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Haloselectivity of Heterocycles Will Gutekunst

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Baran Group Meeting Haloselectivity of Heterocycles Will Gutekunst Background SN(ANRORC) Addition of Nuclophile, Ring Opening, Ring Closure Polysubstituted heterocycles represent some of the most important compounds in the realm of pharmaceutical and material sciences. New and more efficient ways to selectively produce these Br Br molecules are of great importance and one approach is though the use of polyhalo heterocycles. Br NaNH2 N N Consider: Ar N 3 Ar2 NH3(l), 90% NH2 3 Halogenations H NH2 H N CO2Me Ar H 3 Suzuki Couplings 1 N CO2Me - Br H Ar 3 Ar2 1 Triple Halogenation NH2 NH CO Me N N 2 Ar1 H 1 Triple Suzuki Coupling N CO2Me N NH H NH2 Ar H 3 Ar2 1 Triple C-H activation? CO Me N 2 Ar1 H N CO2Me Cross Coupling H Virtually all types of cross coupling have been utilized in regioselective cross coupling reactions: Nucleophilic Substitution Kumada, Negishi, Sonogashira, Stille, Suzuki, Hiyama, etc. SNAr or SN(AE) In all of these examples, the oxidative addition of the metal to the heterocycle is the selectivity determining steps and is frequently considered to be irreversible. This addition highly resembles a nucleophilic substitution and it frequently follows similar regioselectivities in traditional S Ar reactions. Nu N The regioselectivity of cross coupling reaction in polyhalo heterocycles do not always follow the BDE's Nu of the corresponding C-X bonds. N X N X N Nu 2nd 2nd Meisenheimer Complex 1st Br Br 88.9 83.2 S (EA) Br 88.9 N 87.3 Br O O via: st OMe 1 Br NaNH , t-BuONa 2 N N pyrrolidine + Merlic and Houk have determined that the oxidative addition in palladium catalyzed cross coupling N N THF, 40ºC N reactions is determined by the distortion energy of the C-X bond (related to BDE) and the interaction of N the LUMO of the heterocycle to the HOMO of the Pd species. Tetrahedron 1982, 38, 427 SET Mechanism can also be operative (SRN1) OK HetX + Nu HetX + Nu N N O HetX Het + X N Cl h!, NH3(l) N Het + Nu HetNu 88% JOC 1981, 46, 294 HetNu + HetX HetNu + HetX JACS, 2007, 129, 12664; JACS, 2009, 131, 6632 Baran Group Meeting Haloselectivity of Heterocycles Will Gutekunst Predicting Reactivity Pyrroles can also be selectively monoarylated at C-2 under C-H activation conditions. The Handy Method Handy and coworkers disclosed an experimental method in 2006 for predicting the regiochemical + - 1 Ph2I BF4 outcome of multiply halogenated heterocycles using H-NMR of the dehalogenated substrate. The 5% IMesPd(OAc)2 proton that displays the largest chemical shift implies it is attached to the most electron deficient Ph N N carbon atom and, therefore, the preferred site of cross coupling. While this method is not foolproof Me rt, AcOH, 67% Me (it does not take into account sterics, directing groups, or interactions noted by Merlic), it is a good start for predicting regioselectivities of cross coupling reactions. JACS 2006, 128, 4972 Chem. Comm. 2006, 299 Indole Pyrroles 2nd 7.00 7.55 6.45 - Like pyrrole, SNAr is very difficult without strong EWG's nd - Due to the electron rich nature, SNAr reactions do not readily take place last 2 7.08 - Cross coupling occurs first at C-2, with C-4 to C-7 reacting 6.22 without strong EWGs. 7.27 before electron rich C-3. A C-2 vs C-4/7 has not been reported. - Cross coupling reactions occur fastest at the 2/5 positions, in accord with 7.40 N 6.68 st chemical shift prediction. H 1st N 1 H - Monocoupling in 2,5 dihalo substrates is difficult, but 3,4 dihalo (Acetone) (CDCl3) substrates can be easily controlled on steric grounds. - B(OH) S 2 Br Br O O Br S H Cl 2.5 eq EtSH H Cl N 10% Pd(PPh ) N TBS 3 4 TBS TEA, DMSO Na2CO3, Tol/H2O H H reflux, 8 hrs Cl N 86% EtS N 78% Me Me O O Orthogonally, the 3-position could be selectively exchanged with t-BuLi. Tetrahedron 2005, 61, 5831 Br Br Br t-BuLi, MeI Br Br Br Br Cl B(OH) 2 -78º C, THF Br N N N TBS 81% TBS 6% Pd(PPh ) Me Br N Br 3 4 Me K3PO4, Tol/H2O Chem. Pharm. Bull. 1996, 44,1831 90ºC, 12 hrs Cl 71% Tet. Lett. 2009, 49, 1698 The C-H activation conditions for pyrrole are also successful on indole and tolerates aryl bromides MeO MeO OMOM MeO MeO OMe Br + - Br MeO B(OH)2 MeO B(OH)2 Ph2I BF4 TfO OTf MeO 5% IMesPd(OAc)2 2% Pd(PPh3)4 8% Pd(PPh3)4 OMOM Ph MeO C CO Me N 60º C, AcOH, 74% N 2 N 2 aq. Na CO , THF aq. Na CO , THF H H 2 3 2 3 MeO2C CO2Me R reflux, 4 hrs reflux, 20 hrs N 78% 58% R Tet. Lett. 2003, 44, 4443 Baran Group Meeting Haloselectivity of Heterocycles Will Gutekunst Furan Much like the dibromo indole, after the first Negishi coupling, the lithium halogen exchange at C-3 is favored. - Not as resistant as pyrrole, but SNAr reactions still do not readily take place 2nd 6.24 without strong EWGs. Br OMe t-BuLi, MeI OMe - Cross coupling reactions occur fastest at the 2/5 positions, in accord with Br -78ºC, THF Br 7.29 st chemical shift prediction. OMe OMe O 1 54% - Halogenated furans have general stability problems, making cross couplings O O (CDCl3) sometimes troublesome. Synthesis 2003, 6, 925 Br SnMe Br Bu3Sn 4 Thiophene 5% [PdCl (Po-Tol ) ] 2 3 2 - A better substrate for SNAr than furan and two orders of magnitude more nd reactive than benzene, but not many examples of haloselective reactions. MeO2C Br MeO2C 6.99 2 O 4% Pd(PPH3)4 O DMA, 90ºC, 70% - Cross coupling reactions occur fastest at the 2/5 positions and the 3/4 DMA, 90ºC, 79% 7.18 much slower. Selectivity on 2,5 dihalothiophenes is scarcely obtained st S 1 though some success has been seen with Sonogashira reaction and cases with substrate bias. 2 steps (CDCl3) 64% MeO2C O O Br Br NBnMe BnNHCH rosefuran 3 Synlett 1998, 11, 1185 O O + O Br BnMeN Br S 46% S S H H H Furfural can be selectively arylated in the 5- position directly. 4:1 Synlett 2000, 4, 459 OMe PhBr O O O 10% Pd(OH)2, K2CO3 O Ph Br Br H DMA, 130ºC, 75% H S ZnCl Two more Br Br Br cross-couplings S JOC 2005, 70, 7578 S 2.5% [PdCl2(dppf)] S S 54% S Et2O 63% S Eur. JOC 2008, 5, 801 Benzofuran nd 2 BnZnBr p-TolMgCl 7.23 7.63 - Like indole, SNAr is uncommon on benzofuran Br Br Pd(PPh ) NiCl2(dppp) 6.76 - Cross coupling also mimics indole first at C-2, with C-4 to C-7 reacting 3 4 Br last 7.30 before electron rich C-3. Seems to follow Handy rules, though selectivity 52 - 57% quant 7.78 among C-4 through C-7 is unknown. S 7.51 O S st S (acetone) 1 Tet. Lett. 1980, 21, 4017 ClZn OMe Again, Lithium Halogen Exchange shows a different regioselection Br OMe Br OMe Br Br MgBr MeZnCl nBuLi, Et2O OMe -78ºC; H2O Br 5% [PdCl2(PPh ) ] O Br Br O 3 2 10% [NiCl2(dppe)] 10% [PdCl2(dppf)] S Br THF, rt, 75% THF, rt, 86% THF, reflux, 93% 79% S Thiophenes, pg 693 Baran Group Meeting Haloselectivity of Heterocycles Will Gutekunst Benzothiophene Attempts to displace the second chloride leads to mixtures with ring opened products. nd 2 - SNAr occurs readily on benzothiophenes, but they have some strange 7.70 7.5 7.26 7.72 7.56 8.45 7.22 reactions with nucleophiles. last - Cross coupling also mimics indole: first at C-2, with C-4 to C-7 reacting Cl MeS 7.24 N before C-3. S 1) 2 eq Na2S S MeS SMe 7.58 7.33 + 7.79 S N 7.85 9.11 1st NC NC N 2) MeI NC CN Isoquinoline (CCl ) (CCl ) 4 4 Cl SMe JOC 1964, 29, 660 Br Br Pyrazole shows similar reactivity, with a bromide being displaces before an iodide. NH NH Br N N S 106ºC S 200ºC S Me Me 73% Br EtO2C S N N 1.2 eq Na2S, DMF, 100ºC; N JOC 1973, 88,1365 N Ethyl bromoacetate, rt EtO C MeO EtO2C 2 I 80% I MeO B(OH) B(OH)2 2 Syn. Comm. 2008, 38, 674 Br MeO OMe Ph Br 3% Pd(PPh ) 5% Pd(PPh ) S S 3 4 3 4 Br Na2CO3, EtOH/DME Ba(OH)2, H2O/DME Ph 95% 71% S Ph Ph N S Br 4% PdCl2(PPh3)2 N Synthesis 2002, 2, 213 Br CuI, TEA/MeCN, rt Br 56% Br The remaining two bromides were unreactive in further Sonogashira couplings, even at higher temps 1,2-Azoles st 1 MeO Ph Me 8.39 O 8.72 S 7.45 N I Ph N N rd S N 3 7.26 6.28 8.54 S 6.20 8.14 2nd N 2% PdCl2(PPh3)2 4% PdCl2(PPh3)2 7.31 I CuI, TEA/MeCN, rt CuI, TEA/MeCN, 50ºC N Br 45% (also 45% deiodo) 42% Isoxazole (CS ) Isothiazole (CCl4) MeO N-methyl pyrazole (CDCl3) 2 Br - Selective SNAr reactions are only known with EWGs on the 4-position, but strongly favors substitution Russ.
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    pubs.acs.org/JACS Article TetrazineBox: A Structurally Transformative Toolbox Qing-Hui Guo, Jiawang Zhou, Haochuan Mao, Yunyan Qiu, Minh T. Nguyen, Yuanning Feng, Jiaqi Liang, Dengke Shen, Penghao Li, Zhichang Liu, Michael R. Wasielewski, and J. Fraser Stoddart* Cite This: J. Am. Chem. Soc. 2020, 142, 5419−5428 Read Online ACCESS Metrics & More Article Recommendations *sı Supporting Information ABSTRACT: Synthetic macrocycles capable of undergoing allosteric regulation by responding to versatile external stimuli are the subject of increasing attention in supramolecular science. Herein, we report a structurally transformative tetracationic cyclophane containing two 3,6-bis(4-pyridyl)-l,2,4,5-tetrazine (4-bptz) units, which are linked together by two p-xylylene bridges. The cyclophane, which possesses modular redox states and structural post-modifications, can undergo two reversibly consecutive two-electron reductions, affording first its bisradical dicationic counterpart, and then subsequently the fully reduced species. Furthermore, one single-parent cyclophane can afford effectively three other new analogs through box- to-box cascade transformations, taking advantage of either reductions or an inverse electron-demand Diels−Alder (IEDDA) reaction. While all four new tetracationic cyclophanes adopt rigid and symmetric box-like conformations, their geometries in relation to size, shape, electronic properties, and binding affinities toward polycyclic aromatic hydrocarbons can be readily regulated. This structurally transformative tetracationic cyclophane performs a variety of new tasks as a result of structural post-modifications, thus serving as a toolbox for probing the radical properties and generating rapidly a range of structurally diverse cyclophanes by efficient divergent syntheses. This research lays a solid foundation for the introduction of the structurally transformative tetracationic cyclophane into the realm of mechanically interlocked molecules and will provide a toolbox to construct and operate intelligent molecular machines.
  • Non-Empirical Calculations on the Electronic Structure of Olefins and Aromatics

    Non-Empirical Calculations on the Electronic Structure of Olefins and Aromatics

    NON-EMPIRICAL CALCULATIONS ON THE ELECTRONIC STRUCTURE OF OLEFINS AND AROMATICS by Robert H. Findlay, B.Sc. Thesis presented for the Degree of Doctor of philosophy University of Edinburgh December 1973 U N /),, cb CIV 3 ACKNOWLEDGEMENTS I Wish to express my gratitude to Dr. M.H. Palmer for his advice and encouragement during this period of study. I should also like to thank Professor J.I.G. Cadogan and Professor N. Campbell for the provision of facilities, and the Carnegie Institute for the Universities of Scotland for a Research Scholarship. SUMMARY Non-empirical, self-consistent field, molecular orbital calculations, with the atomic orbitals represented by linear combinations of Gaussian-type functions have been carried out on the ground state electronic structures of some nitrogen-, oxygen-, sulphur- and phosphorus-containing heterocycles. Some olefins and olefin derivatives have also been studied. Calculated values of properties have been compared with the appropriate experimental quantities, and in most cases the agreement is good, with linear relationships being established; these are found to have very small standard deviations. Extensions to molecules for which there is no experimental data have been made. In many cases it has been iôtrnd possible to relate the molecular orbitals to the simplest member of a series, or to the hydrocarbon analogue. Predictions of the preferred geometry of selected molecules have been made; these have been used to predict inversion barriers and reaction mechanisms. / / The extent of d-orbital participation in molecules containing second row atoms has been investigated and found to be of trivial importance except in molecules containing high valence states of the second row atoms.