMS DMF δ– O Cl O CHCl , 90 ºC 3 δ+ Me Me O N N Cl CHO Me Me 7070 7071 7072 7073 15%
B TMS N CsF O OH H–Nu + O OTf CH3CN N – HO–Nu N N H 3016 7074 7075 7076 65%
7.2.2 Computational Consideration Regarding the Possibility of Dearomatization Processes Along with the pioneered work by others, our mechanistic elucidation on the reactions of benzyne with thioamide and sulfoxide has renewed and supplemented the generality of reaction manifold with which unsaturated functionalities trap ortho-benzyne (cf. Scheme 61A). The initial adduct displays a spectrum of predisposition toward the following ring opening process on the basis of a thermodynamic argument (Table 10). Accordingly, benzocyclobutene (7077) and benzothietane (7083) are stable entities (entries 1 and 5) whereas the 2-aminobenzothietane 6093 is computed to coexist with the ortho- mercaptophenyliminium betaine 6094 (entry 4, cf. Figures 22 and 24). Geometry optimization of other relevant ring-opened intermediates using DFT theory reveals various degrees of compromised aromaticity, which in turn is proportional to the capability of each substituent to stabilize a positive and a negative charge respectively (entries 2, 3, 6, and 7). Thus, the donor-acceptor mesomeric effect with the zwitterionic species 7006 and 7082 are able to compensate for the attenuation of aromaticity (cf. Schemes 56 and 62A) while ortho-quinone methides like 7080 exhibit explicit reactivity of an exocyclic diene in numerous rearomatization processes (cf. Scheme 61C). On the other hand, reaction occurring at the endocyclic diene (for 7074 and 7080) or latent diene (for 7082 and 7006) Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 107 moiety would constitute a dearomatization methodology where benzyne chemistry could impart greater synthetic utility beyond serving as an aromatic building block.
Table 10 | Degree of aromaticity in the 1,2-bifunctional intermediates.
entry 1 2 3 4 5 6 7
O O S S O O closed form S N NMe2 Me Ph NMe2 Ph Me Ph 7077 7079 7081 6093 7083 7004 7085
O O S S O O open form δ– NMe Me 2 S N
Ph δ+ NMe2 Ph Me Ph 7078 7080 7082 6094 7084 7006 7074
We use the potent dienophile N-methyltriazolinedione (NMTD, 7086) to more faithfully model its Diels-Alder reactions with the four experimentally accessible intermediates of interest (Table 11). It is anticipated that the alternative aromatizational Diels–Alder reaction product 7088 would be discouraged by virtue of the weaker bonds between heteroatoms. Other possible pathways aside, the most electropositive ortho- iminoquinone methide 7080 was predicted to be most inclined toward such a cycloaddition process in a thermodynamic sense (entry 4), whereas the transformation of the betaine 7006 to a more charge-localized sulfonium ylide 7087c would take place with nearly
Table 11 | Computed overall thermodynamic profile of the dearomatizational Diels–Alder pathways. DFT calculations were performed using M06-2X/6-31+G(d,p) and the SMD solvation model (benzene). All values are of free energies in kcal/mol.
O O O Me O O N N N N NMe δ– + NMe O N N δ+ N O X X O O X 7088 7086 7087a-d reactive ΔG entry X intermediate cycloadduct (kcal/mol)
1 CHPh 7080 7087a –12.1
2 CHNMe2 7082 7087b –11.9
3 SMe2 7006 7087c –2.3 4 NPh 7074 7087d –18.8 Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 108 thermal neutrality (entry 3). A closer inspection of the hypothetical Diels–Alder pathway with the highly polarized betaine 7006 instead revealed two unfavorable electrophilic aromatic substitution pathways to arrive at the zwitterions 7090 and 7092, for which we did not attempt to compute the energetic property thereof (Figure 28A). Likewise, the
Figure 28 | Computed reaction pathways: A) electrophilic aromatic substitution, B) Wittig rearrangement, C) secondary addtition reaction with benzyne. DFT calculations were performed using M06-2X/6-31+G(d,p) and the SMD solvation model (benzene). All values are of free energies in kcal/mol.
‡ A O Me ‡ O δ– N N SMe2 N O N O N O N δ– δ– Me O SMe 2 25.9 7006** 7006* 19.8
6.0 0.0 0.4 G O Me N O O N O N ? Me H SMe2 S ? O O N Me N Me O Me N O 7006 S N Me O + Me HN N O 7091 N O 7089 N Me N N O O O O Me 7092 N N SMe 2 + 7086 7090 Me2S
O ‡ B Me C ‡ – δ– δ S O δ+ δ– Me 7093* S 14.3 Me 7016* ? 0.0 0.0 G G
O O + Me Me –14.4 S –17.3 S Me O O 7093 7006 3001 SMe2 SMe 7016 7094 Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 109 DMF-derived “benzenylogous” amide 7082 could behave similarly on the potential energy surface. A Wittig rearrangement of the S-allylsulfoniu betaine 7093 is computed to have a benign kinetic profile to form the cyclohexadienone 7094 in the absence of exogenous agents (Figure 28B). Circumstances in a genuine HDDA reaction cascade would necessarily deviate from the model system-based argument. For instance, the secondary reactions between these ring opened intermediates (i.e., 7006) and benzyne would be disfavored by virtue of the steric congestion incurred of the HDDA-generated benzynes (Figure 28C, cf. Scheme 56C). 7.3 Review and Prospect on the Development of the HDDA Reaction Precursors 7.3.1 Evolution of the HDDA Precursors Tremendous research activities over the past few years, including the majority of the work presented in this Thesis (Chapters 4-7), have led to prolific and insightful understanding of the intrinsic reactivity of ortho-benzyne as well as the resulting synthetic values such innovative approaches have introduced. Meanwhile, mechanistic studies toward the phase of cycloaromatization revealed that a prototypical HDDA reaction is best described as a highly asynchronous process via a rate-determining formation of the fleeting diradical intermediate 7096 (cf. Figure 16). Along this line, and by comparing the rates of reaction of known classes of HDDA precursors, we were able to reach a unified argument from which one could rationalize and predict the behavior of various polyyne substrates toward benzyne generation.117 From a thermodynamic standpoint, a radical stabilizing group in the place of the R1 terminus has been shown to provide rate enhancement, as evident by more rapid rates of HDDA reactions of almost all tetrayne precursors relative to their truncated triyne (i.e., 7098 vs. 7101).In addition, a terminal ynone like 7100 is experimentally deemed an ineffective precursor, and the desilylated analogs of other viable triyne substrates (where R1=H) typically exhibit reduced rate of cycloaromatization (i.e., 4018). However, the influence of the distal substituents (R1 and R2) does not explain the origin of rate differentiation imposed by the nature of linker in a polyyne substrate. On the
117 Woods, B. P.; Baire, B.; Hoye, T. R. Rates of hexadehydro-Diels–Alder (HDDA) cyclizations: impact of the linker structure. Org. Lett. 2014, 16, 4578-4581. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 110
Figure 29 | Rates of cycloaromatization for different HDDA substrates. In each series except for column D, the precursors are ranked according to the experimental rate of reaction from the highest at the top of the column to the lowest at the bottom.
R1 R1 1 2 R ● R R2 ● 2 ● ● R
7095 7096 7097
A B C D O OTBS O O O TMS TMS TMS HN Me Me Me 5070 3037 TBSO TBSO 7102 TBSO 3033 O Me O TMS TBSO O TMS O Me BnN Me 4008 Me 4009 Me Me 4012 O MsN TMS 7103 Me BnN O TMS 5028 TMS Me Me PhN 4012 O N Me Ms N Me 5071 TMS 5069 Ms 5069 O TMS TBSO O 3087 O TMS O AcO TMS TMS 3087 7098 TBSO 3048 TBSO Me O BocN O TMS N Me O Boc 4011 HO OAc 4018 TBSO MeO C 2 7101 MeO C 2 O 3056 HO TBSO R 7100
7099 TBSO contrary, while the presence of a carbonyl group reduces the bond order of its adjacent acetylenic unit, this favorable effect could be countered by the formation of the destabilized Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 111 b-carbonylvinyl radical in 7096. Indeed, the endocyclic olefin moiety is more effective to promote the HDDA reaction for the cyclohexenyl acetate 3048 than the carbonyl group for the saturated ynone 7101 (Column C). Meanwhile, an entropy-based rationale was envoked to account for this discrepancy. In such an argument, the carbonyl activation phenomenon for many HDDA precursors largely reflects the reduced degree of freedom and the shortened bond lengths between the carbonyl carbon atoms and its substituents. These in turn lead to a higher concentration of a tight conformer to facilitate the initial bond forming event. Accordingly, the cyclohexene-templated ynone 3037 undergoes slow HDDA reaction even at room temperature as a result of the enforced cis-relationship between the diyne and diynophile moieties and the shorter C=C double bond relative to that in the aromatic ynone 4009. The geometric restriction of the linker is partially compromised in the amide 4012 and to a greater extent in the ester 3087, even though the C–O bond is shorter than the C–N bond (Column B). In the absence of the element of structural rigidity, the short C–O bond and its small bond angle indeed provide greater driving force for the cycloaromatization reaction of 4008 than of the amides 5028 and 5069 (Column A). The reactive conformer of 4011 suffers steric congestion between the Boc-substituents, leading to its reduced rate of reaction. The feasible HDDA reaction of the malonate derivative 3056 arises from the Thorp-Ingold effect of the quaternary carbon atom (cf. 5070). In the absence of all rate accelerating factors, the tetrayne 7099 is shown to decompose at elevated temperature. Meanwhile, this qualitative analysis does not seem to account for the regioselective mode of cycloaromatization reaction for certain tetrayne substrates. For example, the “normal” triyne 7102 is 30 times more reactive than the “abnormal” triyne 7103. The rate of the “abnormal” HDDA reaction are more competitive for the tetraynes 3033 (cf. Scheme 18A) and 7098; on the other hand, only one mode of HDDA reaction has been observed in the case of ynamide-linked tetraynes (i.e., 5069 and 4011). 7.3.2 Heteroatom-rich HDDA Precursors Meanwhile, heteroatom-rich linkers are synthetically and medicinally attractive subunits. We had successfully synthesize the carbamate-linked triyne 7104 through a Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 112 multi-step sequence (cf. 3093a-g, Table 2) and the differentially-terminated tetrayne 7107 via an ynamide formation reaction reported by Danheiser et al.118 We further envision that
Scheme 63 | Attempted syntheses of heteroatom-rich HDDA precursors.
Me Me TMSO O TMS TMS(C≡CMe) TBS O Me N N Me N Me Alloc Ts Ts TBSO 7104 7105/7106 7107
Me Me TMS TMS R N N Me N Me N Me N Me MeO2C EWG Ts 7108 MeO2C 7109 7111 7113
TMS TMS
N H N H MeO2C MeO2C 7110 7112 TMS TMS TMS TMS 1) NH NH •H O 2 2 2 TMS HO–NPhth CH Cl Cl C=CHCl 2 2 2 O N Me 2) TsCl, Et N Cs CO , DMF Cl PPh3, DIAD 3 2 3 Cl Ts CH Cl 50 ºC NPhth 2 2 NHTs N OH O O O Ts 7114 7115 7116 7117 7120 Cl C=CHCl Cl 2 Cl TBSO NHTs N Cs2CO3, DMF TBSO Ts 7118 50 ºC 7119
MeO2C MeO2C Ts Ts NH N Me NH N Me Ph Ph EtO2C EtO2C NH N Me NH N Me MeO2C MeO2C Ts Ts 7121 7122 7123 7124 the highly functionalized ynamides 7105/7106 could be derived from the readily available diethyl 2-aminomalonate. From a practical standpoint, although carbamates are more easily removed than sulfonamides from an elaborated synthetic intermediate, alkoxy ynamide- containing HDDA precursors are more challenging to access, and in particular, the presence of a Boc-protection group often completely deactivates a substrate toward typical
118 (a) Kohnen, A. L.; Dunetz, J. R. Danheiser, R. L. Synthesis of ynamides by N- alkynylation of amine derivatives. Preparation of N-allyl-N-(methoxycarbonyl)-1,3-decadiynylamine. Org. Synth. 2007, 84, 88-101. (b) For details of ynamide synthesis, see experimental section. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 113 formation conditions. 119 For example, while the tosylanilide-derived triyne 7108 was routinely prepared in gram-scale,120,121 the same protocol for ynamide formation was less efficient with the carbamate 7110 toward synthesis of the triyne 7116, and was eventually not productive with aliphatic carbamate 7112.121 The successful instance with the hydrazide-linked tetrayne 4011 has inspired several analogous polyynes (7113, 7120, 7122, 7124). Although the accessibility of other types of hydrazide-derived substrates like 7113 are yet to be examined, the alkoxylamides 7116 and 7118 did not undergo the otherwise robust dichlorovinylation reaction en route to the corresponding ynamide. On the other hand, simple base-mediated double coupling reaction did not afford the desired products as expected with the base-sensitive aminal derivatives 7121 and 7123.
Scheme 64 | TDDA and propargyl ene reaction manifolds.
●
TDDA ene H H R2 R2
2 R R2 7125 7126 7127 7128
Het Het 2 Het ● R R2 ● 2 ● ● R
7129 7130 7131
With the formulation of the intermediacy of the diradical 7096 during an HDDA reaction, it is conceivable that a handful of radical stabilizing substituents on the diynophile terminus would enforce rate enhancement as well (cf. Table 2). However, placement of an alkenyl or aryl group at the R1 terminus shunts the reaction into the TDDA manifold (7125
119 Zhang, Y.; Hsung, R. P.; Tracey M. R.; Kurtz, K. C. M.; Vera, E. L. Copper sulfate-pentahydrate-1,10- phenanthroline catalyzed amidations of alkynyl bromides. Synthesis of heteroaromatic amine substituted ynamides. Org. Lett. 2004, 6, 1151-1154. 120 Unpublished result from the Hoye group. 121 Mensfield, S. J.; Campell, C. D.; Jones, M. W.; Anderson, E. A. Chem. Comm. 2015, 51, 3316–3319. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 114 to 7126) whereas the presence of an Csp3–H bond enables a propargyic ene pathway (7127 to 7128), which Lee et al. harnessed in an alternative aromatization reaction.122
Scheme 65 | Attempts to synthesize heteroatom-terminated triyne precursors.
Me Ts N
Ts Br Ts CuCl, NH2OH•HCl N PhSCH3 Me MeO2C MeO2C Me + N N MeO2C MeO2C Me Br Me BuNH -H O-DCM N MeO2C Ts 2 2 Ts MeO2C
SPh 7132 7133 7134 7135 O SPh BnHN PhN Me Me
7137 EDC or 7138 PhS CO2H + or or HO DCC O TMS SPh 7136 7114 O TMS 7139
O O K CO I 2 3 SPh SPh + TMS PhN PhHN DMF TMS 7140 7141 O 7142 Cl O TMS Cl O BuLi 7145 OPh PhO Li PhO O –78 ºC to –20ºC Cl TMS 7143 7144 7146 Cl O Ts BuLi Me 7153 N Me N Li N O Me –78 ºC to –20ºC Ts Ts Cl TMS 7147 7148 7149 HO HO OPh CuCl, NH2OH•HCl OPh + Br Me BuNH2-H2O-DCM-hexanes Me 7150 7151 7152
Substitution of a heteroatom (R1 = heteroatom) should similarly facilitate the HDDA reaction to a greater extent than a silyl group by virtue of the radical stabilization in 7130 (Scheme 64). We were initially successful in preparing the malonate derivative 7134 (Scheme 65). However, this “reversed” bis-ynamide did not undergo efficient
122 Karmakar, R.; Yun, S. Y.; Chen, J.; Xia, Y.; Lee, D. Benzannulation of triynes to generate functionalized arenes by spontaneous incorporation of nucleophiles. Angew. Chem. Int. Ed. 2015, 54, 6582-6586. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 115 cycloaromatization reaction in the presence of a few reliable trapping agents (e.g., a sulfide). The subsequent attempted transformations to synthesize heteroatom-terminated carboxylic acid derivatives were disappointing. The readily accessible 3- phenylthiopropiolic acid (7136) was not productive with an amine or alcohol under typical amide/ester coupling reaction conditions. The base-mediated nucleophilic displacement of a propargylic iodide 7141 by the 3-sulphanylpropiolamide 7140 did not deliver the corresponding product. An alternative assembly of such triyne substrates involves the use of the lithio-heteroatom-substituted acetylene species. Thus, lithium phenoxyacetylide (7144), generated from its dichlorovinyl precursor 7143, was quenched in situ with the propargylic chloroformate 7145. This reaction was unfortunately unproductive. On the other hand, we hoped that the more well-precedented reaction of lithio-ynamides (like 7148, the protonation of which gives rise to 7133) with chloroformates would provide a solution. The lability of the ynol ether functionality was further testified in an failed Cadiot- Chadkiewicz reaction with 7150, which incidentally was prepared from 7144 and 2- ethynylbenzaldehyde. Similarly, one could envision the synthesis of an ynamide analog of 7152 by using 7148. 7.3.3 Four-Atom-Linked HDDA Precursors With the sole reported example of a seven-membered ring formation during an HDDA cascade (cf. entry 4, Table1), the substrate scope for intramolecular HDDA reaction by far are limited to the synthesis of five-membered ring fused benzenoid products. Nevertheless, it is conceptually not unique for a linker of particular length to allow for the initial bond forming event (Figure 30). It is also conceivable that the ease with which polyyne precursors bearing linkers of different lengths undergo cycloaromatization reaction would exhibit a continuum of reactivity based on the entropic argument.
Figure 30 | Debated anthraquinone formation and conformation analysis for the viability of such transformation.
TBSO H O O O OTBS O H O H O O R R H O O TBS TBSO R R 7153 7154 7153a 7153b Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 116 A preliminary result from the Hoye group arose from an irreproducible conversion of the phthaloketotetrayne 7153 to the anthraquinone derivative 7154. Although the thermal behavior of 7153 warrants further experimentation, conformational analysis of such diketotetrayne suggests that a cycloaromatization event would seem unlikely as a result of the loss of conjugation stability in a reacting conformer 7153b. One obvious modification to remove excessive geometric restraint is, ironically, the introduction of more structural flexibility. In order to quickly access a lead compound to examine our hypothesis, we aimed to prepare the amide 7159 that is rendered eligible by the bond angle compression effect and the mild rigidity of the amide motif (Scheme 66). Toward this end, the N-Boc-aminomalonate 7155 was subjected to an efficient three-step sequence to arrive at the amine 7158. Although our initial attempt at an EDC-mediated condensation reaction was unsuccessful in giving the desired product, we are optimistic that the rich amide coupling chemistry can provide a solution.
Scheme 66 | Proposed synthesis of possible four-atom-linked HDDA precursors.
Me Me Me
TMS MeO2C CO2Me HC≡CH2Br BrC≡CH2CH3 TFA TMSC≡CCO2H NHBoc NHBoc i NaH CuCl, NH2OH•HCl DCM EDC, HOBt, Pr2NEt MeO2C CO2Me BuNH -H O- NHBoc NH 2 2 2 O DCM-hexanes MeO2C N MeO C CO Me MeO C CO Me 2 2 2 2 MeO2C H 7155 7156 7157 7158 7159 83% 89% quant.
CO2Me CO2Me Me CO2Me Me MeO2C CO2Me MeO C MeO C MeO C 2 2 Me 2 Me HN Ts N Ts N O 7160 7161 7162 7163
Me O OH Ts TMS Ts TMSC CLi ≡ N N Me TMS TMS TsHN NHTs TBSO O 7164 7165 7166 7167 60%
Alternatively, use of a tetrayne could compensate for the reduced level of rigidity in the malonate derivatives 7162/7163 and the ketotetrayne 7167. The N- proparylaminomalonate 7160 would give rise to 7162 via an alkylation reaction and a subsequent Cadiot-Chadkiewicz reaction. On the other hand, the presumably more reactive Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 117 oxygen analog 7163 and the ynamide 7167 would require more lengthy synthetic routes. The plausible substrates are by no means limited to what is exemplified in Scheme 66. We remain optimistic that we can be successful to uncover reliable cycloaromatization of four- atom-linked polyyne precursors to achieve six-membered-ring-fused benzenoid compounds. 7.3.4 Templated HDDA Reaction An intermolecular HDDA reaction adds another layer of complication in that it naturally constitutes a three-component reaction, for which the hierarchy of reactivity of each reactant must be defined. Although pioneered work by Dr. Andrew Michel from the Hoye group showed that the diphenyl silicate 7168 is a thermally stable compound, this is not a discouraging result, as the longer silicon-oxygen bond and the five-atom-linker are expected to be unfavorable elements for an intramolecular HDDA reaction.
Scheme 67 | Proposed substrates for the templated HDDA reaction.
R Ph R O O Ph Si O B O R R B O O R R O R R 7168 7169 7170 HO TMS Me Me Me Me Me O 1) TMSC CLi O 7114 Me ≡ Me Me O B OiPr B TMS Me Me O B TMS O 2) HCl O base Me Me O TMS 7171 7172 HO 7173 TMS Me Me Me Me Me O 1) TMSC CC CLi O 7114 Me ≡ ≡ Me Me O B OiPr B TMS Me Me O B TMS O 2) HCl O base Me Me O t base = KO Bu, NaH, Cs2CO3, Et3N TMS 7171 7174 7175 Me Me Me Me O TMS TMSC CLi Me ≡ Me O B O Me O B TMS(C≡CTMS) O or TMSC CC CLi Me ≡ ≡ O TMS 7176 7173/7175
We envision that the short atomic radius of boron would be beneficial in the context of a templated HDDA reaction. While the analogous esters like 7169 and 7170 might not undergo the HDDA reaction due to the entropic penalty, they would be readily accessible for evaluation of their reactivity. Part II: Intermolecular Trapping of Benzynes Generated fomr the Hexadehydro-Diels–Alder Reaction 118 On the other hand, the alkynyl borate complexes like 7173 and 7175 would represent a more favorable situation, in which the Thorp-Ingold effect would combine with a tighter conformation to facilitate cycloaromatization. Toward this end, the alkynyl pinacol boronic ester 7172 was prepared efficiently from isopropoxypinacol borate (7171) via a net ligand exchange reaction. The diynyl boronic ester 7174 was similarly synthesized in good yield. However, additions of each of excess amounts of these boronic esters to a solution of the propargylic alcohol 7114 in the presence of a wide selection of bases in THF, a solvent capable of trapping benzyne, were unproductive. Although these heterogeneous reactions and the elusive mode of potential cycloaromatization inevitably present a challenge for extensive studies, several alternative approaches are available. For example, 7173/7175 could be produced from the borate 7186 and the corresponding lithiated species in analogy with the initial complex formation with 7171. Catechol boronic esters can be eligible candidates due to their enhanced electrophilicity to facilitate the generation of the polyynyl borate complexes. From a versatility standpoint, more nucleophilic species could be used as the diyne portion in place of the alcohol 7114 to give rise to a less dynamic species. Meanwhile, they would necessarily participate as the trapping agents for the corresponding benzyne as well.
Part III Experimental Procedures and Computational Details 119
◊ Part III ◊
Experimental Procedures
and Computational Details
Part III Experimental Procedures and Computational Details 120
Chapter 8. Experimental Procedures and Compound Characterization Data
General Experimental for Chapters 2, and 4-7 1H and 13C NMR spectra were recorded on Varian Inova 500 (500 MHz), Bruker Avance III HD with SampleXpress (500 MHz), Bruker Avance III with SampleCase (500 1 MHz), and Bruker Avance III HD (400 MHz). H NMR chemical shifts in CDCl3 are referenced to TMS (d 0.00 pm). Non-first order multiplets are abbreviated as “nfom”. Intractable multiplets arising from overlap of one or more non-first order multiplets are designated as “m” and assigned with a range of chemical shifts. 13C NMR chemical shifts in CDCl3 are referenced to CHCl3 (d 77.16 pm) or TMS (d 0.00 pm). The following format is used to report resonances: chemical shift in ppm [multiplicity, coupling constant(s) in Hz when identified, integral, and assignment (when possible)]. 1H NMR assignments are indicated by structure environment, and the proton of interest is in italics. Protons in more complex moleculars are numbered to facilitate resonance assignment. Coupling constant analysis was guided by the reported methods.123 Infrared spectra were recorded on a Midac Corporation Prospect 4000 FT-IR spectrometer. The most intense and/or diagnostic peaks are reported, and all spectra were collected in attenuated total reflectance (ATR) mode as thin films on a germanium window. High-resolution mass spectrometry (HRMS) measurements were performed on a Bruker BioTOF II (ESI-TOF) instrument using PEG or PPG as an internal standard. Samples were introduced as solutions in methanol or acetonitrile or a mixture thereof. MPLC refers to medium pressure liquid chromatography (25-200 psi) using handpacked columns of Silasorb silica gel (18-32 µm, 60 Å pore size), a Waters HPLC pump, a Waters R401 differential refractive index detector, and a Gilson 116 UV detector.
123 (a) Hoye, T. R.; Hanson, P. R.; Vyvyan, J. R. A practical guide to first-order multiplet analysis in 1 H NMR spectroscopy. J. Org. Chem. 1994, 59, 4096-4103. (b) Hoye, T. R.; Zhao, H. A method for easily determining coupling constant values: An addendum to “A practical guide to first-order multiplet analysis in 1 H NMR spectroscopy.” J. Org. Chem. 2002, 67, 4014-4016. Part III Experimental Procedures and Computational Details 121
Flash chromatography was performed using E. Merck silica gel (230-400 mesh). Thin layer chromatography was performed on glass or plastic backed plates of silica gel and visualized by UV detection and/or a solution of potassium permanganate. Reactions requiring anhydrous conditions were performed under an atmosphere of nitrogen in oven dried glassware. Anhydrous THF, Et2O, toluene, and CH2Cl2 were obtained by being passed through a column of activated alumina and stored over 3 angstrom molecular sieves overnight in a sealed flask. Reported (external) reaction temperatures were the temperature of the heating bath. The HDDA reactions, including those that were carried out at temperatures above the boiling point of the solvent, were typically performed in culture tube fitted with an inert, teflonlined cap. Deaerated reaction mixture were achieved by purging N2 gas through the mixture in an ice bath at 0 ºC for 30 minutes or by a freeze-pump-thaw cycle for three times in a liquid nitrogen bath. Cuprous iodide was purified from commercial material by Soxhlet extraction with THF under nitrogen atmosphere for 24 hours. Cuprous chloride was purified by dissolving commercial material in concentrated hydrochloric acid followed by trituration with water. Formatting details: (i) Synthetic intermediates that are not presented in the above chapters of this Thesis are numbered according to the following format: S2xxx, S4xxx, S5xxx, S6xxx, and S7xxx. (ii) Experimental procedures and characterization data for these compounds are grouped together contained within one single set of horizontal bars. (iii) Procedures performed and the corresponding characterization data collected by Mr. Vignesh Palani are are explicitly indicated by “[VP]” before those experimental details.
Part III Experimental Procedures and Computational Details 122
8.1 Procedures and Data for Chapter 2
6-(Trimethylsilyl)hexa-3,5-diyn-2-ol (2011)
OH CuI, TMEDA HO + TMS TMS Me acetone, air Me 2011 54% TMEDA (0.48 mL, 3.2 mmol) was added to a suspension of CuI (300 mg, .1.6 mmol) in acetone (20 mL). The resulting dark green solution was stirred at room temperature for 5 minutes while the reaction flask was open to air. A mixture of but-3-yn-2-ol (2.3 mL, 29 mmol) and ethynyltrimethylsilane (25 mL, 176 mmol) was then added dropwise, and the reaction mixture was further stirred at room temperature until black precipitation started to form. The solvent was removed in vacuo. The residue was treated with Et2O (50 mL) and washed with satd. NH4Cl (50 mL). The organic layer was separated. The aqueous layer was extracted with Et2O (3x30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes:EtOAc = 10:1) to give 2011 as a yellow oil (2.59 g, 15.6 mmol, 54%). 1 H NMR (500 MHz, CDCl3): d 4.57 (dq, J = 6.7, 4.6 Hz, 1H, CH3CHOH), 1.47 (d, J = 7
Hz, 3H, CH3CHOH), and 0.20 [s, 9H, Si(CH3)3]. 13 C NMR (500 MHz, CDCl3): d 87.9, 87.2, 79.4, 69.1, 58.8, 24.0, and –0.4.
(E)-tert-Butyl(hex-3-en-5-yn-2-yloxy)dimethylsilane (2013)
TMS TMS TMS H
LiAlH4 TBSCl, Im K2CO3
Et2O DMF MeOH-Et2O
Me OH Me OH Me OTBS Me OTBS 2011 2012 S2001 2013 quant. [CJH III-142] To a solution of 6-(Trimethylsilyl)hexa-3,5-diyn-2-ol (2011, 660 mg, 4 mmol) in Et2O (20 mL) was added LiAlH4 (190 mg, 5 mmol) in one portion under N2 atmosphere at 0 ºC. The resulting grey suspension was then allowed to warm to room Part III Experimental Procedures and Computational Details 123 temperature and further stirred overnight. The reaction mixture was then carefully poured into 10% ice-cold H2SO4 (10 mL). After gas evolution had subsided, the mixture was transferred into a separatory funnel, and the organic layer was separated. The aqueous layer was extracted with Et2O (3x10 mL). The combined organic layers were washed with satd.
NaHCO3 (20 mL) and then brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product 2012 as a pale yellow oil.
A solution of the crude allylic alcohol obtained above was dissolved in DMF (3 mL). At 0
ºC and under N2 atmosphere, imidazole (814 mg, 12 mmol) and TBSCl (777 mg, 5.1 mmol) were added sequentially. The cloudy reaction mixture was then allowed to warm to room temperature and further stirred overnight. The reaction mixture was then diluted with water
(10 mL). The resulting mixture was extracted with Et2O (3x10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product (S2001) as a yellow oil.
To a solution of the crude TBS ether obtained above in a mixture of MeOH (16 mL) and
Et2O (4 mL) was added K2CO3 (550 mg, 4 mmol) at 0 ºC. The resulting suspension was further stirred at 0 ºC for 30 minutes. The reaction mixture was then diluted with water (20 mL). The resulting mixture was extracted with Et2O (3x20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes:EtOAc = 30:1) to give the terminal enyne 2013 as a yellow oil (870 mg, 4 mmol, quant. over 3 steps).
1-Amino-2-bromo-4-hydroxyanthracene-9,10-dione (2010)
O NH2 O NH2
Br H3BO3, H2SO4 Br
140 ºC O Br O OH 2015 2010 quant. Part III Experimental Procedures and Computational Details 124
[CJH I-166] Boric acid (3 g, 48.5 mmol) was added at room temperature to a solution of 1-amino-2,4-dibromoanthracene-9,10-dione (2015, 5.9 g, 15.5 mmol) in concentrated sulfuric acid (29 mL). The reaction mixture was heated in an oil bath at 140 ºC for 4 hours. A dark purple solution formed immediately, and the color persisted throughout the reaction time. The reaction mixture was then allowed to cool to room temperature and poured into crushed ice (ca. 100 g). The resulting purple suspension was carefully neutralized with 50% aqueous NaOH solution until pH 7. The purple precipitate was collected by vacuum filtration. The filter cake was washed with cold methanol and further dried under vacuum to give 2010 as a purple solid (5.1 g, 16 mmol, quant.). This compound was directly used without further purification. 1 H NMR (500 MHz, CDCl3): d 8.34 (dd, J = 7.7, 1.6 Hz, 1H, H8), 8.31 (dd, J = 7.7, 1.7 Hz, 1H, H5), 7.82 (dt, J = 7.4, 1.7 Hz, 1H, H6), 8.77 (dt, J = 7.6, 1.6 Hz, H7), and 7.58 (s, 1H, H3). mp: > 230 ºC.
1-Azido-2-bromo-4-hydroxyanthracene-9,10-dione (2016)
O NH2 1) iAmONO O N3 Br Br AcOH-EtCO2H, 0 ºC
2) NaN3, 0 ºC - rt O OH O OH 2010 2016 63% [CJH I-169] To a solution of 1-Amino-2-bromo-4-hydroxyanthracene-9,10-dione (2010, 636 mg, 2 mmol) in a mixture of acetic acid (14 mL) and propionic acid (4 mL) was added isoamyl nitrite (0.4 mL, 3.0 mmol) at 0 ºC. The resulting mixture gradually turned from dark purple to a dark brown solution, and was further stirred at 0 ºC for 30 minutes. Sodium azide (198 mg, 3 mmol) was then added in one portion at 0 ºC. After gas evolution had subsided, the reaction mixture was allowed to warm to room temperature and further stirred for 1 hour. The reaction was quenched with ice-cold water (20 mL). The resulting precipitate was collected by vacuum filtration, washed with cold water thoroughly, and the Part III Experimental Procedures and Computational Details 125 solid was further dried under vacuum to give the azide 2016 as a brown powder (432 mg, 1.26 mmol, 63%).
1 H NMR (500 MHz, CDCl3): d 8.33 (dd, J = 7.5, 1.7 Hz, 1H, H8), 8.29 (dd, J = 7.4, 1.8 2H, H5), 7.86 (dd, J = 7.3, 1.6 Hz, 1H, H7), 7.84 (dd, J = 7.3, 1.6 Hz, H6), and 7.65 (s, 1H, H3).
(E)-1-Amino-4-hydroxy-2-(3-hydroxyprop-1-en-1-yl)anthracene-9,10-dione (2019)
CH2OH Bu3Sn O NH2 2018 O NH2 Br PdCl (PPh ) , LiCl 2 3 2 OH DMF, 90 ºC O OH O OH 2010 2019 42% [CJH II-138] To a solution of 1-Amino-2-bromo-4-hydroxyanthracene-9,10-dione (2010, 318 mg, 1 mmol) and the 3-stannylallyl alcohol 2018 (389 mg, 1.1 mmol) in DMF (5 mL) in a culture tube was added palladium bistriphenylphosphine chloride (35 mg, 0.05 mmoL) and lithium chloride (269 mg, 6.3 mmol). The resulting mixture was degassed using freeze- pump-thaw method. The tube was then sealed and heated at 90 ºC for 24 hours. The reaction mixture was then allowed to cool to room temperature and diluted with water (15 mL). The resulting mixture was filtered through Celite®. The filter cake was washed thoroughly with EtOAc. The filtrate was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo . The residue was triturated with hexanes. The resulting precipitate was collected vacuum filtration to give the cinnamyl alcohol derivative 2019 as a dark purple solid (124 mg, 0.42 mmol, 42%). 1 H NMR (500 MHz, CDCl3): d 8.36 (dd, J = 7.7, 1.5 Hz, 1H, H8), 8.33 (dd, J = 7.7, 1.6 2H, H5), 7.81 (dt, J = 7.6, 1.4 Hz, 1H, H7), 7.76 (dt, J = 7.6, 1.5 Hz), 7.24 (s, 1H, H3), 6.77 (dt, J = 15.8, 1.9 Hz, 1H, ArCH=CH), 6.46 (dt, J = 15.6, 4.6 Hz, 1H, ArCH=CH), and
4.45 (ddd, J = 5.7, 5.7, 1.8 Hz, 2H, CH=CHCH2OH).
Part III Experimental Procedures and Computational Details 126
1-Amino-2-bromo-4-((tert-butyldiphenylsilyl)oxy)anthracene-9,10-dione (2022)
O NH2 O NH2 Br TBDPSCl, Im Br
DMF O OH O OTBDPS 2010 2022 72% [CJH II-77] To a solution of 1-Amino-2-bromo-4-hydroxyanthracene-9,10-dione (2010, 796 mg, 2.5 mmol) and imidazole (2.66 g, 39 mmol) in DMF (3 mL) was added TBDPSCl (1.3 mL, 5 mmol). The resulting mixture was then stirred at room temperature overnight. The reaction mixture was diluted with water (10 mL). The insoluble material was collected by vacuum filtration. This wet solid was treated with EtOAc (30 mL). The resulting mixture was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was triturated with hexanes, and the precipitate was collected by vacuum filtration to give the silyl ether 2022 as a maroon solid (1.02 g, 1.8 mmol, 72%). 1 H NMR (500 MHz, CDCl3): d 8.25-8.23 (m, 2H, H5 and H8), 7.78 [dd, J = 8.0, 1.5 Hz,
4H, ArOSi(PhHo2)2], 7.74-7.71 (m, 2H, H6 and H7), 7.59 (s, 1H, H3), 7.46-7.43 [nfom,
2H, ArOSi(PhHp2)2], 7.40 [dd, J = 7.6, 5.9 Hz, 4H, ArOSi(PhHm2)2], 6.72 (s, 1H, H3), and
1.22 [s, 9H, SiC(CH3)3].
(E)-1-Amino-4-((tert-butyldiphenylsilyl)oxy)-2-(3-hydroxyprop-1-en-1- yl)anthracene-9,10-dione (2023)
CH2OH Bu3Sn O NH2 2018 O NH2 Br Pd(PPh ) 3 4 OH toluene, 90 ºC O OTBDPS O OTBDPS 2022 2023 95% [CJH II-78] To a solution of 1-Amino-2-bromo-4-((tert- butyldiphenylsilyl)oxy)anthracene-9,10-dione (2022, 118 mg, 0.21 mmol) and the 3- stannylallyl alcohol 2018 (88 mg, 0.25 mmol) in toluene (1.2 mL) in a culture tube was added palladium tetrakistriphenylphosphine (17 mg, 0.015 mmoL). The resulting mixture Part III Experimental Procedures and Computational Details 127 was degassed using freeze-pump-thaw method. The tube was then sealed and heated at 90 ºC for 24 hours. The reaction mixture was then allowed to cool to room temperature and diluted with water (5 mL). The resulting mixture was filter through Celite®. The filter cake was washed thoroughly with EtOAc. The filtrate was concentrated in vacuo, and the residue was triturated with hexanes. The resulting precipitate was collected vacuum filtration to give the cinnamyl alcohol derivative 2023 as a dark brown solid (108 mg, 0.2 mmol, 95%). 1 H NMR (500 MHz, CDCl3): d 8.28 (m, 1H, H5), 8.25 (m, 1H, H8), 7.80 [dd, J = 8.1, 1.6
Hz, 4H, ArOSi(PhHo2)2], 7.72 (nfom, 2H, H6), 7.70 (nfom, 2H, H7), 7.45-7.42 [nfom, 2H,
ArOSi(PhHp2)2], 7.40 [dd, J = 7.6, 6.0 Hz, 4H, ArOSi(PhHm2)2], 6.72 (s, 1H, H3), 6.45 (dt, J = 15.6, 2.1 Hz, 1H, ArCH=CH), 5.42 (dt, J = 15.5, 4.8 Hz, ArCH=CH), 4.12 (dd, J = 7.2,
7.1 Hz, ArCH=CHCH2OH), and 1.21 [s, 9H, SiC(CH3)3].
1-Amino-4-(benzyloxy)-2-bromoanthracene-9,10-dione (2026)
O NH2 O NH2 Br Br BnBr, Cs2CO3
DMF, 60 ºC O OH O OBn 2010 2026 73% [CJH III-76] To a solution of 1-Amino-2-bromo-4-hydroxyanthracene-9,10-dione (2010, 1.63 g, 5.1 mmol) in DMF (15 mL) was added Cs2CO3 (5 g, 15.3 mmol). The resulting dark blue solution was stirred at room temperature for 30 minutes, and then BnBr (1.9 mL, 15.9 mmol) was added in one portion. The resulting mixture was heated at 60 ºC until the starting material had all been consumed (more BnBr was added when necessary). The reaction mixture was then allowed to cool to room temperature and diluted with water (50 mL), and the resulting mixture was extracted with DCM (3x15 mL). The combined organic layers were washed with satd. K2CO3 (15 mL) and then brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residual oil was triturated with hexanes, and the precipitate was collected to give the benzyl ether 2026 as a dark red powder (1.52 g, 3.7 mmol, 72%). Part III Experimental Procedures and Computational Details 128
1 H NMR (500 MHz, CDCl3): d 8.24 (nfom, 1H, H5), 8.23 (nfom, 1H, H8), 7.74 (nfom,
1H, H6), 7.72 (nfom, 1H, H7), 7.61-7.58 (nfom, 2H, ArOCH2PhHo2), 7.59 (s, 1H, H3),
7.42 (dd, J = 7.5, 7.5 Hz, 2H, ArOCH2PhHm2), 7.34 (tt, J = 7.4, 2.0 Hz, 1H, ArOCH2PhHp), and 5.19, (s, 2H, ArOCH2Ph). 13 C NMR (500 MHz, CDCl3): d 185.3, 182.6, 150.5, 144.1, 136.6, 134.4, 133.6, 133.5, 133.4, 129.6, 128.8, 128.2, 127.5, 126.9, 126.6, 122.2, 118.8, 114.0, and 73.2.
Part III Experimental Procedures and Computational Details 129
8.2 Procedures and Data for Chapter 4
Preparation of a solution of 1-bromoprop-1-yne in hexanes (7159)124
H2O CH3C≡CH KOH + Br2 KOBr CH3C≡CBr –5-0 ºC ca.1.6 H2O/Hexanes equiv 0 °C to r.t. 7159 A 2 L three-neck round-bottom flask containing a magnetic stir bar was charged with a solution of KOH (85% tech. grade, 260 g, 3.94 mol) in 250 mL of water, and the flask was placed in an ice-salt bath. The flask was fitted with a thermocouple, a pressure equalizing dropping funnel, and a rubber septum. When the KOH solution had cooled to –3 ºC (internal temperature), bromine (40 mL, 0.78 mol, ca. 1.5 equiv) was added dropwise to the stirred solution at such a rate so that the internal temperature did not rise above 0 ºC. A precipitate formed over the course of the addition. After the addition was complete, the yellow slurry was stirred for an additional 30 min at 0 ºC. A 250 mL Erlenmeyer flask containing a ground-glass joint was charged with 150 mL of hexanes and the flask was cooled in a dry ice-acetone bath. Gaseous propyne (bp –23 °C, 95%, ca. 30 mL, 0.50 mol) was then slowly introduced via an 18 gauge syringe needle into the headspace of the flask. Condensation is more efficient if the needle tip is close to the surface of the cold hexane. Condensation was allowed to continue until the total volume of the solution had grown to ca. 180 mL. It is advisable to attach a bubbler to the headspace to ensure that the gas is not being introduced too rapidly. The addition funnel on 2 L the three-neck flask was replaced by a Dewar condenser filled with a dry ice-acetone mixture. The hexanes solution of propyne, still at –78 °C, was added slowly to the aqueous KOBr solution, still maintained at ≤0 °C, via cannula over approximately 1 hour. Depending on the rate of addition, the internal temperature of the reaction mixture may or may not increase. The reaction mixture was allowed to warm to room temperature, using internal temperature monitoring to guide the intermittent use of the cooling bath. As the mixture warmed, propyne reflux was observed, and the rate or reflux qualitatively indicated the progress of reaction. After the cessation of propyne reflux
124 Dr. Vedamayee Pogula and Mr. Sean Ross in our laboratories also contributed to the development of this procedure, which has proven useful for support of a number of our past and ongoing studies. Part III Experimental Procedures and Computational Details 130
(ca. 2 h), the reaction mixture was transferred to a 2 L separatory funnel. The aqueous layer was drained and combined with brine (100 mL) to minimize emulsion formation. The combined aqueous layers were extracted with hexanes (2x50 mL), and the combined organic layers were washed with brine (100 mL), dried over Na2SO4, and filtered to give a dried stock solution of 1-bromopropyne (ca. 300 mL total volume). Caution: neat 1- bromopropyne (reported bp 64 °C 125 ) has been reported to ignite upon exposure to oxygen;125 hence, we have opted to titer the hexanes solution by 1H NMR analysis of an aliquot and use that solution directly for subsequent coupling reactions. The concentration of the stock solution described here was judged to be 27 wt%. Such solutions have been stored multiple times in a freezer (ca. –20 °C) for months with no obvious loss in titer (NMR) or discoloration.
1-(Hexa-2,4-diyn-1-yloxy)hexa-2,4-diyne (4008)
CuCl, NH2OH•HCl Me O + Br Me O BuNH2-H2O-DCM-hexanes Me S4001 7159 4008 A 250 mL three-neck round bottom flask fitted with a magnetic stir bar, an internal thermometer, and a pressure equalizing dropping funnel was attached to a N2 inlet and charged with CuCl (306 mg, 3.1 mmol) and NH2OH•HCl (1.11 g, 15.9 mmol). The system was evacuated and backfilled with N2 (3x) and placed in an ice bath. Aqueous n-BuNH2 solution (35 mL, 30 wt%) was added to form a colorless solution. The dropping funnel was charged with a solution of dipropargyl ether (S4001, 1.42 g, 15.1 mmol) and 1- bromopropyne in hexanes [7059, 15.5 g total mass, ~29 wt%, which contained, therefore, ca. 4.5 g, 37.8 mmol (1.25 equiv per alkyne)] in CH2Cl2 (25 mL). When the temperature of the copper catalyst-containing solution in the three-neck flask reached 0 ºC, the solution of dipropargyl ether and bromopropyne in the addition funnel was added dropwise to the reaction mixture at a rate such that the temperature of the reaction mixture was maintained below 10 ºC (addition time on this scale was ca. 50 min). A bright yellow slurry
125 Brandsma, L.; Verkruijsse, H. D. Synthesis 1990, 984–985. Part III Experimental Procedures and Computational Details 131 immediately formed, presumably an indication of the formation of copper acetylide species. During the addition the reaction mixture turned to a peachy yellow slurry having two liquid phases.* The resulting mixture was allowed to stir in the ice bath for 30 min after the addition was finished. Saturated aqueous NH4Cl solution (50 mL) was then added, and the ice bath was removed. The mixture was poured into a separatory funnel, and the organic layer was drained. The blue aqueous layer was extracted with CH2Cl2 (3x15 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product as a brown oil. This material was purified by flash chromatography (hexanes:EtOAc = 30:1) to yield tetrayne 4008 as a pale yellow crystal (1.60 g, 9.4 mmol, 62%). *On some occasions, especially on smaller scales, the reaction mixture in these cross- couplings turned to green/blue prior to the complete consumption of terminal alkyne; if so, an additional quantity of satd. aqueous NH2OH•HCl was added dropwise until the color dissipated and stirring was continued. 1 H NMR (500 MHz, CDCl3): d 4.30 [q, J = 1.1 Hz, 4H, O(CH2)2], 1.94 (t, J = 1.1 Hz, 6H,
C≡CCH3). 13C NMR (125 MHz, CDCl3): d 77.1, 72.1, 70.0, 63.6, 57.0, and 4.3. IR (neat): 3005, 2981, 2921, 2865, 2844, 2258, 1435, 1344, 1243, 1071, 1033, 1018, and 750 cm-1.
TLC: Rf 0.3 in 20:1 hexanes:EtOAc. mp: 40–45 °C HRMS measurements of this compound were not successful. The low molecular weight and lack of functionality more readily adductable than an ether renders the compound poorly ionizable by ESI or APCI conditions. The thermal instability (toward HDDA) of this compound renders it unstable to GC-HRMS conditions. We suggest that all of the products of its subsequent derivatization serve as a means of further characterization of this relatively simple compound.
Part III Experimental Procedures and Computational Details 132
1-(2-Ethynylphenyl)-3-(trimethylsilyl)prop-2-yn-1-ol (4009)
O HO HO O LiC≡CTMS TMS BrC≡CMe TMS MnO2 TMS
Cadiot- Me CH2Cl2 Me Chadkiewicz S4002 S4003 S4004 4009 The synthesis of 4009 was modified based on a known procedure.73
O HO THF TMS + TMS + nBuLi –78 ºC
S4002 S4003 A 100 mL three-neck round bottom flask fitted with a magnetic stir bar and two pressure equalizing dropping funnel was loaded with a solution of ethynyltrimethyl silane (2.9 mL,
20 mmol) in 45 mL of THF under an atmosphere of N2. The solution was stirred in a dry ice-acetone bath while a solution of n-butyllithium (8 mL, 2.5 M in hexanes, 20 mmol) was added dropwise through a dropping funnel. The resulting solution was stirred at –78 ºC for 30 min, and a solution of 2-ethynylbenzaldehyde126 (S4002, 1.42 g, 10.9 mmol) in 20 mL of THF was added dropwise via a second dropping funnel. After the addition was complete, the resulting reaction mixture was allowed to warm to 0 ºC over 3 hours. The mixture was quenched by the addition of a mixture of HOAc (1 mL, 17.5 mmol) and THF (1 mL) at 0 ºC. The mixture was then allowed to warm to room temperature and treated with satd.
NaHCO3 (30 mL). The organic layer was separated. The aqueous layer was extracted with
Et2O (3x15 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product as a yellow oil. This material was pure enough to be used directly in the next step without further purification.
HO HO TMS CuCl, NH2OH•HCl TMS + Br Me BuNH2-H2O-DCM-hexanes Me S4003 7159 S4004 A 100 mL round bottom flask fitted with a magnetic stir bar and a pressure equalizing dropping funnel attached to a N2 inlet was charged with CuCl (120 mg, 1.21 mmol) and
126 Luan, Y; Barbato, K. S.; Moquist, P. N.; Kodama, T.; Schaus, S. E. J. Am. Chem. Soc. 2015, 137, 3233– 3236. Part III Experimental Procedures and Computational Details 133
NH2OH•HCl (500 mg, 7.2 mmol). The system was evacuated and backfilled with N2 (3x) and placed in an ice bath. Aqueous BuNH2 solution (20 mL, 30 wt%) was added to form a colorless solution, which was further stirred at 0 ºC for 30 min. The dropping funnel was charged with a solution of crude 1-(2-ethynylphenyl)-3-(trimethylsilyl)prop-2-yn-1-ol (S4003) and 1-bromopropyne [~29 wt% in hexanes, 6 g, which contained ca. 1.7 g, (15 mmol)] in CH2Cl2 (21 mL). This solution was added dropwise to the reaction mixture. The resulting mixture was allowed to stir in the ice bath for 10 min after the addition was finished. Saturated aqueous NH4Cl solution (30 mL) was added, and the ice bath was removed. The mixture was poured into a separatory funnel, and the organic layer was drained. The blue aqueous layer was extracted with CH2Cl2 (3x 15 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product as a brown oil. This material was purified by flash chromatography (hexanes:EtOAc = 15:1) to yield the known triyne S4004 as a yellow oil (1.96 g, 7.36 mmol, 67% over two steps).
HO O TMS MnO2 TMS
Me CH2Cl2 Me S4004 4009
MnO2 (3.1 g, 36 mmol) was added to a solution of the triyne S4004 (1.96 g, 7.36 mmol) in
CH2Cl2 (70 mL), and the resulting suspension was stirred at room temperature overnight.
The reaction mixture was filtered through Celiteâ with CH2Cl2 as eluent. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography (hexanes:EtOAc = 15:1) to afford the known ketotriyne 4009 as a viscous brown oil (1.70 g, 6.43 mmol, 87%).
N-(Hepta-3,5-diyn-1-yl)-4-methyl-N-(penta-1,3-diyn-1-yl)benzenesulfonamide (4010) Part III Experimental Procedures and Computational Details 134
Ts N Ts TsHN N n Ts Ts HC≡CTMS Cl2C=CHCl BuLi N BrC≡CMe N Cl nBuLi K CO , DMF Cadiot- 2 3 Cl TMS TMS Chadkiewicz Me Me S4005 S4006 S4007 S4008 4010 4-Methyl-N-(4-(trimethylsilyl)but-3-yn-1-yl)benzenesulfonamide (S4006)
TsHN i) nBuLi, –78 ºC TMS ii) TsN S4005 –78 ºC - rt, 12 h TMS S4006
A 250 mL three-neck round bottom flask fitted with a magnetic stir bar, N2 inlet, and two dropping funnels was loaded with a solution of ethynyltrimethyl silane (8.5 mL, 60 mmol) in THF (100 mL). The flask was immersed in a dry ice-acetone bath, and a nBuLi solution (24 mL, 60 mmol, 2.5 M in hexanes) was added dropwise through one dropping funnel under N2 atmosphere. The resulting lithium acetylide solution was warmed to 0 ºC over 1 hour, and a solution of N-tosyl aziridine127 (S4005, 5.03 g, 25.5 mmol) in THF ( 25 mL) was added dropwise from the second dropping funnel. The reaction mixture was stirred at room temperature for 18 hours and then quenched by addition of a mixture of HOAc (4 g,
67 mmol) in THF (10 mL) at 0 ºC. The resulting mixture was treated with satd. NaHCO3 (50 mL) and transferred into a separatory funnel. The organic layer was separated. The aqueous layer was extracted with EtOAc (3x25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes:EtOAc = 8:1) to give the sulfonamide S4006 as an off-white crystal (3.75 g, 12.7 mmol, 50%). The spectroscopic data of the product agreed with those reported. (Z)-N-(1,2-Dichlorovinyl)-4-methyl-N-(4-(trimethylsilyl)but-3-yn-1- yl)benzenesulfonamide (S4007)
127 Dietrich, B.; Hosseini, M. W.; Lehn, J-M.; Sessions, R. B.; Helv. Chim. Acta. 1985, 68, 289–299. Part III Experimental Procedures and Computational Details 135
Ts Ts TsHN N N Cl2C=CHCl Cl + Cl K CO , DMF 2 3 Cl Cl TMS 70 ºC, 19 h TMS H S4006 S4007 S4007'
A mixture of the sulfonamide S4006 (2.96 g, 10 mmol), K2CO3 (4.21 g, 30.5 mmol), and trichloroethylene (2.7 mL, 30 mmol) in DMF (5 mL) was heated at 70 ºC for 19 hours. The reaction mixture was allowed to cool to room temperature, and EtOAc (20 mL) was added.
The solid material was removed by filtration. The filtrate was treated with satd. NH4Cl (30 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a brown oily residue. Flash chromatography (hexanes:EtOAc = 15:1) of the crude product afforded, in order of elution, a partially separable 11:1 mixture of S4007 and known sulfonamide S4007’121 each as a yellow solid with a total mass of 3.47 g (9 mmol, 90%). Data for S4007: 1 H NMR (500 MHz, CDCl3): d 7.80 (d, J = 8.4 Hz, 2H, SO2ArHo2), 7.32 (d, J = 8.0 Hz,
2H, SO2ArHm2), 6.48 (s, 1H, =CHCl), 3.39 (br s, 2H, NCH2CH2), 2.52 (br t, J = 7.6 Hz,
NCH2CH2), 2.43 (s, 3H, ArCH3), and 0.12 (s, 9H, Si(CH3)3). 13 C NMR (125 MHz, CDCl3): d 144.7, 135.2, 129.7, 129.4, 128.2, 121.8, 102.0, 86.9, 46.8, 21.6, 19.8, and 0.1. IR (neat): 3087, 3005, 2980, 2922, 2866, 2844, 2825, 2178, 1597, 1495, 1454, 1364, 1249, 1167, 1143, 1090, 1053, 1032, 1012, 980, 842, 816, and 758 cm-1. + + HRMS (ESI-TOF): Calcd for [C16H21Cl2NNaO2SSi] [(M+Na) ]: 412.0337, 414.0308, found 412.0348, 414.0326.
TLC: Rf 0.5 in 5:1 hexanes:EtOAc. mp: 62-65 ºC. N-Ethynyl-4-methyl-N-(4-(trimethylsilyl)but-3-yn-1-yl)benzenesulfonamide (S4008’)
Ts Ts N N nBuLi Cl THF, –78 ºC Cl TMS(H) TMS(H) S4007/S4007' S4008/S4008' Part III Experimental Procedures and Computational Details 136
To a solution of a mixture of the dichlorovinylsulfonamides S4007 and S4007’ (total mass, 3.46 g) in THF (35 mL) at –78 ºC was added n-butyllithium (5 mL, 2.5 M in hexanes, 12.5 mL) dropwise under a nitrogen atmosphere. The resulting mixture was allowed to warm to –40 ºC over 1 hour. The reaction mixture was recooled to –78 ºC, and a second portion of n-butyllithium solution (5 mL, 2.5 M in hexanes, 12.5 mL) was added. The reaction mixture was further stirred at –78 ºC for 1 hour, and methanol (4 mL) was added. The reaction mixture was warmed to room temperature and quenched with satd. NH4Cl (30 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product containing S4008 and a small quantity of desilylated diyne S4008’ was directly used in the next step without further purification. N-(But-3-yn-1-yl)-N-ethynyl-4-methylbenzenesulfonamide (S4008)
Ts N Ts K2CO3 N
THF-MeOH TMS S4008' S4008
K2CO3 (576 mg, 4.2 mmol) was added in one portion to a solution of diynes S4008 and S4008’ in 1:1 (v:v) THF-MeOH (30 mL) at 0 ºC. The reaction mixture was allowed to warm to room temperature and stirred overnight. The mixture was diluted with EtOAc (15 mL). The insoluble material was removed by filtration. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography (hexanes:EtOAc = 6:1) to give the known bis-terminal diyne S4008121 as a yellow solid (1.37 g, 5.6 mmol, 62% over two steps). N-(Hepta-3,5-diyn-1-yl)-4-methyl-N-(penta-1,3-diyn-1-yl)benzenesulfonamide (4010)
Me CuCl, NH2OH•HCl + Br Me N BuNH2-H2O-DCM-hexanes N Me Ts Ts S4008 7159 4010 A 100 mL round bottom flask fitted with a magnetic stir bar and a pressure equalizing dropping funnel attached to a N2 inlet was charged with CuCl (260 mg, 2.6 mmol) and
NH2OH•HCl (915 mg, 13.2 mmol). The system was evacuated and backfilled with N2 (3x) and placed in an ice bath. Aqueous BuNH2 solution (30 mL, 30 wt%) was added to form a Part III Experimental Procedures and Computational Details 137 colorless solution, which was further stirred at 0 ºC for 30 min. The dropping funnel was charged with a solution of the diyne S4008 (3,09 g 12.5 mmol) and 1-bromopropyne [~ 26 wt% in hexanes, 14 g, which contained ca. 3.6 g (30 mmol) of bromopropyne] in CH2Cl2 (20 mL). This solution was added dropwise to the reaction mixture. The resulting mixture was allowed to stir in the ice bath for 30 min after the addition was finished. Saturated aqueous NH4Cl solution (35 mL) was added, and the ice bath was removed. The mixture was poured into a separatory funnel, and the organic layer was drained. The blue aqueous layer was extracted with CH2Cl2 (3x 15 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product as a brown oil. This material was purified by flash chromatography (hexanes:EtOAc = 12:1) to yield the tetrayne 4010 as an off-white solid (2.78 g, 8.6 mmol, 69 %). 1 H NMR (500 MHz, CDCl3): d 7.79 (d, J = 8.3 Hz, 2H, SO2ArHo2), 7.36 (d, J = 8.2 Hz,
SO2ArHm2), 3.48 (t, J = 7.6 Hz, 2H, SO2NCH2), 2.57 (tq, J = 7.8, 1.1 Hz, 2H,
SO2NCH2CH2), 2.46 (s, 3H, CH3Ar), 1.97 [s, 3H, N(C≡C)2CH3], and 1.91 [t, J = 1.4 Hz,
3H, CH2(C≡C)2CH3]. 13 C NMR (125 MHz, CDCl3): d 145.2, 134.3, 130.0, 127.6, 80.2, 74.4, 71.2, 67.6, 65.8, 64.1, 63.4, 59.3, 49.7, 21.7, 19.1, 4.6, and 4.2. IR (neat): 3005, 2981, 2966, 2938, 2922, 2865, 2844, 2256, 2167, 1596, 1367, 1169, 1090, 1055, 1033, 1017, 950, and 813 cm-1. + + HRMS (ESI-TOF): Calcd for [C19H17NNaO2S] [(M+Na) ] 346.0878, found 346.0872.
TLC: Rf 0.3 in 3:1 hexanes:EtOAc. mp: 75-78 ºC (decomp).
Di-tert-butyl 1-(hexa-2,4-diyn-1-yl)-2-(penta-1,3-diyn-1-yl)hydrazine-1,2- dicarboxylate (4011)
H Me Boc NH HC CCH Br BrC CMe ≡ 2 Boc N ≡ Boc N N TMS N H N Me Boc NaH, DMF Cadiot- Boc Boc Chadkiewicz S4009 S4010 4011 Part III Experimental Procedures and Computational Details 138
Di-tert-butyl 1-ethynyl-2-(prop-2-yn-1-yl)hydrazine-1,2-dicarboxylate (S4010)
i) NaH, DMF, 0 ºC H Boc NH ii) HC CCH Br ≡ 2 Boc N N TMS N H Boc iii) MeOH Boc S4009 S4010 To a suspension of NaH (0.96 g, 60 wt% dispersion in mineral oil, 24 mmol) in DMF (30 mL) at 0 ºC was added dropwise a solution of di-tert-butyl 1- ((trimethylsilyl)ethynyl)hydrazine-1,2-dicarboxylate128,129 (S4009, 3.50 g, 10.7 mmol) in DMF (20 mL). The addition was accompanied by gas evolution. After the reaction had subsided, the mixture was stirred at 0 ºC for 30 min, and propargyl bromide (2.4 mL, 80 wt% in toluene, 21.5 mmol) was added dropwise to the sodium hydrazide solution. The reaction mixture was warmed to room temperature and further stirred for 6 hours. The reaction was cooled at 0 ºC and methanol (4 mL) was added slowly. The reaction mixture was stirred for an additional 2 h at room temperature and then diluted with brine (50 mL). The resulting mixture was extracted with EtOAc (3x30 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes:EtOAc = 15:1) to give the diyne S4010 as a dark red oil. 1 H NMR (500 MHz, CDCl3): d 4.53–4.16 (m, 2H, NCH2C≡CH), 3.02 (br s, 1H, NC≡CH),
2.28 (br t, J = 2.4 Hz, NCH2C≡CH), 1.52 [br s, 9H, (CH3)3CO(O)NC≡CH], and 1.49 [br s,
9H, (CH3)3CO(O)NCH2]. 13 C NMR (100 MHz, C6D6, 70 ºC): d 153.7, 152.8, 84.4, 82.9, 78.3, 76.4, 73.9, 61.4, 39.3, 28.8, and 28.5. IR (neat): 3294, 2980, 2938, 2923, 2866, 2843, 2826, 2146, 1746, 1721, 1370, 1302, 1255, 1242, 1147, 1054, 1033, 1017, 846, and 751 cm-1. + + HRMS (ESI-TOF): Calcd for [C15H22N2NaO4] [(M+Na) ] 317.1477, found 317.1471.
TLC: Rf 0.2 in 10:1 hexanes:EtOAc.
128 Ling, K. B.; Smith, A. D. Chem.Comm. 2011, 47, 373–375. 129 Beveridge, R. E.; Batey, R. A. Org. Lett. 2012, 14, 540–543. Part III Experimental Procedures and Computational Details 139
Di-tert-butyl 1-(hexa-2,4-diyn-1-yl)-2-(penta-1,3-diyn-1-yl)hydrazine-1,2- dicarboxylate (4011)
Me CuCl, NH2OH•HCl Boc N + Br Me Boc N N BuNH2-H2O-DCM-hexanes N Me Boc Boc S4010 7159 4011 A 100 mL round bottom flask fitted with a magnetic stir bar and a pressure equalizing dropping funnel attached to a N2 inlet was charged with CuCl (119 mg, 1.2 mmol) and
NH2OH•HCl (495 mg, 7.1 mmol). The system was evacuated and backfilled with N2 (3x) and placed in an ice bath. Aqueous BuNH2 solution (15 mL, 30 wt%) was added to form a colorless solution, which was further stirred at 0 ºC for 30 min. The dropping funnel was charged with a solution of the diyne S4010 (1.70 g, 5.8 mmol) and 1-bromopropyne [~26 wt% in hexanes, 6.5 g, which contained ca. 1.7 g (14 mmol) of bromopropyne] in CH2Cl2 (15 mL). This solution was added dropwise to the reaction mixture, which was allowed to stir in the ice bath for 30 min after the addition was finished. Saturated aqueous NH4Cl solution (30 mL) was added, and the ice bath was removed. The mixture was poured into a separatory funnel, and the organic layer was drained. The blue aqueous layer was extracted with CH2Cl2 (3x15 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford the crude product as a brown oil. This material was purified by flash chromatography (hexanes:EtOAc = 8:1) to yield the tetrayne 4011 as a yellow solid (1.83 g, 4.9 mmol, 85%). 1 H NMR (500 MHz, CDCl3): d 4.56-4.10 (br m, 2H, NCH2CCCH3), 1.98 [s, 3H,
N(C≡C)2CH3], 1.92 [t, J = 1.1 Hz, 3H, NCH2(C≡C)2CH3], 1.52 [s, 9H,
(CH3)3CO(C=O)NC≡C]], and 1.47 [s, 9H, (CH3)3CO(C=O)NCH2C≡C]. 13 C NMR (125 MHz, C6D6, 70 ºC): d 153.7, 152.7, 84.9, 83.1, 81.8, 76.8, 71.6, 70.0, 67.0, 65.7, 65.2, 61.8, 40.0, 28.7, 28.5, 4.5, and 4.1. IR (neat): 2980, 2974, 2937, 2922, 2866, 2844, 2263, 2172, 1748, 1729, 1476, 1456, 1420, 1369, 1345, 1289, 1254, 1148, 1055, 1033, 1012, 846, and 753 cm-1. + + HRMS (ESI-TOF): Calcd for [C21H26N2NaO4] [(M+Na) ] 393.1782, found 393.1790.
TLC: Rf 0.14 in 10:1 hexanes:EtOAc. Part III Experimental Procedures and Computational Details 140 mp: 67-73 ºC.
N-Benzylprop-2-yn-1-amine (S4011)
HC≡CCH2Br Ph NH Ph N 2 H K2CO3, DMF S4011 A solution of propargyl bromide (2.4 mL, 80 wt% in toluene, 21.5 mmol) in DMF (10 mL) was added over 30 minutes to a mixture of benzylamine (11.5 mL, 105 mmol) and K2CO3 (5.87 g, 42.5 mmol) in DMF (100 mL). The reaction mixture was then stirred at room temperature overnight. The insoluble material was then removed via filtration. The filtrate was treated with brine (100 mL), and the resulting mixture was extracted with Et2O (3x50 mL). The combined organic layers were washed with water (50 mL) and then brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes:EtOAc = 10:1 to 5:1) to give S4011 as a yellow oil (2.47 g, 17 mmol, 79%). N-Benzylhexa-2,4-diyn-1-amine (7145)
CuCl, NH2OH•HCl Ph Ph N + Br Me NH H BuNH2-H2O-DCM-hexanes Me S4011 7159 7137 A 100 mL round bottom flask fitted with a magnetic stir bar and a pressure equalizing dropping funnel attached to a N2 inlet was charged with CuCl (112 mg, 1.1 mmol) and
NH2OH•HCl (718 mg, 10.3 mmol). The system was evacuated and backfilled with N2 (3x) and placed in an ice bath. Aqueous BuNH2 solution (30 mL, 30 wt%) was added to form a colorless solution, which was further stirred at 0 ºC for 30 min. The dropping funnel was charged with a solution N-benzylprop-2-yn-1-amine (S4011 1.57 g, 10.8 mmol) and 1- bromopropyne [~13 wt% in hexanes, 14 g, which contained ca. 1.8 g (15 mmol) of bromopropyne] in CH2Cl2 (10 mL). This solution was added dropwise to the reaction mixture, which was allowed to stir in the ice bath for 1 hour after the addition was finished.
The organic layer was separated. The aqueous layer was extracted with Et2O (3x30 mL). Part III Experimental Procedures and Computational Details 141
The combined organic layers were washed with 30% NH3•H2O and then brine, dried over
Na2SO4, filtered, and concentrated in vacuo to afford the crude product as a brown oil.
TLC: Rf = 0.18 in 5:1 hexanes:EtOAc. N-Benzyl-N-(hexa-2,4-diyn-1-yl)-3-(trimethylsilyl)propiolamide (4012)
O Ph DCC, DMAP Ph TMS NH + TMS CO H 2 N Me CH Cl 2 2 Me 7137 S4012 4012
A solution of DCC (504 mg, 2.4 mmol) in CH2Cl2 (5 mL) was added dropwise to a solution of N-Benzylhexa-2,4-diyn-1-amine (7137, 400 mg, 2.2 mmol), 3-(trimethylsilyl)propiolic 130 acid (S4012, 323 mg, 2.3 mmol) and DMAP (28 mg, 0.23 mmol) in CH2Cl2 (10 mL) at 0 ºC. The reaction mixture was then allowed to warm to room temperature and further stirred overnight. The solvent was evaporated in vacuo, and the residue was treated with EtOAc (10 mL). The insoluble material was removed by filtration. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography (hexanes:EtOAc = 5:1) to give 4012 as a yellow oil (337 mg, 1.1 mmol, 50%). 1 H NMR (500 MHz, CDCl3): d 7.39-7.26 (m, 5H, NCH2ArH5, rotamer a and b), 4.90 (s,
2H, NCH2Ph, rotamer a), 4.72 (s, 2H, NCH2Ph, rotamer b), 4.30 (q, J = 1.3 Hz, 2H,
NCH2C≡C, rotamer b), 4.16 (q, J = 1.4 Hz, 2H, NCH2C≡C, rotamer a), 1.96 (t, J = 1.4 Hz,
3H, C≡CCH3, rotamer b ), 1.94 (t, J = 1.4 Hz, 3H, C≡CCH3, rotamer a ), 0.25 [s, 9H,
Si(CH3)3, rotamer b], and 0.22 [s, 9H, Si(CH3)3, rotamer a].
5-Methyl-4-(prop-1-yn-1-yl)-1,3,6,9-tetrahydro-6,9-epoxynaphtho[1,2-c]furan (4013)
Me
Me PhH O + O Me Me 75 ºC O O
4008 4013
130 Lauber, A.; Zelenay, B.; Cvengros, J. Chem. Comm. 2014, 10, 1195–1197. Part III Experimental Procedures and Computational Details 142
A solution of the tetrayne 4008 (137 mg, 0.8 mmol) and furan (0.6 mL, 8.2 mmol) in benzene (8 mL) was heated at 75 ºC for 12 h. The solvent was evaporated and the residue was purified by flash chromatography (hexanes:EtOAc = 6:1) to give 4013 as an off-white solid (137 mg, 0.58 mmol, 72%). 1 H NMR (500 MHz, CDCl3): d 7.04 (dd, J = 5.6, 2.0 Hz, 1H, OCHaCHa=CHb), 6.99 (dd,
J = 5.6, 2.0 Hz, 1H, OCHbCHbHa), 5.80 (d, J = 1.9 Hz, 1H, OCHaCHa=CHb), 5.66 (d, J =
1.9 Hz, 1H, OCHbCHb=CHa), 5.14 (br d, J = 11.7 Hz, 1H, H1aH1b), 5.04 (t, J = 1.8 Hz, 2H,
H3), 5.01 (br d, J = 12.2 Hz, 1H, H1bH1a), 2.36 (s, 3H, ArCH3), and 2.09 (s, 3H, C≡CCH3).
TLC: Rf 0.45 in 3:1 hexanes:EtOAc.
5-Methyl-6-(trimethylsilyl)-1,4-dihydro-7H-1,4-epoxybenzo[c]fluoren-7-one (4014)
TMS O O Me TMS PhH + O Me 90 ºC O
4009 4014 A solution of the triyne 4009 (262 mg, 1 mmol) and furan (0.36 mL, 5 mmol) in benzene (10 mL) was heated at 90 ºC for 12 h. The solvent was evaporated and the residue was purified by flash chromatography (hexanes:EtOAc = 10:1) to give 4014 as a yellow solid (259 mg, 0.78 mmol, 78%). 1 H NMR (500 MHz, CDCl3): d 7.63 (ddd, J = 7.4, 2.0, 1.1 Hz, 1H, H8), 7.49 (ddt, J = 7.5, 7.5, 1.0 Hz, 1H, H10), 7.47 (dd, J = 7.4, 2.0 Hz, H11), 7.28 (ddt, 7.3, 6.7, 2.0 Hz, 1H, H9), 7.06 (m, 2H, H2+H3), 6.15 (t, J = 1 Hz, 1H, H1), 5.84 (t, J = 0.9 Hz, 1H, H4), 2.42 (d, J =
1.2 Hz, 3H, ArCH3), 0.40 [s, 9H, Si(CH3)3].
5-Methyl-4-(prop-1-yn-1-yl)-1-tosyl-2,3,6,9-tetrahydro-1H-6,9-epoxybenzo[g]indole (4015) Part III Experimental Procedures and Computational Details 143
Me
Me PhH + O Me N Me 90 ºC Ts N O Ts 4010 4015 A solution of the tetrayne 4010 (161 mg, 0.5 mmol) and furan (0.7 mL, 9.6 mmol) in benzene (5 mL) was heated at 90 ºC for 12 h. The solvent was evaporated and the residue was purified by flash chromatography (hexanes:EtOAc = 10:1) to give 4015 as a pale yellow solid (193 mg, 0.49 mmol, 98%). 1 H NMR (500 MHz, CDCl3): d 7.31 (d, J = 8.2 Hz, 2H, SO2ArHo2), 7.27 (dd, J = 5.4, 1.8
Hz, 1H, H8), 7.16 (d, J = 8.1 Hz, 2H, SO2Hm2), 7.05 (dd, J = 5.4, 1.7 Hz, 1H, H7), 6.17 (d, J = 1.6 Hz, 1H, H9), 5.78 (d, J = 1.3 Hz, 1H, H6), 3.98 (ddd, J = 12.4, 9.4, 3.0 Hz, 1H,
H2a), 3.87 (ddd, J = 12.5, 10.5, 8.9 Hz, 1H, H2b), 2.62 (ddd, J = 16.4, 9.0, 3.0 Hz, 1H, H3b),
2.37 (s, 3H, SO2ArCH3), 2.32 (s, 3H, ArCH3). 2.26 (ddd, J = 17.0, 10.5, 10.5 Hz, 1H, H3a), and 2.02 (s, 3H, C≡CCH3).
di-Tert-butyl 5-methyl-4-(prop-1-yn-1-yl)-6,9-dihydro-1H-6,9- epoxybenzo[g]indazole-1,2(3H)-dicarboxylate (4016)
Me
Me PhH BocN + O Me N Me 95 ºC Boc N Boc N O Boc 4011 4016 A solution of the tetrayne 4011 (185 mg, 0.5 mmol) and furan (1 mL, 13.8 mmol) in benzene (5 mL) was heated at 95 ºC for 24 h. The solvent was evaporated and the residue was purified by flash chromatography (hexanes:EtOAc = 10:1) to give 4016 as a pale yellow solid (149 mg, 0.34 mmol, 68%). 1 H NMR (500 MHz, CDCl3): d 7.23 (dd, J = 5.4, 1.8 Hz, 1H, H8), 6.96 (dd, J = 5.5, 1.7 Hz, 1H, H7), 5.98 (d, J = 1.9 Hz, 1H, H9), 5.79 (d, J = 2.4 Hz, 1H, H6), 5.05 (br d, J = 14.9 Part III Experimental Procedures and Computational Details 144
Hz, 1H, H3a), 4.48 (br d, J = 15.1 Hz, 1H, H3b), 2.33 (s, 3H, ArCH3), 2.10 (s, 3H, C≡CCH3),
1.53 [s, 9H, (CH3)3CO(C=O)NAr], and 1.52 [s, 9H, (CH3)3CO(C=O)NCH2Ar].
2-Benzyl-5-methyl-4-(trimethylsilyl)-1,2,6,9-tetrahydro-3H-6,9- epoxybenzo[e]isoindol-3-one (4017)
O TMS O PhH Me TMS + O BnN BnN 95 ºC Me O 4012 4017 A solution of the triyne 4013 (92 mg, 0.3 mmol) and furan (0.45 mL, 6.2 mmol) in benzene (3 mL) was heated at 95 ºC for 24 h. The solvent was evaporated and the residue was purified by flash chromatography (hexanes:EtOAc = 2:1) to give 4019 as a pale yellow oil (114 mg, 0.3 mmol, quant.). 1 H NMR (500 MHz, CDCl3): d 7.34 (nfom dddd, J = 7.0, 7.0, 1.8, 1.8 Hz, 2H,
NCH2ArHm2), 7.30-7.26 (m, 3H, NCH2ArHo2+Hp), 7.08 (dd, J = 5.5, 2.1 Hz, 1H, H7), 6.97, (dd, J = 5.5, 2.0 Hz, 1H, H8), 5.88 (d, J = 2.2 Hz, H9), 5.70 (d, J = 2.1 Hz. H6), 4.81 (d, J
= 14.8 Hz, 1H, ArCHaHbNCH2Ph), 4.69 (d, J = 14.8 Hz, 1H, ArCHbHaNCH2Ph), 4.25 (d,
J = 16.2 Hz, PhCHaHbNCH2Ar), 4.08 (d, J = 16.4 Hz, PhCHbHaNCH2Ar), 2.48 (s, 3H,
ArCH3), 0.47 [s, 9H, Si(CH3)3].
6-Acetoxyhexa-2,4-diyn-1-yl Propiolate (4018)
O HO DCC, DMAP + CO2H O OAc CH2Cl2 OAc S4013 4018 To a solution of 6-hydroxyhexa-2,4-diyn-1-yl acetate131 (S4013, 1.38 g, 9.1 mmol) and DMAP (0.11 g, 0.91 mmol) in 45 mL of dichloromethane was added propiolic acid (1.2
131 Morton, D.; Leach, S.; Cordier, C.; Warriner, S.; Nelson, A. Synthesis of natural-product-like molecules with over eighty distince scaffolds. Angew. Chem. Int. Ed. 2009, 48, 104-109. Part III Experimental Procedures and Computational Details 145 mL, 19.4 mmol) dropwise. The solution was cooled to 0 ºC and DCC (2.8 g, 13.6 mmol) was added in one portion. The reaction mixture, which turned brown quickly, was stirred at 0 °C for two hours. The solvent was removed in vacuo and ethyl acetate (20 mL) was added to the residue. The precipitate was removed by vacuum filtration and thoroughly washed with additional ethyl acetate (15 mL). The filtrate was washed with 1M HCl (20 mL), satd NaHCO3 (20 mL), and brine; dried over Na2SO4; and concentrated in vacuo to give the crude product. Purification by flash column chromatography (5:1, hexanes:EtOAc) provided the ester 4018 (1.02 g, 55%) as a yellow oil. 1 H NMR (500 MHz, CDCl3): d 4.85 (2H, s, OCH2), 4.74 (2H, s, OCH2), 2.98 (1H, s, C≡CH), and 2.11 (3H, s, OAc). 13 C NMR (125 MHz, CDCl3): d 170.1, 151.7, 76.4, 74.4, 73.8, 72.1, 71.5, 70.2, 53.8, 52.3, and 20.7. IR (neat): 3281, 3261, 2992, 2940, 2122, 1746, 1723, 1430, 1378, 1358, 1261, 1209, 1031, and 763 cm-1. + + HRMS (ESI-TOF): [C11H8NaO4] (M+Na ) requires 227.0315; found 227.0332.
TLC: Rf = 0.24 in 3:1 hexanes:EtOAc.
1-(2-Bromophenethyl)-2,5-dimethyl-1H-pyrrole (4024)
Me NH O 2 HOAc Br Br Me + Me N O toluene Me S4014 4024 Acetic acid (0.6 mL, 10.5 mmol) was added to a solution of 2-(o- bromophenyl)ethylamine132 (S4014, 2.13 g, 10.7 mmol) and hexane-2,5-dione (1.46 g, 12.8 mmol) in toluene (55 mL). The resulting biphasic reaction mixture was stirred at room temperature for 4 h. The solvent was removed in vacuo. The residue was purified by flash column chromatography (10:1, hexanes:EtOAc) to give the pyrrole 4024 (2.46 g, 83%) as a yellow solid.
132 Todd, M. H.; Ndubaku, C.; Bartlett, P. A. J. Org. Chem. 2002, 67, 3985. Part III Experimental Procedures and Computational Details 146
1 H NMR (500 MHz, CDCl3): d 7.56 (1H, dd, J = 8.0, 1.4 Hz, BrArHo), 7.22 (1H, ddd, J =
7.5, 7.5, 1.4 Hz, BrArHp), 7.11 (1H, ddd, J = 7.7, 7.6, 1.8 Hz, BrArHm’), 7.04 (1H, dd, J =
7.5, 1.9 Hz, BrArHm), 5.76 [2H, s, CpyrroleH (2x)], 3.96 (2H, t, J = 7.7 Hz, NCH2), 3.04 (2H, t, J = 7.8 Hz BrArCH2), and 2.19 [6H, s, Me (2x)]. 13 C NMR (125 MHz, CDCl3): d 138.0, 133.0, 131.3, 128.6, 127.9, 127.6, 124.6, 105.4, 43.5, 37.9, and 12.5. IR (neat): 3099, 3054, 3007, 2973, 2931, 2863, 1739, 1718, 1568, 1519, 1472, 1440, 1407, 1357, 1300, 1021, and 750 cm-1.
GC-MS: C14H16BrN requires 279, 277; retention time 9.08 min; found 279, 277, 198, 183, 108.
TLC: Rf = 0.56 in 5:1 hexanes:EtOAc.
7,8-Dibromo-5-methyl-4-(prop-1-yn-1-yl)-1,3,6,9-tetrahydro-6,9-epoxynaphtho[1,2- c]furan (4025)
Me
Me Br PhH Me O + O O Me Br 75 ºC O Br Br 4008 4019 4025 A solution of the tetrayne 4008 (362 mg, 2.1 mmol) and 3,4-dibromofuran133 (4019, 1.14 g, 5 mmol) in benzene (21 mL) was heated at 75 ºC for 12 h. The solvent was evaporated and the residue was purified by flash chromatography (hexanes:EtOAc = 10:1) to give 4025 as an off-white solid (428 mg, 1.1 mmol,52%).
133 Mee, S. P. H.; Lee, V.; Baldwin, J. E.; Cowley, A. Total synthesis of 5,5’,6,6’-tetrahydroxy-3,3’-biindolyl, the proposed structure of a potent antioxidant found in beetroot (Beta vulgaris). Tetrahedron 1996, 60, 3695- 3712. Part III Experimental Procedures and Computational Details 147
1 H NMR (500 MHz, CDCl3): d 5.66 (d, J = 1.3 Hz, 1H, H9), 5.51 (d, J = 1.3 Hz, 1H, H6),
5.17 (nfom, 1H, H1a), 5.07 (s, 2H, H3), 5.05 (nfom, 1H, H1b), 2.42 (s, 3H, ArCH3), and
2.10 (s, 3H, C≡CCH3).
TLC: Rf 0.37 in 5:1 hexanes:EtOAc.
Diethyl 5-methyl-4-(prop-1-yn-1-yl)-1,3,6,9-tetrahydro-6,9-epoxynaphtho[1,2- c]furan-7,8-dicarboxylate (4026)
Me
Me EtO2C PhH Me O + O O Me EtO C 75 ºC 2 O
CO2Et CO2Et 4008 4020 4026 A solution of the tetrayne 4008 (183 mg, 1.1 mmol) and diethyl furan-3,4-dicarboxylate (4020, 432 mg, 1.5 mmol) in benzene (11 mL) was heated at 75 ºC for 12 h. The solvent was evaporated and the residue was purified by flash chromatography (hexanes:EtOAc = 5:1) to give 4026 as an off-white solid (238 mg, 0.6 mmol, 54%). 1 H NMR (500 MHz, CDCl3): d 6.06 (d, J = 1.4 Hz, 1H, H9), 5.87 (d, J = 1.4 Hz, 1H, H6),
5.18 (t, J = 2.6 Hz, 1H, H1a), 5.09 (t, J = 2.2 Hz, 1H, H1b), 5.08-5.06 (nfom, 2H, H3), 4.26
(q, J = 7.1 Hz, 2H, O=CCH2aCH3a), 4.25 (q, J = 7.1 Hz, 2H, O=CCH2bCH3b), 2.48 (s, 3H,
ArCH3), 2.10 (s, 3H, C≡CCH3), 1.32 (t, J = 7.1 Hz, 3H, O=CCH2aCH3a), and 1.32 (t, J =
7.1 Hz, 3H, O=CCH2bCH3b).
(6,9-Dimethyl-3-oxo-1,3,6,9-tetrahydro-6,9-epoxynaphtho[1,2-c]furan-5-yl)methyl acetate (4027)
O O Me o-DCB OAc O O + O Me 130 ºC O OAc Me Me 4018 4021 4027 Part III Experimental Procedures and Computational Details 148
A solution of the tetrayne 4018 (20 mg, 0.1 mmol) and 2,5-dimethylfuran (4021, 258 mg, 2.7 mmol) in o-dichlorobenzene (10 mL) was heated at 130 ºC for 12 h. The reaction mixture was cooled to room temperature and purified by flash chromatography (hexanes:EtOAc = 1:1) to give 4027 as a pale yellow oil (14 mg, 0.05 mmol, 50%). 1 H NMR (500 MHz, CDCl3): d 7.63 (1H, s, ArH), 6.89 (1H, d, J = 5.3 Hz, CHa=CHb),
6.87 (1H, d, J = 5.3 Hz, CHa=CHb), 5.43 (1H, d, J = 14.8 Hz, CHaHb), 5.32 (1H, d, J = 13.1
Hz, CHa’Hb’), 5.29 (1H, d, J = 15.1 Hz, CHaHb), 5.19 (1H, d, J = 12.6 Hz, CHa’Hb’), 2.10 (3H, s, OAc), 2.06 (3H, s, Me), and 1.94 (3H, s, Me’). 13 C NMR (125 MHz, CDCl3): d 170.4, 170.0, 158.5, 148.5, 147.2, 147.0, 135.6, 130.0, 125.1, 123.6, 90.8, 87.8, 67.8, 62.4, 20.9, 17.2, and 16.0. IR (neat): 2982, 2937, 1762, 1742, 1450, 1381, 1358, 1308, 1228, 1136, 1106, 861, and 766 cm-1 + + HR ESI-MS: [C17H16NaO5] (M+Na ) requires 323.0890; found 323.0885.
TLC: Rf = 0.3 in 1:1 hexanes:EtOAc.
(6,9-Bis(methoxymethyl)-3-oxo-1,3,6,9-tetrahydro-6,9-epoxynaphtho[1,2-c]furan-5- yl)methyl acetate (4028)
O OMe O o-DCB OAc O + O O 130 ºC O OMe OAc OMe MeO 4018 4022 4028 A solution of the tetrayne 4018 (18 mg, 0.09 mmol) and 2,5-bis(methoxymethyl)furan (4022, 150 mg, 0.96 mmol) in o-dichlorobenzene (10 mL) was heated at 130 ºC for 12 h. The reaction mixture was cooled to room temperature and purified by flash chromatography (hexanes:EtOAc = 1:3) to give 4028 as a pale yellow oil (15 mg, 0.04 mmol, 44%). 1 H NMR (500 MHz, CDCl3): d 7.67 (1H, s, ArH), 7.02 (1H, d, J = 5.4 Hz, CHa=CHb),
6.91 (1H, d, J = 5.4 Hz, CHa=CHb), 5.32 (1H, d, J = 12.7 Hz, CHaHb), 5.31 (1H, d, J = 15.4
Hz, CHa’Hb’), 5.25 (1H, d, J = 15.4 Hz, CHa’Hb’), 5.17 (1H, d, J = 12.7 Hz, CHaHb), 4.41 Part III Experimental Procedures and Computational Details 149
(1H, d, J = 11.3 Hz, MeOCHaHb), 4.20 (1H, d, J = 11.3 Hz, MeOCHaHb), 4.12 (1H, d, J =
10.1 Hz, MeOCHa’Hb’), 4.11 (1H, d, J = 10.2 Hz, MeOCHa’Hb’), 3.57 (3H, s, OMe), 3.52 (3H, s, OMe’), and 2.09 (3H, s, OAc). 13 C NMR (125 MHz, CDCl3): d 170.6, 170.5, 155.4, 146.2, 145.0, 143.8, 136.8, 130.6, 125.0, 124.2, 94.1, 90.7, 70.2, 70.1, 69.2, 63.3, 59.9, 59.8, and 21.1. IR (neat): 2973, 2938, 1762, 1742, 1471, 1456, 1380, 1374, 1231, 1176, 1110, 1019, and 765 cm-1. + + HRMS (ESI-TOF): [C19H20NaO7] (M+Na ) requires 383.1101; found 383.1110.
TLC: Rf = 0.15 in 1:1 hexanes:EtOAc.
Diethyl 5-(acetoxymethyl)-3-oxo-1,3,6,9-tetrahydro-6,9-epoxynaphtho[1,2-c]furan- 7,8-dicarboxylate (4029)
O O OAc EtO2C o-DCB O O + O O 130 ºC EtO2C OAc CO2Et CO2Et 4018 4020 4029 A solution of the tetrayne 4020 (21 mg, 0.1 mmol) and diethyl furan-3,4-dicarboxylate (4022, 229 mg, 1.1 mmol) in o-dichlorobenzene (10 mL) was heated at 130 ºC for 12 h. The reaction mixture was cooled to room temperature and purified by flash chromatography (hexanes:EtOAc = 2:1) to give 4031 as an off-white solid (26 mg, 0.06 mmol, 60%). 1 H NMR (500 MHz, CDCl3): d 7.75 (1H, s, ArH), 6.32 (1H, d, J = 1.2 Hz, bridgehead
CHa), 6.07 (1H, d, J = 1 Hz, bridgehead CHb), 5.45 (1H, d, J = 15.2 Hz, CHaHb), 5.38 (1H, d, J = 13.0 Hz, CHa’Hb’), 5.34 (1H, d, J = 15.2 Hz, CHaHb), 5.27 (1H, d, J = 13.0 Hz,
CHa’Hb’), 4.281 (1H, dq, J = 10.8, 7.2 Hz, CH3CHaHbO), 4.274 (2H, q, J = 7.1 Hz,
CH3’CH2’O), 4.272 (1H, dq, J = 11.0, 7.1 Hz, CH3CHaHbO), 2.14 (3H, s, OAc), 1.34 (3H, t, J = 7.2 Hz, OCH2CH3), and 1.33 (3H, t, J = 7.1 Hz, OCH2’CH3’). 13 C NMR (125 MHz, CDCl3): d 170.6, 169.9, 162.6, 162.0, 152.5, 150.3, 150.2, 141.8, 138.0, 131.6, 125.1, 124.8, 83.8, 83.2, 68.4, 62.7, 62.21, 62.18, 21.0, 14.3, and 14.2. Part III Experimental Procedures and Computational Details 150
IR (neat): 2985, 2940, 1767, 1741, 1636, 1447, 1372, 1303, 1225, 1106, 1015, 865, and 766 cm-1. + + HRMS (ESI-TOF): [C19H20NaO7] (M+Na ) requires 439.1000; found 439.1021.
TLC: Rf = 0.4 in 1:1 hexanes:EtOAc.
(10-Benzoyl-6,9-dimethyl-3-oxo-1,3,6,9-tetrahydro-6,9-epiminonaphtho[1,2-c]furan- 5-yl)methyl acetate (4030)
O O Me OAc O o-DCB O Me O + N Ph 130 ºC N OAc Me Me Ph O 4018 4023 4030 A solution of the tetrayne 4020 (22 mg, 0.09 mmol) and (2,5-dimethyl-1H-pyrrol-1- yl)(phenyl)methanone (4025, 225 mg, 1.1 mmol) in o-dichlorobenzene (10 mL) was heated at 130 ºC for 12 h. The reaction mixture was cooled to room temperature and purified by flash chromatography (hexanes:EtOAc = 2:1) to give 4032 as a yellow solid (24 mg, 0.06 mmol, 67%). 1 H NMR (500 MHz, CDCl3): d 7.66 (1H, s, ArH), 7.48-7.52 [3H, overlapping m,
(O=C)ArHp and (O=C)ArHo], 7.37 [2H, dd, J = 8.6, 7.3 Hz, (O=C)ArHm], 6.80 (1H, d, J =
5.5 Hz, CHa=CHb), 6.78 (1H, d, J = 5.5 Hz, CHa=CHb), 5.36 (1H, d, J = 12.8 Hz, CHaHb),
5.35 (1H, d, J = 14.9 Hz, CHa’Hb’), 5.25 (1H, d, J = 14.5 Hz, CHa’Hb’), 5.22 (1H, d, J =
12.4 Hz, CHaHb), 2.09 (3H, s, OAc), 2.04 (3H, s, NCMe), and 1.74 (3H, s, NCMe’). 13 C NMR (125 MHz, CDCl3): d 174.3, 170.5, 170.0, 158.2, 148.3, 147.8 (alkene), 147.2
(alkene’), 137.4, 136.4, 132.0 [(O=C)ArCo/p], 131.2, 129.0 [(O=C)ArCo/p], 128.4
[(O=C)ArCm], 125.4 (ArCH), 123.7, 76.9, 74.1, 68.1 (CH2O), 62.7 (CH2O'), 21.1
(CH3C=O), 17.7 (NCCH3), and 16.5 (NCCH3'), (assignments deduced from HMQC data). IR (neat): 3062, 2976, 2938, 1764, 1742, 1650, 1448, 1375, 1328, 1232, 1112, 1021, and 766 cm-1. + + HRMS (ESI-TOF): [C24H21NNaO5] (M+Na ) requires 426.1312; found 426.1274. Part III Experimental Procedures and Computational Details 151
TLC: Rf = 0.36 in 1:1 hexanes/EtOAc.
(10-(2-Bromophenethyl)-6,9-dimethyl-3-oxo-1,3,6,9-tetrahydro-6,9- epiminonaphtho[1,2-c]furan-5-yl)methyl acetate (4031)
O Me OAc O O o-DCB Me N O + N 130 ºC Me Me Br OAc Br 4018 4024 4031 A solution of the tetrayne 4018 (19 mg, 0.09 mmol) and (4024, 133 mg, 0.48 mmol) in o- dichlorobenzene (10 mL) was heated at 130 ºC for 12 h. The reaction mixture was cooled to room temperature and purified by flash chromatography (EtOAc) to give 4031 as a yellow solid (23 mg, 0.05 mmol, 56%). 1 H NMR (500 MHz, CDCl3): d 7.60 [1H, s, (AcOCH2)ArH], 7.48 (1H, dd, J = 8.0, 1.2 Hz,
BrArHo), 7.20 (1H, ddd, J = 7.5, 6.9, 1.2 Hz, BrArHp), 7.18 (1H, dd, J = 7.6, 2.1 Hz,
BrArHm’), 7.04 (1H, ddd, J = 8.0, 7.0, 2.1 Hz, BrArHm), 6.77 (1H, d, J = 5.6 Hz, CHa=CHb),
6.76 (1H, d, J = 5.6 Hz, CHa=CHb), 5.41 (1H, d, J = 14.8 Hz, CHaHb), 5.29 (1H, d, J = 14.8
Hz, CHaHb), 5.27 (1H, d, J = 12.7 Hz, CHa’Hb’), 5.20 (1H, d, J = 12.7 Hz, CHa’Hb’), 2.96
(1H, ddd, J = 13.0, 10.0, 6.7 Hz, ArCHaHb), 2.94 (1H, ddd, J = 13.1, 9.9, 6.7 Hz, ArCHaHb),
2.40 (1H, ddd, J = 14.0, 9.9, 7.1 Hz, NCHaHb), 2.33 (1H, ddd, J = 13.9, 10.1, 6.9 Hz,
NCHaHb), 2.10 (3H, s, OAc), 1.98 [3H, s, CH3C(N)CArCArCH2OAc], and 1.83 [3H, s,
CH3C(N)CArCArCH2OC(O)Ar]. 13 C NMR (125 MHz, CDCl3): d 170.5 (MeC=O), 170.2 (ArC=O), 158.5
[MeC(N)CArCArCH2OAc], 148.7, 147.5 (2x, alkenes), 139.5 (BrC=CCH2), 137.9, 133.0, 132.2, 131.1 (BrC=CH), 128.2, 127.7, 125.3 (ArCH), 124.4 (BrC), 123.7, 78.8 (MeCN),
75.7 (MeC'N), 68.2 [ArCH2OC(O)Ar], 62.8 (CH2OAc), 45.3, 38.7, 21.1 (CH3C=O), 16.4
[CH3C(N)CArCArCH2OAc], and 14.9 [CH3C(N)CArCArCH2OC(O)Ar], (assignments deduced from HSQC and HMBC data). Part III Experimental Procedures and Computational Details 152
IR (neat): 2989, 2934, 2889, 2818, 1762, 1747, 1638, 1452, 1373, 1230, 1104, 1021, 868, and 768 cm-1. + + HRMS (ESI-TOF): [C25H24BrNNaO4] (M+Na ) requires 504.0781, 506.0761; found 504.0807, 506.0793.
TLC: Rf = 0.12 (EtOAc).
Part III Experimental Procedures and Computational Details 153
8.3 Procedures and Data for Chapter 5
6-(Hexa-1,5-dien-3-ylthio)-5-methyl-4-(prop-1-yn-1-yl)-1,3-dihydroisobenzofuran (5015) and 7-(Hexa-1,5-dien-3-ylthio)-5-methyl-4-(prop-1-yn-1-yl)-1,3- dihydroisobenzofuran (5015’)
Me Me
Me PhH, 75 ºC, 12 h Me O + S Me + O Me O S S
4008 5003 5015 5015' A solution of tetrayne 4008 (53 mg, 0.31 mmol) and diallyl sulfide (5003, 0.1 mL, 0.78 mmol) in benzene (3 mL) was heated at 80 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (5:1 hexanes:EtOAc as eluent). The filtrate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 10:1) to give, in order of elution, the aryl sulfides 5015’ (15 mg, 0.052 mmol, 17%) and 5015 (47 mg, 0.16 mmol, 52%), each as a yellow oil. Data for 5015’: 1 H NMR (500 MHz, CDCl3): d 7.08 (q, J = 0.8 Hz, 1H, ArH), 5.81 (ddt, J = 17.0, 10.1,
6.9 Hz, 1H, CH=CH2), 5.67 (ddd, J = 17.0, 10.1, 8.9 Hz, 1H, CH=CH2), 5.14 (m, 2H,
CH2OCH2), 5.10 (m, 2H, CH2OCH2), 5.12–5.07 (m, 2H, =CH2), 4.97 (dd, J = 10.1, 1.4 Hz,
1H, =CHZHE), 4.84 (ddd, J = 17.0, 1.0, 1.0 Hz, 1H, =CHZHE), 3.63 (ddd, J = 8.5, 8.1, 6.1
Hz, 1H, ArSCH), 2.49–2.38 (m, 2H, CH2=CHCH2), 2.38 (d, J = 0.7 Hz, 3H, ArCH3), and
2.11 (s, 3H, C≡CCH3). 13 C NMR (125 MHz, CDCl3): d 142.0, 139.6, 139.0, 137.7, 134.7, 132.4, 126.7, 117.4, 116.4, 116.2, 94.2, 75.6, 74.8, 74.4, 51.5, 38.7, 19.9, and 4.6. IR (neat): 3078, 2916, 2851, 2232, 1434, 1260, 1089, 1056, 1027, 915, and 798 cm-1. HRMS (ESI-TOF): In our hands 5015' did not ionize well in the ESI analysis. A small sample of 5015' in DCM was doped with an excess of mCPBA; after 15 min, this solution was concentrated in vacuo and the residue was dissolved MeOH and analyzed for the Part III Experimental Procedures and Computational Details 154
+ + presence of the sulfone derivative: Calcd for [C18H20NaO3S] [(M+Na) ]: 339.1031, found 339.1002.
TLC : Rf 0.3 in 10:1 hexanes:EtOAc. Data for 5015: 1 H NMR (500 MHz, CDCl3): d 7.19 (s, 1H, ArH), 5.83 (ddt, J = 17.0, 10.1, 6.9 Hz, 1H, ),
5.67 (ddd, J = 17.0, 10.1, 8.9 Hz, 1H, ), 5.13-5.07 (overlapping m's, 6H, CH2OCH2, =CH2),
4.94 (dd, J = 10.1, 1.4 Hz, 1H, =CHZHE), 4.84 (ddd, J = 17.0, 1.0 Hz, 1H, =CHZHE), 3.54
(ddd, J = 8.3, 8.3, 6.0 Hz, 1H, ArSCH), 2.54 (s, 3H, ArCH3), 2.49–2.38 (m, 2H,
CH2=CHCH2), and 2.11 (s, 3H, C≡CCH3). 13 C NMR (125 MHz, CDCl3): d 141.5, 141.3, 137.8, 136.3, 134.9, 133.0, 125.6, 118.1, 117.3, 116.1, 93.8, 76.0, 74.1, 73.9, 51.9, 38.7, 18.8, and 4.6. IR (neat): 3078, 3004, 2918, 2857, 2845, 2232, 1769, 1436, 1414, 1358, 1056, 1033, 991, 916, and 764 cm-1. + + HRMS (ESI-TOF): Calcd for [C18H20NaOS] (M+Na ): 307.1133, found 307.1110. A similar derivatization reaction as described above for 5015' also gave the sulfone derived + + from 5015: Calcd for [C18H20NaO3S] (M+Na ): 339.1031, found 339.1018.
TLC : Rf 0.26 in 10:1 hexanes:EtOAc.
6-((1,2-Diphenylethyl)thio)-5-methyl-4-(prop-1-yn-1-yl)-1,3-dihydroisobenzofuran (5019) and 7-((1,2-Diphenylethyl)thio)-5-methyl-4-(prop-1-yn-1-yl)-1,3- dihydroisobenzofuran (5019’)
Me Me
Me PhH, 75 ºC, 12 h Me O + Ph S Ph + Me Ph O Me O S S Ph Ph Ph 4008 5016 5019 5019' A solution of tetrayne 4008 (50 mg, 0.30 mmol) and dibenzyl sulfide (5016, 214 mg, 0.73 mmol) in benzene (3 mL) was heated at 80 ºC for 12 h. The solvent was evaporated and Part III Experimental Procedures and Computational Details 155 the residue was passed through a plug of silica gel (5:1 hexanes:EtOAc as eluent). The filtrate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 20:1) to give, in order of elution, the aryl sulfides 5019’ (5 mg, 0.014 mmol, 5%) and 5019 (29 mg, 0.076 mmol, 25%), each as a yellow oil. Data for 5019’: 1 H NMR (500 MHz, CDCl3): d 7.25–7.14 (m, 8H, ArH8), 7.03-7.01 (m, 2H, ArH2), 6.92
(q, J = 0.8 Hz, 1H, ArH), 5.12-5.05 (m, 2H, CHa2OCHb2), 4.93 (br d, J = 12.5 Hz, 1H,
CHbHb’OCHa2), 4.82 (br d, J = 12.5 Hz, 1H, CHb’HbOCHa2), 4.31 (dd J = 8.5, 6.6 Hz, 1H,
PhCH2CH), 3.24 (dd, J = 13.9, 6.6 Hz, 1H, PhCHaHbCH), 3.21 (dd, J = 13.9, 8.4 Hz, 1H,
PhCHbHaCH), 2.30 (d, J = 0.8 Hz, 3H, ArCH3), and 2.09 (s, 3H, C≡CCH3). 13 C NMR (125 MHz, CDCl3): d 141.9, 141.1, 139.7, 138.8, 138.5, 132.0, 129.1, 128.3, 128.2, 127.8, 127.4, 127.0, 126.5, 116.3, 94.2, 75.6, 74.6, 74.2, 54.9, 42.7, 19.9, and 4.6. IR (neat): 3024, 2980, 2939, 2921, 2863, 2844, 2232, 1770, 1698, 1600, 1494, 1453, 1359, 1312, 1055, 1033, 899, and 761 cm-1. HRMS (ESI-TOF): A similar derivatization reaction as described above for 5015' gave the + + more readily ionizable sulfone derived from 5019’: Calcd for [C26H24NaO3S] (M+Na ): 439.1344, found 439.1347.
TLC: Rf 0.3 in 5:1 hexanes:EtOAc. Data for 5019: 1 H NMR (500 MHz, CDCl3): d 7.23–7.13 (m, 8H, ArH8), 7.02-7.00 (m, 2H, ArH2), 6.97
(s 1H, ArH), 5.05 (br s, 2H, CHa2OCHb2), 4.97 (br s, 2H, CHb2OCHa2), 4.22 (dd J = 8.3,
6.8 Hz, 1H, PhCH2CH), 3.23 (dd, J = 13.9, 6.8 Hz, 1H, PhCHaHbCH), 3.20 (dd, J = 13.9,
8.3 Hz, 1H, PhCHbHaCH), 2.42 (s, 3H, ArCH3), and 2.09 (s, 3H, C≡CCH3). 13 C NMR (125 MHz, CDCl3): d 141.4, 141.2, 141.0, 138.7, 136.3, 133.4, 129.1, 128.3, 128.2, 127.9, 127.2, 126.4, 125.1, 118.0, 93.8, 76.0, 74.0, 73.9, 55.2, 42.7, 18.4, and 4.6. IR (neat): 3024, 2980, 2940, 2920, 2862, 2844, 2231, 1600, 1494, 1453, 1358, 1313, 1265, 1055, 1032, 1014, 901, and 763 cm-1. Part III Experimental Procedures and Computational Details 156
HRMS (ESI-TOF): A similar derivatization reaction as described above for 5015' gave the + + more readily ionizable sulfone derived from 5019: Calcd for [C26H24NaO3S] (M+Na ): 439.1344, found 439.1342.
TLC: Rf 0.2 in 5:1 hexanes:EtOAc.
Di(prop-2-yn-1-yl)sulfane (Dipropargyl sulfide 5020)
MeOH Br S + Na2S • 9H2O
Propargyl bromide (80 wt% in toluene, 12.5 mL, 112 mmol) was added dropwise to a solution of Na2S•9H2O (12.37 g, 52 mmol) in CH3OH (100 mL) at 0 ºC. The reaction mixture was stirred at room temperature for 1 h and the solvent was evaporated. The residue was treated with water (100 mL) and the resulting mixture was extracted with Et2O (3x50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide a yellow liquid. The crude product was further purified by vacuum distallation to give titled compound as a colorless liquid (2.49 g, 23 mmol, 46%). 1H NMR (500 MHz, CDCl3): d 3.44 (d, J = 2.6 Hz, 4H, SCH2C≡CH), 2.26 (t, J = 2.6 Hz, 2H, SCH2C≡CH). 13C NMR (125 MHz, CDCl3): d 79.0, 71.4, and 18.8.
6-(Hexa-4,5-dien-1-yn-3-ylthio)-5-methyl-4-(prop-1-yn-1-yl)-1,3- dihydroisobenzofuran (5023) and 7-(Hexa-4,5-dien-1-yn-3-ylthio)-5-methyl-4-(prop- 1-yn-1-yl)-1,3-dihydroisobenzofuran (5023’) Part III Experimental Procedures and Computational Details 157
Me
Me
Me PhH, 75 ºC, 12 h Me O + + O S Me ● Me O S S ● 4008 5020 5023 5023'
A solution of tetrayne 4008 (307 mg, 1.81 mmol) and dipropargyl sulfide (5020, 244 mg, 2.22 mmol) in benzene (18 mL) was heated at 80 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (3:1 hexanes:EtOAc as eluent). The filtrate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 15:1) to give, in order of elution, the aryl sulfides 5023’ (50 mg, 0.18 mmol, 10%) and 5023 (198 mg, 0.70 mmol, 39%), each as a yellow solid. Data for 5023’: 1 H NMR (500 MHz, CDCl3): d 7.25 (s, 1H, ArH), 5.26 (dd, J = 13.8, 6.7 Hz, 1H,
CH2=C=CH), 5.18 (br t, J = 2.3 Hz, 2H, CHa2OCHb2), 5.16 (br t, J = 2.4 Hz, 2H,
CHb2OCHa2), 4.84 (ddd, J = 11.4, 6.6, 2.2 Hz, 1H, C=CHaHb), 4.79 (ddd, J = 11.4, 6.5, 2.3
Hz, 1H, C= CHbHa), 4.38 (dq J = 7.4, 2.5 Hz, 1H, ArSCH), 2.46 (d, J = 2.6 Hz, 1H, C≡CH),
2.40 (s, 3H, ArCH3), and 2.12 (s, 3H, C≡CCH3). 13 C NMR (125 MHz, CDCl3): d 208.7, 142.2, 140.1, 139.8, 133.8, 124.8, 117.7, 94.8, 89.8, 80.8, 78.5, 75.5, 74.8, 74.5, 73.6, 37.9, 20.0, and 4.6. IR (neat): 3290, 2946, 2914, 2850, 2232, 1951, 1595, 1463, 1434, 1378, 1360, 1055, 898, and 851 cm-1. HRMS (ESI-TOF): A similar derivatization reaction as described above for 5015' gave the + more readily ionizable epoxy sulfone derived from 5023’: Calcd for [C18H16NaO4S] (M+Na+): 351.0667, found 351.0665.
TLC: Rf 0.3 in 10:1 hexanes:EtOAc. mp: 75-81 °C. Data for 5023: 1 H NMR (500 MHz, CDCl3): d 7.35 (s, 1H, ArH), 5.26 (dd, J = 13.9, 6.7 Hz, 1H,
CH2=C=CH), 5.12 (br t, J = 2.3 Hz, 2H, CHa2OCHb2), 5.16 (br t, J = 2.4 Hz, 2H, Part III Experimental Procedures and Computational Details 158
CHb2OCHa2), 4.83 (ddd, J = 11.3, 6.5, 2.2 Hz, 1H, C=CHaHb), 4.76 (ddd, J = 11.3, 6.5, 2.3
Hz, 1H, C= CHbHa), 4.32 (dq J = 7.2, 2.3 Hz, 1H, ArSCH), 2.59 (s, 3H, ArCH3), 2.45 (d,
J = 2.5 Hz, 1H, C≡CH), and 2.12 (s, 3H, C≡CCH3). 13 C NMR (125 MHz, CDCl3): d 208.6, 142.6, 142.2, 136.5, 131.6, 126.6, 118.3, 94.1, 89.7, 80.9, 78.3, 75.9, 74.1, 74.0, 73.5, 38.1, 18.8, and 4.6. IR (neat): 3293, 2915, 2855, 2232, 1951, 1682, 1578, 1523, 1432, 1411, 1376, 1358, 1314, 1266, 1054, 899, and 853 cm-1. HRMS (ESI-TOF): A similar derivatization reaction as described above for 5015' gave the + more readily ionizable epoxy sulfone derived from 5023: Calcd for [C18H16NaO4S] (M+Na+): 351.0667, found 351.0665.
TLC: Rf 0.23 in 10:1 hexanes:EtOAc. mp: 70-82 °C.
Methyl 2-((6-Methyl-7-(prop-1-yn-1-yl)-1,3-dihydroisobenzofuran-5-yl)thio)penta- 3,4-dienoate (5027) and Methyl 2-((6-Methyl-7-(prop-1-yn-1-yl)-1,3- dihydroisobenzofuran-4-yl)thio)penta-3,4-dienoate (5027’)
Me Me
Me PhH, 75 ºC, 12 h Me O + S CO Me + 2 Me ● O Me O S S CO2Me ●
CO2Me 4008 5024 5027 5027' A solution of tetrayne 4008 (52 mg, 0.30 mmol) and methyl (propargylthio)acetate (5024 103 mg, 0.72 mmol) in benzene (3 mL) was heated at 80 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (5:1 hexanes:EtOAc as eluent). The filtrate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 10:1) to give, in order of elution, the aryl sulfides 5027’ (12 mg, 0.037 mmol, 12%) and 5027 (59 mg, 0.19 mmol, 63%), each as a yellow oil. Data for 5027’: Part III Experimental Procedures and Computational Details 159
1 H NMR (500 MHz, CDCl3): d 7.16 (q, J = 0.8 Hz, 1H, ArH), 5.35 (dt, J = 9.2, 6.6 Hz,
1H, CH2=C=CH), 5.16–5.13 (m, 4H, CH2OCH2), 4.85 (ddd, J = 11.6, 6.6, 1.5 Hz, 1H,
C=CHaHb), 4.76 (ddd, J = 11.6, 6.6, 1.5 Hz, 1H, C= CHbHa), 4.30 (dt, J = 9.2, 1.5 Hz, 1H,
ArSCH), 3.71 (s, 3H, CO2CH3), 2.39 (d, J = 0.7 Hz, 3H, ArCH3), and 2.12 (s, 3H, C≡CCH3). 13 C NMR (125 MHz, CDCl3): d 209.1, 170.1, 142.3, 140.0, 133.6, 124.4, 117.8, 95.0, 87.2, 77.6, 75.5, 74.8, 74.4, 52.7, 50.3, 20.0, and 4.6. IR (neat): 3004, 2980, 2950, 2921, 2864, 2844, 2232, 1953, 1736, 1463, 1435, 1358, 1276, 1195, 1152, 1055, 1033, 1015, 899, 850, and 759 cm-1. + + HRMS (ESI-TOF): Calcd for [C18H18NaO3S] [(M+Na) ]: 337.0874, found 337.0866.
TLC: Rf 0.21 in 5:1 hexanes:EtOAc. Data for 5027: 1 H NMR (500 MHz, CDCl3): d 7.27 (s, 1H, ArH), 5.36 (dt, J = 9.3, 6.6 Hz, 1H,
CH2=C=CH), 5.11 (br t, J = 2.2 Hz, 2H, CHa2OCHb2), 5.09–5.08 (m, 2H, CHb2OCHa2),
4.83 (ddd, J = 11.5, 6.6, 1.4 Hz, 1H, C=CHaHb), 4.73 (ddd, J = 11.5, 6.6, 1.5 Hz, 1H,
C=CHbHa), 4.22 (dt, J = 9.3, 1.5 Hz, 1H, ArSCH), 3.69 (s, 3H, CO2CH3), 2.58 (s, 3H,
ArCH3), and 2.11 (s, 3H, C≡CCH3). 13 C NMR (125 MHz, CDCl3): d 209.0, 170.2, 142.9, 142.3, 136.6, 131.2, 126.7, 118.4, 94.2, 87.0, 77.4, 75.8, 74.0, 73.9, 52.6, 50.5, 18.7, and 4.6. IR (neat): 3004, 2981, 2950, 2921, 2864, 2844, 2232, 1953, 1736, 1454, 1435, 1357, 1276, 1193, 1152, 1055, 1033, 1014, 901, 852, and 763 cm-1. + + HRMS (ESI-TOF): Calcd for [C18H18NaO3S] [(M+Na) ]: 337.0874, found 337.0903.
TLC: Rf 0.2 in 5:1 hexanes:EtOAc.
5-Methyl-6-(phenylthio)-4-(prop-1-yn-1-yl)-1,3-dihydroisobenzofuran (5040) and 5- Methyl-7-(phenylthio)-4-(prop-1-yn-1-yl)-1,3-dihydroisobenzofuran (5040 ’) Part III Experimental Procedures and Computational Details 160
Me Me
Me PhSCH , HOAc 3 Me Me O O + O Me PhH, 75 ºC, 12 h Ph S S Ph 4008 5040 5040' A solution of tetrayne 4008 (51 mg, 0.30 mmol), thioanisole (5036, 75 mg, 0.60 mmol), and acetic acid (28 mg, 0.47 mmol) in benzene (3 mL) was heated at 75 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (5:1 hexanes:EtOAc as eluent). The filtrate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc 20:1) to give, in order of elution, the aryl sulfides 5040’ (10 mg, 0.036 mmol, 12%) and 5040 (55 mg, 0.20 mmol, 67%), each as an off-white solid. Data for 5040’: 1 H NMR (500 MHz, CDCl3): d 7.30–7.12 (m, 5H, PhH5), 7.04 (q, J = 0.8 Hz, 1H, ArH),
5.14 (br t, 2H, J = 2.2 Hz, CHa2OCHb2), 4.93 (br t, J = 1.5 Hz, 2H, CHb2OCHa2), 2.36 (d,
J = 0.7 Hz, 3H, ArCH3), and 2.11 (s, 3H, C≡CCH3). 13 C NMR (125 MHz, CDCl3): d 142.7, 140.2, 138.2, 134.7, 131.6, 130.2, 129.2, 127.0, 127.0, 116.9, 94.5, 75.5, 74.6, 74.0, 19.9, and 4.6. IR (neat): 3005, 2981, 2938, 2921, 2864, 2844, 2232, 1771, 1581, 1471, 1439, 1360, 1312, 1056, 1033, 1015, and 899 cm-1. HRMS (ESI-TOF): A similar derivatization reaction as described above for 5015' gave the + + more ionizable sulfone derived from 5040: Calcd for [C18H16NaO3S] (M+Na ): 335.0718, found 335.0718.
TLC: Rf 0.4 in 10:1 hexanes:EtOAc. mp: 102-106 ºC. Data for 5040: 1 H NMR (500 MHz, CDCl3): d 7.29–7.25 (m, 2H, ArHm2), 7.22–7.16 (m, 3H, ArHo2+Hp),
7.10 (s, 1H, ArH), 5.12 (br t, 2H, J = 2.2 Hz, CHa2OCHb2), 5.04 (br s, 2H, CHb2OCHa2),
2.49 (s, 3H, ArCH3), and 2.11 (s, 3H, C≡CCH3). 13 C NMR (125 MHz, CDCl3): d 142.0, 140.7, 137.0, 136.1, 133.0, 129.4, 129.2, 126.4, 124.8, 118.6, 94.2, 75.8, 74.0 ,73.9, 18.3, and 4.5. Part III Experimental Procedures and Computational Details 161
IR (neat): 3005, 2917, 2862, 2844, 2234, 1769, 1580, 1476, 1439, 1376, 1356, 1307, 1264, 1175, 1054, 1033, 1023, and 902 cm-1. HRMS (ESI-TOF): A similar derivatization reaction as described above for 5015' gave the + + more ionizable sulfone derived from 5040: Calcd for [C18H16NaO3S] (M+Na ): 335.0718, found 335.0712.
TLC: Rf 0.2 in 10:1 hexanes:EtOAc. mp: 64-67 °C.
N,N-Di(hexa-2,4-diyn-1-yl) methanesulfonamide (5028)
H CuCl, NH2OH•HCl Me Ms N + Br Me Ms N H BuNH2-H2O-DCM-hexanes Me S5002 S4001 5028 Copper (I) chloride (115 mg, 1.17 mmol) and hydroxylamine hydrochloride (409 mg, 5.84 mmol) were added to a 250 mL 3-neck RBF equipped with a magnetic stir bar, and two addition funnels. The reaction vessel was placed under a nitrogen atmosphere and 40 % (v/v) aqueous butylamine was added and the mixture was cooled to 0 °C. N,N-Dipropargyl methanesulfonamide (S5002,134 2.0 g, 11.7 mmol) in DCM (59 mL) was placed into one addition funnel, and bromopropyne in hexane (1.4 M, 33.4 mL, 46.7 mmol) into the other. The solution of diyne was added dropwise, after approximately 10 % had been added (~6 mL), bromopropyne addition was begun; it was added at approximately the same rate as the diyne until addition of both reactants was complete. The mixture was allowed to warm to room temperature. After 40 minutes the reaction was judged to be complete by TLC (3:1
Hexane:EtOAc). The mixture was quenched by the addition of saturated aqueous NH4Cl (50 mL) and extracted with DCM (50 mL). The combined organic layers were washed with
NH4Cl (50 mL, 1x) and brine (50 mL, 1x), dried (MgSO4), and concentrated to give crude product as an off-white solid. The crude product was purified by column chromatography
134 This compound was prepared in excellent yield by propargylation of methanesulfonamide in acetonitrile promoted by K2CO3 as the base. It was generously provided by Mr. Sean Ross of the Hoye group. Part III Experimental Procedures and Computational Details 162
(3:1 Hex:EtOAc to 2:1 Hex:EtOAc) to yield 5028 as a white crystalline solid (2.69 g, 10.9 mmol, 93%). 1 H NMR (500 MHz, CDCl3): d 4.21 (s, 4H), 2.96 (s, 3H), and 1.94 (s, 6H). 13 C NMR (125 MHz, CDCl3): d 77.3, 71.6, 67.8, 63.6, 38.8, 37.6, and 4.4. IR (neat): 2260, 1430, 1345, 1329, 1154, 1073, 965, 948, 893, and 781 cm-1. + + HRMS (ESI-TOF): Calcd for C13H13NNaO2S [M+Na ] requires 270.0559; found 270.0553. mp: 99-101 °C.
N-(2-Methylhepta-3,5-diyn-2-yl)-3-(trimethylsilyl)propiolamide (5070) via 2- methylhepta-3,5-diyn-2-amine (S5003)
O CuCl TMSC≡CCO2H H N H N TMS 2 NH2OH•HCl 2 S4012 Me HN Me Me Me BuNH2-H2O- Me i Me ClCO2 Bu, N-Memorpholine Me CH2Cl2-MeOH Me S5003 5070 A 100 mL round bottom flask fitted with a magnetic stir bar and a pressure equalizing dropping funnel attached to a N2 inlet was charged with CuCl (160 mg, 1.6 mmol) and
NH2OH•HCl (500 mg, 7.2 mmol). The system was evacuated and backfilled with N2 (3x) and placed in an ice bath. Aqueous BuNH2 solution (30 mL, 30 wt%) was added to form a colorless solution, which was further stirred at 0 ºC for 30 min. The dropping funnel was charged with a solution of 2-methylbut-3-yn-2-amine (1.25 g, 15 mmol) and 1- bromopropyne [ca. 36 wt% in hexanes, 6 g, which contained ca. 2.2 g (18 mmol) of bromopropyne] in a 1:1 (v:v) mixture of MeOH-CH2Cl2 (25 mL). This solution was added dropwise to the reaction mixture. The resulting mixture was allowed to stir in the ice bath for 1 h after the addition was finished. Brine (25 mL) and water (25 mL) was then added, and the ice bath was removed. The mixture was poured into a separatory funnel, and the organic layer was drained. The aqueous layer was extracted with CH2Cl2 (3x15 mL). The combined organic layers were washed with water (5x25 mL), brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (Et2O:MeOH = 1:1) to yield diyne S5003 as a yellow oil (1.43 g, 11.8 Part III Experimental Procedures and Computational Details 163
1 mmol, 79%). H NMR (500 MHz, CDCl3): d 1.93 [s, 3H, N(C≡C)2CH3], 1.90–1.60 (br s, 13 2H, NH2), and 1.40 [s, 6H, C(CH3)2C≡C]. C NMR (125 MHz, CDCl3): d 82.8, 76.3, 65.3, 63.9, 45.6, 31.3, and 4.2. IR (neat): 2959, 2929, 2871, 2260, 1728, 1598, 1462, 1381, 1275, -1 1261, 1158, and 750 cm . TLC: Rf 0.2 in 1:3 hexanes:EtOAc. To a solution of 3-(trimethylsilyl)propiolic acid (S4012, 325 mg, 2.28 mmol) and N- methylmorpholine (0.88 mL, 8.0 mmol) in THF (20 mL) was added isobutyl chloroformate (0.3 mL, 2.3 mmol) dropwise at 0 ºC. After stirring at 0 ºC for 30 min, a solution of diyne S5003 (241 mg, 2.0 mmol) in THF (10 mL) was added dropwise, and the reaction mixture was allowed to warm to room temperature and continue to stir for 3 h. The reaction mixture was quenched with satd. NH4Cl (25 mL) and the organic layer was separated. The aqueous layer was extracted with Et2O (3x10 mL), and the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (hexanes:EtOAc = 5:1) to provide triyne ester 5070 as a yellow solid (345 mg, 1.4 mmol, 70%). 1 H NMR (500 MHz, CDCl3): d 5.89 (br s, 1H, (O=C)NH), 1.92 (s, 3H, C≡CCH3), 1.65 (s,
6H, NC(CH3)2), and 0.22 [s, 9H, Si(CH3)3]. 13 C NMR (125 MHz, CDCl3): d 151.4, 97.8, 90.5, 77.1, 67.0, 63.6, 49.1, 28.5, 4.2, and - 0.7 (one alkyne C not observed). IR (neat): 3350-3100, 2963, 2917, 2900, 2875, 2257, 2165, 1657, 1638, 1531, 1451, 1384, 1362, 1285, 1252, 1186, 1158, 1089. 1024, 994, 934, 846, and 760 cm-1. + + HRMS (ESI-TOF): Calcd for [C14H19NNaOSi] [(M+Na) ] 268.1134, found 268.1130.
TLC: Rf 0.2 in 5:1 hexanes:EtOAc. mp: 66-70 ºC.
N-(Penta-2,4-diyn-1-yl)-N-phenyl-3-(trimethylsilyl)propiolamide (5071)
PhHN Ph O N BrC≡CCMe2OH TMSC≡CCO2H S5005 NaOH PhHN PhHN S4015 OH Cadiot- toluene DCC, DMAP Chadkiewicz TMS S5004 S5006 S5007 5071 Part III Experimental Procedures and Computational Details 164
2-Methyl-7-(phenylamino)hepta-3,5-diyn-2-ol (S5004)
Me CuCl, NH2OH•HCl PhHN PhHN Me + Br OH OH Me BuNH2-H2O-DCM-hexanes Me S5004 S5005 S5006 A 100 mL round bottom flask fitted with a magnetic stir bar and a pressure equalizing dropping funnel attached to a N2 inlet was charged with CuCl (102 mg, 1.0 mmol) and
NH2OH•HCl (696 mg, 10 mmol). The system was evacuated and backfilled with N2 (3x) and placed in an ice bath. An aqueous BuNH2 solution (20 mL, 30 wt%) was added to form a colorless solution, which was further stirred at 0 ºC for 30 min. The dropping funnel was charged with a solution of N-propargyl aniline135 (S5004, 1.37 g, 10.4 mmol) and 4-bromo- 136 2-methylbut-3-yn-2-ol (S5005, 1.71 g, 10.5 mmol) in CH2Cl2 (20 mL), and this solution was added dropwise to the reaction mixture. The resulting mixture was allowed to stir in the ice bath for 30 min after the addition was finished. Saturated aqueous NH4Cl solution (30 mL) was added, and the ice bath was removed. The mixture was poured into a separatory funnel, and the organic layer was drained. The blue aqueous layer was extracted with CH2Cl2 (3x10 mL). The combined organic layers were washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo to afford the crude product as a brown oil. This material was purified by flash chromatography (hexanes:EtOAc = 2:1) to yield diyne S5006 as a yellow oil (1.98 g, 9.3 mmol, 89%). 1 H NMR (500 MHz, CDCl3): d 7.25-7.20 (nfom, 2H, NArHm2), 6.80 (tt, J = 7.3, 1.0 Hz,
1H, NArHp), 6.70-6.66 (nfom, 2H, NArHo2), 4.02 (s, 2H, NCH2C≡C), 3.88 (br s, 1H,
ArNH), 1.95 (br s, 1H, OH), and 1.50 (s, 6H, C≡CC(CH3)2OH). 13 C NMR (125 MHz, CDCl3): d 146.5, 129.3, 118.8, 113.6, 82.1, 77.5, 67.0, 66.8, 65.5, 34.2, and 31.1. IR (neat): 3400–3100, 2984, 2932, 2246, 1603, 1504, 1438, 1314, 1274, 1259, 1149, 957, 911, and 750 cm-1. + + HRMS (ESI-TOF): Calcd for Calcd for [C14H16NO] [(M+H) ] 214.1232, found 214.1229.
135 Chen, Y.; Dubrovskiy, A.; Larock, R. C. Org. Synth. 2012, 89, 294–306. 136 Marino, J. P.; Nguyen, H. N. J. Org. Chem. 2002, 67, 6841–6844. Part III Experimental Procedures and Computational Details 165
TLC: Rf 0.2 in 2:1 hexanes:EtOAc. N-(Penta-2,4-diyn-1-yl)aniline (5071)
O TMSC≡CCO2H TMS PhHN Me NaOH S4012 PhHN PhN OH H Me toluene, 110 ºC DCC, DMAP S5006 S5007 5071 A solution of diyne S5006 (1.93 g, 9.1 mmol) in toluene (45 mL) was heated in the presence of powdered NaOH (0.48 g, 12 mmol) at 110 ºC. The reaction progress was monitored until all of the starting material was consumed (ca. 90 min). The reaction mixture was cooled to room temperature and poured into H2O (100 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (hexanes:EtOAc = 15:1) to give terminal diyne S5007 as a brown oil (1.0 g, 6.5 mmol, 71%). 1 H NMR (500 MHz, CDCl3): d 7.25-7.20 (nfom, 2H, NArHm2), 6.80 (tt, J = 7.4, 1.1 Hz,
1H, NArHp), 6.69-6.66 (nfom, 2H, NArHo2), 4.00 (d, J = 1.0 Hz, 2H, NCH2C≡C), 3.88 (br s, 1H, ArNH), and 2.06 (d, J = 1.1 Hz, 1H, C≡CH). 13 C NMR (125 MHz, CDCl3): d 146.5, 129.3, 118.9, 113.6, 74.2, 67.8, 67.4, 66.8, and 34.1. IR (neat): 3463–3342, 3283, 3052, 3023, 2917, 2273, 2061, 1602, 1503, 1437, 1349, 1314, -1 1257, 1181, 1091, 1062, and 752 cm . TLC: Rf 0.2 in 10:1 hexanes:EtOAc.
A solution of 3-(trimethylsilyl)propiolic acid (S4015, 1.28 g, 9.0 mmol) in CH2Cl2 (15 mL) was cooled at 0 ºC in an ice bath. DMAP (74 mg, 0.61 mmol) was added, followed by dropwise addition of a solution of diyne S5007 (0.91 g, 5.9 mmol) in CH2Cl2 (15 mL). A dark green solution formed. DCC (1.52 g, 7.4 mmol) was then added in one portion, and the reaction mixture immediately turned to an orange suspension. The reaction mixture was stirred at 0 ºC for 3 h and then diluted with EtOAc (30 mL). The precipitate was removed by vacuum filtration, and the dark brown filtrate was concentrated in vacuo. The residue was purified by flash chromatography (hexanes:EtOAc = 15:1, then hexanes:EtOAc = 8:1) to give the triyne amide 5071 as a dark brown oil (0.66 g, 2.4 mmol, 41%). Part III Experimental Procedures and Computational Details 166
1 H NMR (500 MHz, CDCl3): d 7.45-7.40 (nfom, 3H, NArHm2+Hp), 7.36-7.34 (nfom, 2H,
NArHo2), 4.58 (d, J = 1.1 Hz, 2H, NCH2C≡C), 2.09 (t, J = 1.1 Hz, 1H, C≡CH), and –0.03
(s, 9H, Si(CH3)3). 13 C NMR (125 MHz, CDCl3): d 153.1, 140.7, 129.2, 128.7, 128.4, 99.7, 95.8, 71.1, 68.5, 67.6, 67.3, 38.2, and -1.1. IR (neat): 3285, 3238, 3005, 2980, 2966, 2922, 2865, 2844, 2826, 2166, 1638, 1594, 1493, 1346, 1379, 1277, 1252, 1220, 1055, 1033, 1016, 893, 846, and 759 cm-1. + + HRMS (ESI-TOF): Calcd for [C17H17NNaOSi] [(M+Na) ] 302.0977, found 302.0979.
TLC: Rf 0.2 in 5:1 hexanes:EtOAc.
Methyl 2-cyano-5-((2-methyl-9-oxo-1-(trimethylsilyl)-9H-fluoren-3- yl)thio)pentanoate (5079) and Methyl 2-cyano-5-((2-methyl-9-oxo-1-(trimethylsilyl)- 9H-fluoren-4-yl)thio)pentanoate (5079’)
TMS TMS O O O Me TMS CN PhH Me CN + + + S CO Me 90 ºC, 12 h CO2Me CN Me 2 S S CO2Me 4009 5079 5079' A solution of benzoyl linked triyne 4009 (67 mg, 0.25 mmol), thietane (60 µL, 0.83 mmol), and methyl cyanoacetate (150 mg, 1.5 mmol) in benzene (2.5 mL) was heated to 90 ºC (external bath temperature) in a vial that was sealed with a teflon-lined screw-cap. After 12 h the reaction mixture was concentrated and passed through a plug of silica gel (hexanes:EtOAc = 1:1 as eluent). The filtrate was concentrated and the residue was purified by MPLC (hexanes:EtOAc = 3:1) to provide, in order of elution, the fluorenonyl sulfides 5079’ (11 mg, 0.025 mmol, 10%) and 5079 (73 mg, 0.17 mmol, 67%), each as a yellow solid. Data for 5079’: 1 H NMR (500 MHz, CDCl3): d 8.21 (ddd, J = 7.6, 0.9, 0.9 Hz, 1H, H5), 7.61 (ddd, J = 7.3, 1.3, 0.7 Hz, 1H, H8), 7.48 (ddd, J = 7.6, 7.6, 1.3 Hz, 1H, H6), 7.26 (ddd, J = 7.4, 7.4, 0.8
Hz, 1H, H7), 7.13 (s, 1H, H3), 3.80 (s, 3H, CO2CH3), 3.54 (dd, J = 8.0, 5.9 Hz, Part III Experimental Procedures and Computational Details 167
NCCHCO2Me), 3.06 (t, J = 7.0 Hz, ArSCH2), 2.46 (s, 3H, ArCH3), 2.23–2.09 (m, 2H,
ArSCH2CH2CH2), 1.98–1.87 (m, 2H, ArSCH2CH2), and 0.41 (s, 9H, ArSi(CH3)3). 13 C NMR (125 MHz, CDCl3): d 194.9, 166.2, 145.4, 144.0, 141.6, 141.4, 136.3, 134.6, 134.1, 133.7, 132.2, 128.9, 128.3, 124.2, 123.7, 53.6, 36.9, 32.5, 28.7, 26.1, 25.2, and 2.6. IR (neat): 2981, 2954, 2897, 2252, 1748, 1708, 1605, 1449, 1438, 1247, 1192, 976, 907, 845, and 965 cm-1. + + HRMS (ESI-TOF): Calcd for [C24H27NNaO3SSi] [(M+Na) ] 460.1369, found 460.1392.
TLC: Rf 0.2 in 3:1 hexanes:EtOAc. mp: 65-68 ºC. Data for 5079: 1 H NMR (500 MHz, CDCl3): d 7.56 (ddd, J = 7.3, 0.9, 0.9 Hz, 1H, H8), 7.48 (ddd, J = 7.4, 0.9, 0.9 Hz, 1H, H5), 7.44 (ddd, J = 7.4, 7.4, 1.0 Hz, 1H, H6), 7.32 (s, 1H, H4), 7.26 (ddd,
J = 7.3, 7.3, 0.9 Hz, H7) 3.82 (s, 3H, CO2CH3), 3.60 (dd, J = 7.9, 5.9 Hz, NCCHCO2Me),
3.08 (t, J = 7.1 Hz, ArSCH2), 2.47 (s, 3H, ArCH3), 2.26–2.13 (m, 2H, ArSCH2CH2CH2),
2.05–1.92 (m, 2H, ArSCH2CH2), and 0.43 (s, 9H, ArSi(CH3)3). 13 C NMR (125 MHz, CDCl3): d 194.6, 166.2, 143.8, 143.4, 143.1, 142.6, 142.4, 137.0, 134.2, 134.1, 128.9, 123.8, 119.3, 117.5, 116.0, 53.7, 36.9, 31.4, 28.8, 25.8, 21.7, and 2.6. IR (neat): 3005, 2950, 2923, 2867, 2844, 2250, 1748, 1702, 1605, 1575, 1437, 1247, 1059, 1033, 1016, 847, and 764 cm-1. + + HRMS (ESI-TOF): Calcd for [C24H27NNaO3SSi] [(M+Na) ] 460.1369, found 460.1373.
TLC: Rf 0.15 in 3:1 hexanes:EtOAc. mp: 103-107 ºC.
(Z)-3-((4-Acetyl-5-hydroxyhex-4-en-1-yl)thio)-2-methyl-1-(trimethylsilyl)-9H- fluoren-9-one (5080) and (Z)-4-((4-Acetyl-5-hydroxyhex-4-en-1-yl)thio)-2-methyl-1- (trimethylsilyl)-9H-fluoren-9-one (5080’) Part III Experimental Procedures and Computational Details 168
O TMS TMS Me O O Me TMS COMe PhH Me + + O + S Me OH COMe 90 ºC, 12 h Me S Me OH S O 4009 5080 5080' Me A solution of the benzoyl linked triyne 4009 (40 mg, 0.15 mmol), thietane (30 µL, 0.42 mmol), and pentane-2,4-dione (83 mg, 83 mmol) in benzene (1.5 mL) was heated to 90 ºC (external bath temperature) in a vial that was sealed with a teflon-lined screw-cap. After 12 h the reaction mixture was concentrated and passed through a plug of silica gel (hexanes:EtOAc = 1:1 as eluent). The filtrate was concentrated and the residue was purified by MPLC (hexanes:EtOAc = 3:1) to provide, in order of elution, the fluorenonyl sulfides 5080’ (4 mg, 0.01 mmol, 6%) and 5080 (40 mg, 0.09 mmol, 60%), each as a yellow solid. Data for 5080’: 1 H NMR (500 MHz, CDCl3): d 8.21 (d, J = 7.6 Hz, 1H, H5), 7.61 (d, J = 7.0 Hz, 1H, H8), 7.48 (ddd, Hz, J = 7.6, 1.4, 1.4 Hz, 1H, H6), 7.27 (br t, J = 6.9 Hz, 1H, H7), 7.15 (br s, 1H,
H3), 5.43 (s, 1H, C=C(OH)Me), 3.92 [t, J = 5.9 Hz, 2H, C=C(Ac)CH2], 3.16 (t, J = 7.0 Hz,
2H, ArSCH2), 2.46 (s, 3H, ArCH3), 2.28 (s, 3H, CH3CO), 2.13 (s, 3H, CH3C(OH)=C), 2.12
(tt, J = 6.0, 5.7 Hz, 2H, ArSCH2CH2CH2), and 0.41 (s, 9H, ArSi(CH3)3). 13 C NMR (125 MHz, CDCl3): d 197.0, 195.0, 171.7, 146.3, 145.4, 144.0, 141.3, 138.7, 135.8, 134.5, 133.8, 132.6, 128.3, 124.2, 123.7, 100.0, 66.0, 32.0, 29.7, 28.3, 25.2, 19.7, and 2.6. IR (neat): 2981, 2966, 2951, 2923, 2866, 2844, 1712, 1681, 1582, 1466, 1260, 1166, 1054, 1033, 977, and 845 cm-1. + + HRMS (ESI-TOF): Calcd for [C25H30NaO3SSi] [(M+Na) ] 461.1583, found 461.1585.
TLC: Rf 0.25 in 3:1 hexanes:EtOAc. mp: 91-95 ºC. Data for 5080: 1 H NMR (500 MHz, CDCl3): d 7.57 (ddd, J = 7.3, 0.9, 0.9 Hz, 1H, H8), 7.45 (dd, J = 7.3, 0.7 Hz, 1H, H5), 7.44 (ddd, J = 7.4, 7.4, 1.0 Hz, 1H, H6), 7.35 (s, 1H, H4), 7.26 (ddd, 1H, J = 7.4, 6.4, 2.2 Hz, 1H, H7), 5.49 (s, 1H, C=C(OH)Me), 3.96 [t, J = 5.9 Hz, 2H, Part III Experimental Procedures and Computational Details 169
C=C(Ac)CH2], 3.17 (t, J = 7.1 Hz, 2H, ArSCH2), 2.47 (s, 3H, ArCH3), 2.33 (s, 3H, CH3CO),
2.18 (tt, J = 7.1, 5.8 Hz, 2H, ArSCH2CH2CH2), 2.16 (s, 3H, CH3C(OH)=C), and 0.44 (s,
9H, ArSi(CH3)3). 13 C NMR (125 MHz, CDCl3): d 197.0 ,194.6, 171.7, 144.1, 143.4, 143.1, 142.5, 142.2, 136.8, 134.2, 134.1, 128.9, 123.8, 119.2, 117.0, 100.1, 66.2, 32.0, 28.6, 27.8, 21.6, 19.8, and 2.6. IR (neat): 3008, 2938, 2923, 2844, 2828, 1705, 1681, 1578, 1388, 1261, 1166, 1015, and 847 cm-1. + + HRMS (ESI-TOF): Calcd for [C25H30NaO3SSi] [(M+Na) ] 461.1583, found 461.1587.
TLC: Rf 0.2 in 3:1 hexanes:EtOAc. mp: 101-110 ºC.
2,2,2-Trifluoro-N-(4-iodophenyl)-N-(3-((2-methyl-9-oxo-1-(trimethylsilyl)-9H- fluoren-3-yl)thio)propyl)acetamide (5081)
TMS O I O TMS PhH Me I + + H S N Me 90 ºC, 12 h S N COCF3 COCF3 4009 S5008 5081 A solution of the benzoyl linked triyne 4009 (73 mg, 0.28 mmol), thietane (50 µL, 0.68 mmol), and 4-iodotrifluoroacetanilide137 (S5008, 132 mg, 42 mmol) in benzene (3 mL) was heated to 90 ºC (external bath temperature) in a vial that was sealed with a teflon-lined screw-cap. After 12 h the reaction mixture was concentrated and purified by flash chromatography (hexanes:EtOAc = 10:1) to provide the fluorenonyl sulfide 5081 (88 mg, 0.13 mmol, 48%) as a yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.75 (d, J = 8.5 Hz, 2H, NArHm2), 7.57 (dd, J = 7.3, 0.6 Hz, 1H, H8), 7.46 (ddd, J = 7.5, 0.8, 0.8 Hz, 1H, H6), 7.44 (d, J = 7.1 Hz, 1H, H5), 7.30
(s, 1H, H4), 7.27 (ddd, 1H, J = 7.1, 7.1, 1.8 Hz, 1H, H7), 6.95 (d, J = 8.4 Hz, 2H, NArHo2),
137 Melissaris, A. P.; Litt, M. H. J. Org. Chem. 1994, 59, 5818–5821. Part III Experimental Procedures and Computational Details 170
3.90 (t, J = 7.3 Hz, 2H, NCH2), 3.02 (t, J = 7.3 Hz, 2H, ArSCH2), 2.43 (s, 3H, ArCH3),
2.03 (tt, J = 7.4, 7.4 Hz, 2H, ArSCH2CH2CH2), and 0.43 (s, 9H, ArSi(CH3)3). 13 C NMR (125 MHz, CDCl3): d 194.6, 156.7 (q, J = 36.1 Hz), 143.6, 143.4, 143.1, 142.5, 142.5, 138.9, 138.6, 137.1, 134.2, 134.2, 130.0, 128.9, 123.8, 119.3, 117.8, 116.1 (q, J = 288 Hz), 95.0, 51.0, 29.6, 26.2, 21.7, and 2.6. IR (neat): 2981, 2923, 2866, 2844, 1698, 1605, 1575, 1486, 1247, 1198, 1154, 1059, 1033, 1010, 976, 846, and 763 cm-1. + + HRMS (ESI-TOF): Calcd for [C28H27F3INNaO2SSi] [(M+Na) ] 676.0426, found 676.0447. TLC: 0.2 in 5:1 hexanes:EtOAc. mp: 139-141 ºC.
Methyl 4-(3-((5-methyl-4-(prop-1-yn-1-yl)-1-tosylindolin-6-yl)thio)propoxy)benzoate (5082)
Me
CO2Me Me CO2Me PhH + + S Me N Me HO 90 ºC, 12 h O Ts N S Ts 4010 5082 A solution of ynamide tetrayne 4010 (66 mg, 0.20 mmol), thietane (40 µL, 0.54 mmol), and methyl 4-hydroxybenzoate (46 mg, 30 mmol) in benzene (2 mL) was heated to 90 ºC (external bath temperature) in a vial that was sealed with a teflon-lined screw-cap. After 12 h the reaction mixture was concentrated and purified by flash chromatography (hexanes:EtOAc = 3:1) to provide the tosylindolinyl sulfide 5082 (72 mg, 0.13 mmol, 65%) as a yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.97 (d, J = 8.8 Hz, 2H, MeO2CArHo2), 7.64, (d, J = 8.2
Hz, 2H, SO2ArHo2), 7.58 (s, 1H, SArH), 7.20 (d, J = 8.1 Hz, 2H, SO2ArHm2), 6.91 (d, J =
8.8 Hz, MeO2CArHm2), 4.15 (t, J = 6.0 Hz, 2H, ArOCH2), 3.89 (t, J = 8.5 Hz, 2H, TsNCH2),
3.88 (s, 3H, CO2CH3), 3.13 (t, J = 7.0 Hz, 2H, ArSCH2), 2.86 (t, J = 8.5 Hz, 2H, Part III Experimental Procedures and Computational Details 171
TsNCH2CH2), 2.40 (s, 3H, SO2C6H4CH3), 2.35 (s, 3H, SArCH3), 2.16 (tt, J = 6.9, 6.0 Hz,
2H, ArSCH2CH2CH2), and 2.06 (s, 3H, C≡CCH3). 13 C NMR (125 MHz, CDCl3): d 166.8, 162.5, 144.2, 139.8, 134.8, 134.6, 133.8, 132.5, 131.6, 129.7, 127.3, 122.6, 121.6, 114.1, 114.0, 94.1, 76.0, 66.2, 51.8, 49.8, 30.0, 28.7, 28.0, 21.5, 17.8, and 4.5. IR (neat): 3008, 2981, 2950, 2922, 2868, 2844, 2235, 1715, 1605, 1580, 1510, 1434, 1354, 1279, 1251, 1165, 1107, 1056, 1033, 1012, and 769 cm-1. + + HRMS (ESI-TOF): Calcd for [C30H31NNaO5S2] [(M+Na) ] 572.1541, found 572.1531.
TLC: Rf 0.2 in 3:1 hexanes:EtOAc. mp: 119-122 ºC.
Ethyl 2-acetyl-2-methyl-6-((5-methyl-4-(prop-1-yn-1-yl)-1-tosylindolin-6- yl)thio)hexanoate (5083)
Me
O Me PhH CO Et Me + S + Me 2 COMe N Me 90 ºC, 12 h Me Me Ts N S Ts CO2Et 4010 5083 A solution of ynamide tetrayne 4010 (64 mg, 0.20 mmol), tetrahydrothiophene (60 µL, 0.68 mmol), and ethyl 2-methylacetoacetate (59 mg, 41 mmol) in benzene (2 mL) was heated to 90 ºC (external bath temperature) in a vial that was sealed with a teflon-lined screw-cap. After 12 h the reaction mixture was concentrated and purified by flash chromatography (hexanes:EtOAc = 5:1) to provide the tosylindolinyl sulfide 5083 (59 mg, 0.11 mmol, 55%) as a yellow oil. 1 H NMR (500 MHz, CDCl3): d 7.63 (d, J = 8.3 Hz, 2H, SO2ArHo2), 7.51 (s, 1H, SArH),
7.24 (d, J = 8.1 Hz, 2H, SO2ArHm2), 4.20 (q, J = 7.1 Hz, 2H, CO2CH2CH3), 3.88 (t, J = 8.4
Hz, 2H, TsNCH2), 2.93 (t, J = 7.3 Hz, 2H, ArSCH2), 2.87 (t, J = 8.4 Hz, 2H, TsNCH2CH2),
2.38 (s, 3H, SO2C6H4CH3), 2.37 (s, 3H, ArCH3), 2.15 (s, 3H, CH3C=O), 2.06 (s, 3H,
C≡CCH3), 1.92 [nfom, 1H, CHaHbC(Me)(Ac)CO2Et], 1.78 [nfom, 1H,
CHaHbC(Me)(Ac)CO2Et], 1.70 (tt, J = 7, 7 Hz, 2H, ArSCH2CH2CH2), 1.70 (tt, J = 7, 7 Hz, Part III Experimental Procedures and Computational Details 172
2H, ArSCH2CH2CH2), 1.40-1.32 (m, 2H, ArSCH2CH2CH2), 1.35 (s, 3H, AcC(CH3)CO2Et), and 1.26 (t, J = 7.1 Hz, 3H, CO2CH2CH3). 13 C NMR (125 MHz, CDCl3): d 205.6, 172.9, 144.2, 139.8, 135.5, 134.3, 133.8, 132.1, 129.7, 127.3, 121.4, 113.7, 93.9, 76.0, 61.3, 59.6, 49.8, 34.3, 33.2, 29.2, 28.0, 26.1, 23.5, 21.5, 18.8, 17.8, 14.1, and 4.5. IR (neat): 2981, 2938, 2922, 2865, 2844, 2234, 1731, 1712, 1582, 1446, 1355, 1240, 1164, 1056, 1033, 1012, and 814 cm-1. + + HRMS (ESI-TOF): Calcd for [C30H37NNaO5S2] [(M+Na) ] 578.2011, found 578.1989.
TLC: Rf 0.2 in 3:1 hexanes:EtOAc.
4-((5-Methyl-4-(prop-1-yn-1-yl)-1-tosylindolin-6-yl)thio)hex-5-en-1-yl acetate (5084)
Me
Me PhH Me + + HOAc S N Me 90 ºC, 12 h OAc N S Ms Ts 5069 S5009 5084 A solution of amide triyne 5069 (50 mg, 0.20 mmol), 2-vinyltetrahydrothiophene 138 (S5009, 53 mg, 0.46 mmol), and acetic acid (50 µL, 0.87 mmol) in benzene (2 mL) was heated to 90 ºC (external bath temperature) in a vial that was sealed with a teflon-lined screw-cap. After 12 h the reaction mixture was concentrated and purified by flash chromatography (hexanes:EtOAc = 3:1) to provide the mesylindolinyl sulfide 5084 (46 mg, 0.11 mmol, 55%) as a pale yellow oil. 1 H NMR (500 MHz, CDCl3): d 7.27 (s, 1H, SArH), 5.76 (ddd, J = 17.1, 10.5, 6.2 Hz, 1H,
CH2=CH) , 5.23 (d, J = 17.8 Hz, 1H, CH=CHEHZ), 5.23 (nfom, 1H, CHOAc), 5.17 (d, J =
10.6 Hz, 1H, CH=CHZHE), 3.97 (t, J = 8.5 Hz, 2H, MsNCH2), 3.14 (t, J = 8.4 Hz, 2H,
MsNCH2CH2), 2.89 (t, J = 7.0 Hz, 2H, ArSCH2), 2.83 (s, 3H, SO2CH3), 2.42 (s, 3H,
138 Vedejs, E, Hagen, J. P.; Roach, B. L.; Spear, K. L. Ring expansion by [2,3]sigmatropic shift: conversion of five-membered into eight-membered heterocycles. J. Org. Chem. 1978, 43, 1185-1190. Part III Experimental Procedures and Computational Details 173
ArCH3), 2.12 [s, 3H, CH3(C=O)O], 2.06 (s, 3H, C≡CCH3), 1.81-1.73 (m, 2H,
ArSCH2CH2CH2), and 1.73–1.64 (m, 2H, ArSCH2CH2CH2) 13 C NMR (125 MHz, CDCl3): d 170.3, 139.8, 136.1, 135.9, 134.3, 131.5, 121.9, 116.9, 112.4, 94.3, 76.0, 74.2, 50.4, 34.3, 33.2, 33.1, 28.2, 24.4, 21.2, 17.7, and 4.6. IR (neat): 2919, 2855, 2234, 1735, 1582, 1446, 1436, 1347, 1239, 1158, 1108, 1015, and 964 cm-1. + + HRMS (ESI-TOF): Calcd for [C21H27NNaO4S2] [(M+Na) ] 444.1279, found 444.1282.
TLC: Rf 0.13 in 3:1 hexanes:EtOAc.
1-(4-((5-Methyl-4-(prop-1-yn-1-yl)-2,3-dihydro-1H-indazol-6-yl)thio)butyl)-1H- pyrrole-2,5-dione (5085)
Me
O Me PhH O BocN + S + NH Me N Me 95 ºC, 48 h BocN N Boc O N S 4011 Boc 5085 O A solution of hydrazide tetrayne 4011 (50 mg, 0.13 mmol), tetrahydrothiophene (30 µL, 0.34 mmol), and maleimde (59 mg, 0.21 mmol) in benzene (1.5 mL) was heated to 90 ºC (external bath temperature) in a vial that was sealed with a teflon-lined screw-cap. After 48 h the reaction mixture was concentrated and the residue was purified by flash chromatography (hexanes:EtOAc = 5:1) to provide the maleimidosulfide 5085 (39 mg, 0.07 mmol, 54%) as a pale yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.35 (br s, 1H, SArH), 6.69 (s, 2H, C=CH), 5.06 [br d, J =
14.9 Hz, 1H, ArCHaHbN(C=O)], 4.57 [br d, J = 15.0 Hz, 1H, ArCHbHaN(C=O)], 3.54 [t, J
= 7.0 Hz, 2H, CH2N(C=O)2), 2.92 (t, J = 7.2 Hz, 2H, ArSCH2), 2.42 (s, 3H, ArCH3), 2.12
(s, 3H, C≡CCH3), 1.56 [s, 9H, (CH3)3CO(C=O)NAr], and 1.51 [s, 9H,
(CH3)3CO(C=O)NCH2Ar]. 13 C NMR (125 MHz, CDCl3): d 170.8, 138.1, 135.9, 134.8, 134.2, 128.5, 119.0, 114.8, 94.5, 82.7, 82.3, 75.6, 52.1, 37.4, 33.0, 28.4, 28.3, 27.8, 26.0, 17.8, and 4.7 (Boc carbonyl carbons not observed). Part III Experimental Procedures and Computational Details 174
IR (neat): 2974, 2936, 2923, 2867, 2844, 2232, 1737, 1707, 1589, 1454, 1440, 1407, 1367, 1148, 1052, 1033, and 833 cm-1. + + HRMS (ESI-TOF): Calcd for [C29H37N3NaO6S] [(M+Na) ] 578.2301, found 578.2337.
TLC: Rf 0.2 in hexanes:EtOAc. mp: 99-102 ºC.
Di-tert-butyl 6-((5-acetoxy-3-methoxypentyl)thio)-5-methyl-4-(prop-1-yn-1-yl)-1H- indazole-1,2(3H)-dicarboxylate (5086)
Me
OMe Me PhH Me BocN + + HOAc OMe N Me 95 ºC, 48 h BocN Boc S N S OAc Boc 4011 S5010 5086 A solution of hydrazide tetrayne 4011 (38 mg, 0.10 mmol), 4-methoxythiane (S5010, mg, 0.23 mmol), and acetic acid (19 mg, 0.32 mmol) in benzene (1 mL) was heated to 90 ºC (external bath temperature) in a vial that was sealed with a teflon-lined screw-cap. After 48 h the reaction mixture was concentrated and purified by flash chromatography (hexanes:EtOAc = 5:1) to provide the acetoxysulfide 5086 (45 mg, 0.08 mmol, 80%) as a viscous yellow oil. 1 H NMR (500 MHz, CDCl3): d 7.40 (br s, 1H, SArH), 5.06 [br d, J = 14.9 Hz, 1H,
ArCHaHbN(C=O)], 4.57 [br d, J = 14.9 Hz, 1H, ArCHbHaN(C=O)], 4.16 (t, J = 6.5 Hz, 2H,
CH2OAc), 3.46 (tt, J = 8.2, 6.3 Hz, 1H, MeOCH), 3.34 (s, 3H, CH3OCH), 3.01–2.94 (m,
2H, ArSCH2), 2.43 (s, 3H, ArCH3), 2.12 (s, 3H, C≡CCH3), 2.05 (s, 3H, CH3C=O), 1.92–
1.80 (m, 4H, CH2CH(OMe)CH2), 1.56 [s, 9H, (CH3)3CO(C=O)NAr], and 1.51 [br s, 9H,
(CH3)3CO(C=O)NCH2Ar]. 13 C NMR (125 MHz, CDCl3): d 171.0, 138.0, 135.9, 128.3, 118.8, 114.5, 114.3, 94.4, 82.5, 82.1, 75.4, 61.2, 60.4, 57.0, 52.0, 32.8, 32.6, 28.20, 28.16, 21.0, 17.7, 14.2, and 4.6 (Boc carbonyl carbons not observed). Part III Experimental Procedures and Computational Details 175
IR (neat): 2980, 2936, 2870, 2844, 2230, 1738, 1708, 1590, 1454, 1367, 1345, 1248, 1236, 1150, 1048, 1033, 850, and 755 cm-1. + + HRMS (ESI-TOF): Calcd for [C29H42N2NaO7S] [(M+Na) ] 585.2610, found 585.2637.
TLC: Rf 0.2 in 3:1 hexanes:EtOAc.
Di-tert-butyl 6-((3-(3-formyl-2-methyl-1H-indol-1-yl)propyl)thio)-5-methyl-4-(prop- 1-yn-1-yl)-1H-indazole-1,2(3H)-dicarboxylate (5087)
Me
CHO 7 Me PhH S Me BocN + + Me N N Me N 95 ºC, 48 h BocN 4 N Boc H S Me Boc CHO 4011 S5011 5087 A solution of hydrazide tetrayne 4011 (38 mg, 0.10 mmol), thiotane (30 µL, 0.40 mmol), and 2-methyl indole-3-carbaldehyde139 (S5011, 25 mg, 0.16 mmol) in benzene (1 mL) was heated to 90 ºC (external bath temperature) in a vial that was sealed with a teflon-lined screw-cap. After 48 h the reaction mixture was concentrated and passed through a plug of silica gel (hexanes:EtOAc = 1:1 as eluent). The filtrate was concentrated and the residue was purified by MPLC (hexanes:EtOAc = 3:1) to provide the indolosulfide 5087 (30 mg, 0.05 mmol, 50%) as a yellow solid. 1 H NMR (500 MHz, CDCl3): d 10.18 [s, 1H, Ar(C=O)H], 8.28-8.24 (m, 1H, H4), 7.43 (br s, 1H, SArH), 7.34–7.30 (m, 1H, H7), 7.27 (m, 1H, H6), 7.26 (m, 1H, H5), 5.07 [br d, J =
15.2 Hz, 1H, ArCHaHbN(C=O)], 4.58 [br d, J = 15.0 Hz, 1H, ArCHbHaN(C=O)], 4.28 (br t, J = 7.5 Hz, 2H, NCH2), 2.97 (dt, J = 6.7 Hz, 2H, ArSCH2), 2.71 [s, 3H, NC(CH3)=], 2.46
(s, 3H, ArCH3), 2.14 (s, 3H, C≡CCH3), 1.53 [s, 9H, (CH3)3CO(C=O)NAr], and 1.51 [br s,
9H, (CH3)3CO(C=O)NCH2Ar].
139 Robinson, M. W.; Overmeyer, J. H.; Young, A. M.; Erhardt, P. W.; Maltese, W. A. Synthesis and evaluation of indole-based chalcones as inducers of methuosis, a novel type of nonapoptotic cell death. J. Med. Chem. 2012, 55, 1940-1956. Part III Experimental Procedures and Computational Details 176
13 C NMR (125 MHz, CDCl3): d 184.2, 147.0, 138.2, 136.2, 135.0, 134.5, 129.0, 125.9, 123.2, 122.8, 121.0, 119.2, 114.8, 114.5, 109.4, 94.8, 82.6, 82.3, 75.3, 52.1, 41.9, 30.3, 28.5, 28.2, 17.8, 10.6, and 4.6 (Boc carbonyl carbons not observed). IR (neat): 2979, 2866, 2844, 2232, 1706, 1651, 1538, 1456, 1439, 1425, 1368, 1257, 1148, 1054, 1033, and 847 cm-1. + + HRMS (ESI-TOF): Calcd for [C34H41N3NaO5S] [(M+Na) ] 626.2665, found 626.2660.
TLC: Rf 0.15 in 2:1 hexanes:EtOAc. mp: 104 ºC (decomp.)
tert-Butyl ((tert-butoxycarbonyl)oxy)(3-((3,3,6-trimethyl-1-oxo-7- (trimethylsilyl)isoindolin-5-yl)thio)propyl)carbamate (5088)
O O TMS TMS PhH Me HN + S + BocHN OBoc HN Boc Me 90 ºC, 12 h S N Me Me Me Me OBoc 5070 S5012 5088 A solution of amide triyne 5070 (53 mg, 0.22 mmol), thietane (50 µL, 0.68 mmol), and N,O-bis-Boc-hydroxylamine140 (S5012, 86 mg, 0.37 mmol) in benzene (2 mL) was heated to 90 ºC (external bath temperature) in a vial that was sealed with a teflon-lined screw-cap. After 12 h the reaction mixture was concentrated and purified by flash chromatography (hexanes:EtOAc = 1:3) to provide the lactam sulfide 5088 (124 mg, 0.22 mmol, 100%) as a pale yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.27 (s, 1H, SArH), 6.70 [br s 1H, Ar(C=O)NH], 3.78 (br t, 2H, CH2N), 3.05 (t, J = 7.2 Hz, 2H, ArSCH2), 2.51 (s, 3H, ArCH3), 2.02 (app pentet, J =
7.0 Hz, 2H, ArSCH2CH2CH2), 1.52 [s, 9H, (CH3)3CO(C=O)O], 1.51 [s, 6H, ArC(CH3)2)],
1.48 [s, 9H, (CH3)3CO(C=O)N], and 0.46 [s, 9H, ArSi(CH3)3]. 13 C NMR (125 MHz, CDCl3): d 170.4, 154.8, 152.2, 151.7, 141.62, 141.58, 139.6, 132.5, 118.4, 85.0, 82.6, 57.5, 49.1, 29.4, 28.2, 28.1, 27.6, 26.4, 21.5, and 3.3.
140 Stephens, B. E.; Liu, F. A regio- and diastereoselective intramolecular nitrone cycloaddition for practical 3- and 2,3-disubstituted piperidine synthesis from g-butyrolactone. J. Org. Chem. 2009, 74, 254-263. Part III Experimental Procedures and Computational Details 177
IR (neat): 3004, 2980, 2938, 2923, 2866, 2844, 2827, 1783, 1693, 1369, 1322, 1248, 1144, 1096, 1055, 1033, 1013, 845, and 765 cm-1. + + HRMS (ESI-TOF): Calcd for [C27H44N2NaO6SSi] [(M+Na) ] 626.2665, found 626.2660.
TLC: Rf 0.7 in EtOAc. mp: 130-135 ºC.
2-(4-Nitrophenyl)-6-((3,3,6-trimethyl-1-oxo-7-(trimethylsilyl)isoindolin-5- yl)thio)hexanenitrile (5089)
NO2 CN O O TMS TMS PhH Me HN + S + HN Me 90 ºC, 12 h Me S CN Me Me NO2 Me 5070 S5013 5089 A solution of amide triyne 5070 (39 mg, 0.16 mmol), tetrahydrothiophene (35 µL, 0.40 mmol), and 4-nitrobenzyl cyanide141 (S5013, 115 mg, 0.71 mmol) in benzene (1.6 mL) was heated to 90 ºC (external bath temperature) in a vial that was sealed with a teflon-lined screw-cap. After 12 h the reaction mixture was concentrated and purified by flash chromatography (hexanes:EtOAc = 2:1 to 1:3) to provide the lactam sulfide 5089 (55 mg, 0.11 mmol, 69%) as an orange solid. 1 H NMR (500 MHz, CDCl3): d 8.27 (d, J = 8.6 Hz, 2H, O2NPhHo2), 7.54 (d, J = 8.6 Hz,
2H, O2NPhHm2), 7.12 (s, 1H, SArH), 5.95 [br t, J = 1.4 Hz, 1H, Ar(C=O)NH], 3.95 (dd, J
= 8.5, 6.1 Hz, 1H, CH2CH(CN)Ar), 2.97 (t, J = 6.8 Hz, 2H, ArSCH2), 2.50 (s, 3H, ArCH3),
2.05-1.92 (m, 2H, ArSCH2CH2CH2), 1.85–1.75 (m, 2H, ArSCH2CH2CH2), 1.75–1.68 (m,
2H, CH2CH(CN)Ar), 1.50 [d, J = 1.6 Hz, 6H, ArC(CH3)2]], and 0.46 [s, 9H, ArSi(CH3)3]. 13 C NMR (125 MHz, CDCl3): d 170.2, 151.6, 147.8, 142.6, 141.8, 141.5, 139.9, 132.7, 128.3, 124.4, 119.3, 118.5, 57.3, 37.2, 35.2, 32.1, 28.3, 27.7, 26.3, 21.6, and 3.3.
141 Padalkar, V. S.; Phatangare, K. R.; Sekar, N. Synthesis of novel fluorescent 2-{4-[1-(pyridine-2-yl)-1H- pyrazol-3-yl]phenyl}-2H-naphtho[1,2-d][1,2,3]triazolyl derivatives and evaluation of their thermal and phtophyscial propertis. J. Heterocycl. Chem. 2013, 50, 809-813. Part III Experimental Procedures and Computational Details 178
IR (neat): 3300–3050, 3078, 2968, 2944, 2862, 2242, 1690, 1575, 1523, 1345, 1320, 1243, 1186, 1117, and 848 cm-1. + + HRMS (ESI-TOF): Calcd for [C26H33N3NaO3SSi] [(M+Na) ] 518.1910, found 518.1946.
TLC: Rf 0.4 in 1:2 hexanes:EtOAc. mp: 56-74 ºC.
4-(4-((1-Oxo-2-phenyl-7-(trimethylsilyl)isoindolin-5-yl)thio)butoxy)benzaldehyde (5090) and 4-(4-((1-Oxo-2-phenyl-7-(trimethylsilyl)isoindolin-4- yl)thio)butoxy)benzaldehyde (5090’)
Ph CHO CHO O N O TMS O TMS PhH O + S + PhN + PhN 110 ºC, 12 h O S TMS OH S CHO 5071 5090 5090' A solution of amide triyne 5071 (59 mg, 0.21 mmol), tetrahydrothiophene (50 µL, 0.59 mmol), and 4-hydroxybenzaldehyde (41 mg, 0.34 mmol) in benzene (2 mL) was heated to 110 ºC (external bath temperature) in a vial that was sealed with a teflon-lined screw-cap. After 12 h the reaction mixture was concentrated and the residue was passed through a plug of silica gel using hexanes:EtOAc = 1:1 as eluent. The filtrate was washed with satd. K2CO3 (3x5 mL) and concentrated in vacuo. The residue was purified by MPLC (hexanes:EtOAc = 3:1) to provide, in order of elution, the sulfides 5090’ (17 mg, 0.03 mmol, 16%) and 5090 (44 mg, 0.90 mmol, 43%), each as a yellow solid. Data for 5090’: 1 H NMR (500 MHz, CDCl3): ): d 9.87 (s, 1H, ArCHO), 7.87 [d, J = 8.1 Hz, 2H,
(O=C)NArHo2], 7.82 (d, J = 8.7 Hz, 2H, OHCArHo2), 7.61 (d, J = 7.7 Hz, 1H, H5), 7.45
(d, J = 7.7 Hz, 1H, H6), 7.43 [br app t, J = 8.2 Hz, 2H, (O=C)NArHm2], 7.18 (t, J = 7.4 Hz,
1H, (O=C)NArHp), 6.96 (d, J = 8.8 Hz, 2H, OHCArHm2), 4.72 (s, 2H, PhN(C=O)CH2),
4.08 (t, J = 6.0 Hz, 2H, ArOCH2), 3.12 (t, J = 7.1 Hz, 2H, ArSCH2), 2.04–1.98 (m, 2H, Part III Experimental Procedures and Computational Details 179
ArOCH2CH2 or ArSCH2CH2), 1.95-1.88 (m, 2H, ArOCH2CH2 or ArSCH2CH2), and 0.43
[s, 9H, ArSi(CH3)3]. 13 C NMR (125 MHz, CDCl3): d 191.0, 168.4, 164.1, 140.3, 139.8, 136.8, 135.7, 132.7, 132.3, 130.3, 129.9, 129.8, 129.5, 124.8, 119.9, 115.0, 67.8, 50.4, 32.7, 28.4, 26.2, and - 0.21. IR (neat): 3005, 2981, 2966, 2954, 2923, 2865, 2844, 2826, 1750, 1694, 1600, 1577, 1501, 1371, 1256, 1158, 1054, 1033, 1014, 841, and 757 cm-1. + + HRMS (ESI-TOF): Calcd for [C28H31NNaO3SSi] [(M+Na) ] 512.1692, found 512.1707.
TLC: Rf 0.2 in 3:1 hexanes:EtOAc. mp: 84-86 ºC. Data for 5090: 1 H NMR (500 MHz, CDCl3): ): d 9.87 (s, 1H, ArCHO), 7.83 (d, 2H, J = 8.5 Hz,
OHCArHo2), 7.82 [br d, J = 7.6 Hz, 2H, (O=C)NArHo2], 7.52 (d, J = 1.9 Hz, 1H, H6), 7.41
[br app t, J = 8.0 Hz, 2H, (O=C)NArHm2], 7.37 (d, J = 1.7 Hz, 1H, H4), 7.16 (t, J = 7.4 Hz,
1H, (O=C)NArHp), 6.98 (d, J = 8.8 Hz, 2H, OHCArHm2), 4.76 (s, 2H, PhN(C=O)CH2),
4.10 (t, J = 6.0 Hz, 2H, ArOCH2), 3.12 (t, J = 7.1 Hz, 2H, ArSCH2), 2.04–1.99 (m, 2H,
ArOCH2CH2 or ArSCH2CH2), 1.98-1.91 (m, 2H, ArOCH2CH2 or ArSCH2CH2), and 0.43
[s, 9H, ArSi(CH3)3]. 13 C NMR (125 MHz, CDCl3): d 190.7, 168.0, 163.9, 141.4, 141.0, 140.1, 139.6, 134.9, 133.7, 132.0, 130.0, 129.1, 124.3, 121.5, 119.4, 114.7, 67.6, 50.2, 32.4, 28.2, 25.6 and - 0.59. IR (neat): 3005, 2981, 2950, 2923, 2865, 2844, 2826, 1750, 1694, 1600, 1578, 1501, 1384, 1371, 1258, 1158, 1054, 1033, 1014, 842, and 755 cm-1. + + HRMS (ESI-TOF): Calcd for [C28H31NNaO3SSi] [(M+Na) ] 512.1692, found 512.1680.
TLC: Rf 0.1 in 3:1 hexanes:EtOAc. mp: 108-113 ºC.
Part III Experimental Procedures and Computational Details 180
Dimethyl 2-chloro-2-(3-((6-methyl-2-(methylsulfonyl)-7-(prop-1-yn-1-yl)isoindolin- 5-yl)thio)propyl)malonate (5091) and dimethyl 2-chloro-2-(3-((6-methyl-2- (methylsulfonyl)-7-(prop-1-yn-1-yl)isoindolin-4-yl)thio)propyl)malonate (5091’)
Me Ms Me N
MeO C CO Me PhH S 2 2 Cl Me + + Me CO2Me + Cl MsN Cl 90 ºC, 12 h MsN CO2Me CO2Me S CO Me S 2 Me Me 5028 5091 5091' A solution of benzoyl linked triyne 5028 (50 mg, 0.20 mmol), thietane (40 µL, 0.54 mmol), and dimethyl chloromalonate (136 mg, 0.82 mmol) in benzene (2 mL) was heated to 90 ºC (external bath temperature) in a vial that was sealed with a teflon-lined screw-cap. After 12 h the reaction mixture was concentrated and passed through a plug of silica gel (hexanes:EtOAc = 1:1 as eluent). The filtrate was concentrated and the residue was purified by MPLC (hexanes:EtOAc = 2:1) to provide, in order of elution, the mesylisoindolinyl sulfides 5091’ (20 mg, 0.04 mmol, 25%) and 5091 (52 mg, 0.11 mmol, 55%), each as a white solid. Data for 5091’: 1 H NMR (500 MHz, CDCl3): ): d 7.02 (s, 1H, SArH), 4.72 (t, J = 2.2 Hz, 2H,
MsNCHa2CHb2), 4.64 (t, J = 2.2 Hz, 2H, MsNCHb2CHa2), 3.81 (s, 6H, CO2CH3), 2.96 (t, J
= 7.0 Hz, 2H, ArSCH2), 2.89 (s, 3H, SO2CH3), 2.40 (m, 2H, ArSCH2CH2CH2), 2.39 (s, 3H,
ArCH3), 2.11 (s, 3H, C≡CCH3), and 1.75 (m, 2H, ArSCH2CH2CH2). 13 C NMR (125 MHz, CDCl3): d 167.0, 140.6, 139.1, 133.5, 129.7, 128.4, 116.8, 95.0, 75.1, 70.0, 54.7, 54.0, 33.9, 36.6, 34.8, 32.6, 23.8, 20.2, and 4.6. IR (neat): 2953, 2920, 2850, 2231, 1746, 1596, 1437, 1335, 1262, 1249, 1154, 1076, 963, and 826 cm-1. + + HRMS (ESI-TOF): Calcd for [C21H26ClNNaO6S2] [(M+Na) ] 510.0758, found 510.0790.
TLC: Rf 0.33 in 1:1 hexanes:EtOAc. mp: 60-68 ºC. Data for 5091: Part III Experimental Procedures and Computational Details 181
1 H NMR (500 MHz, CDCl3): ): d 7.08 (s, 1H, SArH), 4.68 (s, 4H, MsNCHa2CHb2), 3.81
(s, 6H, CO2CH3), 2.90 (t, J = 7.0 Hz, 2H, ArSCH2), 2.88 (s, 3H, SO2CH3), 2.48 (s, 3H,
ArCH3), 2.42 (m, 2H, ArSCH2CH2CH2), 2.12 (s, 3H, C≡CCH3), and 1.75 (m, 2H,
ArSCH2CH2CH2). 13 C NMR (125 MHz, CDCl3): d 167.0, 139.2, 136.9, 135.7, 133.6, 121.7, 119.8, 95.2, 75.5, 70.1, 54.25, 54.22, 53.9, 36.7, 34.8, 33.1, 23.5, 18.1, and 4.6. IR (neat): 2955, 2919, 2853, 2232, 1746, 1578, 1438, 1336, 1255, 1154, 1077, and 963 cm-1. + + HRMS (ESI-TOF): Calcd for [C21H26ClNNaO6S2] [(M+Na) ] 510.0758, found 510.0795.
TLC: Rf 0.3 in 1:1 hexanes:EtOAc. mp: 116-125 ºC.
3-Methyl-2,3-dihydrobenzo[d]thiazole (5092)
Me Me NaBH N 4 N OSO3Me THF S S S5014 5092 To a suspension of N-methyl benzothiazolium methylsulfate (1.34 g, 5.1 mmol) in THF (25 mL) at 0 ºC was added sodium borohydride (0.23 g, 6.1 mmol) in one portion. The reaction mixture was allowed to warm to room temperature and further stirred for 1 hour.
The resulting mixture was quenched with satd. NH4Cl (30 mL) and extracted with Et2O
(3x10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrate in vacuo. The residue was immediately treated with benzene (3 mL). The insoluble material was removed by passing the mixture through a cotton plug. The concentration of the benzene solution of N-methyl benzothiazoline was estimated by 1H NMR analysis of an aliquot and use that solution directly for subsequent trapping reaction. The concentration of the stock solution described here was judged to be 42 wt%.
Part III Experimental Procedures and Computational Details 182
Di-tert-butyl 5-methyl-6-((2-(methylamino)phenyl)thio)-4-(prop-1-yn-1-yl)-1H- indazole-1,2(3H)-dicarboxylate (5095)
Me
Me Me AcOH Boc N + N Me N Me PhH, 95 ºC, 48 h BocN Boc S N S Boc HN 4011 5092 5095 Me A solution of tetrayne 4011 (74 mg, 0.20 mmol), N-methylbenzothiazoline (~40 wt% in benzene, 150 µL, ca. 0.38 mmol), and acetic acid (60 µl, 1.0 mmol) in benzene (2 mL) was heated to 95 ºC (external bath temperature) in a vial that was sealed with a teflon-lined screw-cap. After 48 h the reaction mixture was concentrated and passed through a plug of silica gel (hexanes:EtOAc = 3:1 as eluent). The filtrate was concentrated and the residue was purified by MPLC (hexanes:EtOAc = 5:1) to provide the diaryl sulfide 5095 (34 mg, 0.07 mmol, 35%) as a off-white powder. 1 H NMR (500 MHz, CDCl3): d 7.42 (dd, J = 7.6, 1.8 Hz, 1H, ArSPhHo), 7.33 (dt, J = 7.9,
1.8 Hz, 1H, ArSPhHp), 6.73 (s, 1H, BocNArH), 6.69 (dt, J = 7.4, 1.4 Hz, ArSPhHoHm),
6.66 [dd, J = 8.5, 1.6 Hz, 1H,ArSPh(NHMe)Hm], 5.00 [br d, J = 15.0 Hz, 1H,
ArCHaHbN(C=O)], 4.85 (br s, 1H, MeNHAr), 4.55 [br d, J = 14.9 Hz, 1H,
ArCHbHaN(C=O)], 2.84 (s, 3H, CH3NHAr), 2.50 (s, 3H, ArCH3), 2.13 (s, 3H, C≡CCH3),
1.48 [s, 9H, (CH3)3CO(C=O)NAr], and 1.31 [s, 9H, (CH3)3CO(C=O)NCH2Ar]. 13 C NMR (125 MHz, CDCl3): d 152.3, 150.7, 138.4, 137.8, 136.1, 132.3, 131.7, 128.1, 119.0, 117.1, 112.5, 112.2, 110.3, 94.5, 82.6, 82.0, 75.3, 51.6, 30.5, 28.2, 28.0, 17.3, and 4.6 (Boc carbonyl carbons not observed). IR (neat): 3387, 2978, 2930, 2870, 2816, 2322, 2232, 1734, 1709, 1592, 1506, 1454, 1367, 1318, 1259, 1148, and 847 cm-1. + + HRMS (ESI-TOF): Calcd for [C28H35N3NaO4S] [(M+Na) ] 532.2246, found 532.2263.
TLC: Rf 0.3 in 3:1 hexanes:EtOAc. mp: 70-90 ºC.
Part III Experimental Procedures and Computational Details 183
5-Methyl-4-(prop-1-yn-1-yl)-1-tosyl-6-(vinylthio)indoline (5110) using thiirane
Me
S Me Me
N Me PhH, 90 ºC, 12 h N S Ts Ts 4010 5110 A solution of tetrayne 4010 (33 mg, 0.10 mmol) and thiirane (200 µL, 3.3 mmol) in benzene (1 mL) was heated to 90 ºC (external bath temperature) in a vial that was sealed with a teflon-lined screw-cap. After 12 h the reaction mixture was concentrated and purified by flash chromatography (hexanes:EtOAc = 3:1) to give the aryl vinyl sulfide 5110 (34 mg, 0.09 mmol, 90%) as a yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.66 (d, J = 8.2 Hz, 2H, NSO2ArHo2), 7.63 (s, 1H, SArH),
7.20 (d, J = 8.2 Hz, 2H, SO2ArHm2), 7.23 (d, J = 8.2 Hz, NSO2ArHm2), 6.46 (dd, J = 16.5,
9.6 Hz, 1H, ArSCH=CH2), 5.36 (d, J = 9.6 Hz, 1H, ArSCH=CHZHE), 5.10 (d, J = 16.5 Hz,
1H, ArSCH=CHEHZ), 3.90 (t, J = 8.5 Hz, 2H, TsNCH2), 2.92 (t, J = 8.5 Hz, 2H,
TsNCH2CH2), 2.40 (s, 3H, SO2C6H4CH3), 2.38 (s, 3H, SArCH3), and 2.07 (s, 3H,
C≡CCH3). 13 C NMR (125 MHz, CDCl3): d 144.2, 140.0, 136.4, 134.4, 133.7, 132.0, 131.2, 130.0, 129.7, 127.6, 127.4, 121.9, 117.5, 114.6, 94.3, 75.9, 49.9, 28.2, 21.5, 17.9, and 4.5. IR (neat): 2957, 2916, 2328, 2236, 1582, 1445, 1433, 1355, 1164, 1109, and 1090 cm-1. + + HRMS (ESI-TOF): Calcd for [C21H21NNaO2S2] [(M+Na) ] 406.0911, found 406.0922.
TLC: Rf 0.25 in 5:1 hexanes:EtOAc. mp: 106-121 ºC.
5-Methyl-4-(prop-1-yn-1-yl)-1-tosyl-6-(vinylthio)indoline (5110) using tetrahydrothiophene
Me
S Me Me
N Me PhH, 90 ºC, 12 h N S Ts Ts 4010 5110 Part III Experimental Procedures and Computational Details 184
A solution of tetrayne 4011 (33 mg, 0.10 mmol) and thiirane (30 µL, 0.34 mmol) in benzene (1 mL) was heated to 90 ºC (external bath temperature) in a vial that was sealed with a teflon-lined screw-cap. After 12 h the reaction mixture was concentrated and purified by flash chromatography (hexanes:EtOAc = 3:1) to give the aryl vinyl sulfide 5110 (16 mg, 0.04 mmol, 40%) as a yellow solid.
Part III Experimental Procedures and Computational Details 185
8.4 Procedures and Data for Chapter 6 General procedure for the preparation of thioamides from amide precursors
MeO S P S O S P S S OMe R2 R2 Ar N Ar N R1 Lawesson'sreagent R1 toluene, 105-110 °C 3 h With the exception of 6112, each amide (1 equiv, 0.8 M) and Lawesson’s reagent (0.6 equiv) were combined in dry toluene and heated for 3 hours under an atmosphere of nitrogen. Toluene was removed in vacuo, and the residue was purified by flash chromatography to give each of the thioamides. The scale of these reactions was generally in the range of 1-5 mmol.
Part III Experimental Procedures and Computational Details 186
N,N-Diethyl-5-methyl-7-phenyl-4-(prop-1-yn-1-yl)-1,3-dihydrothieno[3,2- e]isobenzofuran-8-amine (6046) and N,N-diethyl-4-methyl-2-phenyl-5-(prop-1-yn-1- yl)-6,8-dihydrothieno[2,3-e]isobenzofuran-3-amine (6046’)
Me Me
Me S CH3CN Me Me O + Ph O + O Me NEt2 75 ºC S NEt2 S Et N 2 Ph Ph 4008 6039 6046 6046' [VP] A solution of the tetrayne 4008 (7 mg, 0.04 mmol) and the thioamide 6039 (17 mg, 0.08 mmol) in acetonitrile (0.6 mL) was placed in a culture tube and sealed with a with a Teflon®-lined screw cap. The tube was heated in an oil bath held at 80 ºC for 12 h. the solvent was evaporated and the residue was pass through a plug of silica gel (10:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 30:1) to give, in order of elution, 6046’ 4 mg, 0.005 mmol, 14%) and 6046 (4 mg, 0.01 mmol, 26%), each as a pale yellow solid. Data for 6046’: 1 H NMR (500 MHz, CDCl3): d 7.50-7.46 (m, 2H, PhH), 7.43-7.37 (m, 3H, PhH), and
5.27-5.23 (m, 4H, CH2OCH2), 2.98 (s, 3H, ArCH3), 2.95 (q, J = 6.9 Hz, 2H, NCH2CH3),
2.91 (q, J = 6.6 Hz, 2H, NCH2CH3), 2.15 (s, 3H, C≡CCH3), and 0.98 (t, J = 7.2 Hz, 6H,
NCH2CH3). Data for 6046: 1 H NMR (500 MHz, CDCl3): d 7.52-7.49 (m, 2H, PhH), 7.43-7.37 (m, 3H, PhH), and
5.56 (br s, 2H, CH2OCH2), 5.21 (t, J = 2.5 Hz, 2H, CH2OCH2), 2.91 (q, J = 6.9 Hz, 2H,
NCH2CH3), 2.87 (q, J = 6.6 Hz, 2H, NCH2CH3), 2.59 (s, 3H, ArCH3), 2.15 (s, 3H,
C≡CCH3), and 0.97 (t, J = 7.2 Hz, 6H, NCH2CH3).
N-Methyl-N-(methyl-d3)benzothioamide (6047-d3) Part III Experimental Procedures and Computational Details 187
S CD N 3 CH3
[VP] N-Methyl-N-(methyl-d3)benzothioamide (6047-d3) was prepared from N-methyl-N- 142 (methyl-d3)benzamide, which was made by a literature method, via the thionation described in the general procedure. Purification by flash chromatography (hexanes:EtOAc
= 30:1, then 12:1) gave 6047-d3 (93%) as a pale yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.37-7.27 (m, 5H, PhH5), 3.60 (s, 1.5H, NCH3), and 3.16
(s, 1.5H, NCH3’). 13 C NMR (125 MHz, CDCl3): d 201.3, 201.2, 143.3, 128.5, 128.2, 125.6, 44.0, 43.3 (weak,
CD3), 43.1, and 42.4 (weak, CD3). IR (neat): 3054, 3022, 2926, 1498, 1480, 1443, 1397, 1289, 1125, 1102, 1073, 1030, 1001, 988, 917, and 759 cm-1. HRMS (ESI-TOF):
TLC: Rf = 0.2 in 3:1 hexanes:EtOAc. mp: 65-68 °C.
N,N-Diisopropylbenzothioamide (6055)
S Me
N Me Me Me [VP] N,N-Diisopropylbenzothioamide (6055) was prepared following the general procedure. Purification by flash chromatography (hexanes:EtOAc = 12:1) gave 6055 (97%) as a pale yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.37-7.27 (br dd, J = 7.7, 7.7 Hz, 2H, ArHm), 7.26 (br t,
1H, J = 7.4 Hz, ArHp), 7.15 (br d, J = 7.0 Hz, 2H, ArHo), 4.12 [septet, J = 6.8 Hz, 1H,
142 Lewis, F. D.; Long, T. M.; Stern, C. L.; Liu, W. Structures and excited states of extended and folded mono-, di-, and tri-N-arylbenzmides. J. Phys. Chem. A. 2003, 107, 3254-3262. Part III Experimental Procedures and Computational Details 188
(N(CHMe2)2)a], 4.0 [br s, 1H, (N(CHMe2)2)b], 1.78 [br s, 6H, N(CH(CH3)2)a], and 1.17 [d,
J = 6.8 Hz, 6H, N(CH(CH3)2)b]. 13 C NMR (125 MHz, CDCl3): d 201.3, 201.2, 143.3, 128.5, 128.2, 125.6, 44.0, 43.3, (weak,
CD3), 43.1, and 42.4 (weak, CD3). IR (neat): 3000, 2969, 2931, 2873, 1493, 1481, 1463, 1439, 1380, 1375, 1360, 1341, 1249, 1148, 1068, 1023, 968, and 909 cm-1. + + HRMS (ESI-TOF): Calcd for [C13H19NNaS] (M+Na ): 244.1136, found 244.1135.
TLC: Rf = 0.4 in 3:1 hexanes:EtOAc. mp: 98-105 °C.
Pyridin-3-yl(pyrrolidin-1-yl)methanethione (6057)
S
N N [VP] Pyridin-3-yl(pyrrolidin-1-yl)methanethione (6057) was prepared from pyridin-3- yl(pyrrolidin-1-yl)methanone143 via the he thionation described in the general procedure. Purification by flash chromatography (hexanes:EtOAc = 3:1, then 1:1) gave 6057 (35% from methyl nicotinate) as a pale yellow solid. 1 H NMR (500 MHz, CDCl3): d 8.63 (d, J = 2.0 Hz, 1H, H2), 8.57 (dd, J = 4.9, 1.6 Hz, 1H, H6), 7.73 (ddd, J = 7.9, 1.8, 1.8 Hz, 1H, H4), 7.31 (dd, J = 7.8, 4.9 Hz, 1H, H5), 3.97 [t, J
= 7.0 Hz, 2H, N(CHa2)(CHb2)], 3.50 [t, J = 6.8 Hz, 2H, N(CHa2)(CHb2)], 2.11 [tt, J = 7.0,
7.0 Hz, 2H, N(CH2CHa2)], and 2.01 [tt, J = 6.8, 6.8 Hz, 2H, N(CH2CHb2)]. 13 C NMR (125 MHz, CDCl3): d 193.6, 149.7, 146.1, 139.7, 133.6, 123.1, 53.9, 53.6, 26.6 and 24.6. IR (neat): 2971, 2954, 2874, 1583, 1567, 1490, 1466, 1447, 1408, 1328, 1271, 1177, and 806 cm-1. + + HRMS (ESI-TOF): Calcd for [C10H12N2NaS] (M+Na ): 215.0619, found 215.0637.
143 Karimi, F.; Langstrom, B. Synthesis of [11C]carbon monoxide and in situ activated amines by palladium- mediated carboxaminations. Org. Biomol. Chem. 2003, 1, 541-546. Part III Experimental Procedures and Computational Details 189
TLC: Rf = 0.1 in 1:3 hexanes:EtOAc. mp: 79-80 °C.
N-Methyl-N-phenylbenzothioamide (6058)
S
N Me [VP] N-Methyl-N-phenylbenzothioamide (6058) was prepared from the known N-methyl- N-phenylbenzamide via thionation described in the general procedure. Purification by flash chromatography (hexanes:EtOAc = 30:1 then 12:1) gave 6058 (86% from N-methyl-N- phenylbenzamide) as yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.23–6.99 (m, 10H, ArH), and 3.94 (s, 3H, NCH3Ph). 13 C NMR (125 MHz, CDCl3): d 202.3, 146.5, 143.4, 129.1, 128.3, 127.6, 127.4, 127.1, 126.1, and 46.2. IR (neat): 3059, 3007, 1594, 1504, 1492, 1463, 1446, 1432, 1372, 1315, 1299, 1278, 1214, 1112, 1069, and 759 cm-1. + + HRMS (ESI-TOF): Calcd for [C14H13NNaS] (M+Na ): 250.0666, found 250.0661.
TLC: Rf = 0.6 in 1:1 hexanes:EtOAc. mp: 101-103 °C.
N-(4-methoxyphenyl)-N-methylbenzothioamide (6067)
OMe S
N Me
[VP] N-(4-methoxyphenyl)-N-methylbenzothioamide (6967) was prepared from the known N-(4-methoxyphenyl)-N-methylbenzamide via the thionation described in the general procedure. Purification by flash chromatography (hexanes:EtOAc = 12:1) gave 6067 (83%) as a yellow solid. Part III Experimental Procedures and Computational Details 190
1 H NMR (500 MHz, CDCl3): d 7.21-7.19 (m, 2H, PhHo2), 7.10-7.06 (m, 3H, PhHm2, PhHp),
6.92 (d, J = 8.9 Hz, 2H, MeOArHm2), 6.69 (d, J = 8.9 Hz, 2H, MeOArHo2), 3.91 (s, 3H,
OCH3), and 3.71 (s, 3H, NCH3). 13 C NMR (125 MHz, CDCl3): d 202.1, 158.1, 143.6, 139.4, 128.1, 127.5, 127.4, 127.1, 114.1, 55.3, and 46.4. IR (neat): 3057, 3000, 2960, 2930, 2905, 2849, 2835, 1606, 1583, 1507, 1491, 1462, 1445, 1374, 1295, 1247, 1172, 1116, 1069, 1029, 955, 836, and 768 cm-1. HRMS (ESI-TOF):
TLC: Rf = 0.2 in 3:1 hexanes:EtOAc. mp: 105-110 °C.
N-Methyl-N-(4-(trifluoromethyl)phenyl)benzothioamide (6068)
CF S 3
N Me
[VP] N-Methyl-N-(4-(trifluoromethyl)phenyl)benzothioamide (6068) was prepared from the known N-methyl-N-(4-(trifluoromethyl)phenyl)benzamide via the thionation described in the general procedure. Purification by flash chromatography (hexanes:EtOAc = 20:1) gave 6068 (87%) as a yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.48 (d, J = 8.1 Hz, 2H, F3CArHo2), 7.22 (d, J = 7.2 Hz,
2H, F3CArHm2), 7.19–7.09 (m, 5H, PhH5), and 3.93 (s, 3H, NCH3). 13 C NMR (125 MHz, CDCl3): d 203.1, 149.5, 143.0, 129.0 (q, J = 34.0 Hz), 128.9, 127.8, 127.7 (br q), 126.6, 126.3 (q, J = 3.5 Hz), 123.5 (q, J = 272.4 Hz), and 46.1. IR (neat): 3055, 2928, 1614, 1578, 1515, 1488, 1462, 1446, 1434, 1417, 1367, 1322, 1305, 1218, 1167, 1119, 1065, 1029, 1016, 955, 917, 846, 765, and 756 cm-1. HRMS (ESI-TOF):
TLC: Rf = 0.3 in 5:1 hexanes:EtOAc. mp: 75-83 °C. Part III Experimental Procedures and Computational Details 191
N,N-Diisopropyl-4-nitrobenzothioamide (6069)
S Me
N Me
O2N Me Me [VP] N,N-Diisopropyl-4-nitrobenzothioamide (6069) was prepared following the general procedure. Purification by flash chromatography (hexanes:EtOAc 7:1) gave 6069 as a bright yellow solid. The first portion to elute from the column was the pure material; later fractions contained byproducts derived from the Lawesson’s reagent (95 % yield, assuming 100% purity). 1 H NMR (500 MHz, CDCl3): d 8.21 (br d, J = 8.8 Hz, 2H, ArH3 H5), 7.30 (br d, J = 8.7
Hz, 2H, ArH2H6), 4.00 (br septet, J = 6.5 Hz, 1H, N(CHaMe2)2), 4.10 (br s, 1H,
N(CHbMe2)2), 1.78 (br s, 6H, N(CH(CH3)2)a), and 1.21 (d, J = 6.8 Hz, 6H, N(CH(CH3)2)b). 13 C NMR (125 MHz, CDCl3): d 196.3 (br), 150.7, 146.5, 125.1, 124.1, 56.7 (br), 51.3 (br), 20.2 (br), and 19.2. IR (neat): 2973, 2932, 1519, 1503, 1442, 1371, 1342, 1247, 1149, and 848 cm-1. + + HRMS (ESI-TOF): Calcd for [C13H18N2NaO2S] (M+Na ): 289.0987, found 289.0988.
TLC: Rf = 0.25 in 3:1 hexanes:EtOAc. mp: 170-177 °C.
N-(Cyclopropylmethyl)-N-phenylbenzothioamide (6109)
Br O O S Lawsson's reagent Ph N N N H NaH, DMF, 60 ºC Ph toluene 110 ºC Ph S6001 6109 Sodium hydride (60% dispersion in mineral oil, 108 mg, 2.7 mmol) was added in one portion to a solution of N-methyl-N-phenylbenzamide in DMF (2 mL) at 0 ºC under N2 atmosphere. The resulting green suspension was heated at 60 ºC until gas evolution had ceased (ca. 15 minutes). The mixture was allowed to cool to 0 ºC and cyclopropylmethyl bromide (0.4 mL, 4.1 mmol) was added. The reaction mixture was heated overnight at 60 Part III Experimental Procedures and Computational Details 192
ºC under a N2 atmosphere. The reaction mixture was then cooled to room temperature, quenched with water (10 mL), and extracted with EtOAc (3x5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes:EtOAc = 5:1) to give S6001 (569 mg, 2.3 mmol, 85%) as a colorless oil. 1 H NMR (500 MHz, CDCl3): d 7.31-7.06 (m, 10H, ArH), 3.81, (d, J = 7.1 Hz, 2H,
PhNCH2), 1.11 (ttt, J = 8.2, 7.1, 4.9 Hz, 1H, PhNCH2CH), 0.45 [ddd, J = 8.2, 6.1, 4.4 Hz,
2H, CH2CH(CHaHbCHaCHb)], and 0.18 [ddd, J = 6.0, 4.5, 4.5 Hz, 2H,
CH2CH(CHaHbCHaCHb)]. 13 C NMR (125 MHz, CDCl3): d 170.4, 136.4, 129.3, 129.1, 129.0, 128.6, 128.2, 127.6, 126.6, 54.7, 10.0, and 3.7.
TLC: Rf = 0.28 in 3:1 hexanes:EtOAc. [VP] N-(Cyclopropylmethyl)-N-phenylbenzothioamide was prepared from S6001 via the thionation described in the general procedure. Purification by flash chromatography (10:1 hexanes:EtOAc) gave 6109 (73%) as a green solide. 1 H NMR (500 MHz, CDCl3): d 7.21-7.03 (m, 10H, ArH), 4.39, (d, J = 7.1 Hz, 2H,
PhNCH2), 1.33 (ttt, J = 7.8, 7.8, 5.4 Hz, 1H, PhNCH2CH), 0.48 [ddd, J = 8.0, 6.2, 5.0 Hz,
2H, CH2CH(CHaHbCHaCHb)], 0.18 [ddd, J = 5, 5, 5 Hz, 2H, CH2CH(CHaHbCHaCHb)]. 13 C NMR (125 MHz, CDCl3): d 202.5, 145.2, 144.0, 128.9, 128.0, 127.5, 127.42, 127.40, 127.3, 61.1, 8.9, and 37.8.
TLC: Rf = 0.26 in 3:1 hexanes:EtOAc.
N,N-Diethyl-2-iodobenzothioamide (6110)
I O I O I S 1) SOCl2, 60 ºC Lawsson's reagent OH NEt2 NEt2 2) Et2NH, CH2Cl2 toluene 110 ºC S6002 6110 A suspension of 2-iodobenzoic acid (2.505 g, 10.1 mmol) was suspended in thionyl chloride (10 mL) in a round bottom flask fitted with a reflux condenser and a drying tube filled with CaCl2. The reaction mixture was heated at 60 ºC and turned to a homogeneous Part III Experimental Procedures and Computational Details 193 solution over 1 hour. The reaction mixture was cooled to room temperature and excess thionyl chloride was removed in vacuo. The residual white solid was suspended in CH2Cl2 (10 mL). This suspension was added dropwise to a solution of diethylamine (5.3 mL, 51.2 mmol) in CH2Cl2 (20 mL) at 0 ºC. The reaction mixture was then stirred at room temperature overnight and satd. NH4Cl (30 mL) was added. The organic phase was separated. The aqueous phase was extracted with CH2Cl2 (2x20 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes:EtOAc = 10:1) to give S6002144 (1.553 g, 5.1 mmol, 50%) as a pale yellow oil. [VP] N,N-Diethyl-2-iodobenzothioamide (6110) was prepared from S6002 via the thionation described in the general procedure. Purification by flash chromatography (hexanes:EtOAc = 12:1) gave 6110 (94%) as a pale yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.79 (d, J = 7.9 Hz, 1H, ArH3), 7.35 (dd, J = 7.5, 7.5 Hz, 1H, ArH5), 7.24 (dd, J = 7.6, 1.2 Hz, 1H, ArH6), 6.97 (ddd, J = 7.8, 7.5, 1.3 Hz, 1H, ArH4),
4.60 [dq, J = 13.8, 7.0 Hz, 1H, N(CHaHbCH3)(C2H5)], 3.65 [dq, J = 12.8, 7.1 Hz, 1H,
N(CHaHbCH3)(C2H5)], 3.38 [dq, J = 14.3, 7.1 Hz, 1H, N(C2H5)(CHcHdCH3)], 3.35 [dq, J
= 14.0, 7.0 Hz, 1H, N(C2H5)(CHcHdCH3)], 1.43 [t, J = 7.1 Hz, 3H, N(CH2CH3)(C2H5)], and 1.13 [t, J = 7.1 Hz, 3H, N(C2H5)(CH2CH3)]. 13 C NMR (125 MHz, CDCl3): d 199.1, 147.5, 139.3, 128.8, 128.4, 126.2, 92.8, 47.5, 45.6, 13.4, and 10.6. IR (neat): 3046, 2974, 2932, 2870, 1580, 1557, 1510, 1501, 1456, 1427, 1380, 1360, 1344, 1314, 1287, 1258, 1243, 1192, 1141, 1112, 1096, 1075, 1051, 1012, 981, 944, 923, and 780 cm-1. HRMS (ESI-TOF):
TLC: Rf = 0.3 in 3:1 hexanes:EtOAc. mp: 80-88 °C.
144 Kumar, S.; Bhakuni, B. S.; Yadav, A.; Kumar, S.; Patel, S.; Sharma, S. KOtBu-mediated synthesis of of dimethylisoindolin-1-ones and dimethyl-5-phenylisoindolin-1-ones: selective C–C coupling of an unreactive tertiary sp3 C–H bond. J. Org. Chem. 2014, 79, 2944-2954. Part III Experimental Procedures and Computational Details 194
N,N-Diethyl-1-tosyl-1H-indole-3-carbothioamide (6111)
O S NEt2 NEt2 1) (COCl)2, AlCl3, CH2Cl2 Lawsson's reagent N 2) Et NH, CH Cl toluene, 110 ºC Ts 2 2 2 N N Ts Ts S6003 S6004 6111 N,N-Diethyl-1-tosyl-1H-indole-3-carboamide (S6004) was prepared according to a known procedure.145 Oxalyl chloride (3.6 mL, 42 mmol) was added to a suspension of anhydrous aluminum chloride (5.6 g, 42 mmol) in CH2Cl2 (40 mL) at 0 ºC. The resulting mixture was stirred at 0 ºC for 1 hour, and then a solution of N-tosylindole146 (S6003, 2.17 g, 8 mmol) in CH2Cl2 (10 mL) was added dropwise to the suspension above. The reaction immediately turned dark red. After the addition was complete, the reaction mixture was allowed to warm to room temperature and further stirred for 4 hours. The reaction mixture was then poured into crushed ice (100 g). The mixture was transferred into a separatory funnel. The organic phase was separated. The aqueous phase was extracted with CH2Cl2 (2x20 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The brown residue was taked up in CH2Cl2 (10 mL) and was added dropwise to a solution of diethylamine (2.6 mL, 25.1 mmol) in CH2Cl2 (20 mL) at 0 ºC. the reaction mixture was allowed to warm to room temperature and further stirred for 10 hours. The solvent and excess diethylamine was then removed in vacuo. The resulting residue was purified by flash chromatography (hexanes:EtOAc = 1:1) to give S6004 (2.26 g, 6.1 mmol, 76%) as a yellow solid. [VP] N,N-Diethyl-1-tosyl-1H-indole-3-carbothioamide (6111) was prepared from S6004 via the thionation describe d in the general procedure. Purification by flash chromatography (hexanes:EtOAc = 8:1) gave 6111 as a yellow solid. The first portion to elute from the
145 Perez-Serrano, L.; Casarrubios, L.; Dominguez, G.; Freire, G.; Perez-Castells, J. Preparation of 3,4- enynindoles via directed lithiation and application to the synthesis of 3,4-carbocyclocindoles. Tetrahedron, 2002, 58, 5407-5415. 146 Hostier, T.; Ferey, V.; Ricci, G.; Pardo, D. G.; Cossy, J. TFA-promoted direct C-H sulfenylation at the C2 position of non-protected indoles. Chem. Comm. 2015, 51, 13898-13901. Part III Experimental Procedures and Computational Details 195 column was pure 6111; later fractions contained byproducts derived from the Lawesson’s reagent. The overall yield was >100% of theory, including those impurities. 1 H NMR (500 MHz, CDCl3): d 7.95 (d, J = 8.3 Hz, 1H, H4), 7.79 (d, J = 8.4 Hz, 2H,
O2SArHo2), 7.58 (s, 1H, H2), 7.53 (d, J = 8.0 Hz, 1H, H7), 7.34 (ddd, J = 8.3, 8.3, 1.1 Hz,
1H, H5), 7.28–7.22 (m, 3H, H6, O2SArHm2), 4.17 (q, J = 7.0 Hz, 2H, NCH2), 3.49 (q, J =
6.9 Hz, 2H, NCH2), 2.35 (s, 3H, O2SC6H4CH3), 1.41 (t, J = 7.0 Hz, 3H, NCH2CH3), and
1.13 (t, J = 7.0 Hz, 3H, NCH2CH3). 13 C NMR (125 MHz, CDCl3): d 190.9, 145.4, 134.9, 134.3, 130.0, 128.3, 126.9, 125.3, 125.0, 123.9, 121.7, 120.4, 113.5, 48.1, 46.2, 21.6, 14.2, and 11.4. IR (neat): 2975, 2934, 1731, 1714, 1596, 1557, 1515, 1505, 1494, 1462, 1446, 1427, 1371, 1297, 1267, 1239, 1202, 1188, 1174, 1146, 1125, 1103, 1087, and 995 cm-1. HRMS (ESI-TOF):
TLC: Rf = 0.3 in 3:1 hexanes:EtOAc. mp: 45-56 °C.
Morpholino(naphthalen-2-yl)methanethione (6112)
O O S morpholine P4S10 Cl N N CH2Cl2 O dixane O S6005 71112
A slurry of b-naphthoyl chloride (1.19 g, 6.2 mmol) in CH2Cl2 (7 mL) was added dropwise to a solution of morpholine (2 mL, 23 mmol) in CH2Cl2 (6 mL) at 0 ºC. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with water (15 mL). the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (3x5 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give S6005 (1.27 g, 5.3 mmol, 85%) as an off-white solid. Tetraphosphorous decasulfide (825 mg, 1.8 mmol) was added to a solution of S6005 (734 mg, 3 mmol) in dioxane (15 mL). The resulting suspension was stirred at room temperature, during which time the color of the mixture turned from white to bright yellow to orange. Part III Experimental Procedures and Computational Details 196
After the starting material had been all consumed according to GC-MS, the solvent was evaporated in vacuo. The residue was treated with EtOAc (10 mL) and satd. NaHCO3. The resulting mixture was vigorously stirred for 15 minutes. The organic layer was separated. The aqueous layer was extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 6112 (777 mg, 3 mmol, quant.) as an pale yellow solid that is sufficiently pure for the HDDA reaction. 1 H NMR (500 MHz, CDCl3): d 7.85-7.81 (m. 3H, ArH), 7.76 (d, J = 1.8 Hz, H1), 7.52 (dd, J = 7.0, 7.0 Hz, 1H, H6 or H7), 7.51 (dd, J = 6.9, 6.9 Hz, 1H, H6 or H7), 7.40 (dd, J = 8.4,
1.8 Hz, 1H, H3), 4.50 [t, J = 4.9 Hz, 2H, Ar(C=S)NCHa2], 3.93 [t, J = 5.0 Hz, 2H,
Ar(C=S)NCHb2], and 3.65 (br s, 4H, OCH2CH2). 13 C NMR (125 MHz, CDCl3): d 201.0, 139.7, 133.2, 132.7, 128.41, 128.36, 127.7, 126.95, 126.88, 125.0, 123.8, 66.8, 66.6, 52.6, and 49.6.
N-Benzyl-N-methyl-1H-pyrrole-1-carbothioamide (6113)
i O O S COCl2, Pr2NEt pyrrole, NaH Lawsson's reagent Ph NHMe Ph N Cl Ph N N Ph N N toluene, CH2Cl2 Me DMF Me toluene, 110 ºC Me S6006 S6007 6113 A solution of N-methylbenzylamine (1.2 g, 9.9 mmol) and diisopropylethylamine (3 mL,
17 mmol) in CH2Cl2 (20 mL) was added dropwise to a solution of phosgene (12 mL, 20 wt% in toluene) at 0 ºC over 30 minutes. The resulting mixture was stirred at 0 ºC for 3 hours. The solvents were then removed in vacuo. The residue was treated with Et2O (20 mL). The resulting precipitate was removed by filtration. The filtrate was concentrated in vacuo to give S6006 as a pale yellow liquid (1.82 g, 9.9 mmol, quant.) A solution of pyrrole (338 mg, 5 mmol) in DMF (3 mL) was added dropwise to a suspension of NaH (60% dispersion in mineral oil, 442 mg, 11 mmol) at 0 ºC under N2 atmosphere. The resulting mixture was heated at 70 ºC under N2 atmosphere for 2 hours, during which time the pink reaction mixture turned brown. The resulting mixture was allowed to cool to 0 ºC, and a solution of S6006 (1.45 g, 7.9 mmol) in DMF (2.5 mL) was added to the resulting thick cake. The reaction mixture was heated at 75 ºC under N2 Part III Experimental Procedures and Computational Details 197 atmosphere overnight and satd. NH4Cl (30 mL) was added. The resulting mixture was extracted with EtOAc (3x10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes:EtOAc = 10:1 to 6:1) to give S6007 (760 mg, 3.6 mmol, 72%) as a yellow oil. 1 H NMR (500 MHz, CDCl3): d 7.41-7.37 (nfom, 2H, NCH2PhHm2), 7.34-7.30 (nfom, 1H,
NCH2PhHp), 7.31-7.28 (nfom, 2H, NCH2PhHo2), 7.08 [dd, J = 2.4, 2.4 Hz, 2H,
(C=O)NCHaCHa], 6.23 [dd, J = 2.4, 2.4 Hz, 2H, (C=O)NCHaHbCHbHa], 4.65 (s, 2H,
NCH2Ph), and 3.01 (PhCH2NCH3). N-Benzyl-N-methyl-1H-pyrrole-1-carbothioamide (6113) was prepared from S6007 via the thionation described in the general procedure. Purification by flash chromatography (hexanes:EtOAc = 10:1) gave 6113 (86%) as an air-sensitive yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.37 (ddd, 6.9, 6.9, 1.5 Hz, 2H, NCH2PhHm2), 7.33 (tt, J =
7.3, 1.6 Hz, 1H, NCH2PhHp), 7.28-7.26 (br d, J = 7.2 Hz, 2H, NCH2PhHo2), 7.09 [dd, J =
2.3, 2.3 Hz, 2H, (C=S)NCHaCHa], 6.24 [dd, J = 2.3, 2.3 Hz, 2H, (C=S)NCHaHbCHbHa],
5.01 (br s, 2H, NCH2Ph), and 3.21 (PhCH2NCH3). 13 C NMR (125 MHz, CDCl3): d 184.5, 135.2, 129.0, 128.1, 127.6, 122.1, 111.2, 59.2, and 41.5. TLC: 0.25 in 10:1 hexanes:EtOAc.
Ethyl N-allyl-N-(phenylcarbonothioyl)glycinate (6114)
O S K2CO3, NaI HN PhCOCl, Et3N Lawsson's reagent NH2 + Br CO2Et N N DMF CO2Et CH2Cl2 toluene 105 ºC CO2Et CO2Et S6008 S6009 6114 A solution of ethyl bromoacetate (2.51 g, 15 mmol) in DMF (7 mL) was added dropwise to a mixture of allylamine (4.6 mL, 61.6 mmol), K2CO3 (8.33 g, 60.3 mmol), and NaI (4.59 g, 30.6 mmol) in DMF (30 mL) at 0 ºC. The reaction mixture was then allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with brine (30 mL). The precipitate was removed by vacuum filtration and washed with Et2O (30 mL). Part III Experimental Procedures and Computational Details 198
The filtrates were combined. The organic layer was separated. The aqueous layer was extracted with Et2O (3x30 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to give a mixture of S6008 and DMF as a colorless liquid.
This mixture and Et3N (4.2 mL, 30.1 mmol) was taked up in CH2Cl2 (20 mL). At 0 ºC benzoyl chloride (1.8 mL, 15.5 mmol) was added dropwise to the solution above. The reaction mixture was allowed to warm to room temperature and stirred overnight. The resulting mixture was quenched with satd. NH4Cl (30 mL). The organic layer was separated.
The aqueous layer was extracted with CH2Cl2 (3x10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes:EtOAc = 6:1 to 3:1) to give S6009 (2.51 g, 10.2 mmol, 68% over 2 steps) as a yellow oil. Ethyl N-allyl-N-(phenylcarbonothioyl)glycinate (6114) was prepared from S6009 via the thionation described in the general procedure. Purification by flash chromatography (hexanes:EtOAc = 5:1) gave 6114 (54%) as an air-sensitive yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.37-7.27 (m, 5H, PhH5,), 5.78 (ddt, J = 17.2, 10.2, 5.6 Hz,
NCH2CH=CH2), 5.31 (ddd, J = 10.2, 2.7, 1.4 Hz, 1H, NCH2CH=CHEHZ), 5.23 (ddd, J =
17.1, 3.0, 1.6 Hz, 1H, NCH2CH=CHZHE), 4.28 (q, J = 7.1 Hz, 2H, OCH2CH3), 4.14 (ddd,
J = 5.9, 1.6, 1.6 Hz, 2H, NCH2CH=CH2), and 1.33 (t, J = 7.1 Hz, OCH2CH3). TLC: 0.2 in 4:1 hexanes:EtOAc.
N-Allyl-2,2,2-trifluoro-N-phenylethanethioamide (6131)
S
F3C N Ph [VP] N-Allyl-2,2,2-trifluoro-N-phenylethanethioamide (6131) was prepared from N-allyl- 2,2,2-trifluoro-N-phenylacetamide via the thionation described in the general procedure. Purification by flash chromatography (hexanes:EtOAc = 12:1) gave 6131 (85%) as a yellow oil. Part III Experimental Procedures and Computational Details 199
1 H NMR (500 MHz, CDCl3): d 7.46-7.38 (m, 3H, PhH), 7.20-7.15 (m, 2H, PhH), 5.96 (ddt,
J = 16.7, 10.2, 6.4 Hz, 1H, CH2CH=CH2), 5.28 (dd, J = 10.2, 0.9 Hz, 1H, CH2CH=CHaHb),
5.17 (dd, J = 17.1, 1.2 Hz, 1H, CH2CH=CHaHb), and 4.80 (d, J = 6.4 Hz, 2H, CH2CH=CH2). 13 C NMR (125 MHz, CDCl3): d 183.1, 142.8, 129.2, 128.7, 126.88, 126.87, 120.9, 117.3 (q, J = 280.1 Hz), and 61.7. IR (neat): 1493, 1456, 1421, 1405, 1337, 1297, 1241, 1209, 1141, 1099, 1076, 1004, 992, 970, 934, 853, and 776 cm-1.
TLC: Rf = 0.5 in 5:1 hexanes:EtOAc.
N-Benzyl-2,2,2-trifluoro-N-methylethanethioamide (6132)
S
F3C N Ph Me N-Benzyl-2,2,2-trifluoro-N-methylethanethioamide (6132) was prepared from N-benzyl- 2,2,2-trifluoro-N-methylacetamide via the thionation described in the general procedure. Purification by flash chromatography (hexanes:EtOAc = 15:1) gave 6132 (quant.) as a yellow oil. 1 H NMR (500 MHz, CDCl3): d 7.42-7.17 (m, 5H, NCH2PhH5, rotamers a and b), 5.28 (s,
2H, NCH2Ph, rotamer a), 4.98 (s, 2H, NCH2Ph, rotamer b), 3.34 [q, J = 1.6 Hz, 3H,
F3C(C=S)NCH3, rotamer a], and 3.34 [s, 3H, F3C(C=S)NCH3, rotamer b]. 13 C NMR (125 MHz, CDCl3): d 83. TLC: 0.3 in 10:1 hexanes:EtOAc.
2,5-Dimethyl-1-phenyl-6-(trimethylsilyl)-2,3-dihydrofluoreno[4,3-e][1,3]thiazin- 7(1H)-one (6053) Part III Experimental Procedures and Computational Details 200
S O TMS NMe2 O Me TMS 6047 S Me PhH, 90 ºC, 12 h N
4009 6053 [VP] A solution of the triyne 4009 (31 mg, 0.12 mmol) and the thioamide 6047 (28 mg, 0.17 mmol) in benzene (1.2 mL) was placed in a culture tube and sealed with a Teflon®- lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (12:1 hexanes:EtOAc as eluent). The residue was purified by MPLC (hexanes:EtOAc = 30:1) to give 6053 (23 mg, 0.05 mmol, 46%) as a yellow oil. 1 H NMR (500 MHz, CDCl3): d 7.55 (dd, J = 6.8, 1.5 Hz, 1H, ArH8), 7.35-7.25 (m, 5H,
PhH5), 7.17 (ddd, J = 7.5, 7.5, 1.5 Hz, 1H, ArH10), 7.14 (ddd, J = 7.7, 7.7, 1.2 Hz, 1H, ArH9), 7.00 (br d, J = 7.3 Hz, 1H, ArH11), 5.39 (s, 1H, CHPh), 4.46 (d, J = 12.1 Hz, 1H,
NCHaHbS), 4.01 (dd, J = 12.1, 1.5 Hz, 1H, NCHaHbS), 2.63 (s, 3H, NCH3), 2.49 (s, 3H,
ArCH3), and 0.47 (s, 9H, Si(CH3)3). 13 C NMR (125 MHz, CDCl3): d 194.6, 143.1, 141.8, 141.17, 141.15, 140.2, 140.1, 135.8, 134.9, 133.8, 128.9, 128.8, 128.0, 127.9, 124.6, 123.8, 123.4, 63.9, 51.6, 41.3, 21.6, and 2.9. IR (neat): 3058, 3026, 2973, 2942, 2896, 2808, 1703, 1602, 1522, 1464, 1448, 1285, 1277, 1264, 1247, 1212, 1178, 1093, 1000, 846, and 777 cm-1.
TLC: Rf = 0.2 in 12:1 hexanes:EtOAc.
2-Ethyl-3,5-dimethyl-1-phenyl-6-(trimethylsilyl)-2,3-dihydrofluoreno[4,3- e][1,3]thiazin-7(1H)-one (6060) Part III Experimental Procedures and Computational Details 201
S O TMS NEt2 O Me TMS 6054 S Me PhH, 90 ºC, 12 h N Me Et 4009 6060 [VP] A solution of the triyne 4009 (31 mg, 0.12 mmol) and the thioamide 6054 (34 mg, 0.18 mmol) in benzene (1.2 mL) was placed in a culture tube and sealed with a Teflon®- lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (12:1 hexanes:EtOAc as eluent). The eluate was concentrated and the residue was purified by MPLC (hexanes:EtOAc = 50:1) to give 6060 (31 mg, 0.07 mmol, 58%) as a partially crystalline, yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.56 (d, J = 6.8, 1H, ArH8), 7.37-7.24 (m, 5H, PhH5), 7.19–7.12 (m, 2H, ArH9 and ArH10), 7.00 (d, J = 7.2 Hz, 1H, ArH11), 5.73 (s, 1H, CHPh),
4.63 (q, J = 6.6 Hz, 1H, NCH(Me)S), 3.01 (dq, J = 13.5, 7.2 Hz, 1H, NCHaHbMe), 2.46 (s,
3H, ArCH3), 2.35 (dq, J = 13.3, 6.8 Hz, 1H, NCHaHbMe), 1.45 (d, J = 6.8 Hz, 3H,
NCH(CH3)S), 1.25 (t, J = 7.0 Hz, 3H, NCH2CH3), and 0.46 [s, 9H, Si(CH3)3]. 13 C NMR (125 MHz, CDCl3): d 194.6, 143.7, 143.2, 142.0, 141.0, 140.9, 139.9, 135.7, 134.9, 133.9, 129.1, 128.8, 128.0, 127.6, 124.3, 123.7, 123.4, 62.2, 57.2, 39.2, 21.6, 19.8, 14.2, and 2.9. (Hexanes impurities) IR (neat): 3057, 3025, 2971, 2930, 2897, 2869, 1704, 1604, 1587, 1522, 1492, 1463, 1449, 1383, 1285, 1263, 1246, 1199, 1093, 1058, 994, 846, and 776 cm-1.
TLC: Rf 0.4 in 5:1 hexanes:EtOAc. mp: 51-60 °C.
2-iso-Propyl-3,3,5-trimethyl-1-phenyl-6-(trimethylsilyl)-2,3-dihydrofluoreno[4,3- e][1,3]thiazin-7(1H)-one (6061) Part III Experimental Procedures and Computational Details 202
S TMS i O N Pr2 O Me TMS 6055 S Me PhH, 90 ºC, 12 h Me N Me iPr 4009 6061 [VP] A solution of the triyne 4009 (30 mg, 0.11 mmol) and the thioamide 6055 (37 mg, 0.17 mmol) in benzene (1.2 mL) was placed in a culture tube and sealed with a Teflon®- lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (12:1 hexanes:EtOAc as eluent). The eluate was concentrated and the residue was purified by MPLC (hexanes:EtOAc = 50:1) to give 6061 (33 mg, 0.07 mmol, 60 %) as a partially crystalline, orange solid. 1 H NMR (500 MHz, CDCl3): d 7.58 (nfom, 1H, ArH8), 7.39 (d, J = 7.7 Hz, 2H, PhHo2),
7.22 (br dd, J = 7.1, 7.1 Hz, 2H, PhHm2), 7.16 (br dd, J = 7.4, 7.4 Hz, 1H, PhHp), 7.17–7.12 (m, 2H, ArH9 and ArH10) 6.92 (nfom, 1H, ArH11), 5.86 (s, 1H, CHPh), 3.78 [septet, J =
6.6 Hz, 1H, CH(Me)2], 2.41 (s, 3H, ArCH3), 1.66 {s, 3H, NC[(CHa3)(CHb3)]S}, 1.42 [d, J
= 6.6 Hz, 3H, CH(CHa3)(CHb3)], 1.27 {s, 3H, NC[(CHa3)(CHb3)]S}, 0.94 [d, J = 6.5 Hz,
3H, CH(CHa3)(CHb3)], and 0.47 [s, 9H, Si(CH3)3]. 13C NMR (125 MHz, CDCl3): d 194.7, 144.5, 143.7, 143.5, 142.6, 140.1, 139.8, 135.6, 135.0, 133.9, 129.2, 128.1, 127.9, 127.7, 126.6, 123.7, 123.4, 67.8, 55.1, 48.9, 36.8, 30.9, 24.7, 22.0, 19.2, and 2.8. IR (neat): 3057, 2975, 2951, 2900, 1704, 1602, 1586, 1518, 1491, 1463, 1449, 1384, 1364, 1284, 1262, 1247, 1203, 1179, 1117, 1093, 997, and 847 cm-1.
TLC: Rf = 0.5 in 5:1 hexanes:EtOAc. mp: 78-90 °C.
2-Allyl-5-methyl-1-phenyl-6-(trimethylsilyl)-3-vinyl-2,3-dihydrofluoreno[4,3- e][1,3]thiazin-7(1H)-one (6062) Part III Experimental Procedures and Computational Details 203
S TMS N O Me O TMS 6056 S
Me PhH, 90 ºC, 12 h N
4009 6061 [VP] A solution of the triyne 4009 (31 mg, 0.12 mmol) and the thioamide 6056 (37 mg, 0.17 mmol) in benzene (1.2 mL) was placed in a culture tube and sealed with a Teflon®- lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (12:1 hexanes:EtOAc as eluent). The eluate was concentrated and the residue was purified by MPLC (hexanes:EtOAc = 50:1) to give 6062 (44 mg, 0.09 mmol, 79%) as a partially crystalline, yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.55 (nfom, J = 6.7 Hz, 1H, ArH8), 7.34-7.24 (m, 5H,
PhH5), 7.16-7.11 (m, 2H, ArH9 and ArH10), 6.92 (nfom, 1H, ArH11), 6.01 (dddd, J = 17.9,
9.7, 8.5, 4.0 Hz, 1H, NCH2CH=CH2), 5.96 [ddd, J = 17.3, 10.6, 4.9 Hz, 1H,
SCH(CH=CH2)], 5.73 (s, 1H, CHPh), 5.42 (ddd, J = 17.3, 2.2. 0.7 Hz, 1H,
SCHCH=CHaHb), 5.33 (ddd, J = 10.6, 2.1, 0.7 Hz, 1H, SCHCH=CHaHb), 5.14 (m, 1H,
NCH(vinyl)S), 5.18–5.13 (m, 2H, NCH2CH=CH2), 3.61 (dddd, J = 14.5, 3.8, 1.8, 1.8 Hz,
1H, NCHaHbCHCH2), 2.83 (dd, J = 14.5, 8.5 Hz, 1H, NCHaHbCHCH2), 2.51 (s, 1H,
ArCH3), and 0.48 [s, 9H, Si(CH3)3]. 13 C NMR (125 MHz, CDCl3): d 194.7, 143.1, 142.7, 142.1, 141.3, 140.6, 140.1, 136.0, 135.3, 135.0, 134.8, 134.0, 129.1, 128.8, 128.0, 127.8, 124.3, 123.8, 123.4, 118.9, 118.6, 62.0, 61.3, 49.2, 30.9 (acetone), 21.6, and 2.9. IR (neat): 3082, 3061, 3025, 2977, 2947, 2897, 2842, 1705, 1641, 1603, 1587, 1522, 1491, 1465, 1449, 1388, 1285, 1247, 1182, 1123, 1093, 1064, 1002, 978, and 847 cm-1.
TLC: Rf = 0.5 in 5:1 hexanes:EtOAc. mp: 188-196 °C.
Part III Experimental Procedures and Computational Details 204
5-Methyl-12-(pyridin-3-yl)-6-(trimethylsilyl)-1,2,3,3a-tetrahydrofluoreno[4,3- e]pyrrolo[2,1-b][1,3]thiazin-7(12H)-one (6063)
S
N O TMS Me O N TMS 6057 S Me PhH, 90 ºC, 12 h N
N 4009 6063 [VP] A solution of the triyne 4009 (30 mg, 0.11 mmol) and the thioamide 6057 (34 mg, 0.18 mmol) in benzene (1.2 mL) was placed in a culture tube and sealed with a Teflon®- lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (1:3 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 1:3) to give 6063 (26 mg, 0.06 mmol, 50%) as a partially crystalline, yellow solid. 1 H NMR (500 MHz, CDCl3): d 8.72 (s, 1H, PyH2), 8.54 (d, J = 4.5 Hz, 1H, PyH6), 7.58 (d, J = 7.1 Hz, 1H, ArH8), 7.51 (d, J = 7.8 Hz, 1H, PyH4), 7.27-7.16 (m, 3H, PyH5, ArH9, ArH10), 6.99 (d, J = 7.4 Hz, 1H, ArH11), 5.80 (s, 1H, CHPy), 4.63 (d, J = 5.2 Hz, NCHS),
3.18 (ddd, J = 8.9, 8.9, 3.8 Hz, 1H, NCHaHbCH2), 2.77 (ddd, J = 9.5, 9.5, 7.0 Hz, 1H,
NCHaHbCH2), 2.45 (s, 3H, ArCH3), 2.33-2.25 (m, 1H, SCHCHaHb), 2.19-2.10 (m, 1H,
SCHCHaHb), 2.05-1.97 (m, 2H, NCH2CH2), and 0.46 [s, 9H, Si(CH3)3]. 13 C NMR (125 MHz, CDCl3): d 194.3, 150.5, 148.8, 143.0, 141.43, 141.36, 140.8, 136.1, 135.6, 135.5, 134.9, 133.9, 128.3, 123.7, 123.6, 123.4, 122.1, 62.1, 57.8, 49.5, 33.1, 21.7, 21.1, and 2.9. IR (neat): 3048, 2948, 1704, 1603, 1588, 1576, 1523, 1463, 1419, 1386, 1287, 1246, 1188, 1173, 1136, 1092, 1065, 996, 846, and 778 cm-1.
TLC: Rf = 0.2 in 1:3 hexanes:EtOAc. mp: 84-110 °C.
Part III Experimental Procedures and Computational Details 205
5-Methyl-1,2-diphenyl-6-(trimethylsilyl)-2,3-dihydrofluoreno[4,3-e][1,3]thiazin- 7(1H)-one (6064)
S
N O TMS Me O Me TMS 6058 S Me PhH, 90 ºC, 12 h N Ph 4009 6064 [VP] A solution of the triyne 4009 (31 mg, 0.12 mmol) and the thioamide 6058 (40 mg, 0.18 mmol) in benzene (1.2 mL) was placed in a culture tube and sealed with a Teflon®- lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (12:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 50:1) to give 6064 (29 mg, 0.06 mmol, 50%) as a partially crystalline, yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.60 (d, J = 6.6 Hz, 1H, ArH8), 7.41-7.30 (m, 5H, CPhH),
7.28-7.23 (m, 2H, NPhHm2), 7.23-7.16 (m, 2H, ArH9 and ArH10), 7.12 (d, J = 8.0 Hz, 2H,
NPhHo2), 7.07 (d, J = 6.9 Hz, 1H, ArH11), 6.95-6.91 (m, 1H, NPhHp), 6.43 (s, 1H, CHPh),
4.80 (d, J = 13.0 Hz, 1H, NCHaHbS), 4.76 (d, J = 13.0 Hz, 1H, NCHaHbS), 2.38 (s, 3H,
ArCH3), and 0.44 [s, 9H, Si(CH3)3]. 13 C NMR (125 MHz, CDCl3): d 194.4, 147.6, 142.9, 141.8, 141.3, 141.0, 140.5, 139.8, 135.8, 135.0, 134.1, 129.5, 129.1, 128.9, 128.24, 128.19, 125.9, 123.7, 123.6, 121.3, 117.5, 59.6, 47.3, 21.6, and 2.9. IR (neat): 3060, 2947, 2896, 1704, 1599, 1523, 1496, 1462, 1450, 1388, 1321, 1283, 1270, 1247, 1201, 1180, 1141, 1092, 1067, 1029, 1000, 947, 846, and 779 cm-1.
TLC: Rf = 0.3 in 5:1 hexanes:EtOAc. mp: 75-82 °C.
Part III Experimental Procedures and Computational Details 206
(7R,9S)-8-Allyl-5-methyl-9-phenyl-4-(prop-1-yn-1-yl)-1-tosyl-7-vinyl-1,2,3,7,8,9- hexahydro-[1,3]thiazino[6,5-g]indole (6065)
S Me N
Me 6056 Me N Me PhH, 90 ºC, 12 h Ts N S Ts Ph N
4010 6065 [VP] A solution of the tetrayne 4010 (51 mg, 0.16 mmol) and the thioamide 6056 (48 mg, 0.22 mmol) in benzene (1.5 mL) was placed in a culture tube and sealed with a Teflon®- lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (5:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 12:1) to give 6065 (56 mg, 0.1 mmol, 66 %) as a partially crystalline, white solid. 1 H NMR (500 MHz, CDCl3): d 7.37 (d, J = 7.8 Hz, 2H, O2SArHo2), 7.25-7.14 (m, 5H,
PhH5), 6.99 (d, J = 7.1 Hz, 2H, O2SArHm2), 6.41 (s, 1H, CHPh), 6.12 (dddd, J = 15.9, 10.4,
5.4, 5.4 Hz, 1H, NCH2CH=CH2), 5.92 [ddd, J = 16.2, 10.6, 5.0 Hz, 1H, SCH(CH=CH2)],
5.43 (d, J = 17.0 Hz, 1H, SCHCH=CHaHb), 5.35 (d, J = 17.3 Hz, 1H, NCH2CH=CHaHb),
5.24 (d, J = 10.9, 1H, SCHCH=CHaHb), 5.21 (d, J = 10.5 Hz, 1H, NCH2CH=CHaHb), 5.11
(d, J = 4.3 Hz, 1H, NCH(vinyl)S), 3.90 (dd, J = 12.6, 7.3 Hz, 1H, TsNCHaHbCH2), 3.63
[dd, J = 15.6, 4.4 Hz, 1H, NCHaHbC(H)=], 3.43 (ddd, J = 12.8, 11.6, 7.8 Hz, 1H,
TsNCHaHbCH2), 3.27 (dd, J = 15.6, 5.5 Hz, 1H, NCHaHbC(H)=), 2.56 (s, 3H,
O2SC6H4CH3), 2.40 (s, 3H, ArCH3), 2.33 (dd, J = 15.8, 6.6 Hz, 1H, TsNCH2CHaHb), 2.09
(ddd, J = 16.6, 11.1, 7.7 Hz, 1H, TsNCH2CHaHb), and 2.05 (s, 3H, C≡CCH3). 13 C NMR (125 MHz, CDCl3): d 144.0, 142.4, 140.4, 136.4, 136.2, 135.7, 135.6, 134.7, 134.4, 129.4, 128.6, 128.0, 127.7, 126.9, 122.9, 119.7, 118.0, 116.0, 93.2, 76.0, 62.9, 61.9, 53.3, 49.6, 29.3, 21.6, 17.6, and 4.5. IR (neat): 3081, 2915, 2849, 1640, 1597, 1560, 1491, 1449, 1396, 1351, 1330, 1265, 1239, 1163, 1118, 1089, 1013, 977, 958, 925, 858, and 814 cm-1. Part III Experimental Procedures and Computational Details 207
TLC: Rf = 0.3 in 3:1 hexanes:EtOAc. mp: 71-88 °C.
5-Methyl-11-phenyl-4-(prop-1-yn-1-yl)-1,6a,7,8,9,11-hexahydro-3H- isobenzofuro[4,5-e]pyrrolo[2,1-b][1,3]thiazine (6066) and 5-methyl-6-phenyl-4- (prop-1-yn-1-yl)-3,6,8,9,10,10a-hexahydro-1H-isobenzofuro[5,4-e]pyrrolo[2,1- b][1,3]thiazine (6066’)
S Me Me N
Me 6059 Me Me O + O O Me PhH, 75 ºC, 12 h Ph S S N Ph N 4008 6066 6066' [VP] A solution of the tetrayne 4008 (30 mg, 0.18 mmol) and the thioamide 6059 (48 mg, 0.25 mmol) in benzene (1.8 mL) was placed in a culture tube and sealed with a Teflon®- lined screw cap. The tube was heated in an oil bath held at 75 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (3:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 7:1) to give, in order of elution, 6066’ (10 mg, 0.03 mmol, 16%) and 6066 (38 mg, 0.11 mmol, 60%), each as a pale yellow solid. Data for 6066’: 1 H NMR (500 MHz, CDCl3): d 7.30–7.22 (m, 3H, PhHm2, PhHp), 7.15 (d, J = 7.2 Hz, 2H,
PhHo2), 5.22 (s, 1H, CHPh), 5.17 [s, 2H, C(3)H2OC(1)H2], 5.06 [d, J = 12.2 Hz, 1H,
C(1)HaHbOC(3)H2], 5.01 [d, J = 12.5 Hz, 1H, C(1)HaHbOC(3)H2], 4.72 (d, J = 4.8 Hz, 1H,
NCHS), 3.12 (ddd, J = 8.8, 8.8, 3.4 Hz, 1H, NCHaHb), 2.75-2.70 (ddd, J = 9.3, 9.3, 7.2
Hz,1H, NCHaHb), 2.2–2.0 [12H including 2.17 (s, 3H, ArCH3) and 2.07 (s, 3H, C≡CCH3)], 1.97 (m, 1H), and 1.90 (m, 1H). 13 C NMR (125 MHz, CDCl3): d 140.4, 139.9, 137.9, 132.9, 128.7, 128.53, 128.45, 127.4, 123.5, 112.8, 92.4, 76.2, 74.9, 73.8, 61.8, 59.7, 49.6, 32.6, 21.0, 16.2, and 4.5. Part III Experimental Procedures and Computational Details 208
IR (neat): 3058, 3027, 2952, 2913, 2847, 2202, 1582, 1492, 1450, 1421, 1374, 1359, 1342, 1318, 1287, 1238, 1176, 1156, 1134, 1059, 1028, 1003, 971, 911, 896, 882, and 846 cm-1.
TLC: Rf = 0.2 in 5:1 hexanes:EtOAc. mp: 50-60 °C. Data for 6066: 1 H NMR (500 MHz, CDCl3): d 7.29–7.21 (m, 3H, PhHm2, PhHp), 7.11 (d, J = 7.0 Hz, 2H,
PhHo2), 5.12-5.05 [m, 2H, C(3)H2OC(1)H2], 4.99 [d, J = 12.1 Hz, 1H, C(1)HaHbOC(3)H2], 4.89 (s, 1H, CHPh), 4.74 (d, J = 5.2 Hz, 1H, NCHS), 4.52 [d, J = 12.1 Hz, 1H,
C(1)HaHbOC(3)H2], 3.09 (ddd, J = 8.9, 8.9, 3.5 Hz, 1H, NCHaHb), 2.75 (ddd, J = 9.2, 9.2,
7.5 1H, NCHaHb), 2.42 (s, 3H, ArCH3), 2.25–2.06 [6H, including 2.11 (s, 3H, C≡CCH3)], and 1.99–1.91 (m, 2H). 13 C NMR (125 MHz, CDCl3): d 140.3, 136.3, 135.5, 135.2, 133.0, 128.5, 128.4, 127.5, 120.3, 116.4, 93.2, 76.0, 74.4, 73.1, 61.4, 61.1, 49.8, 32.7, 21.0, 17.1, and 4.6. IR (neat): 3058, 3028, 2952, 2913, 2846, 2235, 1581, 1492, 1450, 1377, 1356, 1303, 1291, 1264, 1244, 1176, 1156, 1129, 1058, 1024, 1006, 966, 903, and 880 cm-1.
TLC: Rf = 0.1 in 5:1 hexanes:EtOAc. mp: 63-71 °C.
5-Methyl-8,9-diphenyl-4-(prop-1-yn-1-yl)-1-tosyl-1,2,3,7,8,9-hexahydro- [1,3]thiazino[6,5-g]indole (6085)
S Me N Me Me 6058 Me N Me PhH, 75 ºC, 12 h Ts N S Ts Ph N Ph 4010 6085 [VP] A solution of the tetrayne 4010 (34 mg, 0.11 mmol) and the thioamide 6058 (35 mg, 0.15 mmol) in benzene (1.1 mL) was placed in a culture tube and sealed with a Teflon®- lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was Part III Experimental Procedures and Computational Details 209 evaporated and the residue was passed through a plug of silica gel (5:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 10:1) to give 6085 (46 mg, 0.08 mmol, 79 %) as a white solid. 1 H NMR (500 MHz, CDCl3): d 7.37-7.23 (m, 9H, CPhH, O2SArHo2, NPhHm2), 7.19–7.15
(m, 3H, NPhHo2, CHPh), 7.12 (d, J = 8.2 Hz, 2H, O2SArHm2), 6.89 (t, J = 7.2 Hz, 1H, PhHp)
4.68 (dd, J = 12.7, 1.3 Hz, 1H, NCHaHbS), 4.66 (br d, J = 12.7 Hz, 1H, NCHaHbS), 3.89
(ddd, J = 12.5, 7.4, 3.9 Hz, TsNCHaHbCH2), 3.61 (ddd, J = 12.9, 8.9, 8.9 Hz,
TsNCHaHbCH2), 2.37 (s, 3H, O2SC6H4CH3), 2.36 (s, 3H, ArCH3), 2.26 (ddd, J = 15.8, 7.6,
3.7 Hz, TsNCH2CHaHb), 2.19-2.12 (m, 1H, TsNCH2CHaHb), and 2.02 (s, 3H, C≡CCH3). 13 C NMR (125 MHz, CDCl3): d 147.8, 144.1, 141.6, 139.4, 136.7, 136.4, 134.7, 133.5, 129.4, 129.1, 128.5, 128.1, 127.7, 127.2, 124.9, 120.4, 120.0, 117.4, 93.5, 75.9, 58.9, 53.7, 46.9, 29.3, 21.6, 17.7, and 4.5. IR (neat): 3059, 3027, 2957, 2915, 2855, 2231, 1596, 1499, 1449, 1392, 1351, 1328, 1305, 1289, 1267, 1240, 1210, 1185, 1164, 1089, 1018, 1004, 952, 947, and 814 cm-1.
TLC: Rf = 0.2 in 3:1 hexanes:EtOAc. mp: 95-110 °C.
8-(4-Methoxyphenyl)-5-methyl-9-phenyl-4-(prop-1-yn-1-yl)-1-tosyl-1,2,3,7,8,9- hexahydro-[1,3]thiazino[6,5-g]indole (6086)
Me OMe S
N Me Me Me 6067 N S N Me PhH, 90 ºC, 12 h Ts Ts Ph N
OMe 4010 6085 [VP] A solution of the tetrayne 4010 (36 mg, 0.11 mmol) and the thioamide 6067 (41 mg, 0.16 mmol) in benzene (1.1 mL) was placed in a culture tube and sealed with a Teflon®- lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was Part III Experimental Procedures and Computational Details 210 evaporated and the residue was passed through a plug of silica gel (3:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 6:1) to give 6086 (48 mg, 0.08 mmol, 74%) as a white solid. 1 H NMR (500 MHz, CDCl3): d 7.34-7.23 (m, 7H, O2SArHo2, PhH5), 7.15–7.12 (m, 4H,
O2SArHm2, MeOArHm2), 6.99 (s, 1H, CHPh), 6.84 (d, J = 9.0 Hz, 2H, MeOArHo2), 4.65
(d, J = 12.5 Hz, 1H, NCHaHbS), 4.55 (d, J = 12.5 Hz, 1H, NCHaHbS), 3.86 (ddd, J = 12.2,
7.0, 3.5 Hz, 1H, TsNCHaHbCH2), 3.74 (s, 3H, ArOCH3), 3.54 (ddd, J = 12.8, 9.3, 8.1 Hz,
1H, TsNCHaHbCH2), 2.38 (s, 6H, O2SC6H4CH3, ArCH3), 2.30–2.17 (m, 2H, TsNCH2CH2), and 2.04 (s, 3H, C≡CCH3). 13 C NMR (125 MHz, CDCl3): d 154.2, 144.0, 142.0, 141.7, 139.4, 136.6, 136.3, 134.8, 133.5, 129.4, 128.5, 128.0, 127.7, 127.1, 124.5, 120.0, 119.9, 114.2, 93.4, 75.9, 59.6, 55.4, 53.7, 48.4, 29.3, 21.6, 17.7, and 4.5. IR (neat): 3057, 3026, 2952, 2914, 2834, 2230, 1596, 1559, 1510, 1493, 1449, 1442, 1351, 1304, 1287, 1244, 1183, 1163, 1089, 1036, 1004, 952, 923, 911, 857, and 816 cm-1.
TLC: Rf = 0.2 in 3:1 hexanes:EtOAc. mp: 81-100 °C.
5-Methyl-9-phenyl-4-(prop-1-yn-1-yl)-1-tosyl-8-(4-(trifluoromethyl)phenyl)- 1,2,3,7,8,9-hexahydro-[1,3]thiazino[6,5-g]indole (6087)
Me CF S 3
N Me Me Me 6068 N S N Me Ts PhH, 75 ºC, 12 h Ts Ph N
CF3 4010 6087 [VP] A solution of the tetrayne 4010 (36 mg, 0.11 mmol) and the thioamide 6068 (45 mg, 0.15 mmol) in benzene (1.1 mL) was placed in a culture tube and sealed with a Teflon®- lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was Part III Experimental Procedures and Computational Details 211 evaporated and the residue was passed through a plug of silica gel (5:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 12:1) to give 6087 (44 mg, 0.07 mmol, 64 %) as a pale yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.53 (d, J = 8.7 Hz, 2H, O2SArHo2), 7.38-7.25 (m, 8H,
PhH, F3CArHo2, CHPh), 7.17-7.12 (m, 4H, O2SArHm2, F3CArHm2), 4.71 (d, J = 12.8 Hz,
1H, NCHaHbS), 4.67 (d, J = 12.7 Hz, 1H, NCHaHbS), 3.94 (ddd, J = 12.7, 7.4, 2.9 Hz, 1H,
TsNCHaHbCH2), 3.62 (ddd, J = 12.8, 9.9, 8.1 Hz, 1H, TsNCHaHbCH2), 2.39 (s, 3H,
O2SC6H4CH3), 2.36 (s, 3H, ArCH3), 2.30 (ddd, J = 16.2, 7.9, 2.7 Hz, 1H, TsNCH2CHaHb),
2.16-2.06 (m, 1H, TsNCH2CHaHb), and 2.03 (s, 3H, C≡CCH3). 13 C NMR (125 MHz, CDCl3): d 150.2, 144.3, 141.1, 139.4, 137.2, 136.6, 134.4, 133.2, 129.5, 128.24, 128.16, 127.7, 127.4, 126.5 (q, J = 3.5 Hz), 125.3, 124.7 (q, J = 270.9 Hz), 121.3 (q, J = 32.6 Hz), 120.3, 115.8, 93.8, 75.7, 58.6, 53.6, 46.0, 29.2, 21.6, 17.7, and 4.5. IR (neat): 3056, 2953, 2917, 2232, 1614, 1577, 1523, 1492, 1449, 1376, 1352, 1327, 1296, 1271, 1240, 1205, 1185, 1163, 1112, 1090, 1072, 1004, 944, 911, 857, 828, 815, and 779 cm-1. HRMS (ESI-TOF):
TLC: Rf = 0.2 in 3:1 hexanes:EtOAc. mp: 90-112 °C.
2-iso-Propyl-3,3,5-trimethyl-1-(4-nitrophenyl)-6-(trimethylsilyl)-2,3- dihydrofluoreno[4,3-e][1,3]thiazin-7(1H)-one (6088)
S
i N Pr2 O TMS Me O O2N TMS 6069 S Me PhH, 90 ºC, 12 h Me N Me iPr O2N 4009 6088 [VP] A solution of the triyne 4009 (30 mg, 0.11 mmol) and the thioamide 6069 (45 mg, 0.17 mmol) in benzene (1.2 mL) was placed in a culture tube and sealed with a Teflon®- lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was Part III Experimental Procedures and Computational Details 212 evaporated and the residue was passed through a plug of silica gel (12:1 hexanes:EtOAc as eluent). The eluate was concentrated and the residue was purified by MPLC (hexanes:EtOAc = 50:1) to give 6088 (42 mg, 0.08 mmol, 70 %) as a bright yellow solid. 1 H NMR (500 MHz, CDCl3): d 8.09 (d, J = 8.8 Hz, 2H, O2NArHo2), 7.65 (nfom, 1H, ArH8),
7.62 (d, J = 8.6 Hz, 2H, O2NArHm2), 7.24-7.21 (m, 2H, ArH9 and ArH10), 6.97 (d, J = 6.4
Hz, 1H, ArH11), 5.90 (s, 1H, CHO2NAr), 3.74 [septet, J = 6.4 Hz, 1H, CH(Me)2], 2.41 (s,
3H, ArCH3), 1.60 {s, 3H, NC[(CHa3)(CHb3)]S}, 1.40 [d, J = 6.6 Hz, 3H, CH(CHa3)(CHb3)],
1.35 {s, 3H, NC[(CHa3)(CHb3)]S}, 0.99 [d, J = 6.4 Hz, 3H, CH(CHa3)(CHb3)], and 0.47 [s,
9H, Si(CH3)3]. 13 C NMR (125 MHz, CDCl3): 194.4, 152.8, 146.7, 143.8, 143.2, 143.0, 140.9, 139.6, 136.5, 135.0, 134.2, 130.0, 128.4, 128.3, 124.0, 123.3, 122.9, 67.5, 55.0, 48.7, 35.5, 30.4, 24.7, 22.1, 19.6, and 2.8. IR (neat): 3068, 2973, 2928, 2900, 2868, 1706, 1602, 1519, 1463, 1387, 1345, 1285, 1246, 1222, 1201, 1179, 1111, 1094, 1060, 998, 847, and 776 cm-1.
TLC: Rf = 0.3 in 5:1 hexanes:EtOAc. mp: 206-219 °C.
7-Cyclopropyl-5-methyl-1-(methylsulfonyl)-8,9-diphenyl-4-(prop-1-yn-1-yl)- 1,2,3,7,8,9-hexahydro-[1,3]thiazino[6,5-g]indole (6116)
S
N TMS Ph O Me Me 6109 N Me S PhH, 90 ºC, 12 h Ms N Ph 5069 6116 [VP] A solution of the tetrayne 5069 (31 mg, 0.13 mmol) and the thioamide 6109 (48 mg, 0.18 mmol) in benzene (1.2 mL) was placed in a culture tube and sealed with a Teflon®- lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (3:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC Part III Experimental Procedures and Computational Details 213
(hexanes:EtOAc = 5:1) to give the benzo[1,3]thiazine 6116 (60.5 mg, 0.12 mmol, 94 %) as a pale yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.42 (d, J = 7.7 Hz, 2H, PhHo), 7.30–7.16 (m, 5H, PhH),
7.10 (t, J = 7.1 Hz, 1H, PhHp), 7.06 (d J = 6.9 Hz, 2H, PhHo), 6.55 (s, 1H, CHPh), 4.10 (dd,
J = 12.3, 7.3 Hz, 1H, MsNCHaHb), 3.80 (d, J = 9.8 Hz, 1H, NCHS), 3.53 (ddd, J = 11.8,
11.8, 8.1 Hz, 1H, MsNCHaHb), 3.22 (ddd, J = 16.5, 11.7, 7.4 Hz, 1H, MsNCH2CHaHb),
2.84 (dd, J = 16.0, 7.3 Hz, 1H, MsNCH2CHaHb), 2.57 (s, 3H, O2SCH3), 2.56 (s, 3H, ArCH3),
2.14 (s, 3H, C≡CCH3), 1.11-1.03 {m, 1H, NCH[CH(CH2)(CH2)]S}, 0.60-0.49 {m, 2H,
NCH[CH(CH2)(CH2)]S}, 0.22-0.15 {m, 1H, NCH[CH(CH2)(CHaHb)]S}, and 0.13-0.06
{m, 1H, NCH[CH(CH2)(CHaHb)]S}. 13 C NMR (125 MHz, CDCl3): d 146.5, 142.2, 139.1, 136.1, 135.8, 135.0, 128.2, 128.1, 128.0, 127.0, 126.6, 124.5, 123.6, 120.2, 93.7, 76.1, 66.3, 63.5, 53.9, 38.5, 30.4, 17.6, 14.7, 5.7, 5.5, and 4.5. IR (neat): 3058, 3024, 3004, 2916, 2851, 2230, 1596, 1580, 1561, 1494, 1448, 1392, 1377, 1347, 1330, 1266, 1241, 1208, 1156, 1126, 1090, 1074, 1041, 1017, 994, 962, 925, 880, 850, 782, and 761 cm-1.
TLC: Rf = 0.2 in 1:1 hexanes:EtOAc. mp: 100-116 °C.
(±)-(1R,3R)-2-Ethyl-1-(2-iodophenyl)-3,5,9,9-tetramethyl-6-(trimethylsilyl)-2,3,8,9- tetrahydro-[1,3]thiazino[5,6-e]isoindol-7(1H)-one (6117) and (±)-(1R,3S)-2-Ethyl-1-(2-iodophenyl)-3,5,9,9-tetramethyl-6-(trimethylsilyl)-2,3,8,9- tetrahydro-[1,3]thiazino[5,6-e]isoindol-7(1H)-one (6117’)
I S
NEt 2 O TMS O TMS O Me Me TMS 6110 HN HN HN S + S Me PhH, 90 ºC, 12 h Me Me Me Me Me Me N Me N Me I Et I Et 5070 6117 6117' Part III Experimental Procedures and Computational Details 214
[VP] A solution of the triyne 5070 (28 mg, 0.11 mmol) and the thioamide 6110 (50 mg, 0.16 mmol) in benzene (1.1 mL) was placed in a culture tube and sealed with a Teflon®- lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (3:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 5:1) to give the mixture of of 6117 and 6117’ (38 mg, 0.07 mmol, overall yield 59%, dr 2.2:1) as a white solid. Difference NOE experiments, showing enhancement of both of the gem-dimethyl groups by each of the benzylic methine protons, confirmed that both compounds were of the same constitution. Data for 6117 (extracted from the spectra of the mixture of 6117 and 6117'): 1 H NMR (500 MHz, CDCl3): d 7.93 (dd, J = 7.9, 1.3 Hz, 1H, ArH3), 7.18 (ddd, J = 7.6, 7.6, 1.1 Hz, 1H, ArH5), 6.94 (ddd, J = 7.7, 7.7, 1.8 Hz, 1H, ArH4), 6.73 (dd, J = 7.8, 1.7 Hz, 1H, ArH6), 6.57 (s, 1H, NH), 5.52 (s, 1H, CHAr), 4.53 (q, J = 6.7 Hz, 1H, NCHS),
3.01 (dq, J = 14.6, 7.4 Hz, 1H, NCHaHbCH3), 2.49 (s, 3H, ArCH3), 2.31 (dq, J = 14.3, 7.2
Hz, NCHaHbCH3), 1.72 [s, 3H, NC(CH3a)(CH3b)Ar], 1.43 [d, J = 6.7 Hz, 3H, NCH(CH3)S],
1.35 (t, J = 7.3 Hz, 3H, NCH2CH3), 0.91 [s, 3H, NC(CH3a)(CH3b)Ar], and 0.47 [s, 9H,
Si(CH3)3]. 13 C NMR (125 MHz, CDCl3): d 169.7, 148.4, 142.5, 141.2,* 140.9,* 140.8,* 140.4,* 138.0, 131.7,* 129.4, 127.9, 123.2, 100.7, 66.8, 58.5, 57.7, 41.2, 27.6, 27.3, 21.5, 20.2, 15.4, and 3.7. Data for 6117’ (extracted from the spectra of the mixture of 6117 and 6117'): 1 H NMR (500 MHz, CDCl3): d 7.91 (dd, J = 7.8, 1.3 Hz, 1H, ArH3), 7.11 (ddd, J = 7.6, 7.6, 1.4 Hz, 1H, ArH5), 6.92 (ddd, J = 7.5, 7.5, 1.7 Hz, 1H, ArH4), 6.75 (dd, J = 7.6, 1.8 Hz, 1H, ArH6), 6.61 (s, 1H, NH), 5.48 (s, 1H, CHAr), 4.61 (q, J = 6.9 Hz, 1H, NCHS),
2.67 (dq, J = 12.8, 7.4 Hz, 1H, NCHaHbCH3), 2.55 (s, 3H, ArCH3), 2.43 (dq, J = 13.5, 6.7
Hz, NCHaHbCH3), 1.72 [s, 3H, NC(CH3a)(CH3b)Ar], 1.19 (t, J = 7.1 Hz, 3H, NCH2CH3),
0.98 [s, 3H, NC(CH3a)(CH3b)Ar], 0.82 [d, J = 7.1 Hz, 3H, NCH(CH3)S], and 0.49 [s, 9H,
Si(CH3)3]. Part III Experimental Procedures and Computational Details 215
13 C NMR (125 MHz, CDCl3): d 169.9, 148.0, 141.3,* 140.8,* 138.1, 131.81,* 131.82,* 130.7, 129.4, 127.8, 126.2, 102.6, 99.9, 67.1, 60.0, 58.3, 51.2, 27.7, 27.5, 25.7, 21.9, 13.9, and 3.7. IR (neat): 3200 (br), 3065, 2969, 2930, 2898, 1694, 1679 (w), 1538, 1458, 1435, 1368, 1324, 1303, 1260, 1244, 1220, 1185, 1163, 1150, 1120, 1085, 1050, 1013, 846, and 769 cm-1.
TLC: Rf = 0.3 in 3:1 hexanes:EtOAc. mp: 122-138 °C. *These resonances could be interchanged with one or more of the other diastereomer; the resolution of HSQC data was not high enough to distinguish these cross-peaks with certainty.
Di-tert-butyl (7R,9S)-8-ethyl-5,7-dimethyl-4-(prop-1-yn-1-yl)-9-(1-tosyl-1H-indol-3- yl)-8,9-dihydro-[1,3]thiazino[6,5-g]indazole-1,2(3H,7H)-dicarboxylate (6118)
S NEt2 Me
N Ts Me Me 6111 BocN Boc N N Me N PhH, 95 ºC, 24 h S Boc Boc N Me Et N Ts 4011 6118 [VP] A solution of the tetrayne 4011 (41 mg, 0.11 mmol) and the thioamide 6111 (62 mg, 0.16 mmol) in benzene (1.1 mL) was placed in a culture tube and sealed with a Teflon®- lined screw cap. The tube was heated in an oil bath held at 100 ºC for 24 h. The solvent was evaporated and the residue was passed through a plug of silica gel (3:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 8:1) to give 6118 (58 mg, 0.08 mmol, 69%) as a yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.92 (d, J = 8.2 Hz, 1H, H4), 7.7 (d, J = 7.2 Hz, 1H, H7),
7.61 (d, J = 8.1 Hz, 2H, O2SArHo2), 7.27 (dd, J = 8.1, 7.3 Hz, 1H, H5), 7.20 (dd, J = 7.7, Part III Experimental Procedures and Computational Details 216
7.3 Hz, 1H, H6), 7.2 (d, J = 8.4 Hz, 2H, O2SArHm2), 6.59 (s, 1H, H2), 6.39 (s, 1H, CHAr),
5.00 (d, J = 14.8 Hz, 1H, BocNCHaHb), 4.48 (q, J = 6.3 Hz, 1H, NCHS), 4.40 (d, J = 14.8
Hz, 1H, BocNCHaHb), 2.93 (dq, J = 12.6, 7.1 Hz, 1H, NCHaHbCH3), 2.56 (dq, J = 13.4,
6.7 Hz, 1H, NCHaHbCH3), 2.42 (s, 3H, O2SC6H4CH3), 2.30 (s, 3H, ArCH3), 2.15 (s, 3H,
C≡CCH3), 1.43 (t, J = 6.9 Hz, 3H, NCH2CH3), 1.42 [s, 9H, (CH3)3CO(C=O)NAr], 1.21
[d, J = 6.7 Hz, 3H, NCH(CH3)S], and 1.09 [s, 9H, (CH3)3CO(C=O)NCH2Ar]. 13 C NMR (125 MHz, CDCl3): d 156.2, 155.8, 144.6, 138.6, 135.9, 134.8, 134.3, 134.1, 130.3, 129.6, 126.7, 126.2, 125.6 (br), 124.6, 123.3, 120.4, 117.9, 117.8, 114.1, 93.9, 82.2, 81.1, 75.5, 56.3, 53.8, 50.9, 39.3, 27.9, 27.6, 21.4, 19.5, 17.1, 14.6, and 4.6. IR (neat): 2978, 2931, 2871, 2200, 1721 (sh), 1704, 1597, 1473, 1448, 1392, 1368, 1326, 1306, 1256, 1217, 1173, 1152, 1096, 1063, 1039, 1019, 977, 955, 936, 911, and 777 cm-1.
TLC: Rf = 0.3 in 3:1 hexanes:EtOAc. mp: 110-130 °C.
(6aR,12S)-5-Methyl-12-(naphthalen-2-yl)-4-(prop-1-yn-1-yl)-1-tosyl- 1,2,3,6a,7,9,10,12-octahydro-[1,4]oxazino[3',4':2,3][1,3]thiazino[6,5-g]indole (6119)
S Me N O Me 6110 Me N Me PhH, 90 ºC, 12 h N Ts S Ts N O 4010 6119 [VP] A solution of the tetrayne 4011 (35 mg, 0.11 mmol) and thioamide 6110 (23 mg, 0.09 mmol) in benzene (1.1 mL) was placed in a culture tube and sealed with a Teflon®-lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (3:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 5:1) to give 6119 (27 mg, 0.05 mmol, 52%) as a pale yellow solid. Part III Experimental Procedures and Computational Details 217
1 H NMR (500 MHz, CDCl3): d 7.792 (dd, J = 7.9, 1.6 Hz, 1H, H8), 7.786 (d, J = 8.7 Hz, 1H, H4), 7.65 (d, J = 7.7, 1.6 Hz, 1H, H5), 7.46 (dd, J = 8.6, 1.6 Hz, 1H, H3), 7.45-7.39
(m, 2H, H6, H7), 7.37 (d, J = 8.2 Hz, 2H, O2SArHo2), 7.17 (d, J = 8.0 Hz, 2H, O2SArHm2), 6.99 (dd, J = 1.7, 0.8 Hz, 1H, H1), 6.59 (s, 1H, CHAr), 4.46 (dd, J = 2.4, 1.4 Hz, 1H,
NCHS), 4.03 (ddd, J = 11.1, 2.5, 2.5 Hz, 1H, OCHaHbCH2N), 3.97 (dd, J = 13.1, 6.8, 1.1
Hz, 1H, TsNCHaHb), 3.88–3.82 (nfom, 1H OCHaHbCH2N), 3.81 [dd, J = 12.5, 2.5 Hz, 1H,
OCHaHbCH(N)(S)], 3.74 [br d, J = 12.3 Hz, 1H, OCHaHbCH(N)(S)], 3.46 (ddd, J = 13.0,
11.9, 8.0 Hz, 1H, TsNCHaHb), 3.20–3.15 (m, 2H, NCH2CH2O), 2.49 (s, 3H, O2SC6H4CH3),
2.42 (s, 3H, ArCH3), 2.34 (dd, J = 16.0, 7.0, 0.9 Hz, 1H, TsNCH2CHaHb), 2.07 (s, 3H,
C≡CCH3), and 1.91 (ddd, J = 16.2, 11.8, 7.5 Hz, 1H, TsNCH2CHaHb). 13 C NMR (125 MHz, CDCl3): d 144.3, 140.0, 138.1, 135.8, 135.5, 134.2, 134.1, 133.1, 132.7, 129.5, 128.1, 127.8, 127.5, 127.3, 127.0, 125.85, 125.77, 120.9, 119.8, 93.3, 76.1, 68.9, 67.0, 62.9, 58.1, 53.3, 46.3, 29.0, 21.6, 17.5, and 4.5. IR (neat): 3055, 2958, 2916, 2852, 2200 (w), 1597, 1561, 1506, 1492, 1439, 1400, 1380, 1348, 1323, 1305, 1269, 1240, 1184, 1164, 1127, 1104, 1089, 1017, 992, 954, 927, 896, 867, 812, and 784 cm-1.
TLC: Rf = 0.2 in 3:1 hexanes:EtOAc. mp: 108-143 °C.
Ethyl 2-((1S,3R)-5-methyl-1-phenyl-6-(prop-1-yn-1-yl)-3-vinyl-7,9-dihydro-1H- isobenzofuro[4,5-e][1,3]thiazin-2(3H)-yl)acetate (6121) and ethyl 2-((2S,4R)-5- methyl-4-phenyl-6-(prop-1-yn-1-yl)-2-vinyl-7,9-dihydro-2H-isobenzofuro[5,4- e][1,3]thiazin-3(4H)-yl)acetate (6121’) Part III Experimental Procedures and Computational Details 218
S Me Me N
CO2Et Me 6114 Me Me O O + O Me PhH, 75 ºC, 12 h S Ph
N S N CO2Et
CO2Et 4008 6121 6121' A solution of the tetrayne 4008 (24 mg, 0.14 mmol) and thioamide 6114 (42 mg, 0.16 mmol) in benzene (1.5 mL) was placed in a culture tube and sealed with a Teflon®-lined screw cap. The tube was heated in an oil bath held at 75 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (1:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 6:1) to give, in order of elution, 6121’ (3 mg, 0.01 mmol, 9%) as a pale yellow oil, and 6121 (36 mg, 0.08 mmol, 57%) as a yellow solid. Data for 6121’: 1 H NMR (500 MHz, CDCl3): d 7.34-7.24 (m, 5H, NCHPhH5), 5.81 (ddd, J = 17.3, 10.7,
4.1 Hz, 1H, CH2=CH), 5.40 (s, 1H, ArCHN), 5.40 (dd, J = 17.3, 1,9 Hz, 1H, CH=CHZHE),
5.31 (dd, J = 10.2, 2.0 Hz, 1H, CH=CHEHZ), 5.20-5.16 (m, 3H, CH2=CHCH and
OC(7)CH2), 5.11 (dt, J = 12.4, 2.4 Hz, 1H, OC(9)H2aH2b), 5.04 (dt, J = 12.4, 2.4 Hz,
OC(9)H2bH2a), 4.23 (m, 2H, OCH2CH3), 3.70 (d, J = 17.5 Hz, 1H, CHaHbC=O), 3.08 (d, J
= 17.5 Hz, 1H, CHbHaC=O), 2.09 (s, 3H, ArCH3), 2.08 (s, 3H, C≡CCH3), and 1.30 (t, J =
7.2 Hz, OCH2CH3). Data for 6121: 1 H NMR (500 MHz, CDCl3): d 7.32-7.21 (m, 5H, NCHPhH5), 5.82 (ddd, J = 17.3, 10.7,
4.1 Hz, 1H, CH2=CH), 5.46 (dd, J = 17.3, 2.1 Hz, 1H, CH=CHZHE), 5.32 (dd, J = 10.7, 2.1
Hz, 1H, CH=CHEHZ), 5.14 (dt, J = 4.2, 2.1 Hz, 1H, CH2=CHCH), 5.10 (t, J = 2.4 Hz, 2H,
OC(7)H2), 5.10 (s, 1H, ArCHN), 4.87 (dt, J = 12.4, 2.4 Hz, 1H, OC(9)H2aH2b), 4.47 (dt, J
= 12.4, 2.5 Hz, OC(9)H2bH2a), 4.23 (m, 2H, OCH2CH3), 3.71 (d, J = 17.5 Hz, 1H,
CHaHbC=O), 3.10 (d, J = 17.5 Hz, 1H, CHbHaC=O), 2.46 (s, 3H, ArCH3), 2.13 (s, 3H,
C≡CCH3), and 1.29 (t, J = 7.1 Hz, OCH2CH3). Part III Experimental Procedures and Computational Details 219
13 C NMR (125 MHz, CDCl3): d 171.3, 140.4, 137.1, 136.5, 135.7, 134.8, 132.5, 129.1, 128.5, 127.4, 120.3, 119.1, 116.7, 93.6, 75.9, 74.4, 73.2, 64.3, 60.85, 60.83, 48.7, 17.1, 14.2, and 4.6.
2-Allyl-4-methyl-7-(methylsulfonyl)-1-phenyl-5-(prop-1-yn-1-yl)-2- (trifluoromethyl)-1,6,7,8-tetrahydro-2H-thiazolo[4,5-e]isoindole (6136) and 2-allyl-4- methyl-7-(methylsulfonyl)-3-phenyl-5-(prop-1-yn-1-yl)-2-(trifluoromethyl)-3,6,7,8- tetrahydro-2H-thiazolo[5,4-e]isoindole (6136’)
S Me Me F3C N Ph
Me 6130 Me Me MsN + MsN MsN Me PhH, 90 °C, 12 h 4 Å MS S N Ph N S Ph CF3 CF3 5028 6136 6136' [VP] A solution of the tetrayne 5028 (31 mg, 0.13 mmol) and the thioamide 6130 (40 mg, 0.16 mmol) in benzene (1.2 mL) was placed in a culture tube in the presence of 4 Å molecular sieves and sealed with a Teflon®-lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (3:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 4:1) to give, in order of elution, 6136’ (12 mg, 0.02 mmol, 20%) and 6136 (30 mg, 0.06 mmol, 49%), each as a yellow solid. Data for 6136: 1 H NMR (500 MHz, CDCl3): d 7.47-7.43 (m, 1H, PhH), 7.41-7.32 (m, 3H, PhH), 7.09-
7.05 (m, 1H, PhH), 5.76 (dddd, J = 17.1, 10.1, 7.0, 7.0 Hz, 1H, CH2CH=CH2), 5.08 (d, J =
10.2 Hz, 1H, CH2CH=CHaHb), 4.99 (d, J = 16.9 Hz, 1H, CH2CH=CHaHb), 4.54 (s, 2H,
N(Ms)CH2), 3.88 (d, J = 14.1 Hz, 1H, CHaHbN(Ms)CH2), 3.39 (d, J = 14.1 Hz, 1H,
CHaHbN(Ms)CH2), 2.71-2.67 (m, 2H, CH2CH=CH2), 2.67 (s, 3H, O2SCH3), 2.33 (s, 3H,
ArCH3), and 2.09 (s, 3H, C≡CCH3). Part III Experimental Procedures and Computational Details 220
13 C NMR (125 MHz, CDCl3): d 140.6, 139.5, 138.7, 132.3, 130.4, 129.9, 129.86, 129.6, 129.2, 128.3, 125.7, 120.2, 117.4, 112.0, 93.1, 74.9, 53.9, 52.1, 36.9, 34.5, 18.9, and 4.5. IR (neat): 2917, 2852, 1581, 1504, 1491, 1470, 1453, 1418, 1373, 1340, 1269, 1249, 1223, 1187, 1154, 1077, 988, 962, 928, 890, 829, 805, and 753 cm-1.
TLC: Rf = 0.22 in 3:1 hexanes:EtOAc. mp: 145-168 °C. Data for 6136’: 1 H NMR (500 MHz, CDCl3): d 7.45-7.39 (m, 1H, PhH) 7.38-7.34 (m, 1H, PhH), 7.27-7.21 (m, 2H, PhH), 6.80-6.76 (m, 1H, PhH), 5.59 (dddd, J = 16.9, 9.5, 6.9, 6.9 Hz, 1H,
CH2CH=CH2), 4.99 (d, J = 10.1, 0.9 Hz, 1H, CH2CH=CHaHb), 4.93 (d, J = 16.8, 1.2 Hz,
1H, CH2CH=CHaHb), 4.72 (dt, J = 13.9, 2.4 Hz, CHaHbN(Ms)CH2), 4.66 (dt, J = 14.0, 2.4
Hz, CHaHbN(Ms)CH2), 4.60 (s, 2H, CH2N(Ms)CH2), 2.92 (s, 3H, O2SCH3), 2.80 (dd, J =
14.9, 6.6 Hz, 1H, CHaHbCH=CH2), 2.53 (dd, J = 14.9, 7.6 Hz, 1H, CHaHbCH=CH2), 2.04
(s, 3H, ArCH3), and 1.75 (s, 3H, C≡CCH3).
TLC: Rf = 0.23 in 3:1 hexanes:EtOAc. mp: Decomposed around 180-195 °C.
2-Benzyl-1,4,8,8-tetramethyl-2-(trifluoromethyl)-5-(trimethylsilyl)-1,2,7,8- tetrahydro-6H-thiazolo[4,5-e]isoindol-6-one (6137) and 1,4,8,8-tetramethyl-2- (trifluoromethyl)-5-(trimethylsilyl)-1,2,7,8-tetrahydro-6H-thiazolo[4,5-e]isoindol-6- one (6138)
S
TMS F3C N Ph O O TMS O Me Me Me TMS 6131 HN HN HN + S S Me PhH, 90 ºC, 12 h Me Me Me Me N Me Me 4 Å MS Ph N Me Me CF3 CF3 5070 6137 6138 A solution of the triyne 5070 (49 mg, 0.2 mmol) and the thioamide 6131 (56 mg, 0.24 mmol) in benzene (2 mL) was placed in a culture tube in the presence of 4 Å molecular sieves and sealed with a Teflon®-lined screw cap. The tube was heated in an oil bath held Part III Experimental Procedures and Computational Details 221 at 90 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (1:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 3:1) to give, in order of elution, 6138 (8 mg, 0.002 mmol, 10%) and 6137 (20 mg, 0.04 mmol, 20%), each as a yellow oil. Data for 6138: 1 H NMR (500 MHz, CDCl3): d 6.08 (br s, 1H, O=CNH), 4.09, (q, J = 6.8 Hz, 1H, CF3CH),
2.93 (s, 3H, NCH3), 2.47 (s, 3H, ArCH3), 1.69 [s, 3H, HNC(CH3a)CH3b], 1.52 [s, 3H,
HNC(CH3b)CH3a], and 0.44 [s, 9H, Si(CH3)3]. Data for 6137: 1 H NMR (500 MHz, CDCl3): d 7.39-7.28 (m, 5H, PhH5), 6.50 (br s, 1H, O=CNH), 3.66
(d, J = 14.2 Hz, PhCHaHbCCF3), 3.55 (d, J = 14.2 Hz, PhCHbHaCCF3), 2.99 (s, 3H, NCH3),
2.39 (s, 3H, ArCH3), 1.71 [s, 3H, HNC(CH3a)CH3b], and 1.55 [s, 3H, HNC(CH3b)CH3a], and 0.42 [s, 9H, Si(CH3)3]. 13 C NMR (500 MHz, CDCl3): d 169.4, 145.7, 137.3, 137.2, 136.9, 136.6, 135.2, 134.2, 130.3, 128.3, 127.6, 84.0 (q, J = 27 Hz), 58.1, 38.6, 37.5, 30.9, 28.9, 27.1, 23.9, and 3.4.
Ethyl 5-Methyl-2-(methylsulfonyl)-4-(prop-1-yn-1-yl)-2,3,7,8,10,11-hexahydro- 1H,6aH-[1,4]oxazepino[5',4':2,3]thiazolo[4,5-e]isoindole-6a-carboxylate (6139)
S Me
EtO2C N O Me 6132 Me MsN MsN Me PhH, 90 °C, 12 h S 4 Å MS N CO2Et
O 5028 6139 [VP] A solution of the tetrayne 5028 (30 mg, 0.12 mmol) and thioamide 6132 (36 mg, 0.18 mmol) in benzene (1.2 mL) was placed in a culture tube in the presence of 4 Å molecular sieves and sealed with a Teflon®-lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (1:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude Part III Experimental Procedures and Computational Details 222 product mixture was purified by MPLC (hexanes:EtOAc = 1:1) to give 6139 (29 mg, 0.06 mmol, 53%) as a yellow solid. 1 H NMR (500 MHz, CDCl3): d 4.76 (d, J = 11.4 Hz, 1H, CHaHbN(Ms)CH2), 4.62 (d, J =
11.4 Hz, 1H, CHaHbN(Ms)CH2), 4.62 (d, J = 11.4 Hz, 1H, CH2N(Ms)CHaHb), 4.56 (d, J =
11.4 Hz, 1H, CH2N(Ms)CHaHb), 4.24 (q, J = 7.0 Hz, 2H, CO2CH2CH3), 3.97 [ddd, J =
13.5, 6.5, 1.9 Hz, 1H, OCHaHbCH2C(CO2Et)], 3.91 [ddd, J = 12.9, 7.6, 2.2 Hz, 1H,
OCHaHbCH2C(CO2Et)], 3.83 (dd, J = 12.4, 2.6 Hz, 1H, OCHaHbCH2N), 3.70 (dd, J = 15.9,
2.9 Hz, 1H, OCH2CHaHbN), 3.54 (dd, J = 10.3, 10.3 Hz, 1H, OCHaHbCH2N), 3.42 (dd, J
= 15.8, 10.0 Hz, 1H, OCH2CHaHbN), 2.88 (s, 3H, O2SCH3), 2.61 (ddd, J = 16.2, 6.4, 2.0
Hz, 1H, OCH2CHaHbC(CO2Et)], 2.55 (ddd, J = 16.2, 7.4, 2.1 Hz, 1H,
OCH2CHaHbC(CO2Et)], 2.19 (s, 3H, ArCH3), 2.07 (s, 3H, C≡CCH3), and 1.29 (t, J = 7.1
Hz, 3H, CO2CH2CH3). 13 C NMR (125 MHz, CDCl3): d 171.4, 140.0, 139.2, 132.0, 122.5, 111.9, 109.7, 92.3, 79.2, 75.0, 69.3, 65.6, 62.2, 53.6, 53.3, 48.8, 41.9, 34.7, 18.5, 14.0, and 4.5. IR (neat): 2956, 2916, 2854, 1734, 1648, 1596, 1572, 1561, 1465, 1446, 1418, 1399, 1336, 1296, 1269, 1238, 1189, 1154, 1127, 1106, 1082, 1048, 1028, 965, 892, 848, 834, 779, and 755 cm-1.
TLC: Rf = 0.1 in 1:1 hexanes:EtOAc. mp: 85-106 °C. Part III Experimental Procedures and Computational Details 223
8.5 Procedures and Data for Chapter 7
3-Hydroxy-2-methyl-4-(methylthio)-1-(trimethylsilyl)-9H-fluoren-9-one (7022)
TMS O O TMS DMSO, TFA Me
Me CH3CN, 90 ºC OH SMe 4009 7022 A solution of the tetrayne 4009 (54 mg, 0.2 mmol), DMSO (32 mg, 0.4 mmol), and TFA (50 µL, 0.6 mmol) in benzene (2 mL) was placed in a culture tube with a Teflon®-lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was evaporated and the residue was purified by flash chromatography (10:1 hexanes:EtOAc) to give 7022 (33 mg, 0.1 mmol, 50%) as a yellow solid. 1 H NMR (500 MHz, CDCl3): d 8.40 (dt, J = 7.6, 0.9 Hz, 1H, H5), 7.87 (s, 1H, ArOH), 7.58 (ddd, J = 7.3, 1.0, 1.0 Hz, 1H, H8), 7.47 (ddd, J = 7.6, 7.6, 1.3 Hz, 1H, H6), 7.29 (ddd,
J = 7.4, 7.4, 1.1, Hz, 1H, H7), 2.38 (s, 3H, SCH3), 2.34 (s, 3H, ArCH3), and 0.43 [s, 9H,
Si(CH3)3].
4-((3-Hydroxy-2-methyl-9-oxo-1-(trimethylsilyl)-9H-fluoren-4-yl)thio)butyl acetate (7024)
O S TMS O O TMS , HOAc Me
Me PhH, 90 ºC OH S OAc 4009 7024 A solution of the tetrayne 4009 (74 mg, 0.28 mmol), tetrahydrothiophene 1-oxide (75 µL, 0.83 mmol), and acetic acid (50 µL, 0.83 mmol) in benzene (2.8 mL) was placed in a culture tube with a Teflon®-lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (3:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 6:1) to give 7024 (32 mg, 0.07 mmol, 25%) as a yellow oil. Part III Experimental Procedures and Computational Details 224
1 H NMR (500 MHz, CDCl3): d 8.39 (d, J = 7.6 Hz, 1H, H5), 7.81 (s, 1H, ArOH), 7.57 (dd, J = 7.3, 1.2 Hz, 1H, H8), 7.45 (ddd, J = 7.6, 7.6, 1.5 Hz, 1H, H6), 7.28 (ddd, J = 7.4, 7.4,
1.0, Hz, 1H, H7), 4.04 (t, J = 6.1 Hz, 2H, CH2OC=O), 2.77 (t, J = 7.22 Hz, 2H,
ArSCH2CH2), 2.38 (s, 3H, ArCH3), 2.34 (s, 3H, CH3C=O), 1.77-1.65 (m. 2H,
ArSCH2CH2CH2CH2), and 0.43 [s, 9H, Si(CH3)3]. 13 C NMR (125 MHz, CDCl3): d 193.4, 171.0, 159.5, 146.8, 145.5, 143.1, 135.0, 133.9, 132.8, 130.1, 129.0, 123.4, 123.0, 115.0, 63.6, 35.6, 27.8, 26.4, 20.9, 17.6, and 2.7.
2-((6-Methyl-4-(phenylthio)-7-(prop-1-yn-1-yl)-1,3-dihydroisobenzofuran-5- yl)oxy)ethyl acetate (7043)
Me
Me O PhH O + S + HOAc Me Me Ph 75 ºC O OAc O SPh 4008 7041 7043 A solution of the tetrayne 4008 (44 mg, 0.26 mmol), phenyl vinyl sulfoxide (92 mg, 0.6 mmol), and acetic acid (30 µL, 0.5 mmol) in benzene (2.6 mL) was placed in a culture tube with a Teflon®-lined screw cap. The tube was heated in an oil bath held at 75 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (3:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 5:1) to give 7043 (57 mg, 0.15 mmol, 58%) as a yellow oil. 1 H NMR (500 MHz, CDCl3): d 7.22 (dd, J = 7.1, 7.1 Hz, 2H, ArSPhHm2), 7.16-7.11 (m,
3H, ArSPhHo2+Hp), 5.12-5.09 (nfom, 2H, OCHa2CHb2), 4.84-4.82 (nfom, 2H, OCHb2CHa2),
4.36-4.34 (nfom, 2H, ArOCH2CH2OAc), 4.14-4.09 (nfom, 2H, ArOCH2CH2OAc), 2.39 (s,
3H, ArCH3), 2.12 (s, 3H, C≡CCH3), and 2.07 (s, 3H, CH3OC=O). 13 C NMR (125 MHz, CDCl3): d 170.1, 157.2, 142.0, 138.1, 135.8, 133.6, 129.2, 128.2, 126.3, 120.1, 119.6, 95.4, 75.6, 74.7, 74.5, 71.2, 63.6, 21.0, 14.5, and 4.8. Part III Experimental Procedures and Computational Details 225
TLC: Rf = 0.25 in 5:1 hexanes:EtOAc.
5-Methyl-7-(phenylthio)-4-(prop-1-yn-1-yl)-6-(vinyloxy)-1,3-dihydroisobenzofuran (7045)
Me
Me O PhH O + S + MeO2C CO2Me Me Me Ph 75 ºC O O SPh 4008 7041 7045 A solution of the tetrayne 4008 (44 mg, 0.26 mmol), phenyl vinyl sulfoxide (78 mg, 0.51 mmol), and dimethyl malonate (99 mg, 0.75 mmol) in benzene (2.5 mL) was placed in a culture tube with a Teflon®-lined screw cap. The tube was heated in an oil bath held at 75 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (3:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 5:1) to give 7045 (72 mg, 0.24 mmol, 92%) as a yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.21 (dd, J = 7.4, 7.4 Hz, 2H, ArSPhHm2), 7.17-7.14 (m,
3H, ArSPhHo2+Hp), 6.55 (dd, J = 14.0, 6.4 Hz, 1H, ArOCH=CH2), 5.12 (t, J = 2.0 Hz, 2H,
OCHa2CHb2), 4.81-4.80 (nfom, 2H, OCHb2CHa2), 4.17 (dd, J = 6.4, 2.3 Hz, 1H,
ArOCH=CHEHZ), 4.07 (dd, J = 14.0, 2.3 Hz, ArOCH=CHZHE), 2.32 (s, 3H, ArSCH3), and
2.12 (s, 3H, C≡CCH3).
5-Methyl-1-(methylsulfonyl)-7-(phenylthio)-4-(prop-1-yn-1-yl)indolin-6-ol (7047)
Me
Me O PhH + S + NC CN Me N Me Ph 90 ºC Ms N OH Ms SPh 5069 7041 7047 Part III Experimental Procedures and Computational Details 226
A solution of the tetrayne 5069 (50 mg, 0.2 mmol), phenyl vinyl sulfoxide (108 mg, 0.71 mmol), and malononitrile (34 mg, 0.52 mmol) in benzene (2 mL) was placed in a culture tube with a Teflon®-lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (1:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 3:1) to give 7045 (43 mg, 0.12 mmol, 60%) as a yellow solid. 1 H NMR (500 MHz, CDCl3): d 7.21 (dd, J = 7.6, 7.6 Hz, 2H, ArSPhHm2), 7.14 (tt, J = 7.3,
1.4 Hz, 1H, ArSPhHp), 6.98 (dt, J = 7.4, 1.7 Hz, ArSPhHo2), 6.56 (s, J = 14.0, 6.4 Hz, 1H,
ArOH), 4.14 (t, J = 7.3 Hz, 2H, ArN(Ms)CH2CH2), 3.18 (s, 3H, NSO2CH3), 3.12 (t, J =
7.2 Hz, 2H, ArN(Ms)CH2CH2), 2.32 (s, 3H, ArSCH3), and 2.14 (s, 3H, C≡CCH3). 13 C NMR (125 MHz, CDCl3): d 154.4, 143.7, 135.0, 130.3, 129.3, 126.4, 126.3, 124.2, 123.5, 108.8, 95.1, 76.0, 53.1, 41.7, 31.1, 14.4, and 4.6.
2-(2-((5-Methyl-1-(methylsulfonyl)-7-(phenylthio)-4-(prop-1-yn-1-yl)indolin-6- yl)oxy)allyl)malononitrile (7051)
Me
Me O PhH + + NC CN Me S ● CN N Me Ph 90 ºC Ms N O CN Ms SPh 5069 7048 7051 Allenyl phenyl sulfoxide was prepared according to a known procedure.147 A solution of the tetrayne 5069 (50 mg, 0.2 mmol), allenyl phenyl sulfoxide (118 mg, 0.72 mmol), and malononitrile (35 mg, 0.53 mmol) in benzene (2 mL) was placed in a culture tube with a Teflon®-lined screw cap. The tube was heated in an oil bath held at 90 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel
147 Ma, S.; Ren, H.; W, Q. Highly regio- and stereoselective halohydroxylation reaction of 1,2-allenyl phenyl sulfoxides: reaction scope, mechanism, and the corresponding Pd- or Ni-catalyzed selective coupling reactions. J. Am. Chem. Soc. 2003, 125, 4817-4830. Part III Experimental Procedures and Computational Details 227
(1:1 hexanes:EtOAc as eluent). The eluate was concentrated and the crude product mixture was purified by MPLC (hexanes:EtOAc = 3:1) to give 7045 (40 mg, 0.08 mmol, 40%) as a red oil. 1 H NMR (500 MHz, CDCl3): d 7.25 (dd, J = 7.8, 7.8 Hz, 2H, ArSPhHm2), 7.16 (tt, J = 7.2,
1.2 Hz, 1H, ArSPhHp), 7.02 (dt, J = 7.3, 1.4 Hz, ArSPhHo2), 4.30 (d, J = 3.3 Hz, 1H,
ArOC=CHEHZ), 4.17 (t, J = 7.3 Hz, 2H, ArN(Ms)CH2CH2), 3.94 (d, J = 3.2 Hz, 1H,
ArOC=CHZHE), 3.49 (t, J = 7.5 Hz, 2H, CH(CN)2CH2), 3.26 (s, 3H, NSO2CH3), 3.18 (t, J
7.2 Hz, 2H, ArN(Ms)CH2CH2), 2.81 (d, J = 7.5 Hz, 2H, CH(CN)2CH2), 2.23 (s, 3H,
ArSCH3), and 2.15 (s, 3H, C≡CCH3). 13 C NMR (125 MHz, CDCl3): d 151.6, 151.2, 144.8, 137.2, 137.0, 131.6, 129.0, 126.0, 125.8, 123.0, 117.7, 122.2, 96.2, 91.0, 75.5, 52.8, 42.4, 35.9, 31.6, 20.2, 14.6, and 4.6.
4-((5-Hydroxy-6-methyl-7-(prop-1-yn-1-yl)-1,3-dihydroisobenzofuran-4- yl)thio)pent-4-en-1-yl acetate (7056)
Me
Me O PhH Me O + S + HOAc O Me 75 ºC OH S OAc
4008 7052 7056 2-Methylenetetrahydrothiophene 1-oxide was prepared from a known procedure with minor modification.148 A solution of the tetrayne 4008 (45 mg, 0.26 mmol), 2-methylenetetrahydrothiophene 1- oxide (7052, 99 mg, 0.51 mmol), and acetic acid (30 µL, 0.5 mmol) in benzene (2.6 mL) was placed in a culture tube with a Teflon®-lined screw cap. The tube was heated in an oil bath held at 75 ºC for 12 h. The solvent was evaporated and the residue was passed through a plug of silica gel (1:1 hexanes:EtOAc as eluent). The eluate was concentrated and the
148 Bell, R.; Cottam, P. D.; Davies, J.; Jones, D. N, Synthesis of allenyl sulfoxides by intramolecular and intermolecular addition of sulfenic acid to alkynes. J. Chem. Soc., Perkin Trans. 1, 1981, 7, 2106-2115. Part III Experimental Procedures and Computational Details 228 crude product mixture was purified by MPLC (hexanes:EtOAc = 6:1) to give 7056 (36 mg, 012 mmol, 46%) as a yellow solid. 1 H NMR (500 MHz, CDCl3): d 6.50 (s, 1H, ArOH), 5.13 (t, J = 2.4 Hz, OCHa2Hb2), 5.06
(t, J = 2.6 Hz OCHb2Ha2), 5.02 (d, J = 0.8 Hz, 1H, ArSC=CHEHZ), 4.56 (s 1H,
ArSC=CHZHE), 4.09 (t, J = 6.5 Hz, 2H, CH2OAc), 2.36 (s, 3H, ArCH3), 2.29 [dt, J = 7.1,
1.1 Hz, ArSC(=CH2)CH2], 2.12 (s, 3H, C≡CCH3), 2.06 (s, 3H, O=CCH3), and 1.91 (tt, J
= 7.0, 7.0 Hz, CH2CH2OAc). 13 C NMR (125 MHz, CDCl3): d 171.1, 154.7, 141.3, 141.2, 133.2, 125.7, 120.5, 109.9, 107.7, 94.9, 75.5, 74.9, 74.4, 63.2, 32.5, 27.4, 20.9, 14.2, and 4.6.
Part III Experimental Procedures and Computational Details 229
Chapter 9. Computational Data
General Computational Details
DFT calculations were performed using the Gaussian 09 149 software package. The geometries were optimized using the M06-2X functional;150 the double-ζ split-valence 6- 31+G(d, p) basis set was used. The SMD continuum solvation model151 using benzene as the solvent was utilized during both geometry optimization and the frequency calculation. Harmonic vibrational frequency calculations were carried at 298 K and used for thermal correction of the enthalpies. Conformation search was not performed on the intermediates, and therefore the energetic and geometric properties only represent the geometry of the particular conformer of interest shown in this section. The value for the “Sum of electronic and thermal Free Energies=” was then used to arrive at the free energy (G) of both the transition state structure and the reactant and product for the reaction. The optimized reactant, intermediate, and product geometries were found to have no imaginary frequencies except for 5073 and 5078, in which a methyl rotational motion would account for the single imaginary frequency for each of them. The optimized transition state structure geometries were found to have only one imaginary frequency.
149 Gaussian 09, Revision A.1, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr., J. A.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian, Inc., Wallingford CT, 2009. 150 Zhao, Y.; Truhlar, D. G. The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: Two new functionals and systematic testing of four M06 functionals and twelve other functionals. Theor. Chem. Acc. 2008 , 120 , 215–241. (b) Zhao, Y.; Truhlar, D. G. Density functionals with broad applicability in chemistry. Acc. Chem. Res. 2008, 41, 157-167. 151 Marenich, A. V.; Cramer, C. J.; Truhlar, D. G. J. Phys. Chem. B, 2009, 113, 6378-6396. Part III Experimental Procedures and Computational Details 230
Computational Results (Geometries and Energies) Energy and geometry for 5053
Sum of electronic and thermal free energies = –708.649781 a.u.
------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -2.250446 -1.169408 -0.118852 2 6 0 -0.856082 -1.281980 -0.344286 3 6 0 -0.240360 -0.051348 -0.217473 4 6 0 -0.794940 1.202110 0.059110 5 6 0 -2.172466 1.229633 0.257663 6 6 0 -2.896322 0.034948 0.170492 7 1 0 -2.870969 -2.064570 -0.178776 8 1 0 -0.216324 2.120069 0.119422 9 1 0 -2.671588 2.168736 0.475749 10 1 0 -3.973132 0.053687 0.325479 11 16 0 1.569611 -0.174641 -0.525832 12 6 0 2.055325 -1.308365 0.792023 13 1 0 1.429287 -2.189261 0.639891 14 1 0 3.113542 -1.544827 0.676012 15 1 0 1.844144 -0.849737 1.759533 16 6 0 2.301930 1.363929 0.076391 17 1 0 3.383956 1.230749 0.105268 18 1 0 2.052791 2.156156 -0.629843 19 1 0 1.914674 1.596150 1.070183 ------
Part III Experimental Procedures and Computational Details 231
Energy and Geometry for 5054*
Sum of electronic and thermal free energies = –708.682582 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -1.980959 1.290803 0.343895 2 6 0 -0.601738 1.151631 0.109945 3 6 0 -0.200838 -0.106654 -0.228222 4 6 0 -0.999536 -1.234328 -0.392144 5 6 0 -2.362303 -1.059432 -0.158666 6 6 0 -2.846988 0.202859 0.209658 7 1 0 -2.400241 2.255612 0.626140 8 1 0 -0.600484 -2.202984 -0.688374 9 1 0 -3.044899 -1.896770 -0.267468 10 1 0 -3.912568 0.332117 0.383541 11 6 0 2.031595 1.456441 -0.170323 12 1 0 2.633412 1.547137 0.733466 13 1 0 2.514087 1.906052 -1.036065 14 16 0 1.662071 -0.229419 -0.509326 15 6 0 2.110811 -1.085717 1.021726 16 1 0 1.639114 -2.069024 1.009734 17 1 0 1.743645 -0.501110 1.866817 18 1 0 0.738780 1.793576 0.051094 19 1 0 3.195751 -1.187506 1.055123 ------
Part III Experimental Procedures and Computational Details 232
Energy and geometry for 5054
Sum of electronic and thermal free energies = –708.646893 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -0.721791 1.175017 0.158830 2 6 0 -0.155982 -0.043503 -0.189429 3 6 0 -0.952333 -1.170829 -0.391141 4 6 0 -2.331432 -1.074496 -0.216522 5 6 0 -2.907130 0.143699 0.149292 6 6 0 -2.103562 1.267011 0.334099 7 1 0 -0.078405 2.044598 0.279232 8 1 0 -0.507371 -2.117035 -0.691582 9 1 0 -2.957414 -1.947812 -0.373019 10 1 0 -3.982008 0.216488 0.281684 11 1 0 -2.550971 2.217109 0.610004 12 16 0 1.669379 -0.130486 -0.463739 13 6 0 2.019700 -1.205694 0.959494 14 1 0 1.401161 -2.102385 0.908818 15 1 0 3.078115 -1.459112 0.905321 16 1 0 1.807824 -0.648162 1.873995 17 6 0 2.490876 1.281740 -0.157309 18 1 0 2.727808 1.853879 -1.043773 19 1 0 2.321116 1.792534 0.785254 ------
Part III Experimental Procedures and Computational Details 233
Geometry for 5012
------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 2.018577 0.341539 0.013358 2 6 0 1.874849 1.715882 0.010390 3 6 0 0.774153 2.304366 -0.006452 4 6 0 -0.515258 1.806708 -0.008999 5 6 0 -0.454284 0.377232 -0.000733 6 6 0 0.777809 -0.305325 0.006704 7 6 0 1.032216 -1.786838 0.037854 8 1 0 0.717999 -2.227464 0.994531 9 1 0 0.528990 -2.322695 -0.773275 10 8 0 2.445872 -1.923821 -0.132367 11 6 0 3.119011 -0.678167 0.053184 12 1 0 3.644852 -0.666216 1.017714 13 1 0 3.852810 -0.552271 -0.748422 14 6 0 -1.811626 2.558600 -0.019621 15 1 0 -2.400934 2.296839 -0.903790 16 1 0 -2.412028 2.301081 0.858300 17 1 0 -1.631453 3.633565 -0.021243 18 6 0 -1.674942 -0.376569 0.001193 19 6 0 -2.704210 -1.015565 0.005220 20 6 0 -3.945033 -1.790153 0.008801 21 1 0 -4.116218 -2.249022 -0.968410 22 1 0 -3.900260 -2.585354 0.757311 23 1 0 -4.798308 -1.148157 0.240817 ------
Part III Experimental Procedures and Computational Details 234
Geometry for 5072
------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -1.148552 1.313822 -0.003398 2 6 0 -0.662069 2.606611 -0.004480 3 6 0 0.576730 2.781253 0.000757 4 6 0 1.692597 1.975371 0.007596 5 6 0 1.263017 0.600937 0.004970 6 6 0 -0.121719 0.323797 0.002284 7 6 0 -0.839611 -1.006603 0.012931 8 6 0 3.106287 2.487793 0.020731 9 1 0 3.647572 2.142926 0.904086 10 1 0 3.658954 2.162319 -0.862910 11 1 0 3.096683 3.578087 0.032716 12 14 0 2.509691 -0.877226 -0.006263 13 6 0 4.332460 -0.377509 -0.036989 14 1 0 4.625242 0.177427 -0.931559 15 1 0 4.657213 0.176017 0.847256 16 1 0 4.887471 -1.324007 -0.048026 17 6 0 2.267645 -1.860556 -1.590956 18 1 0 1.243799 -2.208638 -1.728111 19 1 0 2.553833 -1.245972 -2.451229 20 1 0 2.927727 -2.735186 -1.573395 21 6 0 2.311852 -1.854009 1.588205 22 1 0 1.291169 -2.200134 1.752189 23 1 0 2.970760 -2.729122 1.557020 24 1 0 2.619936 -1.236135 2.438518 25 8 0 -0.353169 -2.118122 0.029532 26 6 0 -2.306502 -0.701428 0.005254 27 6 0 -2.483312 0.687057 -0.003898 28 6 0 -3.381235 -1.572838 0.007421 29 1 0 -3.222673 -2.647047 0.014791 30 6 0 -4.668813 -1.021438 -0.000507 31 1 0 -5.536067 -1.673409 0.000471 32 6 0 -4.847910 0.363052 -0.009673 33 1 0 -5.854851 0.768803 -0.015639 34 6 0 -3.754049 1.238887 -0.011324 35 1 0 -3.897982 2.315012 -0.018300 ------Part III Experimental Procedures and Computational Details 235
Geometry for 5073
------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -0.553642 -0.126935 -0.526202 2 6 0 -0.155075 1.196555 -0.479138 3 6 0 -1.009559 2.088998 -0.290840 4 6 0 -2.374964 2.099691 -0.122041 5 6 0 -2.827464 0.740558 -0.172949 6 6 0 -1.933746 -0.329699 -0.365245 7 6 0 -2.215776 -1.810332 -0.399164 8 1 0 -2.415081 -2.179683 0.613536 9 1 0 -3.073329 -2.064206 -1.026943 10 6 0 -3.297888 3.260298 0.090873 11 1 0 -4.058466 3.296085 -0.694952 12 1 0 -3.821207 3.162631 1.046869 13 1 0 -2.742358 4.198138 0.086963 14 6 0 -4.226455 0.472663 -0.006161 15 6 0 -5.409029 0.253904 0.138714 16 6 0 -6.835606 -0.014592 0.318550 17 1 0 -7.434368 0.620927 -0.338768 18 1 0 -7.062697 -1.058212 0.087799 19 1 0 -7.136503 0.181436 1.351039 20 6 0 -0.903483 -2.380944 -0.977672 21 1 0 -0.599735 -3.333712 -0.543202 22 1 0 -0.977488 -2.501720 -2.061131 23 7 0 0.151445 -1.345105 -0.737360 24 16 0 1.267859 -1.759288 0.476942 25 6 0 2.499148 -0.508428 0.258548 26 6 0 2.651127 0.472373 1.232389 27 6 0 3.288375 -0.534005 -0.889617 28 6 0 3.623451 1.451477 1.045576 29 1 0 2.014305 0.463984 2.110817 30 6 0 4.250459 0.453673 -1.058015 31 1 0 3.145341 -1.311569 -1.633379 32 6 0 4.432678 1.455848 -0.094807 33 1 0 3.751564 2.225778 1.796508 Part III Experimental Procedures and Computational Details 236
34 1 0 4.871225 0.449378 -1.949502 35 8 0 1.794761 -3.059807 0.078271 36 8 0 0.681076 -1.606538 1.806067 37 6 0 5.502471 2.500568 -0.275094 38 1 0 6.458037 2.136973 0.117442 39 1 0 5.647121 2.738777 -1.331575 40 1 0 5.250937 3.420075 0.257990 ------
Part III Experimental Procedures and Computational Details 237
Geometry for 5074
------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 0.532465 0.473676 -0.525758 2 6 0 0.388359 1.851504 -0.481491 3 6 0 -0.758294 2.307129 -0.272600 4 6 0 -2.013689 1.790201 -0.071230 5 6 0 -1.888630 0.362331 -0.121988 6 6 0 -0.646871 -0.263214 -0.338068 7 6 0 -0.313230 -1.733099 -0.362195 8 1 0 -0.335044 -2.139936 0.655750 9 1 0 -1.006100 -2.316029 -0.973744 10 6 0 -3.314138 2.493134 0.168760 11 1 0 -4.041050 2.228617 -0.604994 12 1 0 -3.737784 2.193091 1.131752 13 1 0 -3.173300 3.573929 0.166291 14 6 0 -3.062501 -0.438228 0.069160 15 6 0 -4.057573 -1.109468 0.231894 16 6 0 -5.255511 -1.924524 0.431706 17 1 0 -6.063513 -1.589817 -0.223791 18 1 0 -5.046719 -2.974178 0.211435 19 1 0 -5.601423 -1.853442 1.466161 20 6 0 1.109772 -1.740467 -0.960413 21 1 0 1.776316 -2.482983 -0.523287 22 1 0 1.072814 -1.896715 -2.041337 23 7 0 1.659915 -0.365977 -0.746830 24 16 0 2.916798 -0.228903 0.386613 25 6 0 3.746245 1.232321 -0.191548 26 8 0 3.774132 -1.390230 0.174356 27 8 0 2.394562 0.035505 1.723945 28 1 0 4.098642 1.045238 -1.204799 29 1 0 3.043729 2.065912 -0.156367 30 1 0 4.577288 1.400635 0.495162 ------
Part III Experimental Procedures and Computational Details 238
Geometry for 5075
------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -1.140913 0.906879 -0.749786 2 6 0 -1.656846 1.697252 -1.752426 3 6 0 -2.895551 1.767775 -1.900695 4 6 0 -3.978048 1.202607 -1.265462 5 6 0 -3.477857 0.368057 -0.212274 6 6 0 -2.099279 0.239987 0.024874 7 6 0 -1.375740 -0.525555 1.103365 8 1 0 -1.501102 -0.060927 2.087733 9 1 0 -1.656607 -1.577694 1.172182 10 6 0 -5.439986 1.367262 -1.549002 11 1 0 -5.880212 0.416432 -1.865754 12 1 0 -5.971839 1.689607 -0.649096 13 1 0 -5.596391 2.105159 -2.335956 14 6 0 -4.406755 -0.335882 0.623338 15 6 0 -5.193004 -0.931738 1.326043 16 6 0 -6.138841 -1.656395 2.174225 17 1 0 -7.157001 -1.547135 1.792917 18 1 0 -5.893393 -2.721093 2.200140 19 1 0 -6.111529 -1.273254 3.197497 20 7 0 0.033424 -0.441089 0.653625 21 7 0 0.157130 0.599856 -0.292823 22 6 0 0.692171 -1.640772 0.385719 23 6 0 1.135481 1.585451 -0.170792 24 8 0 0.388324 -2.669294 0.957537 25 8 0 1.080540 2.610161 -0.816556 26 8 0 1.680079 -1.475607 -0.484205 27 8 0 2.090931 1.211076 0.670225 28 6 0 2.564621 -2.593133 -0.821584 29 6 0 3.259346 2.067955 0.885574 30 6 0 4.112322 1.230044 1.829797 31 1 0 5.012247 1.785764 2.106397 32 1 0 3.552814 0.988656 2.737588 33 1 0 4.411026 0.296801 1.343693 Part III Experimental Procedures and Computational Details 239
34 6 0 2.823387 3.367230 1.554320 35 1 0 3.710779 3.950580 1.817181 36 1 0 2.197100 3.963010 0.888779 37 1 0 2.270354 3.150001 2.473095 38 6 0 3.992452 2.307136 -0.431028 39 1 0 4.960011 2.770950 -0.217285 40 1 0 4.172880 1.353963 -0.937096 41 1 0 3.424615 2.960108 -1.093762 42 6 0 1.765783 -3.687065 -1.522701 43 1 0 1.228972 -3.268368 -2.379314 44 1 0 2.454234 -4.454035 -1.889931 45 1 0 1.051625 -4.150926 -0.840731 46 6 0 3.274997 -3.100565 0.429263 47 1 0 2.585159 -3.606537 1.105203 48 1 0 4.057514 -3.804070 0.129376 49 1 0 3.747079 -2.266297 0.956921 50 6 0 3.558816 -1.946658 -1.777767 51 1 0 4.110635 -1.152255 -1.266985 52 1 0 4.271011 -2.694860 -2.135815 53 1 0 3.037804 -1.514858 -2.636595 ------
Part III Experimental Procedures and Computational Details 240
Geometry for 5076
------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 1.745276 0.758764 -0.020651 2 6 0 1.564578 2.133434 -0.032835 3 6 0 0.390128 2.559927 -0.004000 4 6 0 -0.875841 2.010724 0.038822 5 6 0 -0.754726 0.583923 0.031398 6 6 0 0.545830 0.020520 0.017082 7 6 0 0.959614 -1.423782 0.080193 8 6 0 2.966468 -0.125046 -0.024926 9 7 0 2.321570 -1.434655 0.028148 10 8 0 0.249772 -2.416115 0.174462 11 14 0 -2.286514 -0.594933 -0.024497 12 6 0 -2.400995 -1.548891 1.589339 13 1 0 -2.581467 -0.858068 2.420064 14 1 0 -3.247710 -2.243017 1.542474 15 1 0 -1.493425 -2.120363 1.786867 16 6 0 -2.169843 -1.653081 -1.575259 17 1 0 -2.208613 -1.012423 -2.463102 18 1 0 -1.262130 -2.256117 -1.604306 19 1 0 -3.035188 -2.324768 -1.613070 20 6 0 -3.943563 0.298780 -0.207130 21 1 0 -4.690890 -0.499118 -0.301073 22 1 0 -4.226537 0.907071 0.654907 23 1 0 -4.011061 0.910058 -1.111055 24 1 0 2.833198 -2.303399 0.096892 25 6 0 3.838594 0.117376 1.210219 26 1 0 4.678955 -0.584071 1.223449 27 1 0 4.238196 1.135256 1.188439 28 1 0 3.252852 -0.012482 2.123834 29 6 0 3.774610 0.046264 -1.314686 30 1 0 4.174728 1.062553 -1.371636 31 1 0 4.612460 -0.657977 -1.331803 32 1 0 3.141945 -0.134479 -2.187349 33 6 0 -2.143143 2.819356 0.102009 34 1 0 -2.732200 2.716307 -0.811989 35 1 0 -2.767289 2.512068 0.942782 36 1 0 -1.895720 3.873933 0.228458 ------Part III Experimental Procedures and Computational Details 241
Geometry for 5077
------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -0.199946 2.150908 0.000326 2 6 0 -1.102581 3.201204 0.000064 3 6 0 -2.328082 2.957305 -0.000159 4 6 0 -3.059984 1.786369 -0.000141 5 6 0 -2.199526 0.657645 0.000092 6 6 0 -0.807913 0.885818 0.000355 7 6 0 0.285740 -0.125915 0.000478 8 6 0 1.290254 2.018518 0.000281 9 1 0 1.737296 2.474011 -0.890676 10 1 0 1.737592 2.474280 0.890951 11 6 0 2.783898 0.012955 0.000241 12 6 0 3.003358 -1.374255 0.000412 13 6 0 3.890482 0.876180 -0.000313 14 6 0 4.305507 -1.866899 0.000073 15 1 0 2.163447 -2.052346 0.000777 16 6 0 5.184877 0.363958 -0.000604 17 1 0 3.756531 1.951330 -0.000501 18 6 0 5.404555 -1.010793 -0.000425 19 1 0 4.455032 -2.942253 0.000194 20 1 0 6.023997 1.052619 -0.001013 21 1 0 6.414293 -1.407539 -0.000660 22 7 0 1.484982 0.568817 0.000515 23 8 0 0.147071 -1.339337 0.000460 24 14 0 -3.002122 -1.083491 -0.000148 25 1 0 -4.139062 1.701713 -0.000499 26 6 0 -2.549387 -2.009461 1.568506 27 1 0 -2.835047 -1.429822 2.452215 28 1 0 -3.090582 -2.961568 1.601544 29 1 0 -1.477829 -2.214140 1.608659 30 6 0 -2.548838 -2.008774 -1.569066 31 1 0 -2.833433 -1.428273 -2.452559 32 1 0 -1.477321 -2.213881 -1.608502 33 1 0 -3.090447 -2.960587 -1.603343 34 6 0 -4.869122 -0.814353 -0.000269 35 1 0 -5.361496 -1.793173 -0.000208 36 1 0 -5.212289 -0.275398 0.889050 37 1 0 -5.212156 -0.275585 -0.889759 ------Part III Experimental Procedures and Computational Details 242
Geometry for 5078
------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 0.122399 -1.774194 -0.056881 2 6 0 1.088921 -2.763041 -0.039294 3 6 0 2.313791 -2.526064 -0.023208 4 6 0 3.017370 -1.337860 -0.008343 5 6 0 2.079503 -0.258624 -0.021927 6 6 0 0.689445 -0.493298 -0.047939 7 6 0 -0.400918 0.541929 -0.040120 8 1 0 -0.466760 1.049234 0.931397 9 1 0 -0.264695 1.296626 -0.822074 10 6 0 -1.376508 -1.721027 -0.049536 11 1 0 -1.780854 -2.039411 0.919134 12 1 0 -1.838008 -2.325054 -0.833410 13 6 0 4.499937 -1.122773 0.017173 14 1 0 4.820921 -0.555518 -0.861897 15 1 0 4.788627 -0.545015 0.900434 16 1 0 5.025388 -2.077592 0.032309 17 6 0 2.565650 1.090490 -0.006067 18 6 0 2.977087 2.229742 0.012433 19 6 0 3.474651 3.604898 0.039301 20 1 0 2.948077 4.220174 -0.694591 21 1 0 3.327558 4.048821 1.027239 22 1 0 4.541946 3.631030 -0.193627 23 7 0 -1.606231 -0.277024 -0.314880 24 16 0 -3.074967 0.346378 0.153164 25 8 0 -4.019363 -0.765600 0.116953 26 8 0 -2.936133 1.134456 1.376653 27 6 0 -3.453974 1.474709 -1.169725 28 1 0 -2.663362 2.223686 -1.228389 29 1 0 -3.532226 0.903364 -2.093523 30 1 0 -4.403668 1.946599 -0.913502 ------
Part III Experimental Procedures and Computational Details 243
Energy and geometry for 6093
Sum of electronic and free energies = –1033.043430 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -1.481914 -1.043072 -1.470794 2 6 0 -1.123678 -0.283007 -0.372441 3 6 0 -1.870572 -0.272033 0.798220 4 6 0 -3.030037 -1.019956 0.936157 5 6 0 -3.409440 -1.784621 -0.176239 6 6 0 -2.656957 -1.799374 -1.354765 7 1 0 -0.888496 -1.057031 -2.380551 8 1 0 -3.617850 -1.021711 1.847902 9 1 0 -4.311897 -2.386139 -0.119989 10 1 0 -2.986468 -2.410609 -2.188704 11 16 0 -0.880194 0.834043 1.769426 12 6 0 0.027570 0.639431 -0.009861 13 7 0 0.117525 1.836116 -0.753334 14 6 0 1.071571 2.792631 -0.204538 15 1 0 1.194477 3.618786 -0.908120 16 1 0 0.709701 3.197058 0.756502 17 1 0 2.041598 2.319743 -0.045731 18 6 0 -1.144159 2.488380 -1.085396 19 1 0 -0.935762 3.307251 -1.777538 20 1 0 -1.822134 1.785646 -1.570284 21 1 0 -1.634371 2.896989 -0.188272 22 6 0 1.358006 -0.093609 0.065452 23 6 0 2.065122 -0.248090 -1.135618 24 6 0 1.868966 -0.669613 1.228214 25 6 0 3.256884 -0.965332 -1.169117 26 1 0 1.675385 0.208667 -2.040648 27 6 0 3.066135 -1.386816 1.192817 28 1 0 1.333618 -0.555369 2.163899 29 6 0 3.763287 -1.539176 -0.002184 30 1 0 3.791298 -1.074533 -2.107994 31 1 0 3.452603 -1.823425 2.108624 32 1 0 4.694018 -2.097276 -0.026025 ------Part III Experimental Procedures and Computational Details 244
Energy and geometry for 6094
Sum of electronic and thermal free energies = –1033.041030 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 1.805863 -0.312425 -1.557356 2 6 0 1.160767 -0.045396 -0.346635 3 6 0 1.670262 -0.448484 0.904138 4 6 0 2.849854 -1.226354 0.870053 5 6 0 3.479648 -1.527233 -0.329706 6 6 0 2.975059 -1.065526 -1.554399 7 1 0 1.384609 0.052612 -2.492447 8 1 0 3.265821 -1.571503 1.811971 9 1 0 4.387664 -2.123892 -0.317848 10 1 0 3.482054 -1.296897 -2.484853 11 16 0 0.877313 0.108039 2.346979 12 6 0 -0.132855 0.678319 -0.318875 13 7 0 -0.146654 1.968122 -0.511124 14 6 0 -1.350234 2.774787 -0.735431 15 1 0 -1.621926 3.293242 0.187896 16 1 0 -1.110686 3.514199 -1.502046 17 1 0 -2.173693 2.149112 -1.070848 18 6 0 1.094352 2.755632 -0.455076 19 1 0 0.857985 3.711039 0.015617 20 1 0 1.833899 2.224199 0.140722 21 1 0 1.469193 2.928188 -1.467428 22 6 0 -1.382835 -0.110589 -0.219077 23 6 0 -1.492367 -1.277624 -0.981306 24 6 0 -2.425126 0.261589 0.639938 25 6 0 -2.659310 -2.037754 -0.925750 26 1 0 -0.665194 -1.589209 -1.611198 27 6 0 -3.576464 -0.511735 0.708508 28 1 0 -2.302160 1.123061 1.288945 29 6 0 -3.700088 -1.655858 -0.083803 30 1 0 -2.743801 -2.936632 -1.527427 31 1 0 -4.371503 -0.233599 1.392415 32 1 0 -4.601846 -2.257475 -0.028598 ------Part III Experimental Procedures and Computational Details 245
Energy and geometry for 6094*
Sum of electronic and thermal free energies = –1032.994296 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 1.229724 -1.590340 -1.208485 2 6 0 0.967102 -0.455884 -0.430021 3 6 0 1.890400 -0.038803 0.555570 4 6 0 3.126031 -0.699583 0.643273 5 6 0 3.389345 -1.802617 -0.159672 6 6 0 2.435210 -2.266617 -1.074553 7 1 0 0.487884 -1.913663 -1.934560 8 1 0 3.856898 -0.358783 1.371089 9 1 0 4.341034 -2.316867 -0.064676 10 1 0 2.644843 -3.137148 -1.687366 11 6 0 -0.236855 0.380915 -0.556147 12 16 0 1.468954 1.179627 1.786679 13 7 0 -0.016187 1.678446 -0.786085 14 6 0 -0.554797 2.691080 -0.014337 15 1 0 0.572136 2.201460 1.070405 16 1 0 -0.519032 3.682607 -0.454092 17 1 0 -1.438692 2.430792 0.557412 18 6 0 1.182939 2.096176 -1.533905 19 1 0 1.509927 1.288902 -2.185436 20 1 0 0.907045 2.969338 -2.126855 21 1 0 1.979084 2.366608 -0.834681 22 6 0 -1.566157 -0.120712 -0.185120 23 6 0 -2.735107 0.429042 -0.741477 24 6 0 -1.682624 -1.213124 0.685519 25 6 0 -3.980388 -0.096112 -0.427553 26 1 0 -2.656087 1.267310 -1.428871 27 6 0 -2.935429 -1.737077 0.999702 28 1 0 -0.785052 -1.638568 1.124998 29 6 0 -4.086953 -1.181689 0.447805 30 1 0 -4.873274 0.334585 -0.870138 31 1 0 -3.008796 -2.577896 1.682248 32 1 0 -5.062517 -1.589761 0.692662 ------Part III Experimental Procedures and Computational Details 246
Energy and geometry for 6095
Sum of electronic and thermal free energies = –1033.007872 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 0.834536 -1.637333 -0.990519 2 6 0 0.931149 -0.410904 -0.307001 3 6 0 2.151265 -0.124991 0.351082 4 6 0 3.222504 -1.019578 0.274890 5 6 0 3.096144 -2.222479 -0.412710 6 6 0 1.891068 -2.537292 -1.042025 7 1 0 -0.103470 -1.872365 -1.486307 8 1 0 4.157655 -0.783336 0.775007 9 1 0 3.935257 -2.909858 -0.450069 10 1 0 1.780596 -3.473956 -1.579138 11 16 0 2.277712 1.374113 1.292372 12 6 0 -0.230107 0.488045 -0.231558 13 7 0 -0.085100 1.787152 -0.642492 14 6 0 -0.975969 2.828410 -0.077762 15 1 0 -1.667610 2.378911 0.628105 16 1 0 -0.338549 3.546824 0.441435 17 1 0 -1.516782 3.328837 -0.881986 18 6 0 0.889587 2.241909 -1.414233 19 1 0 1.569084 1.539454 -1.874370 20 1 0 1.044047 3.309065 -1.474042 21 1 0 3.453996 1.076404 1.862804 22 6 0 -1.563193 -0.056017 0.012904 23 6 0 -1.738450 -1.112223 0.931070 24 6 0 -2.704931 0.410102 -0.667427 25 6 0 -2.993968 -1.653977 1.171889 26 1 0 -0.871035 -1.494572 1.462610 27 6 0 -3.965998 -0.124281 -0.411230 28 1 0 -2.597072 1.181296 -1.425664 29 6 0 -4.121124 -1.158879 0.509238 30 1 0 -3.098630 -2.461444 1.890667 31 1 0 -4.828137 0.257049 -0.951041 32 1 0 -5.102129 -1.581251 0.701831 ------Part III Experimental Procedures and Computational Details 247
Energy and geometry for 6095*
Sum of electronic and thermal free energies = –1033.002426 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 0.925939 -1.417086 -1.172235 2 6 0 0.972216 -0.355900 -0.267057 3 6 0 2.133612 -0.149176 0.516357 4 6 0 3.232021 -0.998072 0.350854 5 6 0 3.175849 -2.039365 -0.574233 6 6 0 2.025465 -2.259055 -1.333704 7 1 0 0.018547 -1.580615 -1.749719 8 1 0 4.123211 -0.848403 0.952532 9 1 0 4.035214 -2.693055 -0.692602 10 1 0 1.984626 -3.080479 -2.041774 11 16 0 2.059950 1.178748 1.669762 12 6 0 -0.164241 0.585014 -0.039526 13 7 0 -0.094780 1.798052 -0.757174 14 6 0 -1.029199 2.869642 -0.346318 15 1 0 -1.321746 3.448340 -1.222183 16 1 0 -1.902988 2.433345 0.127261 17 1 0 -0.501587 3.504209 0.369898 18 6 0 0.913022 2.154340 -1.498262 19 1 0 1.667689 1.424135 -1.757028 20 1 0 0.981877 3.185559 -1.818661 21 1 0 0.584995 1.157820 1.205307 22 6 0 -1.506962 -0.025707 0.113243 23 6 0 -1.732965 -0.898745 1.188874 24 6 0 -2.544386 0.175022 -0.809243 25 6 0 -2.960610 -1.532217 1.346347 26 1 0 -0.930431 -1.072185 1.901777 27 6 0 -3.780808 -0.448680 -0.642940 28 1 0 -2.378445 0.811542 -1.676214 29 6 0 -3.994961 -1.303814 0.435287 30 1 0 -3.115451 -2.202301 2.186574 31 1 0 -4.570361 -0.277410 -1.368566 32 1 0 -4.954847 -1.794040 0.562767 ------Part III Experimental Procedures and Computational Details 248
Energy and geometry for 6097
Sum the electronic and thermal free energies = –1033.063316 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -0.422756 -1.836056 0.359413 2 6 0 -0.766902 -0.578607 -0.139985 3 6 0 -2.130481 -0.260703 -0.282954 4 6 0 -3.110262 -1.209136 0.028241 5 6 0 -2.744640 -2.476560 0.470688 6 6 0 -1.398299 -2.787722 0.650449 7 1 0 0.623534 -2.076977 0.518592 8 1 0 -4.158876 -0.944460 -0.071946 9 1 0 -3.512929 -3.210137 0.694492 10 1 0 -1.105365 -3.764682 1.021318 11 16 0 -2.671132 1.332498 -0.846853 12 6 0 0.228285 0.537694 -0.424978 13 7 0 -0.168312 1.729081 0.347861 14 6 0 -1.216515 2.430352 -0.312474 15 6 0 -0.445885 1.481008 1.764921 16 1 0 0.317793 0.816659 2.175426 17 1 0 -0.403730 2.433396 2.300533 18 1 0 0.094637 0.822560 -1.479072 19 6 0 1.695305 0.182955 -0.265771 20 6 0 2.231222 -0.846021 -1.050577 21 6 0 2.548050 0.892966 0.579973 22 6 0 3.580683 -1.175629 -0.971445 23 1 0 1.582366 -1.390441 -1.733339 24 6 0 3.902058 0.561884 0.663807 25 1 0 2.157708 1.724329 1.157284 26 6 0 4.421806 -0.475357 -0.105163 27 1 0 3.977360 -1.974751 -1.590180 28 1 0 4.550537 1.125674 1.327609 29 1 0 5.475036 -0.730324 -0.041153 30 1 0 -1.427183 1.017559 1.938887 31 1 0 -1.629478 3.195192 0.346887 32 1 0 -0.855119 2.886468 -1.235593 ------Part III Experimental Procedures and Computational Details 249
Energy and geometry for 6105
Sum of electronic and thermal free energies = –1110.376057 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 2.004781 0.073628 -1.634356 2 6 0 1.416912 -0.190235 -0.410648 3 6 0 2.162692 -0.491249 0.721191 4 6 0 3.547432 -0.560878 0.691589 5 6 0 4.152780 -0.312265 -0.548042 6 6 0 3.404054 -0.000317 -1.687326 7 1 0 1.418080 0.324329 -2.513620 8 1 0 4.138183 -0.793582 1.571198 9 1 0 5.235101 -0.358033 -0.624820 10 1 0 3.916793 0.191632 -2.624267 11 16 0 0.847280 -0.661495 1.899567 12 6 0 0.001601 -0.205971 0.142010 13 7 0 -0.848324 -1.214456 -0.367099 14 6 0 -2.075922 -1.392802 0.415477 15 1 0 -1.870419 -2.034107 1.290834 16 1 0 -2.386130 -0.412650 0.791752 17 6 0 -0.219289 -2.496013 -0.671778 18 1 0 -0.976265 -3.157346 -1.096794 19 1 0 0.579321 -2.364067 -1.401632 20 1 0 0.193230 -2.965636 0.234965 21 6 0 -0.645761 1.170590 0.113324 22 6 0 -1.440971 1.490547 -0.995877 23 6 0 -0.408554 2.151365 1.078460 24 6 0 -1.993829 2.761777 -1.128881 25 1 0 -1.623092 0.731268 -1.750175 26 6 0 -0.963216 3.423884 0.942815 27 1 0 0.204941 1.915658 1.941053 28 6 0 -1.758254 3.734497 -0.158160 29 1 0 -2.609693 2.991704 -1.993061 30 1 0 -0.774775 4.172375 1.706266 31 1 0 -2.191945 4.724468 -0.259248 32 6 0 -3.186980 -1.971590 -0.412527 33 6 0 -3.855539 -3.080027 -0.100109 34 1 0 -3.444183 -1.410720 -1.311049 35 1 0 -4.672515 -3.442948 -0.715491 36 1 0 -3.606470 -3.656871 0.787732 ------Part III Experimental Procedures and Computational Details 250
Energy and geometry for 6106
Sum of electronic and thermal free energies = –1110.373082 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 0.642296 1.548960 -1.649810 2 6 0 0.507718 1.068765 -0.360123 3 6 0 0.870894 1.818164 0.751546 4 6 0 1.398697 3.094752 0.636619 5 6 0 1.551497 3.585842 -0.667347 6 6 0 1.183894 2.835304 -1.787773 7 1 0 0.345285 0.965189 -2.516385 8 1 0 1.681139 3.688217 1.499564 9 1 0 1.964845 4.579733 -0.811151 10 1 0 1.315892 3.259258 -2.777923 11 16 0 0.429761 0.670431 2.030180 12 6 0 -0.038586 -0.189064 0.294742 13 7 0 0.658988 -1.392573 0.028739 14 6 0 0.217191 -2.508769 0.858684 15 1 0 0.449348 -2.316519 1.921173 16 1 0 -0.857246 -2.663396 0.753100 17 6 0 2.121271 -1.307291 -0.009025 18 1 0 2.397116 -0.353411 -0.468176 19 1 0 2.538414 -1.316694 1.011295 20 6 0 -1.536100 -0.340691 0.071503 21 6 0 -1.938542 -0.955920 -1.122265 22 6 0 -2.509619 0.150862 0.939922 23 6 0 -3.287719 -1.074563 -1.437893 24 1 0 -1.180575 -1.351940 -1.791965 25 6 0 -3.863206 0.028659 0.621945 26 1 0 -2.209178 0.628328 1.865892 27 6 0 -4.257794 -0.581674 -0.564478 28 1 0 -3.582768 -1.555741 -2.365516 29 1 0 -4.608655 0.412606 1.311504 30 1 0 -5.311540 -0.676643 -0.807362 31 1 0 0.738352 -3.415248 0.546008 32 6 0 2.701891 -2.427666 -0.824169 33 6 0 3.641466 -3.263984 -0.387844 34 1 0 2.311678 -2.521862 -1.837410 35 1 0 4.052354 -4.039947 -1.025577 36 1 0 4.034952 -3.190930 0.623475 ------Part III Experimental Procedures and Computational Details 251
Energy and geometry of 6107
Sum of electronic and thermal free energies = –1110. 371134 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -1.719017 -0.882044 -1.542619 2 6 0 -1.279750 -0.398091 -0.307135 3 6 0 -2.155618 -0.046031 0.739271 4 6 0 -3.535349 -0.125165 0.444639 5 6 0 -3.982376 -0.570514 -0.791837 6 6 0 -3.084013 -0.964977 -1.794157 7 1 0 -0.996152 -1.171340 -2.303823 8 1 0 -4.244355 0.153795 1.218618 9 1 0 -5.050874 -0.625373 -0.981714 10 1 0 -3.445546 -1.322985 -2.752006 11 16 0 -1.479841 0.355441 2.288764 12 6 0 0.165588 -0.212429 -0.036839 13 7 0 0.908331 -1.262117 0.188226 14 6 0 2.386210 -1.264774 0.216512 15 1 0 2.707797 -1.404120 1.254614 16 1 0 2.734894 -0.293786 -0.134166 17 6 0 0.284351 -2.560459 0.499464 18 1 0 0.960230 -3.102577 1.161231 19 1 0 -0.666386 -2.380440 0.999473 20 1 0 0.135140 -3.140442 -0.413966 21 6 0 0.739184 1.147177 -0.172112 22 6 0 0.359896 1.923495 -1.271167 23 6 0 1.607212 1.677926 0.791269 24 6 0 0.887985 3.203439 -1.433678 25 1 0 -0.348081 1.527208 -1.992445 26 6 0 2.113833 2.961157 0.635417 27 1 0 1.835127 1.099673 1.681749 28 6 0 1.764043 3.721442 -0.483850 29 1 0 0.600128 3.798268 -2.294058 30 1 0 2.768100 3.377382 1.394198 31 1 0 2.162449 4.724062 -0.602315 32 6 0 2.927615 -2.356508 -0.664024 33 6 0 3.743154 -3.312155 -0.225764 34 1 0 2.642102 -2.310976 -1.714297 35 1 0 4.148957 -4.060010 -0.898673 36 1 0 4.037933 -3.369511 0.819442 ------Part III Experimental Procedures and Computational Details 252
Energy and geometry for 6108
Sum of electronic and thermal free energies = –1110.373810 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -0.913412 1.729038 -1.540239 2 6 0 -0.632385 1.013858 -0.373310 3 6 0 -1.011120 1.452760 0.911288 4 6 0 -1.651949 2.710550 0.970456 5 6 0 -1.911156 3.442837 -0.180207 6 6 0 -1.555432 2.959622 -1.447079 7 1 0 -0.624044 1.327399 -2.509711 8 1 0 -1.953606 3.088518 1.942766 9 1 0 -2.408858 4.405087 -0.095549 10 1 0 -1.774025 3.533955 -2.340746 11 16 0 -0.733697 0.406221 2.273347 12 6 0 0.119655 -0.265613 -0.422176 13 7 0 -0.483965 -1.372159 -0.757657 14 6 0 -1.962233 -1.472443 -0.798091 15 1 0 -2.247438 -1.778758 -1.810037 16 1 0 -2.369050 -0.482565 -0.591833 17 6 0 0.201995 -2.645137 -1.013638 18 1 0 -0.351399 -3.163425 -1.798596 19 1 0 1.223984 -2.459718 -1.335918 20 1 0 0.194519 -3.264530 -0.114484 21 6 0 1.586843 -0.219332 -0.212648 22 6 0 2.325088 0.768445 -0.872332 23 6 0 2.232196 -1.110542 0.653916 24 6 0 3.707691 0.828422 -0.708503 25 1 0 1.818797 1.488325 -1.507484 26 6 0 3.607060 -1.030045 0.832892 27 1 0 1.643660 -1.822308 1.223985 28 6 0 4.348516 -0.068759 0.141777 29 1 0 4.277443 1.589161 -1.231612 30 1 0 4.099254 -1.706034 1.524223 31 1 0 5.422999 -0.009149 0.283542 32 6 0 -2.441564 -2.463725 0.225911 33 6 0 -3.163447 -3.536878 -0.088308 34 1 0 -2.187768 -2.221944 1.257189 35 1 0 -3.533067 -4.212130 0.676266 36 1 0 -3.422573 -3.764649 -1.120196 ------Part III Experimental Procedures and Computational Details 253
Energy and geometry for 6107*
Sum of electronic and thermal free energies = –1110.334292 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 1.959780 -1.489575 -1.115043 2 6 0 1.333203 -0.477358 -0.374385 3 6 0 2.075630 0.303987 0.542789 4 6 0 3.470981 0.141039 0.581712 5 6 0 4.085752 -0.839553 -0.185674 6 6 0 3.331512 -1.675876 -1.021119 7 1 0 1.358609 -2.101288 -1.783206 8 1 0 4.056056 0.765364 1.250834 9 1 0 5.162203 -0.968801 -0.123752 10 1 0 3.819803 -2.449592 -1.604252 11 6 0 -0.088245 -0.131220 -0.493611 12 16 0 1.286387 1.346297 1.748135 13 7 0 -0.359508 1.153300 -0.762925 14 6 0 -1.204474 1.897853 0.066905 15 1 0 0.006836 1.941474 1.023011 16 1 0 -1.818368 1.275952 0.715560 17 6 0 0.573683 1.947045 -1.575530 18 1 0 1.283520 1.284427 -2.063642 19 1 0 -0.004703 2.475859 -2.334859 20 1 0 1.100845 2.666956 -0.941621 21 6 0 -1.153358 -1.078058 -0.149931 22 6 0 -2.441944 -0.954623 -0.703068 23 6 0 -0.878064 -2.169114 0.687439 24 6 0 -3.422556 -1.894030 -0.419962 25 1 0 -2.661618 -0.120177 -1.364159 26 6 0 -1.866528 -3.109911 0.968578 27 1 0 0.110467 -2.265583 1.126678 28 6 0 -3.139487 -2.976958 0.418781 29 1 0 -4.409466 -1.790015 -0.859886 30 1 0 -1.640373 -3.945512 1.623362 31 1 0 -3.908313 -3.711478 0.636636 32 6 0 -1.803422 3.151585 -0.366402 33 6 0 -2.913520 3.660612 0.192534 34 1 0 -1.287612 3.736880 -1.124266 35 1 0 -3.288955 4.636931 -0.092169 36 1 0 -3.458233 3.119672 0.961981 ------Part III Experimental Procedures and Computational Details 254
Energy and geometry for 6107**
Sum of electronic and thermal free energies = –1110.373737 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -1.763680 -1.816058 0.749838 2 6 0 -1.301540 -0.575294 0.280072 3 6 0 -2.153349 0.262141 -0.483048 4 6 0 -3.501462 -0.113755 -0.626872 5 6 0 -3.953409 -1.326065 -0.125967 6 6 0 -3.081383 -2.194550 0.548353 7 1 0 -1.079579 -2.456175 1.301807 8 1 0 -4.172383 0.541125 -1.175287 9 1 0 -4.991345 -1.610174 -0.272055 10 1 0 -3.441640 -3.145622 0.926188 11 6 0 0.039898 -0.055415 0.553800 12 16 0 -1.547915 1.662795 -1.387059 13 7 0 0.084718 1.177846 1.085132 14 6 0 0.764484 2.259508 0.504044 15 1 0 -0.423117 2.321170 -0.449994 16 6 0 -1.004367 1.628371 1.969042 17 1 0 -1.463143 0.767284 2.450198 18 1 0 -0.558396 2.280349 2.722665 19 1 0 -1.753092 2.188465 1.401404 20 6 0 1.253568 -0.795053 0.207037 21 6 0 2.465168 -0.562886 0.882278 22 6 0 1.207489 -1.794179 -0.778830 23 6 0 3.596587 -1.308253 0.574145 24 1 0 2.507986 0.200194 1.654419 25 6 0 2.343518 -2.538180 -1.082517 26 1 0 0.279685 -1.967818 -1.315871 27 6 0 3.541182 -2.298623 -0.408882 28 1 0 4.524492 -1.120272 1.105114 29 1 0 2.294140 -3.302025 -1.852245 30 1 0 4.426674 -2.878933 -0.647982 31 6 0 1.810054 2.082510 -0.496868 32 6 0 2.876999 2.888840 -0.587508 33 1 0 1.649554 1.314241 -1.250764 34 1 0 3.577361 2.802040 -1.410897 35 1 0 3.068912 3.660145 0.154127 36 1 0 0.888968 3.098008 1.187491 ------Part III Experimental Procedures and Computational Details 255
Energy and geometry for 6108*
Sum of electronic and thermal free energies = –1110.326248 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 0.554363 -1.785673 -1.584097 2 6 0 0.563126 -0.972758 -0.442511 3 6 0 1.434121 -1.264953 0.632749 4 6 0 2.380979 -2.290321 0.472366 5 6 0 2.386209 -3.065421 -0.680543 6 6 0 1.458940 -2.831808 -1.705104 7 1 0 -0.150081 -1.563726 -2.381762 8 1 0 3.081359 -2.492979 1.277438 9 1 0 3.108394 -3.870131 -0.779682 10 1 0 1.461214 -3.451767 -2.595444 11 6 0 -0.285382 0.214904 -0.263335 12 16 0 1.248756 -0.498420 2.229172 13 7 0 0.360956 1.351821 0.023414 14 6 0 0.065109 2.136026 1.120842 15 1 0 0.826787 0.952994 1.942827 16 1 0 -0.921863 1.994424 1.547446 17 6 0 1.720658 1.586089 -0.527782 18 1 0 1.881165 0.855599 -1.322079 19 1 0 2.453549 1.416658 0.268845 20 6 0 -1.744231 0.107866 -0.141195 21 6 0 -2.584624 1.189711 -0.461405 22 6 0 -2.327507 -1.112070 0.229585 23 6 0 -3.964145 1.052949 -0.404377 24 1 0 -2.143352 2.136393 -0.762368 25 6 0 -3.713966 -1.245463 0.286373 26 1 0 -1.686289 -1.950117 0.486466 27 6 0 -4.536516 -0.166721 -0.027915 28 1 0 -4.599312 1.894988 -0.661168 29 1 0 -4.149351 -2.194373 0.583108 30 1 0 -5.615857 -0.270796 0.016945 31 1 0 0.463654 3.144220 1.099660 32 6 0 1.827563 2.980663 -1.074442 33 6 0 2.771476 3.841648 -0.700726 34 1 0 1.097342 3.254123 -1.835114 35 1 0 2.845258 4.828269 -1.146008 36 1 0 3.503558 3.580188 0.059324 ------Part III Experimental Procedures and Computational Details 256
Energy and geometry for 6149
Sum of electronic and thermal free energies = –1138.976184 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 3.708392 0.423605 -0.900071 2 6 0 2.425596 1.008089 -1.090538 3 6 0 1.604790 0.715526 -0.014354 4 6 0 1.890668 0.006091 1.163008 5 6 0 3.160851 -0.543767 1.261385 6 6 0 4.069104 -0.336089 0.212767 7 1 0 4.470062 0.568197 -1.667932 8 1 0 1.167337 -0.111751 1.967352 9 1 0 3.444944 -1.112809 2.141407 10 1 0 5.068204 -0.761923 0.284320 11 16 0 -0.049008 1.497791 -0.103801 12 6 0 -1.248146 0.292715 -0.045763 13 6 0 -0.958098 -1.204421 -0.279119 14 9 0 -1.028041 -1.872417 0.882603 15 9 0 0.213376 -1.431153 -0.833445 16 9 0 -1.887008 -1.714190 -1.105410 17 7 0 -2.506983 0.627473 0.160097 18 6 0 -3.632699 -0.311776 0.319456 19 1 0 -4.301961 0.116266 1.064958 20 1 0 -4.161210 -0.424972 -0.629593 21 1 0 -3.291174 -1.279231 0.674706 22 6 0 -2.847066 2.050274 0.263790 23 1 0 -2.325216 2.491081 1.119610 24 1 0 -2.540616 2.574408 -0.644986 25 1 0 -3.922657 2.142133 0.393200 ------
Part III Experimental Procedures and Computational Details 257
Energy and geometry for 6150
Sum of electronic and thermal free energies = –1139.098514 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 1.628565 -0.178194 -1.524225 2 6 0 0.877504 0.040381 -0.384476 3 6 0 1.448849 0.172204 0.874164 4 6 0 2.817584 0.089774 1.071911 5 6 0 3.590800 -0.127361 -0.076979 6 6 0 3.016737 -0.258090 -1.345758 7 1 0 1.174396 -0.281527 -2.505024 8 1 0 3.274434 0.187567 2.050578 9 1 0 4.669966 -0.197357 0.021616 10 1 0 3.658882 -0.427743 -2.203751 11 16 0 -0.029936 0.413395 1.833081 12 6 0 -0.590839 0.179928 -0.042721 13 7 0 -1.289089 1.223398 -0.672832 14 6 0 -2.676838 1.408631 -0.252677 15 1 0 -2.746936 1.606969 0.829421 16 1 0 -3.084389 2.264634 -0.792058 17 1 0 -3.281054 0.535582 -0.496953 18 6 0 -0.574158 2.498060 -0.715051 19 1 0 -0.495114 2.947949 0.285965 20 1 0 0.427254 2.360835 -1.122135 21 1 0 -1.125408 3.176766 -1.367968 22 6 0 -1.328870 -1.167175 -0.121076 23 9 0 -2.390470 -1.235618 0.700550 24 9 0 -1.775617 -1.388098 -1.368899 25 9 0 -0.525628 -2.187475 0.199699 ------
Part III Experimental Procedures and Computational Details 258
Energy and geometry for 6151
Sum of electronic and thermal free energies = –1139.044322 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -2.409137 1.299558 -0.119052 2 6 0 -1.300511 0.468389 -0.075509 3 6 0 -1.414945 -0.918222 -0.018401 4 6 0 -2.683715 -1.499242 -0.008194 5 6 0 -3.805676 -0.676302 -0.056820 6 6 0 -3.674603 0.712499 -0.116937 7 1 0 -2.312436 2.379275 -0.158048 8 1 0 -2.786918 -2.578628 0.025548 9 1 0 -4.794528 -1.123458 -0.058468 10 1 0 -4.555817 1.342534 -0.163521 11 16 0 0.126818 -1.730048 0.042307 12 6 0 0.918509 -0.195281 -0.569639 13 6 0 2.339085 -0.186320 -0.157139 14 9 0 2.980129 0.960312 -0.504590 15 9 0 2.989736 -1.209606 -0.745610 16 9 0 2.645372 -0.327735 1.185067 17 7 0 0.101604 0.948024 0.034745 18 6 0 0.309693 2.182925 -0.786726 19 1 0 1.367426 2.431342 -0.765421 20 1 0 -0.004744 1.959869 -1.803920 21 1 0 -0.269007 3.001008 -0.355753 22 6 0 0.358630 1.276190 1.489722 23 1 0 1.362736 1.690103 1.578157 24 1 0 -0.387934 2.000151 1.819542 25 1 0 0.279801 0.350498 2.060130 ------
Part III Experimental Procedures and Computational Details 259
Energy and geometry for 6152*
Sum of electronic and thermal free energies = –1139.041760 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -1.386526 -1.657208 0.612469 2 6 0 -0.714273 -0.491103 0.213948 3 6 0 -1.424425 0.576000 -0.392887 4 6 0 -2.826907 0.501048 -0.444905 5 6 0 -3.481843 -0.646810 -0.021864 6 6 0 -2.764302 -1.739842 0.486047 7 1 0 -0.818683 -2.474196 1.047758 8 1 0 -3.383164 1.333930 -0.865371 9 1 0 -4.563419 -0.703143 -0.100242 10 1 0 -3.287827 -2.636323 0.800826 11 6 0 0.710043 -0.231399 0.419157 12 16 0 -0.593106 1.901683 -1.232860 13 7 0 1.054611 0.886275 1.057219 14 6 0 1.896464 1.825915 0.504906 15 1 0 0.735059 2.202009 -0.373618 16 1 0 2.291722 2.562774 1.196937 17 1 0 2.565141 1.474605 -0.276231 18 6 0 0.164389 1.425945 2.100390 19 1 0 -0.399891 0.612597 2.550923 20 1 0 0.797485 1.908952 2.845320 21 1 0 -0.513011 2.160897 1.656454 22 6 0 1.765102 -1.002400 -0.317410 23 9 0 2.962159 -0.944401 0.295625 24 9 0 1.414592 -2.296927 -0.390943 25 9 0 1.962992 -0.584654 -1.584308 ------
Part III Experimental Procedures and Computational Details 260
Energy and geometry for 6165*
Sum of electronic and thermal free energies = –815.714721 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 1.748887 1.134347 -0.726653 2 6 0 1.748904 1.134315 0.726711 3 1 0 1.801734 2.023735 1.344070 4 1 0 1.801720 2.023793 -1.343973 5 6 0 -0.593068 -0.513461 -0.000012 6 6 0 -0.654471 0.777205 -0.000022 7 6 0 -1.645053 -1.406999 0.000006 8 1 0 -1.550143 -2.488328 0.000014 9 6 0 -1.865325 1.455446 -0.000012 10 1 0 -1.965636 2.536758 -0.000017 11 6 0 -2.897417 -0.768573 0.000014 12 6 0 -3.002938 0.627937 0.000005 13 1 0 -3.989683 1.083234 0.000012 14 1 0 -3.800120 -1.372256 0.000026 15 16 0 1.576118 -1.099589 -0.000025 16 7 0 1.817655 -0.061033 -1.259801 17 7 0 1.817649 -0.061084 1.259808 ------
Part III Experimental Procedures and Computational Details 261
Energy and geometry for 6166
Sum of electronic and thermal free energies = –815.760101 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 1.040369 1.226798 -0.448114 2 6 0 1.594640 1.001915 1.036696 3 1 0 1.704779 1.837955 1.724678 4 1 0 1.159748 2.241357 -0.825256 5 6 0 -0.352654 -0.654377 -0.112232 6 6 0 -0.397220 0.729217 -0.277599 7 6 0 -1.466828 -1.425364 0.144527 8 1 0 -1.405016 -2.500068 0.281023 9 6 0 -1.608491 1.391416 -0.179244 10 1 0 -1.670982 2.470283 -0.286109 11 6 0 -2.697390 -0.754073 0.210127 12 6 0 -2.764108 0.628129 0.048759 13 1 0 -3.728128 1.124335 0.100473 14 1 0 -3.606520 -1.319852 0.385801 15 16 0 1.406264 -1.061577 -0.324012 16 7 0 1.756850 0.224547 -1.197715 17 7 0 1.808292 -0.186083 1.378580 ------
Part III Experimental Procedures and Computational Details 262
Energy and geometry of 6166*
Sum of electronic and thermal free energies = –815. 760221 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 1.039593 1.204275 -0.502845 2 6 0 1.578789 1.040968 1.047851 3 1 0 1.671716 1.940358 1.653784 4 1 0 1.172802 2.209297 -0.900237 5 6 0 -0.347536 -0.663864 -0.126639 6 6 0 -0.387455 0.716970 -0.320341 7 6 0 -1.465673 -1.420294 0.168141 8 1 0 -1.408151 -2.491696 0.329558 9 6 0 -1.595169 1.389522 -0.217953 10 1 0 -1.651694 2.466086 -0.348019 11 6 0 -2.688199 -0.740414 0.237271 12 6 0 -2.749581 0.640059 0.043892 13 1 0 -3.710209 1.142450 0.098127 14 1 0 -3.598163 -1.295498 0.440196 15 16 0 1.389190 -1.096253 -0.327326 16 7 0 1.784762 0.192757 -1.173757 17 7 0 1.784958 -0.111940 1.457691 ------
Part III Experimental Procedures and Computational Details 263
Energy and geometry for 7005/7006
Sum of electronic and thermal free energies = –783.918094 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -0.878525 1.041695 0.198300 2 6 0 -2.295027 0.890594 0.018470 3 6 0 -2.867080 -0.347747 -0.189296 4 6 0 -2.102319 -1.531765 -0.237606 5 6 0 -0.728277 -1.449684 -0.068146 6 6 0 -0.152872 -0.195816 0.147166 7 1 0 -2.900097 1.791712 0.051177 8 1 0 -3.944492 -0.413974 -0.319745 9 1 0 -2.576609 -2.493051 -0.397901 10 1 0 -0.126787 -2.353762 -0.091901 11 8 0 -0.268206 2.139640 0.372008 12 16 0 1.565510 0.103905 0.443199 13 6 0 2.321615 -1.517578 0.222054 14 1 0 3.401550 -1.375502 0.273563 15 1 0 1.998642 -2.157271 1.043805 16 1 0 2.036979 -1.946363 -0.739974 17 6 0 2.126676 0.927275 -1.070509 18 1 0 3.200789 1.097725 -0.983230 19 1 0 1.884129 0.299910 -1.928848 20 1 0 1.578232 1.869134 -1.096806 ------
Part III Experimental Procedures and Computational Details 264
Energy and geometry for 7007
Sum of electronic and thermal free energies = –783.787095 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 1.065163 1.362550 0.000076 2 6 0 2.480163 1.191861 0.000044 3 6 0 3.117080 -0.044324 -0.000017 4 6 0 2.373106 -1.238019 -0.000056 5 6 0 0.991390 -1.162740 -0.000033 6 6 0 0.443119 0.134731 0.000034 7 1 0 3.114773 2.078611 0.000069 8 1 0 4.203697 -0.100163 -0.000035 9 1 0 2.869207 -2.203298 -0.000101 10 1 0 0.395443 -2.074584 -0.000054 11 8 0 -1.986530 1.528102 0.000351 12 16 0 -1.371176 0.195830 0.000043 13 6 0 -1.941757 -0.751579 -1.404857 14 1 0 -3.031770 -0.782450 -1.369188 15 1 0 -1.594766 -0.214400 -2.289010 16 1 0 -1.508920 -1.751924 -1.367370 17 6 0 -1.941777 -0.752259 1.404477 18 1 0 -3.031789 -0.783119 1.368777 19 1 0 -1.508943 -1.752587 1.366512 20 1 0 -1.594800 -0.215509 2.288896 ------
Part III Experimental Procedures and Computational Details 265
Energy and geometry for 7008
Sum of electronic and thermal free energies = –783.844521 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 1.027608 1.203552 0.103173 2 6 0 2.419490 1.174094 0.025719 3 6 0 3.088685 -0.044656 -0.075748 4 6 0 2.373281 -1.242773 -0.098147 5 6 0 0.982574 -1.228513 -0.020403 6 6 0 0.330351 -0.001112 0.080172 7 1 0 2.978968 2.103464 0.049777 8 1 0 4.172437 -0.062415 -0.134218 9 1 0 2.897400 -2.189995 -0.172902 10 1 0 0.401769 -2.145105 -0.021884 11 8 0 -1.797299 1.499263 0.455564 12 16 0 -1.462133 0.075376 0.150392 13 6 0 -1.997690 -0.193935 -1.542318 14 1 0 -3.085014 -0.287788 -1.512746 15 1 0 -1.709785 0.689823 -2.111295 16 1 0 -1.536910 -1.100600 -1.930463 17 6 0 -1.942517 -1.258487 0.983408 18 1 0 -3.002320 -1.468041 0.873738 19 1 0 -1.513693 -1.323598 1.978827 20 1 0 0.478969 2.135099 0.195246 ------
Part III Experimental Procedures and Computational Details 266
Energy and geometry for 7016
Sum of electronic and thermal free energies = –1014.713823 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -0.380456 0.778791 0.425864 2 6 0 -0.055724 2.095989 0.090886 3 6 0 -1.039840 2.934672 -0.416366 4 6 0 -2.349779 2.484028 -0.605806 5 6 0 -2.678545 1.165297 -0.309555 6 6 0 -1.684440 0.327725 0.192968 7 1 0 0.965404 2.434010 0.231538 8 1 0 -0.785201 3.959363 -0.667717 9 1 0 -3.109066 3.152463 -0.995762 10 1 0 -3.689808 0.809638 -0.473333 11 8 0 0.477785 -0.089182 0.994977 12 16 0 -1.885032 -1.414369 0.532767 13 6 0 -3.626570 -1.710260 0.173597 14 1 0 -3.776632 -2.786160 0.271261 15 1 0 -4.226727 -1.186970 0.918692 16 1 0 -3.872579 -1.384114 -0.837450 17 6 0 -1.065186 -2.154399 -0.900091 18 1 0 -1.007372 -3.228440 -0.718003 19 1 0 -1.652897 -1.924193 -1.790515 20 1 0 -0.049151 -1.693311 -0.976857 21 6 0 1.787900 -0.177009 0.386308 22 6 0 2.838910 0.187680 1.223193 23 6 0 1.845746 -0.644439 -0.918890 24 6 0 4.131328 0.090377 0.705991 25 1 0 2.653831 0.532328 2.238029 26 6 0 3.181988 -0.715396 -1.374762 27 6 0 4.298326 -0.361581 -0.604757 28 1 0 4.987966 0.363397 1.315618 29 1 0 3.378254 -1.071886 -2.388628 30 1 0 5.300263 -0.441623 -1.022440 ------
Part III Experimental Procedures and Computational Details 267
Energy and geometry for 7094a
Sum of electronic and thermal free energies = –1006.851912 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 0.675052 1.208215 -0.003270 2 6 0 0.001417 0.054709 0.716700 3 6 0 -1.730898 1.820735 0.100205 4 6 0 -0.318140 2.282606 -0.300667 5 6 0 -0.758964 0.615418 1.908245 6 6 0 -1.674282 1.536740 1.585800 7 1 0 -2.494513 2.524133 -0.224504 8 1 0 0.677336 -0.757893 0.973673 9 6 0 -1.709946 -1.634685 0.064552 10 8 0 -1.247801 -2.671092 0.493037 11 6 0 -3.224975 -0.038382 -0.547233 12 8 0 -4.279080 0.530806 -0.725611 13 7 0 -3.028901 -1.380394 -0.266274 14 6 0 -4.088915 -2.367528 -0.177533 15 1 0 -5.014599 -1.877804 -0.478764 16 1 0 -3.870060 -3.202386 -0.844889 17 1 0 -4.175038 -2.733073 0.847153 18 7 0 -1.006103 -0.471089 -0.238626 19 7 0 -1.949277 0.533218 -0.614778 20 8 0 -0.079049 3.369245 -0.774998 21 1 0 -2.336523 2.031371 2.287212 22 1 0 -0.578592 0.246990 2.912149 23 6 0 3.011869 0.310305 -0.260152 24 6 0 4.313694 0.701659 0.082859 25 6 0 2.756935 -1.042230 -0.532274 26 6 0 5.327547 -0.244225 0.200465 27 1 0 4.523610 1.751598 0.268394 28 6 0 3.775805 -1.984989 -0.426306 29 1 0 1.768725 -1.349484 -0.864541 30 6 0 5.059375 -1.590376 -0.049773 31 1 0 6.328335 0.069165 0.479924 32 1 0 3.567724 -3.027104 -0.646677 33 1 0 5.851524 -2.327491 0.035188 34 6 0 1.958398 1.330906 -0.370543 35 1 0 2.245636 2.294900 -0.792432 ------Part III Experimental Procedures and Computational Details 268
Energy and geometry for 7094b
Sum of electronic and thermal free energies = –909.810418 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -1.477915 -0.529057 0.098419 2 6 0 -0.469202 0.426381 0.709290 3 6 0 0.625904 -1.811350 0.243640 4 6 0 -0.872815 -1.839476 -0.128560 5 6 0 0.147014 -0.222096 1.942376 6 6 0 0.730800 -1.399407 1.696191 7 1 0 1.121925 -2.740809 -0.026945 8 1 0 -0.836165 1.429046 0.902435 9 6 0 1.663632 1.461919 -0.074661 10 8 0 1.552443 2.619482 0.278044 11 6 0 2.600960 -0.558435 -0.576033 12 8 0 3.431478 -1.429455 -0.724107 13 7 0 2.832673 0.795879 -0.400049 14 6 0 4.146917 1.408670 -0.406457 15 1 0 4.801625 0.787806 -1.017693 16 1 0 4.062412 2.408005 -0.833902 17 1 0 4.547314 1.477686 0.607352 18 7 0 0.634882 0.552342 -0.284324 19 7 0 1.212855 -0.715816 -0.583197 20 8 0 -1.412684 -2.850997 -0.548131 21 1 0 1.257161 -2.003415 2.426475 22 1 0 0.138394 0.278340 2.904834 23 6 0 -3.108118 2.038665 -0.008613 24 6 0 -5.013596 0.556744 -0.550207 25 1 0 -2.965668 2.204684 1.065871 26 1 0 -5.243185 -0.482811 -0.784173 27 1 0 -2.168454 2.220108 -0.537076 28 1 0 -3.847092 2.754796 -0.370658 29 1 0 -5.596770 0.855885 0.327528 30 1 0 -5.304234 1.184410 -1.397936 31 6 0 -2.791743 -0.380066 -0.252452 32 1 0 -3.271953 -1.302908 -0.576425 33 7 0 -3.588443 0.696451 -0.288678 ------
Part III Experimental Procedures and Computational Details 269
Energy and geometry for 7094c
Sum of electronic and thermal free energies = –1214.522526 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -1.591494 -0.411729 0.229411 2 6 0 -0.522520 0.453188 0.847144 3 6 0 0.380044 -1.806246 0.205500 4 6 0 -1.124825 -1.691123 -0.173604 5 6 0 0.111740 -0.289520 2.014458 6 6 0 0.584072 -1.491759 1.671731 7 1 0 0.794987 -2.749874 -0.141746 8 1 0 -0.840283 1.465429 1.100615 9 6 0 1.656038 1.403118 0.061974 10 8 0 1.624315 2.545096 0.478862 11 6 0 2.435494 -0.647429 -0.565896 12 8 0 3.204989 -1.561725 -0.772943 13 7 0 2.771202 0.673223 -0.311031 14 6 0 4.133258 1.169569 -0.291468 15 1 0 4.601232 0.995413 -1.261489 16 1 0 4.087224 2.238268 -0.082556 17 1 0 4.708164 0.662153 0.485448 18 7 0 0.560438 0.583792 -0.184455 19 7 0 1.040926 -0.703952 -0.568143 20 8 0 -1.703274 -2.599104 -0.770468 21 16 0 -3.019106 0.183693 -0.466574 22 6 0 -3.898017 1.084257 0.836978 23 1 0 -4.208633 0.345511 1.575453 24 1 0 -3.239946 1.827061 1.291593 25 1 0 -4.770443 1.568149 0.394521 26 6 0 -2.556685 1.595461 -1.517276 27 1 0 -1.961897 2.309310 -0.943913 28 1 0 -1.967749 1.190700 -2.340371 29 1 0 -3.468511 2.061981 -1.894526 30 1 0 1.111014 -2.169101 2.334437 31 1 0 0.201693 0.163605 2.995793 ------
Part III Experimental Procedures and Computational Details 270
Energy and geometry for 7094d
Sum of electronic and thermal free energies = –1022. 891894 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 0.738771 1.216589 -0.072685 2 6 0 0.074540 0.066634 0.688467 3 6 0 -1.684301 1.828015 0.078160 4 6 0 -0.292790 2.296184 -0.375863 5 6 0 -0.636980 0.672090 1.884898 6 6 0 -1.562944 1.585579 1.568122 7 1 0 -2.464862 2.519808 -0.231272 8 1 0 0.757909 -0.743590 0.934747 9 6 0 -1.634156 -1.634144 0.086948 10 8 0 -1.147696 -2.660093 0.509033 11 6 0 -3.182831 -0.056263 -0.490825 12 8 0 -4.246482 0.500857 -0.642476 13 7 0 -2.963011 -1.394274 -0.209413 14 6 0 -4.011440 -2.390763 -0.084811 15 1 0 -4.924049 -1.956980 -0.492545 16 1 0 -3.730533 -3.280508 -0.649130 17 1 0 -4.161704 -2.654703 0.963742 18 7 0 -0.949292 -0.461444 -0.241670 19 7 0 -1.915128 0.528111 -0.599797 20 8 0 -0.060277 3.364885 -0.873729 21 1 0 -2.191121 2.106151 2.282021 22 1 0 -0.414684 0.342414 2.893740 23 7 0 1.939486 1.365993 -0.444574 24 6 0 2.892916 0.335888 -0.287360 25 6 0 4.130320 0.667280 0.273104 26 6 0 2.660329 -0.962696 -0.757283 27 6 0 5.107817 -0.312771 0.416683 28 1 0 4.304998 1.688762 0.595547 29 6 0 3.655601 -1.929202 -0.633653 30 1 0 1.714709 -1.200190 -1.238406 31 6 0 4.875164 -1.611752 -0.037137 32 1 0 6.060510 -0.057166 0.869675 33 1 0 3.474570 -2.932461 -1.006050 34 1 0 5.645406 -2.369423 0.062893 ------Part III Experimental Procedures and Computational Details 271
Energy and geometry for 7096
Sum of electronic and thermal free energies = –1214.509179 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 1.888800 0.678000 0.236926 2 6 0 1.646309 0.962369 1.530956 3 6 0 -0.364760 1.631920 -0.415004 4 6 0 1.026821 1.186997 -0.845035 5 6 0 0.489575 1.760314 1.918585 6 6 0 -0.438688 2.105778 1.012211 7 1 0 -0.730495 2.384464 -1.117524 8 1 0 2.289255 0.590073 2.323316 9 6 0 -1.771364 -1.497757 0.259019 10 8 0 -1.838590 -2.663328 0.678868 11 6 0 -2.570541 0.528919 -0.426822 12 8 0 -3.277074 1.511808 -0.651635 13 7 0 -2.935776 -0.712380 0.000342 14 6 0 -4.295734 -1.143117 0.215809 15 1 0 -4.255456 -2.204799 0.462150 16 1 0 -4.755307 -0.590827 1.040386 17 1 0 -4.888691 -0.989228 -0.688849 18 7 0 -0.690442 -0.767206 -0.036952 19 7 0 -1.196326 0.441735 -0.561820 20 8 0 1.384766 1.165091 -2.006161 21 16 0 3.189858 -0.385341 -0.362880 22 6 0 3.592394 -1.338897 1.115534 23 1 0 4.131109 -0.692177 1.807951 24 1 0 2.673691 -1.732069 1.554357 25 1 0 4.251045 -2.145969 0.792720 26 6 0 2.231742 -1.619252 -1.299549 27 1 0 1.271370 -1.767723 -0.793414 28 1 0 2.083320 -1.204964 -2.295234 29 1 0 2.846686 -2.519151 -1.338614 30 1 0 -1.339019 2.641980 1.297865 31 1 0 0.382417 2.020592 2.965640 ------
Part III Experimental Procedures and Computational Details 272
Energy and geometry for 7006*
Sum of electronic and thermal free energies = –1214.477554 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -1.688443 -0.408281 0.710060 2 6 0 -0.959720 0.325450 1.613235 3 6 0 0.276155 -1.812244 0.348388 4 6 0 -1.159371 -1.591161 0.067469 5 6 0 0.272954 -0.169984 2.126810 6 6 0 0.829977 -1.289284 1.566919 7 1 0 0.680346 -2.731531 -0.062308 8 1 0 -1.325223 1.272839 1.998213 9 6 0 1.631621 1.427113 -0.364012 10 8 0 1.648475 2.631360 -0.201613 11 6 0 2.401679 -0.685834 -0.571041 12 8 0 3.086726 -1.681616 -0.609856 13 7 0 2.770331 0.596110 -0.304837 14 6 0 4.111502 1.031510 0.008323 15 1 0 4.114071 2.121838 -0.023198 16 1 0 4.408888 0.689268 1.003248 17 1 0 4.808244 0.629044 -0.729559 18 7 0 0.550750 0.631856 -0.722123 19 7 0 0.963132 -0.622067 -0.856725 20 8 0 -1.803914 -2.234178 -0.766005 21 16 0 -3.157307 0.153373 -0.106691 22 6 0 -3.289327 1.859738 0.466907 23 1 0 -3.540272 1.850726 1.528135 24 1 0 -2.347776 2.382800 0.284700 25 1 0 -4.104280 2.319260 -0.093580 26 6 0 -2.558865 0.458487 -1.799471 27 1 0 -1.581969 0.945465 -1.725858 28 1 0 -2.466237 -0.520522 -2.268737 29 1 0 -3.313783 1.069250 -2.297688 30 1 0 1.781007 -1.679090 1.916331 31 1 0 0.755156 0.357806 2.941408 ------
Part III Experimental Procedures and Computational Details 273
Energy and geometry for 7097
Sum of electronic and thermal free energies = –1214.518098 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 0.834090 0.036594 0.141025 2 6 0 1.052135 0.293962 1.600476 3 6 0 2.173863 2.211736 -0.260901 4 6 0 1.509561 1.041690 -0.838660 5 6 0 1.722743 1.378487 2.012198 6 6 0 2.302830 2.339836 1.071629 7 1 0 2.578557 2.929921 -0.965042 8 1 0 0.532012 -0.365421 2.288754 9 6 0 -2.519724 -0.766332 0.459764 10 8 0 -3.526856 -1.351515 0.866286 11 6 0 -1.341659 0.970972 -0.448842 12 8 0 -0.971954 2.073891 -0.838563 13 7 0 -2.587389 0.533149 -0.142171 14 6 0 -3.790824 1.320711 -0.278772 15 1 0 -4.612619 0.700339 0.080427 16 1 0 -3.723880 2.233497 0.318623 17 1 0 -3.955454 1.588317 -1.324986 18 7 0 -1.240553 -1.169508 0.469211 19 7 0 -0.532235 -0.138309 -0.189808 20 8 0 1.553484 0.755009 -2.018603 21 16 0 1.773910 -1.590879 -0.317206 22 6 0 1.381463 -2.729392 1.032075 23 1 0 1.958862 -2.420237 1.903326 24 1 0 0.306173 -2.700481 1.214550 25 1 0 1.719096 -3.713186 0.700519 26 6 0 0.759186 -2.248627 -1.659958 27 1 0 -0.252843 -2.397954 -1.280330 28 1 0 0.788517 -1.504729 -2.455449 29 1 0 1.233351 -3.179537 -1.975095 30 1 0 2.828419 3.196488 1.482766 31 1 0 1.799112 1.592825 3.073461 ------
Part III Experimental Procedures and Computational Details 274
Energy and geometry for 7006**
Sum of electronic and thermal free energies = –1214.487197 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 1.057678 0.608144 -0.215063 2 6 0 0.943170 1.994865 0.179376 3 6 0 -0.644481 0.957050 -1.950207 4 6 0 0.590401 0.264878 -1.588947 5 6 0 -0.145994 2.664113 -0.267616 6 6 0 -0.998627 2.087962 -1.287070 7 1 0 -1.204188 0.573775 -2.797354 8 1 0 1.558023 2.406241 0.971172 9 6 0 -2.255879 0.208203 1.105711 10 8 0 -3.306113 0.707497 1.474004 11 6 0 -0.877749 -1.260848 0.096688 12 8 0 -0.405053 -2.208886 -0.498266 13 7 0 -2.180932 -0.942919 0.290369 14 6 0 -3.304407 -1.624170 -0.310782 15 1 0 -3.440765 -1.309210 -1.349483 16 1 0 -3.127805 -2.700677 -0.281258 17 1 0 -4.193405 -1.370117 0.267064 18 7 0 -0.971777 0.562862 1.460296 19 7 0 -0.120125 -0.278862 0.874472 20 8 0 1.170473 -0.569538 -2.279122 21 16 0 2.673622 -0.133488 0.133490 22 6 0 2.822937 0.232077 1.898857 23 1 0 3.183266 1.252591 2.016661 24 1 0 1.844645 0.086144 2.362571 25 1 0 3.560332 -0.462706 2.302424 26 6 0 2.396610 -1.918921 0.209694 27 1 0 1.655124 -2.133329 0.977388 28 1 0 2.031112 -2.225769 -0.768470 29 1 0 3.371702 -2.352249 0.438462 30 1 0 -1.901137 2.622073 -1.568522 31 1 0 -0.381430 3.648771 0.120768 ------
Part III Experimental Procedures and Computational Details 275
Energy and geometry for 7100
Sum of electronic and thermal free energies = –861.248106 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -0.975520 -1.070224 -0.497909 2 6 0 -2.301076 -1.539011 -0.191173 3 6 0 -3.233051 -0.726548 0.416117 4 6 0 -2.952361 0.614843 0.758284 5 6 0 -1.702811 1.132221 0.462480 6 6 0 -0.757877 0.311563 -0.163921 7 1 0 -2.532396 -2.568813 -0.445753 8 1 0 -4.217998 -1.130207 0.638220 9 1 0 -3.702792 1.234957 1.234735 10 1 0 -1.480604 2.167005 0.706426 11 8 0 -0.051530 -1.774939 -0.995379 12 16 0 0.852374 0.828058 -0.669374 13 6 0 0.819369 2.613287 -0.395819 14 1 0 1.788379 3.000639 -0.711059 15 1 0 0.033362 3.034586 -1.023034 16 1 0 0.641692 2.843846 0.655654 17 6 0 1.983427 0.379453 0.724088 18 1 0 2.838989 1.056603 0.631680 19 1 0 1.416401 0.612629 1.630792 20 6 0 2.412270 -1.051994 0.660593 21 6 0 3.690362 -1.397977 0.514020 22 1 0 1.628605 -1.800506 0.730787 23 1 0 3.987700 -2.440814 0.488860 24 1 0 4.476523 -0.653021 0.415148 ------
Part III Experimental Procedures and Computational Details 276
Energy and geometry for 7100*
Sum of electronic and thermal free energies = –861.225316 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 -1.087170 -0.861561 -0.701741 2 6 0 -2.483454 -0.733307 -0.311395 3 6 0 -2.952704 0.392090 0.297233 4 6 0 -2.099290 1.500103 0.607897 5 6 0 -0.771698 1.435302 0.300400 6 6 0 -0.217613 0.253510 -0.297357 7 1 0 -3.137903 -1.561422 -0.564995 8 1 0 -4.007705 0.459939 0.550112 9 1 0 -2.510514 2.384219 1.081796 10 1 0 -0.123575 2.274501 0.532706 11 8 0 -0.629092 -1.856558 -1.288235 12 16 0 1.318002 0.203537 -1.100871 13 6 0 2.093586 1.755794 -0.591873 14 1 0 3.104545 1.733803 -1.001558 15 1 0 1.558480 2.611293 -1.005587 16 1 0 2.146038 1.827404 0.496933 17 6 0 2.395009 -1.141902 0.763891 18 1 0 2.082749 -2.040961 0.240003 19 1 0 3.440324 -0.861310 0.670127 20 6 0 1.580052 -0.596163 1.736794 21 6 0 0.217231 -0.880056 1.692666 22 1 0 1.935560 0.239922 2.335401 23 1 0 -0.487868 -0.397634 2.363154 24 1 0 -0.099120 -1.816735 1.242644 ------
Part III Experimental Procedures and Computational Details 277
Energy and geometry for 7101
Sum of electronic and thermal free energies = –861.275649 a.u. ------Center Atomic Atomic Coordinates (Angstroms) Number Number Type X Y Z ------1 6 0 0.935443 -0.164666 1.156268 2 6 0 2.322566 -0.505840 0.818032 3 6 0 2.642216 -0.992995 -0.398173 4 6 0 1.641433 -1.202249 -1.438194 5 6 0 0.354093 -0.885631 -1.223820 6 6 0 -0.126794 -0.253182 0.046205 7 1 0 3.060842 -0.360743 1.599934 8 1 0 3.675137 -1.247660 -0.620689 9 1 0 1.956303 -1.623307 -2.387360 10 1 0 -0.388993 -1.032477 -2.002807 11 8 0 0.621878 0.195612 2.279041 12 16 0 -0.633524 1.476523 -0.392113 13 6 0 0.990446 2.241229 -0.650310 14 1 0 0.798434 3.232870 -1.063183 15 1 0 1.535544 2.343662 0.290728 16 1 0 1.580871 1.667263 -1.369607 17 6 0 -3.715444 -0.330336 0.017616 18 1 0 -3.823974 0.233949 0.940872 19 1 0 -4.568141 -0.357597 -0.653332 20 6 0 -2.577728 -0.959150 -0.275106 21 6 0 -1.377023 -0.959032 0.628190 22 1 0 -2.504956 -1.518668 -1.207118 23 1 0 -1.081216 -1.991564 0.855693 24 1 0 -1.613734 -0.463871 1.574098 ------
Bibiliography 278 Bibliography and Notes
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