Rollover in the synthesis of polycyclic indoles, and a one-pot Zipper-Click reaction
A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy (PhD) in the Faculty of Engineering and Physical Science
2015
Sinead Balgobin
School of Chemistry
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Contents
1. C–H activation for alkyne insertion ...... 1
1.1. Introduction ...... 1
1.1.1. C–H bond activation and functionalisation ...... 1
1.1.2. Palladium in C–H bond activation and functionalisation ...... 5
1.1.3. Rhodium in C–H bond activation and functionalisation ...... 13
1.1.4. Ruthenium in C–H bond activation and functionalisation ...... 20
1.1.5. This work ...... 30
1.2. Results and Discussion ...... 31
1.2.1. Introduction ...... 31
1.2.2. Pd-catalysed alkyne insertion ...... 36
1.2.3. Rh-catalysed alkyne insertion ...... 48
1.2.4. Ru-catalysed alkyne insertion ...... 65
1.3. Recent literature developments ...... 69
1.4. Conclusion ...... 72
2. A one-pot zipper-click reaction ...... 73
2.1. Introduction ...... 73
2.1.1. Migration of unsaturation ...... 73
2.1.2. The acetylene zipper reaction ...... 79
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2.1.3. Azide-alkyne cycloadditions: click reactions ...... 90
2.1.4. This work ...... 101
2.1. Results and discussion ...... 102
2.1.1. One-pot zipper-click reaction ...... 102
2.1.2. Other one-pot zipper reactions ...... 114
2.1.3. Alternative zipper conditions ...... 120
2.1.4. Conclusions ...... 125
2.1.5. Future Work ...... 126
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Abstract
The University of Manchester School of Chemistry Sinead Balgobin Doctor of Philosophy 2015
Rollover in the synthesis of polycyclic indoles, and a one-pot Zipper-Click
reaction
This thesis contains two chapters, the first concerning the use of C–H activation in the synthesis of polyaromatic indoles, and the second concerning an investigation into the acetylene zipper reaction.
C–H activation provides a convenient, atom efficient route for the construction of C–C bonds, without the prerequisite for stoichiometric organometallic precursors or pre-functionalisation of the substrates. In this research the use of C–H activation for the insertion of an alkyne into an N-(hetero)arylated indole system has been investigated; the transformation was achieved using Rh catalysis in moderate to good yields. The concept of rollover has also been discussed. This is where, after a metallation step, the molecule undergoes a bond rotation allowing further reaction at a different part of the molecule.
The acetylene zipper reaction is a powerful contrathermodynamic reaction which allows the migration of an internal alkyne to the terminal position. The alkyne moiety is a useful handle for many reactions, not least the robust CuI-catalysed azide alkyne cycloaddition (CuAAC, also known as a click reaction), which can be used to synthesis useful triazole products. In this research a one-pot zipper-click reaction has been investigated to provide 1,4-disubstituted-1,2,3-triazoles.
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Declaration
No portion of the work referred to in the thesis has been submitted in support of an application for another degree or qualification of this or any other university or other institute of learning.
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Copyright Statement i. The author of this thesis (including any appendices and/or schedules to this thesis) owns certain copyright or related rights in it (the “Copyright”) and she has given The University of Manchester certain rights to use such Copyright, including for administrative purposes. ii. Copies of this thesis, either in full or in extracts and whether in hard or electronic copy, may be made only in accordance with the Copyright, Designs and Patents Act 1988 (as amended) and regulations issued under it or, where appropriate, in accordance with licensing agreements which the University has from time to time. This page must form part of any such copies made. iii. The ownership of certain Copyright, patents, designs, trademarks and other intellectual property (the “Intellectual Property”) and any reproductions of copyright works in the thesis, for example graphs and tables (“Reproductions”), which may be described in this thesis, may not be owned by the author and may be owned by third parties. Such Intellectual Property and Reproductions cannot and must not be made available for use without the prior written permission of the owner(s) of the relevant Intellectual Property and/or Reproductions. iv. Further information on the conditions under which disclosure, publication and commercialisation of this thesis, the Copyright and any Intellectual Property and/or reproductions described in it may take place is available in the University IP Policy (see http://documents.manchester.ac.uk/DocuInfo.aspx?DocID=487), in any relevant thesis restriction declarations deposited in the University Library, The University Library’s regulations (see http://www.manchester.ac.uk/library/aboutus/regulations) and in The University’s policy on Presentation of Theses
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Just like moons and like suns,
With the certainty of tides,
Just like hopes springing high,
Still I’ll rise.
Maya Angelou, 1928-2014
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Acknowledgments
Thanks must of course be extended to my supervisor Mike, for making this possible and for providing invaluable guidance, advice and support. Thank you as well to the staff of the School of Chemistry, past and present, technical and administrative.
To The Girls, Sam and Rachel, for being fantastic housemates and chemistry buddies, and making my time in Manchester a pleasure. Thanks also to Matt, for giving me a place to stay in my final few months and being a generally brilliant Post-Doc (brilliant Post-Doc thanks also go to Smith and Storr). The Holy Trinity and attendees of GCB: you have been amazing, and continue to be. I can always count on you to brighten up my day. Sarah, Sarah, Sam, Rachel, Chris, Gabri, Boris, Tom, Craig, James and Catherine; you will probably never know just how much your friendship has meant to me in the time we have known each other. You, knowingly and unknowingly, have helped me through some incredibly difficult and challenging times, and for this I will be forever grateful.
To everyone who proof read or edited this, I apologise for it being a hot mess. I have not good English. Thanks for making it readable.
Thanks also go to the rest of the Greaney and Procter group members, past and present: thank you for making the lab a fun and distracting place to work (OK, maybe I will take responsibility for the distracting part). I am grateful we helped each other make it through the long lab days. Also the demonstrating gang, for pretty much the same reason: Debbie, Rachel, Maddie, Rob, Catherine, Sarah, Sarah and Boris.
Thank you to my friends outside of the department, who were always there for me. You have kept me sane and stopped me from losing myself into the PhD. Laura, Scott and John; Reiss, Marcus and Liam: sorry I’m rubbish at replying to messages, but know that you all mean so much to me.
To my family, who always stand by and support me.
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Abbreviations
Ac - acetyl
Acac - acetylacetone
AcOH - acetic acid tAmOH - tert-amyl alcohol
Ar - aryl
ArF - 4-(CF)3C6F4
AP - affinity-purification
APCI - atmospheric pressure chemical ionization
Asc - ascorbate atm - atmosphere
Boc - tert-butoxycarbonyl b.p. - boiling point nBuLi - n-butyl lithium sBuLi - sec-butyl lithium tBuLi - tert-butyl lithium tBu - tert-butyl tBuOH - tert-butanol
Bz - benzoyl
CAL-B - Candida antarctica lipase B cat. - catalytic/catalyst
CMD - concerted-metalation-deprotonation
Cp - cyclopentyldienyl
Cp* - pentamethylcyclopentadienyl
viii cod - cyclooctadiene
CuAAC - Copper-Catalysed Azide-Alkyne Cycloaddition
Cy - cyclohexyl
DAP - diaminopropane dba - dibenzylideneacetone
DCM - dichloromethane
DEPT - distortionless enhancement by polarization transfer
DFT - density functional theory
DG - directing group
DIPEA - N,N-diisopropylethylamine
DMA - N,N-dimethylacetamide
DCE - 1,2-dichloroethane
DMAD - dimethylacetylene dicarboxylate
DME - dimethoxyethane
DMF - N,N,-dimethylformamide
DMSO - dimethylsulfoxide
EDA - ethylene diamine
EDG - electron donating group equiv. - equivalent
Et - ethyl
EtOAc - ethyl acetate
EtOH - ethanol
EI - electron impact
ES - electrospray
ESI - electrospray ionisation
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EWG - electron withdrawing group
FT-IR - fourier transform infra-red spectroscopy
Gly - glycine het - heteroaryl hex - hexane
HFIP - hexafluoroisopropanol
HMDS - hexamethyldisilazane
HMPA - hexamethylphosphoramide
HRMS - high resolution mass spectrometry h/hrs - hours
Imid. - imidazole
KAPA - potassium 3-aminopropylamide
KMBA - potassium N-methylbutylamide
LA - Lewis acid
LAETA - lithium 2-aminoethylamine
LC-MS - liquid chromatography mass spectrometry
LiAPA - lithium 3-aminopropylamide
LRMS - low resolution mass spectrometry m - meta
M - molar, mol dm-3
Me - methyl
Mes - mesitylene
MeCN - acetonitrile
MeOH - methanol min - minutes
x m.p - melting point
MW/µW - microwave n - normal
NaAPA - sodium 3-aminopropylamide
NHC - N-heterocyclic carbene
NMI - N-methylimidazole
NMP - N-methylpyrrolidone
NMR - nuclear magnetic resonance o - ortho
OAc - acetoxy
OMe - methoxy
OMs - mesylate
OTf - triflate
OTs - tosylate p - para
PCy3 - tricyclohexylphosphine
Ph - phenyl
Phen - phenanthroline
Phth - Phthalate
PhCl - chorobenzene
PhMe - toluene
PivOH - pivalic acid
PMHS - polymethylhydrosiloxane
PPh3 - triphenylphosphine ppm - parts per million
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Pr - propyl iPr - isopropyl py - pyridine
Rf - retention factor
RT - room temperature
RuAAC - Ruthenium-Catalyzed Azide-Alkyne Cycloaddition s - secondary sec - secondary
SIMes∙HCl - 1,3-bis(2,4,6-trimethylphenyl)imidazolinium chloride
SM - starting material
T - temperature t - tertiary
TBDPS - tert-butyldiphenylsilyl
TBS - tert-butyldimethylsilyl
TBME - tert-butyl methyl ether
TEA - triethylamine tert - tertiary
TFA - trifluoroacetic acid
THF - tetrahydrofuran
TLC - thin layer chromatography
TM - transition metal
TMDS - tetramethyldisiloxane
TMS - trimethylsilane
TMSCF3 - (trifluoromethyl)trimethylsilane tol - toluene
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Val - valine
Xantphos - 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
Unit Abbreviations
µl - 10-6 L mg - 10-3 g ml - 10-3 L mmol - 10-3 mol
NMR abbreviations
Singlet (s), broad singlet (br. s) doublet (d), triplet (t), quartet (q), doublet of doublets (dd), triplet of doublets (td), doublet of triplets (dt), doublet of doublet of doublets (ddd), multiplet (m)
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1. C–H activation for alkyne insertion
1.1. Introduction
1.1.1. C–H bond activation and functionalisation
A contemporary sub-discipline within transition metal-catalysis is C–H activation.1–5 C–H activation is a general term used to describe the activation of a
C–H bond using a metal catalyst.6 The aromatic C–H bond is one of the strongest in organic compounds (~110 kcal mol-1 (ca. 460 kJ mol-1))7,8, and has long been considered difficult to functionalise. C–H activation provides a convenient route for the construction of C–C bonds without the need for pre- functionalisation to a more reactive C–X (where X is a halogen) or C–M (where
M is a metal) bond.1–6,9 It is thus highly efficient and atom economic.1,9
Within this discipline, both C–H activation and C–H functionalisation are commonly used terms.1 C–H activation refers to the initial reaction between the metal and the C–H bond; C–H functionalisation refers to the overall reaction wherein the H atom is replaced by another moiety (Scheme 1).1,10 The mechanism of C–H activation is thought to occur via oxidative addition to the metal centre.1,9,10
1
C–H activation
H M FG 1 2 3
H M FG R R R
4 5 6
C–H functionalisation
Scheme 1. General scheme for C–H activation and functionalisation
Reports regarding the first C–H activation reaction are disputed.10 There are claims it dates back to 1898: Otto Dimroth’s reaction of benzene with mercury(II) acetate appears at first to be a fine early example (Scheme 2), but due to the mechanistic implications of C–H activation, it cannot be classed as such.10 The Dimroth reaction consists of an electrophilic attack on an arene π- system, followed by deprotonation of the resulting cation (a Wheland intermediate); C–H activation, in contrast, is thought to proceed via oxidative addition, foregoing the Wheland intermediate.11 As such, C–H activation according to the modern organic chemistry definition did not appear until much later.10
Hg(OAc)2 AcOH Hg(OAc) via H
7 8 9
Hg(OAc)2 AcOH
Scheme 2. Mercuration of benzene via Wheland intermediate
2
Despite the renaissance of organometallic chemistry in the 1950s and early
1960s, it was not until 1965 that the field of C–H activation found its beginnings.10 Chatt’s example of the oxidative addition of a Ru0 complex is thought to be the first true C–H activation reaction (Scheme 3, (1)).10,12 In the
0 paper, Chatt reported the generation of Ru (dmpe)2, which led to the activation of a C–H bond of naphthalene. Another notable example in the development of
C–H activation is Shilov chemistry, wherein a catalytic system for the selective functionalisation of alkanes was achieved using mild conditions.10,13
In 1972, Shilov described the addition of a stoichiometric PtIV oxidant to the
2– aqueous reaction of PtCl4 with methane, which led to the selective oxidation of methane to methanol, with chloroform as a side product (Scheme 3, (2)).14 The major drawback to this system is the use of stoichiometric PtIV, but it is mechanistically catalytic in PtII.15 The reaction proceeds via a methylplatinum(II)
2– intermediate, formed by reaction of PtCl4 with methane. This is followed by oxidation to a methylplatinum(IV) species, and finally reductive elimination or nucleophilic attack on carbon produces the functionalised product.15 The area of
“Shilov chemistry” remained largely unrecognised outside of the Soviet Union during the 1970s but it became a popular area of research after the work was
“unearthed” by Western scientists in the 1980s.10,13,16,17
3
Na e Cl PM 2 Me e 2 M 2 e P P 11 M 2P H uII RuII R (1) Me P P P 2 e e M 2 M 2 e Cl PM 2 10 12
- - 2 alkane 2 activation Cl Cl - Cl Cl PtII R H PtII HCl Cl Cl Cl R
13 14 + (2) ROH + H
H2O - RCl 2 PtCl4 Cl - PtCl Cl Cl Cl 2 PtIV functionalisation Cl R oxidation Cl 15
Scheme 3. Early examples of C–H activation and functionalisation
Recent advances in this methodology have made it possible to access new reactivity and new disconnections in molecules, making it an invaluable tool in organic synthesis.1,9 Synthetic routes can be dramatically shortened, which exemplifies why this reaction is praised for its cost and atom efficiency.1
The use of a directing group is an important factor in the reactivity of substrates towards C–H bond activation and functionalisation.1,18,19 Moieties such as pyridyl groups and amides, which are Lewis bases, can ligate to a metal centre.18,19 This induces selectivity as is can effectively bring the metal catalyst close to the desired reactive site (C–H bond); the stable chelate formed has a long enough lifetime to enable subsequent reactions to take place.
4
The remainder of this introduction will focus on the transition metals used within this chapter of research, and their recent applications in C–H bond activation and functionalisation; the breadth and diversity of this field is extensive and continues to expand, and as such this introduction is a brief review of important advances made in the last five years, rather than providing a comprehensive overview of the field.
1.1.2. Palladium in C—H bond activation and
functionalisation
Palladium is a versatile catalyst with respect to C–H bond activation and functionalisation, and, with the addition of ligands, many new modes of reactivity have been discovered.20–32 There are many choices of pre-catalyst for
Pd-catalysed C–H activation, but commonly Pd(OAc)2, Pd(TFA)2 and
20,33,34 Pd(MeCN)2Cl2 are used, with a variety of ligands. A pre-catalyst is converted to the active species in situ; pre-catalysts are used because they are easy to store and handle.3,4,6 The addition of ligands can tune the reactivity of the catalysts, giving access to different products depending on the catalyst and ligand used.1,34 Several different mechanisms for Pd-catalysed C–H activation exist, and are system dependent;1 three are shown below (Scheme 4, Scheme 5, Figure 1).
The first proceeds via a Pd0/PdII cycle, and often requires high temperatures;1 the second is a PdII/PdIV catalytic cycle, which can occur at room temperature;35 the final example includes the concerted metallation-deprotonation method described by Fagnou.11,25,27
5
The Pd0/PdII mechanism, shown below (Scheme 4), involves the oxidative addition of a substrate to a Pd0 catalyst, followed by a C–H activation step
(where X is a ligand/halide). The desired product is then released in a C–C bond forming reductive elimination step, regenerating the Pd0 catalyst.20 In an example of C–H activation by oxidative coupling (involving two C–H activation steps), the palladation of the substrate occurs using the PdII catalyst, which after reductive elimination to give Pd0 must be oxidised by an external oxidant to regenerate the PdII catalyst.36
ox a ve id ti C–H addition 1 C–H activation R H oxidation R1 1 activation II R X II Pd Ln Pd Ln R2 H X HX R1
II x a ve Pd Ln O id ti 0 C–X/C–H ou lin Pd Ln cou n X C p g pli g R1 II Pd Ln 2 R2 R H R1
– II C H Pd Ln activation 2 1 2 1 2 re uc ve e m na on R R R R R d ti li i ti
Scheme 4. A simple example of a Pd0/PdII catalytic cycle for C–H activation20
Sanford and co-workers have discussed the PdIV mechanism in detail.37 It involves an initial C–H activation step to give 16 followed by oxidation to give
PdIV metallacycle 17 (Scheme 5); reductive elimination gives the coupled product and the regenerated PdII catalyst. In 2009, Sanford also provided evidence for a potential bimetallic transition state in the PdII/PdIV mechanism.35 In this reaction a directing group is employed to assist the C–H activation step, in the form of the pyridine nitrogen.
6
C–H activation or via N oxidation II N Pd Ph Ac [Ph2I]X N O H PdIV PdII PhI O Ac N 16 X 19 20 II IV II X Pd /Pd Ph Pd N X PdIV
Ac N O 17 PdII PdII N Ph Ph L O Ac N reductive elimination X 21 18
Scheme 5. Proposed PdII/PdIV catalytic cycles
Fagnou et al. reported another alternative mechanistic theory in the form of concerted metallation-deprotonation (CMD) (Figure 1).11,38 This is often assisted by an acetate or pivalate ligand as shown below, and requires a carboxylate additive to enhance the reactivity; it is thought that this promotes proton shuttling from the substrate to a base in the reaction.11
Ar
II Ln Pd O H O R 22 CMD intermediate
Figure 1. Intermediate in acetate-assisted concerted metallation-deprotonation
7
Direct arylation is a common application of Pd-catalysed C–H activation/functionalisation. In 2012 Itami and Yamaguchi disclosed
Pd-catalysed methods for the direct arylation of 1H- and 2H-indazoles 23 and 26
39 with haloarenes (Scheme 6). These reactions employed PdCl2/phenanthroline
(phen), with stoichiometric Ag2CO3 and K3PO4, but also required high temperatures (165 °C).
H Ar I PdCl2/phen AgCO3, K3PO4 N N 2 (1) N R DMA N R1 165 °C, 12 h R1 23 24 25 11-88%
PdCl H I 2/phen Ar AgCO3, K3PO4 1 1 (2) N R R2 DMA N R N 165 °C, 12 h N 26 24 27 68-87%
Scheme 6. Pd-catalysed direct arylation of 1H- and 2H-indazoles
Sanford reported the arylation of 2,5-disubstituted pyrroles using diaryliodonium
salts 29 and catalytic Pd(MeCN)2Cl2, resulting in moderate to good yields of tri- substituted products 30 (Scheme 7, (1)).40 Even more recently, Doucet described the use of benzenesulfonyl chlorides 31 for the β-arylation of thiophenes 32: the best yields were produced using electron-deficient benzenesulfonyl chlorides
(Scheme 7, (2)).41 These reactions did however require elevated temperatures
(>140 °C) and extended reaction times (~40 h).
8
R2 R2 BF4 R1 N R3 Pd(MeCN)2Cl2 R1 N R3 4 R (1) I DCE H R4 H H Ar 84 °C, 2 h
28 29 30 34-88%
R1 Pd(MeCN)2Cl2 H R2 Li2CO3 (2) R1 R2 SO2Cl R3 dioxane S 140 °C, 40 h 3 S R 31 32 33 31-88%
Scheme 7. Arylation of pyrroles and thiophenes
The Greaney group, in 2014, reported the Pd-catalysed cross-dehydrogenative- coupling of 1,3,5-trialkoxybenzenes 34 with arenes (Scheme 8).42 Arylated
1,3,5-trialkoxybenzenes were isolated in low to excellent yields after treatment
with Pd(OAc)2, K2S2O8 and trifluoroacetic acid (TFA), however the substrate scope was limited to simple arenes. The group suggested either a Pd0/PdII mechanism, or a potential PdII/PdIV catalytic cycle due to the strong oxidising
nature of the K2S2O8.
OR1 OR1 H Pd(OAc)2 R2 H K S O R2 2 2 8 TFA, 50 °C, 18 h R1O OR1 R1O OR1 34 4 35 12-93%
Scheme 8. Greaney’s cross-dehydrogenative-coupling of arenes and
trialkoxybenzenes
9
Yu and co-workers have made significant contributions to the field of C–H bond activation/functionalisation. In 2013 the group published research describing the
ortho- and meta-C–H olefination of phenol derivatives 37 using Pd(OAc)2 and an amino-acid derived ligand (Scheme 9).43 The use of a directing nitrile template promoted the selective synthesis of the meta-substituted products. This is an example of remote (or distal) direction for activation of a C–H bond. According to Yu, proximal direction for C–H activation occurs when the directing group is fewer than six bonds away from the target C–H bond, and close in space (for examples, see earlier- Scheme 5).35,44 Remote C–H activation, where the C–H bond is more than 6 bonds away from the directing group, can be more challenging, especially if the directing group and target C–H bond are also geometrically inaccessible.
X X X Pd(OAc)2 O Pd(OAc)2 O O Boc-Val-OH Ac-Gly-OH R R R H KHCO H AgOAc 3 HFIP H tAmOH H COOEt 90 °C, 24 h O2, 90 °C 37 COOEt 36 24 h 39 X = COOK COOEt X = nitrile template 58-91% 38 58-91%
CN CN N
nitrile template
Scheme 9. Ortho- and meta- olefination of phenol derivatives
10
Yu et al. have had further success in this field, reporting another meta-C–H
activation using amines, an amino-acid derived ligand and catalytic Pd(OAc)2, in 2014.44 A drawback to this method is that the directing groups/templates must be covalently included in the substrate and then removed in a subsequent synthetic step. meta-C–H activation continues to be a challenge in organic synthesis, and the Yu group has expanded upon this work in subsequent publications, tuning the template,45,46 and investigating the mechanism and selectivity computationally.47
In 2015, Yu disclosed a method for meta-C–H activation which employed a transient norbornene mediator (Scheme 10). Inspired by the Catellani reaction,48 the group was able to use norbornene to selectively meta-alkylate and meta- arylate arenes. The development of the reaction required extensive screening of
N-heterocyclic ligands before a suitable set of conditions was found for the desired transformation; the formation of a benzocyclobutene side-product was unavoidable.
R-I Y Y Pd(OAc)2, ligand OMe norbornene NHArF NHAr F X X O O AgOAc DCE, 95 °C, 16 h N O R 40 41 42 = or aryl <10-91% ligand X, Y = generic R alkyl substiuents
Ar = 4-( F F CF3)C6 4
Scheme 10. meta-C–H activation using a transient mediator (traceless directing
group)
11
This is an example of an in situ generated “traceless” directing group, in combination with a more traditional ortho-directed activation. Other groups have also reported the use of traceless directing groups.1,49 In 2014 Larrosa reported
the use of CO2 as the directing group to improve upon previous methodology for the meta-C–H functionalisation of phenols.50 This method benefits from the use of the carboxylic acid directing group which is known to direct C–H activation reactions.18,22,51 The decarboxylation reaction can be performed using transition metal-catalysis.52–54
Yu and co-workers have also exemplified the use of amide-directed Csp3–H arylation for the synthesis of unnatural amino acids 45 (Scheme 11).55 Using
Pd(TFA)2, electron-deficient phthalimide-protected -amino acids 43 were reacted with aryl iodides to furnish unnatural phenylalanineα derivatives in high yields. The products were formed with high chemoselectivity, and with little bis-arylation seen. Other groups have reported similar reactivity, using amide groups as directing groups for C–H functionalisation.56,57
Pd(TFA)2, Ligand NPhth TFA, NPhth H Ag2CO3 R H H N R N Ar Ar F I DCE, 100 °C, 20 h F O O 43 24 45 - R = Me, OMe, 25-91% ArF = 4 (CF3)C6F4 X, CF3,CO2Me N 44 ligand
Scheme 11. Amide-directed sp3 arylation of -amino acids
α
12
An extensive amount of research has been conducted into Pd-catalysed C–H activation, yet new modes of reactivity continue to be discovered.58 The examples discussed thus far demonstrate a variety of C–H activation methods including undirected activation or employing different directing groups.42,43,46,50 A number of mechanisms have been discussed.1,35,38 While the use of transition metal-catalysed synthesis opens up routes to novel compounds, it can be difficult to develop mild and convenient methods. High temperatures are often necessary, and reactions can be sensitive to the properties of the substrates.1,9,28,31,32 By controlling the reaction conditions, carefully designing the substrates used and with the addition of ligands, Pd-catalysed reactions are versatile and can be very robust.1,9,28,31,32 It is, however, not the only transition metal capable of this type of reactivity, and in recent years different catalysts have become the focus of much research.
1.1.3. Rhodium in C—H bond activation and
functionalisation
Rh-catalysed C–H activation is a relatively small field with respect to the palladium alternative, but in the past few years many important developments have come to light.21,59–66 Typical catalysts used are the
dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer ([Cp*RhCl2]2) and the 1,5-cyclooctadienerhodium(I) chloride dimer ([RhCl(cod)]2), and most general mechanisms are thought to proceed via a RhI/RhIII redox couple mechanism, an example of which, proposed by Shibata, is shown below
(Scheme 12).67,68 As exemplified in this section, directing groups are often key to 13 the reactivity of these substrates; Scheme 12 shows a pyridine group employed as a directing group.67,68
N
[O] Cp*Rh(III)X2 46
Cp*Rh(I) HX N Cp* X Rh R Rh(I)/Rh(III) N
49 47 Cp* R N Rh R Y
48
Scheme 12. An example of a Rh-catalysed C–H activation reaction
In 2010, Schipper et al. published work reporting the intermolecular hydroarylation of alkynes with indoles, using Rh catalysis (Scheme 13).69 This work continued research initiated by Fagnou, and employed the pre-formed
cationic catalyst [Cp*Rh(MeCN)3](SbF6)2 along with an acidic additive (pivalic acid, PivOH). The group was able to hydroarylate the alkenes with
N,N-dimethylcarbamoyl-protected indoles in moderate to excellent yields. The
non-cationic catalyst [Cp*RhCl2]2 was unreactive, although the group does not discuss the effect of using a AgSbF6 additive to this set of conditions. This reaction is an example of an amide-directed C–H activation.
14
2 Cp*Rh(MeCN)3(SbF6)2 R 1 R R1 R3 PivOH N N R3 2 O R iPrOAc, 90 °C O N N 15 h 50 51 52 55-99%
Scheme 13. Hydroarylation of alkynes using RhIII catalysis
Following this, in 2011 Guimond (again building on findings by Fagnou) reported an improved method for the synthesis of heterocycles 55 and 56 using
RhIII catalysis (Scheme 14).70 In this method the stabilising acetate ligand was incorporated into the substrate, with the use of hydroxamic acid-type moieties; in this case the pivaloyl group was found to be the most effective. The use of this internal oxidant led to improvements in the yield, and in addition the group found that they could lower the catalyst loading from 5 mol% [Rh] to 1 mol%
[Rh], and conduct the reaction at room temperature. The directing group in this case has a dual functionality, directing the selectivity of the reaction but also acting as an oxidant. These mild conditions were appropriate for the insertion of both alkenes and alkynes in moderate to excellent yields. A mechanism was proposed and supported by density functional theory (DFT) calculations
(Scheme 15).
15
O
1 NH R3 R R3 R2 2 O [Cp*RhCl2]2 R 51 CsOAc 55 OPiv N or or R1 H MeOH O R5 RT, 16 h 4 NH 53 R R1 54 R5 R4 56 49-99%
Scheme 14. Synthesis of isoquinolinones and dihydroisoquinolinones
O O O O NH N H 55a 57 AcOH AcOH RhCp(OAc)2
O O RhCp(OAc) O N O N
64 RhCp(OAc) 58 O O O O N O N O Rh Rh Cp(HOAc) 63 Cp 59 AcOH O O O O O N N O RhCp O Rh Cp O 60 62 N O Rh Cp 51a 61
Scheme 15. DFT calculated catalytic cycle
16
Recently Glorius and co-workers published a Rh-catalysed method for the arylation of Csp3–H bonds (Scheme 16).71 The group has published many reports in the field of Rh-catalysed C–H activation/functionalisation;59,60,71–77 this paper extended work away from Csp2–H bond focussed research. In the paper they
reported the use of [Cp*Rh(MeCN)3](SbF6)2 as a catalyst to effect the activation of a benzylic Csp3–H bond. The heterocyclic directing groups were essential to reactivity of these substrates, allowing this unprecedented transformation; the
C–H activation would be extremely difficult without chelation control through the pyridyl lewis base. The desired products, upon reaction with triarylboroxines as the aryl source, were isolated in moderate to good yields.
R3 [Cp*Rh(MeCN)3](SbF6)2 R3 N Ag2O N (ArBO)3 (1) DMF R H R Ar 1 66 100 °C, 24 h 1 R2 argon, R2 65 67 50-85%
1 1 2 Ar H [Cp*Rh(MeCN)3](SbF6)2 Ar Ar Ag2O 2 N (Ar BO)3 N (2) DMF 66 argon, 80 °C, 24 h 68 69 60-82%
Scheme 16. Rh-catalysed Csp3–H arylation
With respect to the activation of the Csp2–H bond, Glorius et al. reported a rhodium-catalysed oxidative olefination of acetophenones and benzamides
72 (Scheme 17). The reaction employed [RhCp*Cl2]2 as a catalyst, and resulted in moderate to excellent yields for both electron rich and electron poor products.
17
This reaction uses the ketone or amide moiety of the molecule as a chelating directing group to aid the reaction.
R1 O R1 O [RhCp*Cl2]2 2 2 5 R H AgSbF6 R R R5
3 3 R 71 Cu(OAc)2 R R4 tAmOH, 120 °C, 16 h R4 70 72 40-99%
Scheme 17. Oxidative olefination of acetophenones or benzamides
Ellman and Bergman have also reported extensive research into Rh-catalysed
C–H activation.61–64,78–80 In 2014, they reported the RhIII-catalysed asymmetric synthesis of -branched amines with either an amide or azobenzene directing group (Schemeα 18).80 The reaction was not possible with N-tert-butanesulfinyl imines, and so the more activated N-perfluorobutanesulfinyl imines 74 had to be used. In addition, co-ordinating solvents reduced the yield of the reaction and
instead of the commonly used AgSbF6 halide abstractor, the non-coordinating alternative AgB(C6F5)4 was necessary to promote higher yields. The group was able to isolate the products in moderate yields, but with excellent diastereoselectivity. The sulfinyl group could be easily removed with HCl to provide the enantiomerically enriched amine hydrochlorides.
18
(CF2)3CF3 (CF2)3CF3 [Cp*RhCl2]2 N O N O AgB(C6F5)4 S S HN O O N (1) DCE 2 R1 1 R R2 50 °C, 48 h R 74 73 75 24-60% >99:1 dr
2 R2 R 2 3CF3 (CF ) [Cp*RhCl2]2 (CF2)3CF3 AgB(C6F5)4 N S N S N O N N HN (2) DCE O CO Et 50 °C, 48 h 1 2 CO Et R R1 2 74a 76 77 51-74% >98:2 dr
Scheme 18. RhIII-catalysed asymmetric synthesis of -branched amines
α Recently Ellman reported the preparation of styrene derivatives using
RhIII-catalysed direct vinylation (Scheme 19).79 By using the inexpensive vinyl source vinyl acetate, the group was able to synthesise styrene derivatives with either amide or pyridine directing groups in moderate to good yields. A
[1,2]-RhIII-alkenyl addition adduct was isolated and characterised by X-ray crystallography, the first of this kind. The reaction tolerated a range of directing groups, resulting in moderate yields for substrates incorporating a pyridyl group, in addition to amides with a range of steric and electronic properties: the electronically deactivated morpholine benzamide, hindered N,N-diisopropyl benzamide and relatively unhindered N,N-dimethyl benzamide all underwent vinylation. As with the previous example, however, the reaction had large
19 drawbacks: not only did it require long reaction times, but also relatively large loadings of catalyst (10-20 mol% [Rh]).
Cp* DG [Cp*RhCl2]2 DG O F Rh AgB(C6 5)4 DG Me OAc O R MeOH R 79 65 or 100 °C, 40 h B(C6F5)4 78 80 33-80% 81
Scheme 19. RhIII-catalysed direct C–H vinylation.
While Rh-catalysed C–H activation can be a powerful and versatile tool, and can give access to novel products, the main drawback remains that its cost is very high, preventing common use of this reagent- especially when catalyst loading is relatively high. The examples discussed in this chapter rely heavily on chelating directing groups, although research into undirected Rh-catalysed C–H activation is ongoing.81 By designing substrates and reaction conditions, unprecedented reactions are possible, often exploiting dual functionalities such as a directing group which also acts as an internal oxidant.70 As chemists continue research in the area of C–H bond activation/functionalisation, research is being increasingly focussed on more cost efficient methods.
1.1.4. Ruthenium in C—H bond activation and
functionalisation
Ruthenium catalysis is fast becoming a popular choice for C–H bond functionalisation.2,82–89 It is significantly cheaper than both of the metals
20 previously discussed in this introduction (palladium and rhodium),* and exhibits similar reactivity.82 Commonly, the reaction employs a ruthenium(II) catalyst,
82 for example [Ru(p-cymene)Cl2]2 or RuCl2(PPh3)3. An example of a Ru- catalysed C–H activation mechanism is shown below (Scheme 20).2,82 As with the Rh-catalysed C–H activation reactions discussed earlier, a directing group is often essential to the reactivity of these systems;2 in the example shown below, the directing group is a pyridine moiety.
N K2CO3
46 N II Ru X2 Ar KX, KHCO3
84
N N IV II Ru X2 Ru X Ar
83 82
r r A B
Scheme 20. Mechanism for the direct arylation of 2-phenylpyridine
The mechanism shown above exemplifies the use of Ru as a catalyst for direct arylation via C–H activation/functionalisation. It is thought that the reaction proceeds through ruthenacycle 83 shown above, where the initial Ru insertion
* As of writing, Rh has a value of ~$850/oz, Pd ~$630/oz and Ru ~$40/oz. Source: Johnson
Matthey, plc.
21 occurs on the aromatic ring, assisted by a directing group (in this case, the nitrogen of the pyridine ring) followed by oxidative addition of the aryl halide.90
The most common solvents used in Ru-catalysed direct arylation chemistry are
NMP, toluene, xylene, and dioxane, however recent efforts to perform the arylation in green solvents have proved successful.82 Dixneuf et al. reported in
2012 the catalytic arylation of aryl imines and oxazolines in water using a ruthenium(II)-acetate catalyst (Scheme 21): the imine acted as the directing group.91 The group found that the use of water in place of NMP as a solvent favoured the formation of the diarylated ketimines, although the difference was less marked with respect to aldimines. A drawback to this method was the extended reaction times, with good yields achieved after >36 h.
R1 R1
Br [Ru(p-cymene)Cl2]2 Ar Ar PPh3 N R N R KOAc, K2CO3 H O, 100 °C, 36 h R3 2 86 R2 R2 85 87 53-88% R = H, Me
Scheme 21. Diarylation of ketimines using Ru-catalysis
The Ackermann group has published prolifically in the area of Ru-catalysed
C–H activation/functionalisation. In 2011, Ackermann and Pospech reported an oxidative alkenylation in water under mild conditions using a
[Ru(p-cymene)Cl2]2 catalyst (Scheme 22). Benzoic acids were reacted with
22 alkenes to directly furnish the annulated products in good to excellent yields.
This was an example of the carboxylate group as a directing group.
O O [Ru(p-cymene)Cl2]2 Cu(OAc)2·H2O 1 R2 R O 1 OH R H O, 80 °C, 16-24 h 71 2 R2 88 89
Scheme 22. Ackermann’s oxidative alkenylation in water
In 2015, the group reported a C–H activation/alkyne annulation to furnish a number of isocoumarins in good to excellent yield (Scheme 23).92 By using a
weakly co-ordinating directing group (a carboxylate) and O2 as the external oxidant, the ruthenation followed by alkyne insertion successfully took place.
The carboxylate directing group has been described by Yu as a hemi-labile ligand, which can direct the C–H activation step:18 it is not a strongly chelating moiety, but can be used similarly to other directing groups, such as amides. The proposed mechanism, shown below (Scheme 24) suggests Ru0 sandwich complex 95 is formed following the reductive elimination of the ruthenium catalyst to yield the isocoumarin product. This is then reoxidised by molecular oxygen to the active catalytic species.
O O 2 R [Ru(p-cymene)Cl2]2 O OH 1 1 NaOAc, MeOH, 45 °C, 18 h R R 2 O R H R2 2 R2 88 51 90 54-94%
Scheme 23. Synthesis of isocoumarins using ruthenium catalysis
23
½ [Ru(p-cymene)Cl2]2
O 2 NaOAc O O R1 i OH Pr Me R1 R2 H 3 Ru O R MeO C 88 90 2 O ½ O2 Me 2 AcOH 2 AcOH 91
iPr Me iPr Me O Ru L Ru R3 O 1 R2 R O O 1 95 R 92 L R2
R3 51 L iPr Me iPr Me R2 O Ru O Ru O L R2 O R3 R3 1 R1 L R 94 93
Scheme 24. Proposed catalytic cycle for the synthesis of isocoumarins via Ru-
catalysed C–H activation/functionalisation
Dixneuf and co-workers disclosed in 2011 an example of the use of nitrogen- containing heterocyles as directing groups for oxidative alkenylation.93 The
reaction employed a [Ru(p-cymene)(OAc)2]2 catalyst with catalytic
Cu(OAc)2∙H2O and air as the terminal oxidant to couple N-phenylpyrazole 96 with alkenyl substrates (Scheme 25). The reaction proceeded easily with styrenes, but was slower when acrylamides or alkyl acrylates were used; the use
of stoichiometric Cu(OAc)2∙H2O solved this problem, promoting the reaction to
24 achieve almost quantitative yields. In the absence of an alkene, the homocoupling reaction took place in good yields. The reaction also proceeded in
DMF under a nitrogen atmosphere when stoichiometric amounts of the oxidant
94 Cu(OAc)2∙H2O were used.
[Ru(p-cymene)(OAc)2]2 Cu(OAc)2·H2O
N AcOH, 100 °C N (1) N N 97 air, 5 h 96 98 77%
[Ru(p-cymene)(OAc)2]2 R Cu(OAc)2·H2O R
N O AcOH, 100 °C N O (2) N air, 5 h N 99
96 100 66-77%
p N [Ru( -cymene)(OAc)2]2 N Cu(OAc)2·H2O
N AcOH, 100 °C (3) N N air, 5 h N 96 101 64%
Scheme 25. Alkenylation of N-phenylpyrazoles
Another commonly used directing group is the amide moiety.2,82 Li, Wang and co-workers reported the reaction of N-methoxybenzamides 102 with alkyl
acrylates in the presence of [Ru(p-cymene)Cl2]2 and NaOAc in methanol to furnish the Heck-type product (Scheme 26). 3,4-Dihydroisoquinolines 107 and
108 were produced in similar conditions, using styrenes or norbornadiene and in 25
2,2,2-trifluoroethanol. The group suggested that the selectivity of the reaction towards either the Heck-type or annulated product was dependent on both the alkene substrate and the solvent. Electron withdrawing groups on the alkene and using methanol as a solvent favoured β-elimination leading to the Heck-type product; alkyl/aryl groups on the alkene and 2,2,2-trifluoroethanol as the solvent favoured the annulated product, via reductive elimination.
OMe O NH O [Ru(p-cymene)Cl2]2 2 NaOAc CO R NH2 (1) 2 R1 MeOH, 60 °C, 8 h 2 103 CO2R 1 R 104 102 20-84%
O
NH R1 Ar OMe Ar 107 p-cymene)Cl O NH 105 [Ru( 2]2 NaOAc 47-62% or or (2) CF3CH3OH, 50 °C O 24-36 h R1 NH 102 106
108 87%
Scheme 26. C–H activation/functionalisation of N-methoxybenzamides
Amide directing groups are also often used in the alkenylation of arene C–H bonds with alkenes.82 Miura and co-workers demonstrated the hydroarylation of
II alkynes with benzamides using Ru catalysts in the presence of a Cu(OAc)2∙H2O oxidant (Scheme 27, (1)). Good yields required the use of an AcOH additive; the
26 same conditions could be used for the hydroarylation of alkynes with phenylpyrazole (Scheme 27, (2)).
1 1 O NR [Ru(p-cymene)Cl2]2 R N O 2 2 R3 R3 AgSbF6 R2 R2 AcOH (1) 51 dioxane, 100 °C, 5 h 109 110 42-79%
N [Ru(p-cymene)Cl2]2 N N R3 AgSbF6 Ph N Ph Ph Ph R2 AcOH (2) dioxane, 100 °C, 5 h 51 96 112 85%
Scheme 27. Ru-catalysed hydroarylation of alkynes with benzamides and N-
phenylpyrazole
The Ackermann group reported in 2011 the synthesis of isoquinolones 114 via alkyne insertion (Scheme 28).95 The dehydrogenative annulation required a RuII catalyst and a stoichiometric oxidant, and was carried out in tAmOH at 100 °C.
Previous attempts to synthesise these products required harsher conditions and often more expensive Rh catalysts.82 The group was able to isolate the desired products in moderate to good yields, although a mixture of C2–H and C6–H activated products were seen when meta-substituted benzamides were used. The amide group acted as both a directing group and a reaction partner, displaying a dual functionality.
27
O O 1 4 [Ru(p-cymene)Cl2]2 R R1 R N R2 2 N R H 3 4 R Cu(OAc)2·H2O R 51 tAmOH, 100 °C, 22 h R3 113 114 42-78%
Scheme 28. Dehydrogenative annulation of functional arenes with alkynes
In 2013 Jeganmohan (Scheme 29, (1)), and Li and Wang (Scheme 29, (2)) independently disclosed a carbamate directed oxidative ortho-C–H alkenylation,
96,97 using the [Ru(p-cymene)Cl2]2 catalyst (Scheme 29). Both papers report good to excellent yields of substituted alkene derivatives, which could be deprotected with a base to give the corresponding phenols. The carbamate directing group is both key to the reactivity of the substrates, inducing the selectivity of the C–H activation step, and is also a labile handle for further functionalisation or deprotection.
28
O NEt2 p-cymene)Cl O NEt2 R [Ru( 2]2 O AgSbF6 R O 115 (1) Cu(OAc)2·H2O DME, 100 12 h °C, CO2Me CO2Me 116 103a 42-93%
NMe2 NMe2 O O [Ru(p-cymene)Cl2]2 O O AgSbF6 CO2Et (2) Cu(OAc)2 THF, 110 °C, 30 h 117 118 60-93% CO2Et 103b
Scheme 29. Carbamate-directed Ru-catalysed alkenylation
In the same year Li and Wang also reported a hydroarylation procedure using
Ru catalysis (Scheme 30).96 Using the carbamate directing group and
[Ru(p-cymene)Cl2]2 as a catalyst, the group was able to isolate the desired hydroarylated products 120 in good yields.
O NMe2 [Ru(p-cymene)Cl2]2 O R1 O AgSbF6 H Me2N O Ph 119 PivOH Ph PhCl R1 120 °C,18-30 h Ph Ph 120 51b
Scheme 30. Carbamate-directed Ru-catalysed hydroarylation
As shown by the examples discussed in this section, Ru catalysis can be a mild and efficient method for a variety of C–H activation and functionalisation reactions. It has become an indispensable tool for C–C and C–Het bond 29 formation, especially due to the robustness of some of the reactions.2,82As with the rhodium-catalysed C–H activation reactions discussed earlier, much of this methodology relies on the use of directing groups, which are often integral parts of the substrate.2,93,96–99 The field of ruthenium-catalysed C–H activation continues to grow, as the relatively cheap price makes it an attractive catalyst and new modes of functionality are discovered.
1.1.5. This work
The methods described above, among others in their field, provide a wide scope of reactivity. Through transition metal-catalysed C–H activation and functionalisation, it is possible to access many complex organic molecules efficiently, but there are still new transformations to be discovered.
Contemporary approaches include the use of traceless directing groups,49,50 further advances in the use of ligands,100 additives101 and oxidants,1,2,31 and directing group free C–H activation.60 In this research, the alkyne insertion onto indoles to form annulated polycyclic indoles was investigated, using a number of different C–H activation/functionalisation techniques.
30
1.2. Results and Discussion
1.2.1. Introduction
The chemistry explored in this research project is an extension of work published previously in the Greaney group.36 In 2011, the group reported the use of oxidative C–H coupling in the synthesis of medium rings using substrates
containing the indole ring system, utilising catalytic Pd(OAc)2, an excess of
Cu(OAc)2 and with dimethylacetamide (DMA) as the solvent (Scheme 31).
CHO CHO Pd(OAc) 2 (10 mol%) H K2CO3 (1 equiv.) N Cu(OAc)2 (3 equiv.) N DMA, 90 °C, 16 h
121 122 77%
Scheme 31. Intramolecular oxidative coupling of indole with arenes to form
annulated seven-membered rings36
The group synthesised a number of annulated indoles in good to high yields. In order for the reaction to proceed it was necessary for the substrate to have an electron-withdrawing group (EWG) at the indole C3 position; aldehyde, cyano and nitro groups all provided good yields. The group also reported the successful coupling of the indole with heteroaromatic systems to give heterobiaryls in moderate to high yields. To form the 8-membered ring, it was found that a heteroatom in the tether was necessary to relieve transannular strain, and possibly to provide stabilisation of the intermediates in the reaction.
31
The proposed mechanism is shown below (Scheme 32). It is presented as a
Pd0/PdII catalytic cycle which consists of palladation of the indole at the C2 position, followed by a concerted-metallation-deprotonation (CMD) step.
Reductive elimination affords the annulated medium ring products and Pd0 which is re-oxidised to PdII by the excess CuII.
CHO
PdOAc N Base-assisted Pd(OAc)2 metalation- 121 123 deprotonation HOAc
PdII CHO O O 2CuI Pd H N 2CuII
Pd0 124
CHO
122 Pd HOAc reductive N elimination
125
Scheme 32. Catalytic cycle for the intramolecular C–H coupling36
The group found that using a fairly simple palladium-catalyst system they were able to synthesise medium-ring containing biaryls. This is a good example of palladium-catalysed oxidative coupling onto indoles and has inspired further research into the topic within the group including the work reported here.
32
The focus of this project is the use of palladium-catalysed C–H activation for alkyne insertion onto indoles. Indoles and their derivatives are seen in nature and are often biologically active.102,103 The synthesis of polycyclic indoles often requires the use of multistep routes,104,105 and an important challenge is the development of new methodologies which allow the rapid construction of these complex indole cores. Throughout the literature there are examples of C–H activation used in the synthesis of substituted indoles,24–26,106–110 thus it was proposed that C–H activation could be used as a powerful and convenient method to access these compounds.
In this research project, the proposed reaction includes two coupling reactions between an N-arylated indole and an alkyne, the first at the C2 position of the indole and the second at the ortho-position of the N-aryl ring (Scheme 33). This presents a challenge due to the different nature of each of the desired transformations. It is also of interest to probe the reaction mechanism to see where the initial coupling occurs and why. This research could potentially be applied to a multi-component reaction, where the aryl group must also be incorporated during the reaction.
R1 R 2 1 R1 R N 2 R2 R3 N N R M 3 [ ] [M] 126
127 128 R2 R3 51
Scheme 33. Alkyne insertion proposed in this research 33
Previous research in the group has shown that C–H activation can be used to form polycyclic indoles. In 2011 a tandem indole C–H alkenylation/arylation for tetra-substituted alkene synthesis was reported.111 The optimised conditions used
Pd(OAc)2 as a catalyst with an N-heterocyclic carbene (NHC) ligand, Cs2CO3 and chlorobenzene as the solvent (Scheme 34). The method was versatile with moderate to good yields of variously substituted products.
2 mol R Pd(OAc) 2 (5 %) Ar Ar2IBF4 equiv.) (1.05 R2 R1 SIMes.HCl (10 mol%) R1 N N Cs2CO3 (1 equiv.) chlorobenzene, 30 °C 3 R3 R 129 130
N N
131 SIMes
Scheme 34. Intramolecular C–H alkenylation/arylation111
The group suggests two possible mechanisms (Scheme 35). They state that the reaction is generally Z-selective, suggesting that a key step is alkyne syn- carbopalladation. Path A shows direct indole palladation at C2 giving the PdII intermediate, followed by intramolecular 6-exo-dig carbopalladation.
Intermediate 132 then reacts with the very oxidising iodonium salt to give first the reactive PdIV intermediate followed by reductive elimination to the final
Z-product. PdIV is a very electron poor metal centre and thus is very reactive, which allows the chemistry to proceed at lower temperatures than in Pd0/PdII catalytic cycles. 34
Ar2IX, Pd(OAc)2
ArI PdOAc R1 R2 ArPd(OAc)2X N carbopalladation carbo- Pd(OAc)2 palladation 1 X OAc R 131 N Pd Ar AcO R3 R2 129 AcOPd R3 R2 1 135 R Path B Path A N
R3 132 reductive 130 reductive elimination elimination Ar OAc X OAc X Pd Ar2IX Ar 2 R1 Pd R oxidation R1 N PdII PdII R2 N
R3 134 R3 133 Scheme 35. Possible mechanistic pathways111
The second mechanism differs from the first in that the initial step is the
IV intermolecular alkyne carbopalladation using ArPd (OAc)2X to give intermediate 135. This is followed by intramolecular C–H activation at the indole C2 position. The final product is produced by reductive elimination of
PdII.
In conclusion, the group found that it was possible to synthesise tetra-substituted alkenes under mild conditions using PdII/PdIV catalysis in moderate to high yields. The method was tolerant of a wide range of functional groups and substitution. The research is a good example of the use of C–H activation in the synthesis of polycyclic indoles.
35
Miura has reported the synthesis of heteroaromatic compounds using decarboxylative annulation.112 One of the side products formed in the reaction matched a target proposed for this project (Scheme 36). The conditions were considered in the selection of screening conditions in this project.
Ph Ph 51b Ph Ph CO2H Ph Pd(OAc)2 (3 mol%) Ph ·H Cu(OAc)2 2O (1.3 equiv.) N N Ph N Ph MS 4Å/LiOAc (2 equiv.) DMA
138 136 137 36 % 14%
Scheme 36. Miura’s decarboxylative coupling of indoles with alkynes112
1.2.2. Pd-catalysed alkyne insertion
Research in the group has shown that including an electron withdrawing substituent at the C3 position on the indole is key to the reactivity of the substrates toward C–H activation at the C2 position. This could be due to the increased acidity of the C–H bond or stabilisation of intermediates.36 The indole derivatives shown below have been proposed as feasible substrates for the alkyne insertion reaction (Scheme 37).
36
R1 R2 R2 R1 51b R2 oxidative addition N N R2
X X
139 X = CH, R1 = CHO 143 X = CH, R1 = CHO
140 X = N, R1 = CHO 144 X = N, R1 = CHO
141 X = CH, R1 = CN 145 X = CH, R1 = CN 1 1 142 X = N, R = CN 146 X = N, R = CN
Scheme 37. A general scheme for the alkyne insertion reaction
These are N-arylated indoles with either an aldehyde or cyano moiety at the C3 position. These substrates were not commercially available, and it was found that the easiest way to access the desired substrates was via N-arylation of the C3 substituted indoles 147 and 148. The N-arylation was performed according to literature conditions (Scheme 38).113
ArI or ArBr (2 equiv.) R R Cu2O (0.1 equiv.) K2CO3 (2 equiv.)
DMF N N ° H 153 C Ar = 139-142 147 R CHO 148 R = CN 63-68%
Scheme 38. N-arylation of C3 substituted indoles using copper(I) oxide113
Initial studies into the alkyne insertion were using the conditions previously used within the Greaney group for biaryl synthesis, as these are common conditions for C–H activation.36 The general conditions employ a palladium(II) catalyst, a stoichiometric oxidant and a basic additive. The alkynes used were diphenylacetylene or dimethylacetylene dicarboxylate (DMAD).
37
The conditions were extensively screened as shown in the tables below; however the desired product was not isolated. Several hypotheses were tested during screening; Table 1 shows screening of oxidants and alkynes, to find an appropriate reagent for the oxidation of the catalyst to regenerate the active species. The oxidants screened are commonly used in Pd-catalysed C–H functionalisation.1,19–21,34–36 The different alkynes used were chosen for their different reactivity. Table 2 shows the screening of several basic additives often used to improve yields and reactivity in C–H functionalisation.1,19–21,34–36
Throughout screening, the reactions were run at several temperatures; Pd- catalysed C–H functionalisation often requires elevated temperatures1, but depending on the mechanism, the reaction can proceed at lower temperatures31,35
When the indole substrate contained an aldehyde group, this moiety was often oxidised to give the acid with no further reaction. The 3-cyanoindole was also unreactive in these conditions. An N-pyridyl group was used in an attempt to direct co-ordination of the palladium to the substrate but gave no conversion of the starting material (Table 5). Unless otherwise stated, yields were determined from isolated products.
38
Table 1. Alkyne and oxidant screening for the Pd-catalysed alkyne insertion onto
indole 139
CHO alkyne (1.5 equiv.) CHO Pd(OAc)2 (10 mol%) R oxidant (2 equiv.) N N R K2CO3 (2 equiv.) DMA or DMF temperature, 18 h 139 143
Yield Alkyne Oxidant Temp. (%)
a 1 DMAD Cu(OAc)2 90, 120 °C 0 DMAD or 2 CuCO 90, 120 °C 0a diphenylacetylene 3 DMAD or 3 CuCl 90, 120 °C 0b diphenylacetylene DMAD or 4 Ag CO 90, 120 °C 0a diphenylacetylene 2 3 DMAD or 5 AgOAc 90, 120 °C 0b diphenylacetylene DMAD or 6 K S O 90, 120 °C 0b diphenylacetylene 2 2 8
a 7 dec-5-yne Cu(OAc)2 90, 120 °C 0
a 8 oct-4-yne Cu(OAc)2 90, 120 °C 0
a 9 diphenylacetylene Cu(OAc)2 90, 120 °C 0
astarting material recovered; boxidation of aldehyde moiety
39
Table 2. Alkyne and oxidant screening for the Pd-catalysed alkyne insertion onto
indole 139
CHO alkyne (1.5 equiv.) CHO mol%) Pd(OAc)2 (10 R Cu(OAc)2 (2 equiv.) N N R additive (2 equiv.) DMA or DMF temperature, 18 h 139 143
Alkyne Additive Yield (%)
a, b 1 DMAD K2CO3 0
a 2 DMAD Cs2CO3 0
3 DMAD LiOAc 0a
4 DMAD CsOPiv 0a
5 DMAD NaOtBu 0c
6 DMAD none 0c astarting material recovered; b3 equiv. c Cu(OAc)2; oxidation of aldehyde moiety
40
Table 3. Alkyne and oxidant screening for the palladium-catalysed alkyne
insertion onto indole 141
CN CN alkyne (1.5 equiv.) R Pd(OAc)2 (10 mol%) oxidant N (2 equiv.) N R
K2CO3 (2 equiv.) DMA or DMF temperature, 18 h 141 145
Yield Alkyne Oxidant Temperature (%) 30, 60, 90, 1 DMAD Cu(OAc) 0a, b, c, d 2 120 °C 30, 60, 90, 2 dec-5-yne Cu(OAc) 0a 2 120 °C 30, 60, 90, 3 oct-4yne Cu(OAc) 0a 2 120 °C 30, 60, 90, 4 diphenylacetylene Cu(OAc) 0a 2 120 °C 30, 60, 90, 5 diphenylacetylene CuCO 0a 3 120 °C 30, 60, 90, 6 diphenylacetylene CuCl 0a 120 °C 30, 60, 90, 7 diphenylacetylene Ag CO 0a 2 3 120 °C 30, 60, 90, 8 diphenylacetylene AgOAc 0a 120 °C 30, 60, 90, 9 diphenylacetylene K S O 0a 2 2 8 120 °C aStarting material recovered; b3 equiv. oxidant; calkyne dimerisation; dDMA as solvent
41
Table 4. Additive screening for the Pd-catalysed alkyne insertion onto indole 141
CN CN alkyne (1.5 equiv.) R Pd(OAc)2 (10 mol%) N N R Cu(OAc)2 (2 equiv.) additive (2 equiv.) DMA, temperature, 18 h
Yield Alkyne Additive Temperature (%) 30, 60, 90, 1 diphenylacetylene Cs CO 0a 2 3 120 °C 30, 60, 90, 2 diphenylacetylene LiOAc 0a 120 °C 30, 60, 90, 3 diphenylacetylene CsOPiv 0a 120 °C 30, 60, 90, 4 diphenylacetylene NaOtBu 0a 120 °C 30, 60, 90, 5 diphenylacetylene none 0a 120 °C
6 diphenylacetylene LiOAc 120 °C 0a, b
a, c, d 7 diphenylacetylene K2CO3 30, 120 °C 0
a b Starting material recovered; 30 mol% Pd(OAc)2, 1.3 equiv. oxidant; calkyne dimerisation; dDMF as solvent
42
Table 5. Attempted alkenylation of N-pyridyl substrate 142
CN CN alkyne (1.5 equiv.) R Pd(OAc)2 (10 mol%) N N R Cu(OAc) 2 (2 equiv.) N K2CO3 (2 equiv.) N DMF, temperature, 18 h
142 146
Yield Alkyne Temperature (%)
1 diphenylacetylene 30, 60, 90, 120 °C 0a,b
2 phenylacetylene 30, 90°C 0a,b
3 DMAD 30, 60, 90, 120 °C 0a
4 4-octyne 30, 60, 90, 120 °C 0a
aStarting material recovered; balkyne dimerisation
To examine the reactivity of the chosen substrates towards the first bond forming step in the reaction, indoles 141, 148 and 149 were subjected to conditions developed by Fujiwara for the Pd-catalysed alkenylation of heteroaromatic compounds (Table 6).114,115 This reaction is a PdII-mediated electrophilic aromatic substitution. The literature reaction (entry 1), where there was no substitution on the indole nitrogen, was repeated successfully. When the 3-cyano substrates were used, the reactions proceeded but gave a lower yield, as was the case when there was a substituent on the indole nitrogen. This suggested that both including the electron withdrawing group at C3 and the inclusion of an N-aryl group led to reduced reactivity towards the reaction under these conditions potentially implying and explaining the difficulty of the alkyne insertion at the heart of this
43 research. Palladium catalysis was not suitable for the desired reaction, and thus further research into the reactivity at the C2 position was carried out.
Table 6. Fujiwara alkenylation reactions114,115
Ph CO2Me R1 51c R1
Pd(OAc)2 (5 mol%) Ph
N AcOH N CO2Me R2 RT R2 141, 148, 149 150a-c
# R1 R2 Yield (%)
1 148 Me H 63
2 149 CN H 38
3 141 CN Ph 21
In 2012, Yoshikai proposed a cobalt-catalysed alkenylation of N-pyrimidyl
indoles using CoBr2, the ligand pyphos 153 and the Grignard reagent neopentylmagnesium bromide at 20 °C (Scheme 39).116–118 The general hydroarylated products 152 were isolated in moderate to good yields. It was thought that this initial bond forming step could be followed by an oxidative coupling to access the desired annulated product, either by using the cobalt catalyst or an additional oxidant.
44
R2
R2 CoBr2 (10 mol% N R1 N mol%) 1 pyphos (10 N N R N N t 51 BuCH2MgBr (60 mol%) 1.5 equiv THF, 20 °C 12 h 152 151 1 2 R = R = alkyl, aryl, TMS
Ph2P N 153 pyphos
Scheme 39. Yoshikai’s cobalt-catalysed hydroarylation116–118
Indoles 141 and 142 were subjected to the conditions shown in Scheme 39
(Table 7). The hydroarylation took place on the N-pyridyl indole 142 in a moderate to good yields (up to 70%) to give product 155. However the second oxidative C–C bond forming reaction did not occur. The non-directed substrate,
N-phenyl indole 141, was unreactive suggesting that a directing group was necessary for the reaction to occur. The mechanisms of these cobalt-catalysed reactions are still poorly understood, especially with respect to the Grignard.
45
Table 7. Cobalt-catalysed hydroarylation of indole 141 or 142
CN CN diphenylacetylene Ph cobalt(II) catalyst (10 mol%) ligand (10 mol%) N N Ph Grignard (60 mol%) X THF, RT, 16 h X
141 X = CH 154 X = CH 142 X = N 155 X = N
X Catalyst Ligand Grignard Yield (%)
t 1 N CoBr2 pyphos BuCH2MgBr 65
t 2 N CoBr2 - BuCH2MgBr 56
t a 3 CH CoBr2 pyphos BuCH2MgBr –
4 N CoBr2 pyphos PhMgBr 50
t 5 N Co(acac)2 pyphos BuCH2MgBr 70
a Starting material recovered
A stoichiometric oxidant was added to the reaction either initially or after 18 h with the hope that the secondary cyclisation could be facilitated (Table 8) but the desired product was not isolated. A palladium(II)-catalysed coupling reaction was attempted on compound 155 to test whether the annulation took place, but the reaction did not afford the desired product: most of the starting material was reisolated from the reaction. The stereochemistry of the product was determined by analogy with the literature, where it was determined by X-ray crystallography. At this point in the research it became pertinent to examine new methods of C–H functionalisation in order to effect this transformation.
46
Table 8. Attempted cobalt-catalysed hydroarylation of indole 145 with a second
oxidative coupling step
CN CN CN CoBr mol%) Ph 2 (10 Oxidative Ph mol%) Pyphos (10 coupling N N Ph N Ph t BuCH2MgBr (60 mol%) N N N alkyne (1.5 equiv.) THF, RT, 16 h 142 155 146a
Addition of Oxidant Reaction time Yield (%) oxidant
a 1 Cu(OAc)2 0 h 24 h - Cleavage of 2 Cu(OAc) after 18 h 18 h + 24 h 2 alkene
a 3 K2S2O8 0 h 24 h -
a 4 K2S2O8 after 18 h 18 h + 24 h -
5 benzoquinone 0 h 24 h -a
6 benzoquinone after 18 h 18 h + 24 h -a
a Starting material recovered
CN CN Ph Ph Pd(OAc)2 (10 mol%) N Ph Cu(OAc)2 (2 equiv.) N X Ph TFA N (2 equiv.) N 1,2-DCE, 18 h
155 146a
Scheme 40. Attempted palladium-catalysed C–H activation for the annulation of
indole 155
47
1.2.3. Rh-catalysed alkyne insertion
68,69,72,119–124 A common catalyst for C–H activation is [Cp*Rh(Cl2)]2. In 2011,
Miura described a series of rhodium-catalysed oxidative reactions between phenylazoles and internal alkynes (Scheme 41).119 Of particular interest was the reaction detailed in Scheme 41, wherein a phenylpyrazole is reacted with phenylacetylene to give 3 major products. They were able to optimise the conditions to isolate 158 as the major product in moderate to good yields. This is directly comparable to the desired products of this project and hence these conditions were considered for investigation.
N N Ph N Ph N Ph Ph Ph N Ph N [Cp*RhCl2]2 Ph 158 ·H 157 Ph Cu(OAc)2 2O base 51a N 96 N Ph Ph
159
Scheme 41. Miura’s rhodium-catalysed oxidative reaction between
phenylpyrazole and phenylacetylene119
Shibata reported, in 2012, a rhodium-catalysed intramolecular alkenylation
(Scheme 42).68 This paper also discussed the concept of rollover. This is where, after a metallation step, the molecule undergoes a bond rotation, usually of directing groups allowing further reaction at a different part of the molecule. This
48 fundamental change in the configuration of the molecule during the transformation unlocks a dual purpose in the molecule in which a moiety may act as a directing group, potentially lowering the energy of transition states via hemi-labile ligation in order to promote the reaction, and after rollover it is part of the molecule which may be used for further reaction. In this case, it was decided that the N-pyridyl substrate would be a suitable candidate for rollover due to the necessary rotation of the C–N bond shown in Scheme 43 to allow for the second bond formation.
2 N [Cp*RhCl2]2 N N R Cu(OAc)2 R2 [Rh] R2
R1 R1 R1 160 161 162
Scheme 42. Shibata’s rhodium-catalysed rollover reaction68
1 R1 R R1 2 R2 R2 R R2 51 R2 N N N R2 N N [M] N
163 164 165
Scheme 43. Proposed rollover transformation for the alkyne insertion
Contemporary to the research discussed in this chapter, Dong and Chen published two papers detailing alkyne insertion onto N-phenyl benzimidazoles
and N-alkenyl or N-phenyl imidazoles or pyrroles using [Cp*RhCl2]2 (Scheme
44, Scheme 45).120,121 They were able to isolate the desired products in good
49 yields. These conditions were also used to influence the screening for the desired products in this project.
N N
Ph * mo [Cp RhCl2]2 (5 l%) Ph N u c · . e u v. N C (OA )2 H2O (1 2 q i ) Ph Ph toluene, Ar R ° R 51a 110 C 166 167 - 48 94%
Scheme 44. Alkyne insertion onto an N-phenyl benzimidazole120
3 3 R 1 R R Cp*RhCl 5 mol [ · 2]2 ( . %) . u Ac H 1 2 e uiv N X N C (O )2 2O ( q ) X H 1 2 toluene, Ar R 4 H R 4 R ° R R2 51 110 C 168 169 - 22 99%
Scheme 45. Alkyne insertion onto N-alkenyl or N-phenyl imidazoles or
pyrroles121
After screening literature conditions for rhodium-catalysed C–C bond forming reactions, it was found that the conditions used in the work by Miura and the work by Dong gave the most promising results.119–121 Upon initial screening, only one of the desired products was isolated, and in a low yield (Table 9).
50
Table 9. Initial screening of the Rh-catalysed alkyne insertion
1 1 R R mol%) [Cp*RhCl2]2 (2.5 R2 Cu(OAc)2·H2O (2 equiv.) N N R2 Na2CO3 (1 equiv.) X alkyne (2 equiv.) X p-xylene, 150 °C, 18 h
139-142 143-146
X R1 R2 Yield (%)
1 CH CHO Ph 0a,b
a,b 2 CH CHO CO2Me 0
3 N CHO Ph 0a,b
a,b 4 N CHO CO2Me 0
5 CH CN Ph 0a
a 6 CH CN CO2Me 0
7 N CN Ph 32a
a 8 N CN CO2Me 0
astarting material recovered; bdecarbonylation
It was not possible to improve the reaction further by optimisation (Tables
10-14), and after screening several variables in the reaction, the final conditions used mirrored those of Dong et al. (Scheme 46). The conditions chosen for screening reflected literature precedent with respect to catalyst loading, temperature, solvent, additive and oxidant.68,119–121 It was thought that the low yield in table 9 could be improved by increasing the amount of catalyst, as the number of reaction turnovers may have been limited. Indeed, the yield was
51 increased, however by only a small amount, and due to the price of the rhodium catalyst, it was decided to keep a lower loading of catalyst. The solvents used were used in the literature examples discussed above,68,119–121 and it was found that xylene and toluene appeared to give the best conversion to the desired product.
Important to note from the optimisation results is that the reaction appears to require elevated temperatures to produce the desired product. There was lower conversion of the starting material as the temperature was lowered from 150 °C to 130 °C, and the reaction stopped completely below 110 °C: the starting material was isolated in high yields. This suggests that the desired transformation is difficult even in these conditions, and thus moderate yields were expected for most examples. Unless otherwise stated, all yields were calculated from isolated products.
52
Table 10. Screening of catalyst loading
CN CN [Cp*RhCl2]2 (X mol%) Ph Cu(OAc)2·H2O (2 equiv.) N N Na2CO3 (1 equiv.) Ph N diphenylacetylene (2 equiv.) p-xylene, 150 °C, 18 h N
142 146a
Catalyst loading (X) Yield (%)
1 0 mol% 0a
2 0.5 mol% 10a,b
3 1 mol% 17a,c
4 2.5 mol% 36a,c
5 5 mol% 38a,c
6 10 mol% 41a,c astarting material recovered; byield by NMR; cisolated yield
53
Table 11. Screening of reaction solvents
CN [Cp*RhCl2]2 (2.5 mol%) CN Cu(OAc)2·H2O (2 equiv.) Ph
Na CO N 2 3 (1 equiv.) N Ph N diphenylacetylene (2 equiv.) solvent, N 150 °C, 18 h 142 146a
Solvent Yield (%)
1 p-xylene 35a
2 o-xylene 33a
3 toluene 37a
4 1,4-dioxane 0a
5 1,2-dichloroethane 0a astarting material recovered
Table 12. Screening of reaction temperature
CN CN [Cp*RhCl2]2 (2.5 mol%) Ph Cu(OAc)2·H2O (2 equiv.) N N Ph Na2CO3 (1 equiv.) N diphenylacetylene (2 equiv.) N p-xylene, temperature, 18 h 142 146a
Temperature ( C) Yield (%) °
1 110 0a
2 130 12a
3 150 32a astarting material recovered
54
Table 13. Screening of additives
CN CN Ph [Cp*RhCl2]2 (2.5 mol%) Cu(OAc)2·H2O (2 equiv.) N N Ph N additive (1 equiv.) diphenylacetylene (2 equiv.) N p-xylene, 150 °C, 18 h 142 146a
Additive Yield (%)
a 1 Na2CO3 34
a 2 NaHCO3 24
a 3 Li2CO3 12
a 4 Cs2CO3 21
a 5 K2CO3 13
6 AcOH 0b
b 7 PivOH 0
8 TFA 0b
9 none 0a astarting material recovered; bcomplex mixture of products
55
Table 14. Screening of oxidants
CN CN
[Cp*RhCl2]2 (2.5 mol%) Ph oxidant (2 equiv.) N N Ph N Na2CO3 (1 equiv.) diphenylacetylene (2 equiv.) N p-xylene, 150 °C, 18 h 142 146a
Oxidant Yield (%)
a 1 Cu(OAc)2∙H2O 34
a,b 2 Cu(OAc)2∙H2O 32
a 3 Cu(OAc)2 24
4 CuCl 0a,c
5 CuBr 0a,c
a,c 6 Cu2O 0
7 CuO 12a
a 8 Ag2CO3 22
a 9 AgNO3 0
a 10 K2S2O8 0
a 11 PhI(OAc)2 0
a 12 PhI(CO2CF3)2 0
13 none 0a astarting material recovered; b1 equiv. oxidant; cdimerisation products detected by NMR
56
CN CN R2 [Cp*RhCl2]2 (2.5 mol%) Cu(OAc)2·H2O (1 equiv.) N N 2 R N Na2CO3 (1 equiv.) N alkyne (2 equiv.) p-xylene, 150 °C, 18 h 142 146
Scheme 46. Optimised reaction conditions
Several products were isolated in moderate to good yields (Scheme 47), and demonstrate the scope of the reaction. Symmetrical alkynes were used to good effect, although only those with alkyl or phenyl groups attached. The group at
C3 could be changed, with the best results seen when using an ester moiety.
Interestingly, installing a methyl group at the indole C3 did not detrimentally affect the yield; a lower yield was expected as previous work in the group had indicated that an electron withdrawing group was necessary at the C2 position to promote the palladation step.36 This suggests that while in the Pd-catalysed reaction it was necessary to increase the acidity of the C–H bond,36 in the
Rh-catalysed reaction the introduction of the pyridyl directing group was more important for the desired reaction to proceed. It was, however, found that substitution was necessary at the C3 position as there was a preference for attack at this position. Changing the directing group to a pyrazyl group gave the desired product in good yields, however using a thiophene led to almost complete stalling of the reaction (<5% conversion by LC-MS). This is probably due to higher energy of the intermediate rhodaycle with the ligated thiophene, as it was found in previous research that this substrate is suitable for the reaction albeit with lower yields than for other examples.120
57
R1 R1 2 [Cp*RhCl2]2 (2.5 mol%) R Cu(OAc)2·H2O (1 equiv.) N N 2 R Na2CO3 (1 equiv.) X X Y alkyne (2 equiv.) Y p-xylene, 150 °C, 18 h 142, 170-174 146, 175-179
CN CN CN Ph C3H7 C4H9
N Ph N C3H7 N C4H9
N N N
146a 146b 146c 39% 65% 69%
O O O Ph Ph Ph N Ph N Ph N Ph N N N
175 176 177 37% 58% 72%
O O O H O O Ph Ph C3H7
N Ph N Ph N C3H7
N N N N N N
178 179a 179b 35% 91% 42%
Scheme 47. Rh-catalysed alkyne insertion substrate scope
Substrates which did not work are detailed in Scheme 48. Introducing variation away from heteroaryl groups on the indole nitrogen was researched in some detail; no other suitable directing group could be found. Acetyl groups showed no reaction at all, with complete recovery of the starting material found. N-
58 phenylacetyl groups were also ineffective for the desired reaction, any reactivity seen was only on the benzene of the phenylacetyl moiety itself amongst a complex mixture of by-products. These structures were chosen because they included a known directing group for C–H activation (C=O),21 but would be novel substrates for the desired reaction.The lack of reactivity seen suggests that the initial ligation to the pyridyl nitrogen of the previous examples is necessary to promote the reaction.
1 R1 R [Cp*RhCl2]2 (2.5 mol%) R3 Cu(OAc)2·H2O (1 equiv.)
X N 3 N Na2CO3 (1 equiv.) R R2 alkyne (2 equiv.) p-xylene, 150 °C, 18 h 180-182 183
CN CN CN N N N O O O
180 OMe Cl 181 182
Scheme 48. Limitations of the substrate scope for the reaction: directing groups
Concerning the alkyne component of the reaction, it was found that unsymmetrical alkynes do not react well in the reaction, resulting in low yields and mixtures of isomers. This indicates that the reaction is not selective with respect to the alkynyl moiety. In addition, terminal alkynes are completely unreactive under the reaction conditions, suggesting that the differing reactivity of terminal and internal alkynes is an important factor in the reaction.
59
R1 R2 CN 51 CN CN . 1 * mo R1 R [Cp RhCl2]2 (2 5 l%) u c · e u v. (1) C (OA )2 H2O (1 q i ) N N 2 N 2 . R R Na 1 e uiv N - 2CO 3 ( q ) p xylene, 150 °C, 18 h N N
142 184a 185a CN CN R2 R2
N R1 N R1
N N
184b 185b
low yields; complex mixture
R H CN CN CN 51c R H * . mo [Cp RhCl2]2 (2 5 l%) u c · e u v. N C (OA )2 H2O (1 q i ) N N H R (2) X . N Na 1 equiv - 2CO 3 ( ) N N p xylene, 150 °C, 18 h
142 186 186
Scheme 49. Limitations of the substrate scope for the reaction: alkynes
Oxidised alkynes (also referred to as alkyne equivalents), reported by Glorius
(Scheme 50, (1))125 were also used in the reaction, but without the desired reactivity (Scheme 50, (2)). Alkyne equivalents are described by Glorius to be oxidised alkynes; they are prepared as -halo or -pseudohalo ketones and were used in the synthesis of N-heterocycles usingα RhIIIα catalysis. Under the conditions for the desired reaction in this work, no reaction was seen.
60
O O III OMe O [Rh ] OMe N N H X R (1) H 188 R 187 "oxidised alkynes" 189 X = OMs, OTs, Cl
CN CN [Cp*RhCl2]2 (2.5 mol%) O Cu(OAc)2·H2O (1 equiv.) N X X N R (2) R Na2CO3 (1 equiv.) N p-xylene, 150 °C, 18 h 188 N
190 142
Scheme 50. Limitations of the substrate scope for the reaction: alkyne
equivalents
Due to the complex nature of the 1H NMR and 13C NMR of compound 146a, it was necessary to obtain an X-ray crystal structure to elucidate the structure. The compound was synthesised in good purity and recrystallised to give a single crystal. From this the crystal structure shown in figure 1 was obtained. It shows the insertion of the alkyne at the C2 position of the indole and annulation onto the pyridine ring. Still, this does not provide solid evidence that the reaction proceeds via a rollover mechanism, thus further investigation was needed.
61
Figure 2. X-ray crystal structure of compound 146a
The reaction does not occur when an N-phenyl group is used. This implies that the N-pyridyl group plays a key role in the reaction, presumably through co- ordination of rhodium to the pyridine nitrogen. In order to test this, substrate
171d was synthesised. With the nitrogen now in the meta-position, it would be more difficult for co-ordination and thus directed insertion to happen, so it was expected that the reaction would not occur. Pleasingly, no reaction was seen using this substrate, suggesting that the ortho-nitrogen does co-ordinate to the rhodium to assist the initial C–H insertion.
62
CN CN mol%) [Cp*RhCl2]2 (2.5 R Cu(OAc)2·H2O (1 equiv.) (1) N X N R Na2CO3 (1 equiv.) alkyne (2 equiv.) p-xylene, 150 °C, 18 h 146 141 0%
CN CN mol%) [Cp*RhCl2]2 (2.5 R Cu(OAc)2·H2O (1 equiv.) (2) N X N R Na2CO3 (1 equiv.) alkyne (2 equiv.) N p-xylene, 150 °C, 18 h N
191 171d 0% R R
mol%) [Cp*RhCl2]2 (2.5 R Cu(OAc)2·H2O (1 equiv.) N X N N (3) Na2CO3 (1 equiv.) R N alkyne (2 equiv.) N N p-xylene, 150 °C, 18 h
192 170b 193 0%
Scheme 51. Control reactions to examine the mechanism of the reaction
The reaction was carried out with stoichiometric [RhCp*Cl2]2 in order to isolate any intermediate rhodacycles. Shown below in Figure 3 is the isolated metallacycle, depicting the insertion at the C2 position, and the co-ordination to the nitrogen on the pyridine directing group. This evidence corroborates the theory that the reaction takes place via a rollover mechanism, as the rhodacycle formed must undergo a bond rotation in order for the reaction to take place on the distal carbon.
63
Figure 3. A crystal structure showing rhodacycle 194 formed in the reaction,
crystallised with CHCl3
The above rhodacycle was then used as the catalyst in the alkyne insertion reaction, and the desired product was indeed formed in a 44% yield. This demonstrates that the proposed and isolated rhodacycle intermediate is a competent catalyst within the reaction.
The suggested mechanism for this reaction is below (Scheme 52). Based on literature postulation,67,68,124and the evidence previously discussed, it is thought that the reaction proceeds via a RhI/RhIII cycle. The rhodium catalyst reacts at the C2 position on the indole to give 194. This is followed by insertion of the alkyne to form the 7-membered rhodacycle 196 and following the rollover step the final Rh–C bond is formed. Following a reductive elimination step the desired annulated indole 146a is produced, and the resulting RhI species must be oxidised to the active RhIII species using the copper oxidant. 64
NC
N N 2CuX2 * Cp Rh(III)X2 CN 142 2CuX Ph Cp*Rh I ( ) CN HX N Ph RhCp*X N N N c c e a Rh(I)/Rh(III) y l 146 194 CN Ph CN Ph Ph Ph Ph N 51b * Ph RhCp N N RhCp*X N
196 195 HX
Scheme 52. Proposed mechanism for the rhodium-catalysed alkyne insertion
1.2.4. Ru-catalysed alkyne insertion
Rhodium is an expensive and precious resource. In an attempt to make the reaction cheaper and more sustainable, research into an alternative for this
transformation was carried out. [Ru(p-cymene)Cl2]2 has been shown to have similar catalytic activity to the [RhCp*Cl2]2 in certain C–H activation reactions and thus various literature conditions were screened (Table 15).94,95,125–
136 None of these conditions were appropriate for the desired transformation and afforded only the starting material or the hydroarylated product after 24-48 h at high temperatures. The hydroarylation product was detected by LC-MS and
NMR, but was not fully characterised.
65
Table 15. Attempted ruthenium-catalysed alkyne insertion with a number of
literature conditions94,95,125–136
CHO R R CHO 51 R (2 equiv.) N [Ru(p-cymene)Cl2]2 (5 mol%) N R
N oxidant (2 equiv.) N additive(s) (20 mol%) solvent, 140 144 N2, temperature, 6-18 h
Temp. R Oxidant Additive(s) Solvent Yield (°C)
t a, b 1 C3H7 Cu(OAc)2·H2O AgSbF6 AmOH 80 trace
t a 2 C3H7 Cu(OAc)2·H2O none AmOH 100 0
t a, b, c 3 C3H7 Cu(OAc)2·H2O none AmOH 120 trace
CO M 4 2 Cu(OAc) AgSbF THF 110 0d e 2 6 CO M 5 2 Cu(OAc) H O none tAmOH 100 0a, d e 2· 2
t a 6 Ph Cu(OAc)2·H2O none AmOH 100 0
PivOH 1,4- 7 Ph Cu(OAc) H O 100 0a 2· 2 (5 equiv.) dioxane AgSbF , 6 1,4- 8 Ph none PivOH (5 100 0a dioxane equiv.) AgSbF , 6 1,4- 9 Ph none AcOH (4 100 0a dioxane equiv.) AgBF 4 1,4- 10 Ph none (1.1 100 0a dioxane equiv.) astarting material recovered; bunder air; ccomplex mixture of by- products; dproduced hydroarylation product
66
The reaction was also attempted using N-aryl pyrroles 197 and 198, based on previous precedent that these substrates could be used in alkyne insertion reactions (Scheme 53, Table 16, Table 17). Unfortunately none of the desired annulated product was detected by NMR or LC-MS; the starting material was recovered and, in the case of using a PivOH additive, a small quantity of a hydroarylated product (either at C2 or C3) was detected by LC-MS (Scheme 53,
(3)). This reaction was not investigated further, but there could be potential for further research into ruthenium as a catalyst for C–H activation.
p-cymene)Cl mol%) [Ru( 2]2 (5 Ph AgSbF6 (20 mol%) N Cu(OAc)2 (2 equiv.) N X Ph (1) X diphenylacetylene (1.5 equiv.) THF X 110 °C, air, 18 h
= = 197 X CH 199 X CH 0% 198 X = N 200 X = N 0%
p-cymene)Cl mol%) Ph [Ru( 2]2 (5 N Cu(OAc)2 (2 equiv.) N Ph (2) X X diphenylacetylene (1.5 equiv.) X t AmOH, 100 °C, N2, 18 h
= = 197 X CH 199 X CH 0% 198 X = N 200 X = N 0%
p-cymene)Cl mol%) [Ru( 2]2 (5 Ph AgSbF6 (20 mol%) PivOH N (5 equiv.) N X Ph (3) X diphenylacetylene (1.5 equiv.) X 1,4-dioxane 100 °C, N 18 h 2, = = 197 X CH 199 X CH 0% 198 X = N 200 X = N 0%*
Scheme 53. Attempted Ru-catalysed alkyne insertion reactions95,96,98,126–137
*hydroarylated product detected by LC-MS
67
Table 16. Attempted Ru-catalysed alkyne insertion using
diphenylacetylene95,96,98,126–137
[Ru(p-cymene)Cl 2]2 (5 mol%) Ph AgSbF6 (20 mol%) N PivOH (5 equiv.) N Ph N diphenylacetylene (1.5 equiv.) N oxidant (2 equiv.) solvent 198 200 100 °C, N2, 18 h
Solvent Oxidant Yield (%)
1 1,4-dioxane none 0a,b
2 toluene none 0a,b
3 THF none 0a,b
4 tAmOH none 0a,c
5 1,4-dioxane none 0a,b
a,b 6 1,4-dioxane Cu(OAc)2∙H2O 0
t a,b 7 AmOH Cu(OAc)2∙H2O 0
a,b 8 1,4-dioxane air 0
9 tAmOH air 0a,b
10 1,4-dioxane none 0a,d
11 1,4-dioxane none 0a,e
12 1,4-dioxane none 0a,f astarting material recovered; bhydroarylation product detected by LC-MS; cAcOH used in place of d e PivOH; without [Ru(p-cymene)Cl2]2; without f AgSbF6; without PivOH
68
Table 17. Attempted Ru-catalysed alkyne insertion95,96,98,126–137
[Ru(p-cymene)Cl 2]2 (5 mol%) R1 AgSbF6 (20 mol%) N PivOH (5 equiv.) N R2 N alkyne (1.5 equiv.) N oxidant (2 equiv.) solvent 198 100 °C, N2, 18 h 200
Yield alkyne solvent oxidant (%)
1 oct-4-yne 1,4-dioxane none 0a,b
2 oct-4-yne 1,4-dioxane air 0a,b
a,b 3 oct-4-yne 1,4-dioxane Cu(OAc)2∙H2O 0
4 oct-4-yne tAmOH none 0a,b
5 DMAD 1,4-dioxane none 0a
6 dec-5-yne 1,4-dioxane none 0a,b
methyl 7 1,4-dioxane none 0a 3-phenylpropiolate
astarting material recovered; bhydroarylation product detected by LC-MS
1.3. Recent literature developments
Recently, other groups have successfully been able to use rhodium to promote an alkyne insertion reaction. In 2015, Li et al. reported the RhIII-catalysed oxidative annulation of 2-phenylimidazo[1,2-a]pyridines 201 with alkynes to furnish either
69
– the rollover product 202, or the salt with BF4 203 in moderate to good yields
138 (Scheme 54). Using [RhCp*Cl2]2 as the catalyst the group were able to control which product was given through the choice of oxidant, either AgOAc or
Cu(OAc)2.
N
[RhCp*Cl2]2 N AgSbF6 R2 N R1 AgOAc 202 DCE, 100 °C N 21-93% H H R2 201 [RhCp*Cl2]2 R1 AgBF4 R1 R2 N 51 Cu(OAc)2 DCE, 100 °C N BF4 203 33-89%
Scheme 54. Li’s RhIII-catalysed oxidative annulation
Later in the same year, Miura (whose previous work is referenced herein124) published work similar to that reported in this thesis.139 The group was able to perform the double C–H activation via rollover to perform the insertion of an alkyne into an N-pyridyl-protected indole (Scheme 55). Also using the
[RhCp*Cl2]2 catalyst, in this example AgOAc was used as the oxidant and chlorobenzene as the solvent. As with the research contained in this report, the reaction appeared to be difficult to promote, requiring high temperatures and specific substrates. Most variation on the substrate appears in remote locations
(e.g. on the indole C7 position) where it will not affect the reactivity of the substrate.
70
H R1 N N [RhCp*Cl2]2 H N AgOAc N R2 PhCl, 140 °C N2 204 205 R1 R2 61-95% 51
Scheme 55. Miura’s RhIII-catalysed dehydrogenative coupling via rollover
cyclometallation
The choice of solvent appeared to be a key factor in this reaction: chlorinated solvents (eg. PhCl) provide the desired products in good yields, whereas the use of o-xylene resulted in much lower yields. The use of 1,2-dichloroethane or
1,1,2,2-tetrachloroethane gave the hydroarylated product almost quantitatively.
In addition, the oxidant used affected the product given in the reaction:
Cu(OAc)2∙H2O resulted in low yields with poor selectivity for the product, whereas AgOAc supressed the formation of the hydroarylated product almost completely. The reaction did not occur when N-phenylindole was used, and as such the group suggested a rollover cyclorhodation mechanism, involving the pyridyl group as a directing group. The group found that the annulated products showed solid-state fluorescence- this was also seen in the products synthesised during the research of this thesis.
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1.4. Conclusion
In this research a number of different methods for C–C coupling were investigated which were largely ineffective for the desired transformation. These include alkyne insertion and annulation, and hydroarylation followed by oxidative coupling. The substrates were unreactive towards palladium-catalysed
C–H activation with no alkyne insertion products produced. The first bond forming reaction was found to be possible using cobalt catalysis, leading to hydroarylation. The second bond forming reaction could not be performed in situ or from the isolated hydroarylated product using oxidative coupling.
The desired transformation was indeed achieved using rhodium catalysis in low to moderate yields. The reaction was optimised and several examples were synthesised. It is important to allow for the analysis of the two bond forming reactions. Finally, ruthenium catalysis was investigated. The desired product was not isolated using these conditions.
The difficulties in the project arose from the reactivity of the compounds toward certain metal catalysts and the challenge of attempting two bond forming events in the same reaction. It was found that both cobalt and ruthenium catalysis were suitable for the initial bond forming reaction step but formed only the hydroarylated product. Rhodium catalysis was more suitable for the two bond formations however only gave moderate yields. Recently, Miura has published work similar to this, using rhodium catalysis and an AgOAc oxidant. Further work into this project could comprise of investigation into the area of ruthenium- catalysed C–H functionalisation.
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2. A one-pot zipper-click reaction
2.1. Introduction
2.1.1. Migration of unsaturation
The ability to migrate functionality within a molecule is a valuable tool.
Sigmatropic shifts in particular comprise some of the most famous and well used named reactions in chemistry:140 the Cope141 and Claisen142 rearrangements, and the Fischer indole synthesis,143,144 to name but a few (Scheme 56). Sigmatropic shifts occur when a σ-bond is changed to another σ-bond in an intramolecular process.145 The reaction can be promoted by heat, Lewis acids (LA), or acidic or basic conditions;140,145 recent examples often employ other methods of catalysis such as transition metal chemistry.146,147
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Fischer Indole Synthesis, 1883 R1 R2 R4 R1 R2 1 2 N O R R N R3 206 H acid cat. 209 3 3 R NH2 N R N N -H2O R2 R1 R4 R4 R4 N N R3 207 208 H 210 R1 R2 1) [3,3] R2 R1 R4 R4 2) -NH2H N N R3 R3 211 212
Claisen, 1912 heat O heat OH O O or LA or LA [3,3] [3,3] 213 214 215 216
Cope, 1940 (Z) heat R1 heat R1 [3,3] R2 [3,3] (E) R2 217 218 219 220
Scheme 56. Examples of migration of unsaturation via sigmatropic shifts in
classical organic chemistry
Migration of a double bond along an alkyl chain can occur when a metal catalyst is used. Most of these methods migrate the double bond a single position along the chain; less common is the long-range migration.148 Examples of an allyl to propenyl isomerisation have been reported as an unwanted side product during
Grubbs metathesis (Scheme 57).149 Hanessian et al. expanded this observation in
74 a report in 2006, in which they used thermally modified Grubbs II catalyst 222 to isomerise allyl groups to propenyl groups in a diverse array of compounds, in good to excellent yields.150 The group reported low levels of dimerised or cross- metathesised side products.
Mes N N Mes Cl Ph Ru Cl PCy3 222 R R 221 MeOH, 60 °C 223 75-95% (mostly E)
Scheme 57. Alkene isomerisation using a thermally modified Grubbs II catalyst
In 2007 Grotjahn reported an alkene zipper reaction (Scheme 58).151 Where previous research into the long range migration of alkenes had depended on stoichiometric amounts of metal (for example, use of the Schwartz reagent,152–154 discussed later in this chapter), this was the first example to perform the reaction catalytically. It also holds the apparent record for the longest double bond movement. Grotjahn also discussed a possible mechanism for the reaction
(Scheme 59), but as ruthenium catalysis is often used for both alkene hydrogenation155 and oxidation of alcohols,156 more evidence is required to support this hypothesis.
75
OH [Ru] cat. O PF6 Cp R R [Ru] n acetone-d6 n P CH3CN 224 225 N n = 2-28 N R = H or Me 61-97% 226
[Ru] cat. OTBS OTBS acetone-d6 227 228 90%
Scheme 58. An alkene zipper reaction
P P P [Ru] Cat. N N N [Ru] [Ru] H [Ru] H H H H R H R R R 221 229 230 231
R P P N N R 232 E-alkene [Ru] H [Ru] R H R 235 H H Z-alkene 233 234
Scheme 59. Grotjahn’s proposed zipper mechanism
There have also been a few examples of the positional isomerisation of a triple bond, one position along an alkyl chain. The isomerisation of internal alkynes can be effected using basic conditions in moderate to good yields (Scheme 60).157
For simple branched alkynes, the rearrangement can occur using sodium amide in ethylenediamine, whereas in the case of alkynoic acids the sodium amide
76 must be used in liquid ammonia (Scheme 60, (1) and (2)).158,159 In this example, there were also side-products produced, including isomers and dimerisation products. –Acetylenic acetals can be rearranged to their β-derivatives using tBuOK;α this can be accompanied by loss of an alcohol molecule to furnish the alkoxyenyne.160
NaNH2 R 2 R 3 R R (1) 2 ethylenediamine
236 237a R = sBu 56%
237b R = CHMePr 31%
NaNH /NH R 2 3 CO H 2 (2) CO2H or 10% aq. KOH R
238 = 239a R Me 70-90% = 239b R Et 85% 239c R = Pr 27%
t R BuOK OEt OEt (3) R OEt OEt DMSO 240 241 R = Me, Et, Pr 50-70%
Scheme 60. Base-catalysed isomerisation of internal alkynes
Basic conditions can also be used to isomerise an alkyne to the terminal position of a molecule. An example from Mulvaney et al. in 1967 detailed the use of BuLi for the transformation (Scheme 61, (1)).161 The authors suggested that the mechanism requires the lithiation of all possible sites around the alkyne; upon treatment with 6 equivalents of nBuLi and subsequent quench with deuterium oxide, the rearranged compound (3-phenylpropyne) containing no aliphatic protons was isolated. The isomerisation of enynamines produced propargylic
77 amines such as 245 in good yields upon treatment with potassium amide in liquid ammonia (Scheme 61, (2)), with an E/Z ratio of ~96:4.162
n 1) BuLi (1) 2) H2O 243 242 61%
KNH2/NH3 NMe (2) NMe2 2 245 244 80%
Scheme 61. Base-catalysed isomerisation of alkynes to the terminal position
There is also evidence for acid-catalysed alkyne migration: the use of both mineral acids163,164 and solid phase acids (silica gel, alumina and zeolites)165,166 are seen in the literature (Scheme 62). Yields and rates of reaction are much higher when the solid phase acids are used, but the method consistently produces complex mixtures of isomers which are difficult to work with. Metallotropic shift has also been discussed as a method of alkyne isomerisation (Scheme 63); examples of possible metals that would produce the necessary carbene include rhodium and ruthenium.167–169
H+ •
246 247 248
249 250
Scheme 62. Acid-catalysed alkyne isomerisation
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R2 [1,3] R1 (1) R1 R2 251 252
2 1 R [1,3] R R1 R2 (2) MLn LnM 253 254
Scheme 63. An example of metallotropic shift for alkyne isomerisation (M = Rh,
Ru)170
While interesting, these methods are rare and poorly developed; often there are multiple by-products generated in the reaction, making it a challenging transformation to optimise. An equally underdeveloped, but nonetheless powerful, addition to this toolbox of reactions is the acetylene zipper reaction.
2.1.2. The acetylene zipper reaction
The isomerisation of acetylenic hydrocarbons under alkaline conditions was initially discovered by Favorskii in 1888.171 This was clarified and discussed in the 1950s,158 but it wasn’t until the 1970s that further research in this area was carried out, with initial results reported by Wotiz and co-workers.157,172,173 Much of the early work in this area led to mixtures of isomers, and in the work of
Wotiz a significant build-up of the terminal isomer: this exemplified the use of the reaction, but ultimately made the reaction impractical in synthetic situations.
The acetylene zipper reaction as used in this chapter was first reported by Brown in 1974.174 In this paper a method using potassium 3-aminopropylamide (KAPA) to isomerise an internal alkyne to a terminal alkyne was disclosed. KAPA is 79 formed from the reaction between potassium hydride and 1,3-diaminopropane
(1,3-DAP), and promotes the reaction in several reversible steps by deprotonation of the alkyne to form the allene (Scheme 64).175
H R H R H R N N N H H H H R R C H R H H
K K K
NH2 NH NH2 NH NH2 NH
I II III
H R N H H R R C R H K H K 256 255 NH2 NH
IV
Scheme 64. Mechanism of the acetylene zipper reaction
The allene then rearranges and the alkyne bond is migrated to the terminal position, where the acetylide anion produced in the reaction is stabilised by the potassium counter ion. The stability of the potassium acetylide drives the reaction, as thermodynamically an internal alkyne would be more favourable.
Thus, Brown describes the reaction as contrathermodynamic. The rate of the reaction was also unprecedented; the number of proton transfers required for the reaction, especially in the case of the longer chain alkynes, would imply longer reaction times, yet the reaction was complete within minutes.
80
Brown reported further on this reaction in 1976,176 applying the technique to further examples, including those with heteroatoms in the molecule (Scheme 65).
In the same year, another group used the KAPA zipper method to perform the isomerisation of acetylenes.177 The isomerisation of alcohol-containing substrates was successful, but acids produced complicated mixtures of isomers, including the dienoic acids.
1. KAPA OH OH 2. H2O 258 257 >80% (NMR)
Scheme 65. Isomerisation of acetylenic alcohols using the KAPA zipper method
While there are examples of this reaction used and investigated over the decades, it remains an underused and overlooked part of chemistry. The reason for this is, presumably, the harsh conditions that the reaction requires. KAPA is often described as a superbase and is very reactive, thus it does not tolerate a wide array of functionality within substrates. Its use has primarily been in the early stages of the total synthesis of natural products containing long chains, such as macrocycles.178,179 In a number of these cases, the reaction was carried out successfully in the presence of an alcohol group on the substrate.178–181
The sodium variant of this reaction was reported by Abrams (née Macaulay) in
1980.182,183 Abrams had difficulty repeating many of the KAPA reactions described by Brown, mostly because of difficulty handling the reagents; this made it difficult to incorporate the zipper reaction into the synthesis of fatty acid derivatives. She described the use of sodium diaminopropane (NaAPA) as a
81 suitable alternative, achieving up to 81% yield of an alkynol (Table 18, entries 1 and 2). The transformation was also possible with the lithium amide (LiAPA)
(Table 18, entry 3).184 Abrams also reported a mixed alkali metal amide zipper method.185,186 Using first lithium diaminopropane, and then adding potassium tert-butoxide, Abrams was able to improve upon the lithium method in both rate of reaction and yield (Table 18, entries 4 and 5).
Table 18. Various alkali-metal mediated isomerisations of alkynes by Abrams
R conditions R n n+1
259 260
Starting Material Product Conditions Yield
1 2-decyne-1-ol 9-decyne-1-ol NaAPA, 50 °C 69%a
2 2-tetradecyne-1-ol 13-tetradecyne-1-ol NaAPA, 55 °C 81%
3 2-decyne-1-ol 9-decyne-1-ol LiAPA, 70 °C 51% LiAPA/tBuOK, 4 2-decyne-1-ol 9-decyne-1-ol 76% 70 °C LiAPA/tBuOK, 5 7-tetradecyne 13-tetradecyne 86% 70 °C amixture of isomers; terminal alkyne major product
Balova et al. have carried out much research in this field.187–192 In 2002 and 2003 the group reported the use of a lithium-based zipper reaction for the migration of two neighbouring alkynes to a terminal position, followed by a Sonogashira cross-coupling reaction (Scheme 66). This was followed by a full paper in 2005.
In this example, both alkynes moved in the same direction along the molecule, giving a single terminal alkyne. The reaction was promoted by lithium 2-
82 aminoethylamine (LAETA). The reaction mixture was then quenched and filtered to remove unwanted salts and by-products and the solvent reduced in vacuo. The product, in solution, was then used in a traditional Sonogashira cross- coupling reaction, to give the coupled aryldialkynes in good yields. This was not a one-pot reaction, however, since it was necessary to filter the product to separate it from the reaction by-products before use in the Sonogashira cross-coupling reaction.
LAETA 1) H Ar n THF, benzene hexane ArI
Pd(PPh3)2Cl2 n 2) H2O 2n+1 2n+1 PPh , Et N, 3 3 261a n = 2 262 CuI, DIPA 263 DMF 261b n = 3 72-95%
Scheme 66. Balova’s Li promoted zipper reaction
Balova has subsequently found an application of this work by using the products of the zipper-Sonogashira reaction in a Bergman-like electrophilic cyclisation reaction (Scheme 67).191 The zipper-Sonogashira reaction was used to synthesise ortho-functionalised (buta-1,3-diynyl)arenes 263. The triple bond was then
activated by using an external electrophile (such as I2), followed by an intramolecular nucleophilic attack of the ortho-heteroatom. The final proposed
step of the mechanism is an SN2 substitution reaction which leads to the elimination of a leaving group from the heterocycle (Scheme 68). The heterocyclic products 264 and 265 could then be elaborated further by reaction at the C3 position.
83
X R3 1) LAETA EDA/THF ArI 2 R1 R2 R3 H 2 2 2) H2O Pd(PPh3)2Cl2 261 262 CuI, DIPA DMF Y 263a
I I I E Y Y R3 R3 MeCN or X X Cl CH2Cl2 264 265 E = I2, ICl, IPyBF4 15-97% 38-59%
Scheme 67. Synthesis of heterocycles using ortho-functionalised
(buta-1,3-diynyl)arenes
R E Y EY R X X
265 267
E E E R + R X δ X H R H X Y - H δ Y 270 268 269
Scheme 68. The proposed mechanism for the electrophilic cyclisation
Nantz et al. showed that it is not necessary to start from an acetylene moiety to perform the zipper reaction; in 1996 the group reported the base-mediated isomerisation of allenes to terminal acetylenes (Scheme 69).193 The use of KAPA led to the desired alkynes in good yields, and the deuterium studies carried out
84 by the group corroborated earlier theories about the mechanism. It was also found that when an allene on a cyclohexyl ring was subject to the zipper reaction, the reaction could be stereogenically controlled by the choice of base: the secondary monoamide base potassium N-methylbutylamide (KMBA) yielded the equatorial alkyne product in good selectivity.
a) KAPA R H or KMBA R 1 • 1 + H (1) H O R2 H b) 3 R2 271 272
Me Me Me KMBA H • + (2) i H O i i Pr b) 3 PrH Pr
273 7 : 1 274 275 77%
Scheme 69. Isomerisation of an allene using KAPA or KMBA
Most work using the zipper reaction has seen its application in the synthesis of small molecules containing long carbon chains. An example of this is in the work of Reddy et al., who published several syntheses of the cladispolide family of natural products, along with other macrocyclic compounds in 2012-2013
(Figure 4).178–181
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OH OH OH
OH HO O OH O O O O O 276 277 278 Cladospolide A Cladospolide B iso-Cladospolide B
OH OH O OH OH O O OH O O OH O O 279 280 281 Cladospolide C Cladospolide D (+)-Aspicilin
Figure 4. Macrocycles (or derivatives) synthesised by Reddy
To synthesise these macrocycles, Reddy often employed a Yamaguchi macrolactonisation as the final key step. The acetylene zipper is used much earlier in the synthesis to furnish the required long chain precursors. In each of the syntheses shown below (Scheme 70) an epoxide ring opening with a terminal alkyne was followed by a KH mediated zipper reaction to form an alkynol. The alkyne was subsequently reacted with different reaction partners, to give the desired precursor. In example (1), the terminal alkyne was reacted with formaldehyde using nBuLi, to give the propargylic alcohol. Example (2) showed the conversion of the alkyne to the vinyl boronic acid via hydroboration with dibromoborane-dimethyl sulphide. The final example, (3), showed the use of a
Sonogashira cross-coupling reaction to couple the alkyne with a vinyl iodide to give 289. These examples all demonstrated use of the zipper reaction early in a synthesis; there were no substrates used that contained complex functionality.
Again, the harsh conditions prevented the zipper reaction from being used in
86 combination with preceding or subsequent steps, although the desired products were isolated in good yields.
nBuLi, THF a) HCHO, 78% OH b) OH (1) n+2 286 OH BHBr ·SMe OH OH O a) 2 2 n n 1) , BuLi n+2 B (2) 260 b) H2O–Et2O (1:3) OH 282 n+2 HMPA/THF, 84-86% 284 51% or or 287 KH, O 2) 1,3-DAP OH 81%
283 n+2 285
OTBS BnO I 288 CuI, Pd(PPh3)2Cl2 Et3N, 84%
OTBS BnO OH (3)
n+2 289
Scheme 70. Examples of the use of the zipper reaction in the synthesis of
macrocyclic precursors
Earlier work by Hoye provided an example of an acetylene zipper reaction in which the starting material contained an aromatic ring.194 In the synthesis of elenic acid (Scheme 71), the group prepared their internal alkyne using a
Sonogashira cross-coupling. KAPA produced by reacting lithium wire with 1,3- diaminopropane, followed by the addition of potassium tert-butoxide, was then used to effect the desired zipper reaction, although at higher temperatures (65 87
°C) and for a longer period of time than previously reported. The yield was also much lower than for simple alkyne substrates, reported at 41%. The lower yield, despite more forcing conditions, may have been a result of the conjugation of the triple bond into the phenyl ring.
I Pd(PPh3)4 KAPA HO CuI 16 1,3-DAP 290 iPr NH 2 HO 41% 88% 292 16 291
1) AlMe3, Cp2ZrCl2 H 2) MeLi 2 3) CO2R 17 17 1 H R1O TfO CO2Me R O 295 1 1 2 293 R = H 4) NaHCO3 296 R = TBDPS, R = Me 91% over 4 steps 1 1 2 294 R = TBDPS 297 R = R = H
Scheme 71. Synthesis of elenic acid
A sodium-zipper method was employed by Aldrich in 2012 to afford a terminal alkynol.195 3-Octyne-1-ol was subjected to the conditions shown below (Scheme
72), the alcohol protected, and used to synthesise mechanism-based inhibitors of an aminotransferase used in the synthesis of biotin. As in many examples, the zipper step is very early in the synthesis and the terminal alkyne reacted with formaldehyde to give an alcohol which was used for further functionalisation of the molecule. In this case unsaturation was required internally in the molecule.
88
n a) BuLi 1) (NH2CH2)2, NaH 0 °C to 65 °C, 72% THF, -78 C OTBS OH 4 2) TBSCl, Imid., THF b) (CH2O)n 298 95% 299 -78 °C to 25 °C 85%
OH
OTBS HO 4 4
300 NH2
301
Scheme 72. The use of acetylene zipper reaction in the synthesis of based
inhibitors of an aminotransferase
Using the KAPA method, Toyooka and Tezuka reported in 2014 the synthesis of long-chain fatty acids from a propargyl alcohol (Scheme 73).196 A bromoalkane is reacted with the propargyl alcohol, which is then subjected to the KAPA zipper conditions. This terminal alkyne is then reacted with another bromoalkane and reduced to the cis-double bond using a Lindlar hydrogenation. Following a Jones oxidation, these fatty acids were then used to screen for activity against
Alzheimer’s disease.
89
HO Br n 1) , NaH 1) 8 , BuLi 303 305 Br HMPA/THF, 87% HO HMPA/THF, 62% 8 9 2) KH, APA, 95% 2) Lindlar Hydrogenation 302 304
Jones oxidation HO2C 9 9 45% in 2 steps HO 307 10 9 1. H2, 10% Pd/C, EtOAc 2. Jones oxidation HO C 306 2 20 43% in 3 steps 308
Scheme 73. Synthesis of fatty acids using the acetylene zipper reaction
The zipper reaction is a powerful and simple, yet underused bond migration. In this research we plan to exploit the utility of this reaction by exploiting the terminal acetylide ion or acetylene produced in the reaction by combining it in one-pot with another reaction. As discussed above, the reaction takes place under harsh conditions, limiting the substrates that can be used in the reaction, and the potentially affecting the type of reaction it can be combined with. Thus, the second reaction must be robust.
2.1.3. Azide-alkyne cycloadditions: click reactions
In 1961, in a lecture given before the Society at the Royal Institution in London,
Rolf Huisgen described the 1,3-dipolar cycloaddition of an alkyne and an azide
(Scheme 74).197 This was not the first report of this reaction, but he summarised the importance and simplicity of the transformation, and went on to carry out much research in the area. The Hüisgen 1,3-dipolar cycloaddition was the
90 favoured method for the synthesis of 1,2,3-triazoles for many years; it is simple, efficient, and atom economic. The starting materials are relatively easy to make, and generally stable to biological and organic conditions: this lends the chemistry to biomolecular chemistry and bioconjugation.
N R2 N N R2 N >100 °C N N N N R1 N 2 R R1 R1 309 310 311 312
~1:1 mixture of isomers
Scheme 74. Huisgen 1,3-dipolar cycloaddition of an alkyne and azide
The method does have drawbacks, however. The reaction must be carried out at high temperatures (>100 °C) for extended reaction times, limiting the substrate scope, and is not regioselective: both 1,4- and 1,5-substituted products are formed as a mixture. The isomers are often difficult to separate,198 and separation leads to a maximum 50% yield if a single isomer is required. The selectivity of the reaction can be tuned, to an extent, through the use of highly electron deficient terminal alkynes,199 although this does not broaden the scope significantly.
This work was described in a 2003 review by Barry Sharpless as the “premiere example of a click reaction.”200 Sharpless coined and defined the term click chemistry, and has had a prolific career in this field. Click chemistry, as defined in the 2001, must fulfil specific criteria: it must be modular, wide in scope, and high yielding, amongst other requirements.201 With no by-products and clean, selective reactivity for the triazole, 1,3-dipolar cycloadditions were obvious examples of this idea. In fact, the reaction has become almost synonymous with
91 the term click chemistry. However, until the work of Sharpless,202 and concurrently Meldal,203 who pioneered the use of CuI catalysis for alkyne-azide cycloadditions (CuAAC), the field was underdeveloped, and the reaction rarely used. Sharpless ascribes this to an “irrational fear” of working with azides which can be both toxic and explosive (especially at the high temperatures need for the reaction), although they had been shown to be stable to certain conditions.
Addition of the copper catalyst not only increases the rate of the reaction by several orders of magnitude,199 but also gives access to a single regioisomer of the triazole, and is thus an extremely powerful addition to the organic chemists’ toolkit; it solves many of the problems associated with early examples of click chemistry. In the first example, by Meldal,203 a solid-supported peptide containing a terminal alkyne was used in the regioselective synthesis of the
1,4-substituted-1,2,3-triazole (Scheme 75). The method employed 1 mol% CuI at
25 °C, and was not solvent specific.
N N N N N R peptide N CuI (1-5 mol%) R 310 314 examples DIPEA 33 Cu peptide 75-99% purity >95% conversion 313
Scheme 75. Meldal’s 1,2,3-triazole synthesis203
It was necessary to immobilise the alkyne in this way to avoid the Glaser-type homocoupling of the alkyne, as is often seen in copper-mediated reactions involving terminal alkynes. The azide substrate scope was much broader, including primary, secondary, tertiary, aryl and even sugar-bound azides. 92
Electron deficient alkynes were found to be more reactive under the conditions, in accordance with literature in cycloaddition chemistry. It was suggested that the mechanism is step-wise, however Meldal did not discuss the mechanism in detail until his review in 2008.199 The reaction was presumed to proceed via a copper acetylide, based on literature knowledge that this species can be formed under basic conditions.204 The work demonstrated an early example of CuAAC in bioconjugation, one of the method’s most popular advantages.
The first example from Sharpless, published just after Meldal’s in 2002, described another regioselective synthesis of 1,4-disubstituted-1,2,3-triazoles, but using copper sulfate pentahydrate as a catalyst (Scheme 76).202 This is a CuII source, which was reduced in situ to the catalytically active CuI by sodium ascorbate
(NaAsc). This method, like Meldal’s, avoided the unwanted Glaser side reaction, maximising yields and reducing by-products. The use of CuII salts is also advantageous as they are a cheaper alternative to CuI salts, which work well in the reaction, but are more expensive and can degrade rapidly in light and air.
N N · N N N CuSO 5H O, 1 mol% N 4 2 mol% 315 sodium ascorbate, 5 O
t O H2O/ BuOH (2:1) RT, 8 h 317 91% 316
Scheme 76. Sharpless’ initial 1,2,3-triazole synthesis202
The reaction is incredibly robust, and tolerates a wide range of solvents; it can even be carried out in or on water, without an organic co-solvent. The reaction is insensitive to pH, and tolerates an extensive range of functionality. Sharpless 93 discussed possible mechanistic pathways, agreeing with Meldal by proposing a step-wise mechanism: a concerted mechanism was disfavoured according to
DFT calculations.199,205
The mechanism for this reaction has been the subject of much dispute and many revisions since it was first reported.199 The mechanism suggested by Sharpless is shown below in Scheme 77. It involves an initial insertion of copper at the terminal alkyne, followed by formation of a six-membered intermediate, after ligation of the azide (favouring the step-wise pathway). Further research has suggested the existence of polynuclear pathways; Straub and co-workers reported the isolation of a CuI triazolide first in 2007,206,207 then again in 2015.208 Also in
2015, Bertrand reported the isolation of bis(copper) intermediates from the
CuAAC reaction, as well as including direct kinetic investigations of the reaction to explain the pathway (Figure 5, Scheme 78).209
R1 CuL n R1
1 N N 2 R • N R N N 2 CuLn N R 318 N N 312 N R2 320
DIRECT [LnCu]
1 R CuLn
N R2 N N R1 H 319 309 1 STEP-WISE R CuLn N 309b N N R2 310
Scheme 77. Sharpless’ initial proposed CuAAC mechanism202,205 94
TfO TfO LCu N LCu N N CuL LCu LCu TfO LCu 311 322 323
Figure 5. Bimetallic complexes isolated by Bertrand.209
The revised mechanism suggests that the reaction proceeds via the bimolecular intermediates shown in Scheme 78. The reaction proceeds rapidly in the presence of the bimetallic acetylide complex 326, which supports the pathway shown on the right being the dominant reaction mechanism. The authors stress that both pathways are probably active in the CuAAC reaction. The reaction is limited to the use of terminal alkynes as the copper acetylide must be formed for the reaction mechanism described to go ahead; the reaction is also specific to the synthesis of 1,4-disubstituted-1,2,3-triazoles.
95
LCuX R1 H 309
N 2 N N R -HX 2 R N3 LCu X 310 R1 H LCuX R1 CuL 312 R1 CuL 324 326
R1 H SLOW FAST X 309 N R2 N 2 N N N 2 N N R LCu N N R R1 H 1 1 R CuL 312 R CuL 325 R1 H 327 309
Scheme 78. Bertrand’s revised mechanism209
This reaction has subsequently been widely used across organic and bioorganic chemistry.199 It is a very selective transformation, and is thus amenable to use in multicomponent and one-pot reactions.210 A simple example involves the formation of the azide in situ from an alkyl or aryl halide and sodium azide followed by the CuAAC reaction, a method put to use by several groups
(Scheme 79).211–215 The reaction of sodium azide with alkynes is relatively slow in comparison to the organic azide produced, and as such high yields of the desired product can be isolated. In situ formation of the azide is the most common one- pot reaction incorporating the CuAAC reaction.210
96
X = Br R1 N R2 NaN , DMSO 1) 3 N N 2) CuSO4, NaAsc 312 H2O, alkyne 56-97% R1 X = I, Br
NaN3, alkyne, CuI, N R2 diamine ligand, NaAsc, N N DMSO/H2O 5:1 328 R X 38-98% R1 R= alkyl/aryl X = NH2
t 1) BuONO, TMSN3, N R2 CH CN 3 N N 2) aq. CuSO4, NaAsc, 328 alkyne 79-88% R1 X = B(OH)2
1) CuSO4, NaN3 N R2 MeOH N 2) alkyne N 328 63-96%
Scheme 79. Examples of one-pot CuAAC reactions initiated by azide
generation211–215
Less common is the practice of generating the alkyne moiety in situ.210 Examples of this include aliphatic substitution and the Sonogashira cross-coupling. In the synthesis of the bioactive triazol-4-yl-methanamine 331, a three component sequence involving the reaction of an amine, a propargyl bromide, and an arylazide in the presence of CuI in water at room temperature gave the desired products in high yields and purity (Scheme 80, (1)).216
Another example is the chemoenzymatic three component reaction to form 334, using the enzyme Candida antarctica lipase B (CAL-B, Novozyme ® 435) to effect
97 the aminolysis of an ester substrate to furnish the propargylic amide.217 This goes on to form amide-ligated 1,2,3-triazoles via CuAAC in moderate to good yields.
With respect to the Sonogashira coupling, an example is shown below in
Scheme 80 (3).218 Coupling of aryl halides with a TMS acetylene is followed by fluoride-mediated desilylation, CuAAC is then performed in the same pot to afford the desired 1,4-disubstituted-1,2,3-triazoles in moderate to excellent yield.
H N R1 R2 N 329 R1 N N CuI (10 mol%), NEt3 N R3 R3 N R 3 2 310 H2O, RT, 7-24 h aerobic atmosphere 331 X 20 examples, 70-98% 330 X = Br, I
O Novozyme 435 N N R1 OMe TBME, 45 °C, 4-24 h H R1 N N 332 R2 then: R CH N NH2 2 2 3 O Cu2O (4 mol%) 334 PhCO2H (8 mol%) MeOH/H O 4-24 h 14 examples, 51-85% 333 2 (1:1),
Pd(PPh3)4 (5 mol%), CuI (10 mol%) N 1 MeOH, iPr) NEt N R N3 ( 2 N R2 120 °C (MW), 20 min 310 R1 TMS 312 335 then: R2N3, TBAF 11 examples, 53-99% CuI (10 mol%) or CuF2 (200 mol%) 120 °C (MW), 20 min
Scheme 80. Examples of one-pot CuAAC reactions initiated by alkyne
generation216–218
98
A particularly elegant example is the multicomponent reaction for the synthesis of polysubstituted triazoles, combing the Wittig, Knoevenagel, Diels-Alder and
CuAAC reactions, reported in 2004 by Barbas (Scheme 81).219 In the reaction, a domino Wittig/Knoevenagel/Diels-Alder reaction is performed to produce a dispiro[5.2.5.2]hexadecane, with two identical terminal alkyne moieties. Upon
addition of benzyl azide, CuSO3 and Cu wire, the expected spirotrione-1,2,3-triazole 339 was isolated in up to 94% yield. The entire process involves the formation of four C–C σ bonds and four C–N σ bonds in one-pot.
O N R O N N O Ph Ph P Ph O O L-Proline (20 mol%) 336 CHO EtOH (0.5 M) 65 °C, 3-12 h 337 O then: RN CuSO Cu O O 3, 4, RT 15-48 h O N N N R CHO O 338 337 339 6 examples, 80-94%
Scheme 81. A Wittig/Knoevenagel/Diels-Alder/cycloaddition one-pot
reaction219
The regioselectivity of the CuAAC reaction is mechanistically restricted to
1,4-disubstituted-1,2,3-triazoles using terminal alkynes, and thus other methods of azide-alkyne cycloaddition must be used in order to access different triazoles.
A popular method for the synthesis of 1,5-disubstituted-1,2,3-triazoles utilises Ru
220–223 catalysis, most often using a RuCp*Cl(PPh3)2 catalyst (Scheme 82). This method is discussed later in this chapter. Other methods that have been
99 successfully employed to form the 1,5-regioisomer include the use of magnesium acetylides,224 iridium,225 samarium,226 and without any metal catalyst.227 Within the Greaney group, research has been reported into the zinc mediated synthesis of 1,5-disubstituted-1,2,3-triazoles (Scheme 83) for the potential treatment of
Sleeping Sickness (African Trypanosomiasis).228
1 N R N3 N 1 mol%) N R 310 Cp*RuCl(PPh3)2 (1 H R2 H toluene or dioxane, 80 °C R2 309 311
Scheme 82. Ru-catalysed azide-alkyne cycloaddition
N N 1 aq. NH4Cl N R H N 2 R1 N N R 3 ZnEt2 (1.5 equiv.) N R1 310 NMI (10 mol%) 311 XZn 49-76% R2 H R2 THF, RT, 18 h 309 340 N N E+ N R1 E R2 341 52-76%
Scheme 83. Previous work in the Greaney group: Zn-mediated synthesis of 1,5-
and 1,4,5-substituted-1,2,3-triazoles
In this research, it is proposed that we can combine the zipper reaction with a further reaction at the produced terminal alkyne; it is pertinent that the further reaction be compatible with the conditions of the acetylene zipper. Hence, reactions that fall under the umbrella term of click reactions (and particularly the
CuAAC) are ideal: simple, robust, and high yielding.
100
2.1.4. This work
The zipper and CuAAC “click” reactions are two powerful and important transformations. Click reactions have been studied intensely since the term was coined in 2001, and long before that in examples such as 1,3-dipolar cycloadditions. The zipper reaction has been paid much less attention, with most modern examples using the reaction in the synthesis of natural products or macrocycles, without investigating further into the reaction itself. There is much scope for research into the zipper reaction, both in the use of the acetylide salt for further reaction, and to improve and investigate the transformation itself, which is underrepresented in the literature.
We proposed that by using Brown’s KAPA reagent followed by standard
CuAAC conditions we could combine these reactions to promote the fast and facile synthesis of 1,4-disubstituted-1,2,3-triazoles in a one-pot procedure
(Scheme 84). In addition, we planned to see if we could combine the zipper reaction with other reactions involving an alkyne moiety, for example the reaction with a carbonyl group, or the Sonogashira cross-coupling reaction.
· R KH CuSO4 5H2O 1,3-diaminopropane R Na ascorbate n+1 R H n n+1 N RT, N2 Ar-N3 N 342 343 Ar N 344
Scheme 84. Proposed one-pot zipper-click reaction
101
2.1. Results and discussion
2.1.1. One-pot zipper-click reaction
The research was begun by repeating the literature reaction described by
Brown.174 The KAPA must be prepared first; alkyne is then added to this mixture. To prepare KAPA, KH in mineral oil was washed with hexane or pentane and dried under a flow of nitrogen. To this was added 1,3- diaminopropane in excess, which also acts as the solvent. This provides KAPA as an approximate 1.2 M solution in 1,3-DAP. Aliphatic symmetrical alkynes were tolerated well in the reaction (Table 19, entries 1 and 2), giving high yields and few side products (internal isomers, polymeric side products etc.). The reaction, as expected, was less tolerant of other functionality within the substrates, and degradation or possible polymerisation was a common outcome.
It was decided that the aliphatic alkynes would be taken forward to use in the combined zipper-click procedure.
102
Table 19. Attempted acetylene migration of internal alkynes
KH (30% in mineral oil, 1.4 equiv.) 1,3-diaminopropane R R n H n+1 RT, N2 1-16 h 342 a-f 343 a-f
# R n Yield (%)
1 343a C3H7 2 76
2 343b C4H9 3 83
3 343c CH2OH 4 0
4 343d CHO 4 0
5 343e CO2Et 1 0
6 343f CH2Ph 0 0
Using literature conditions, a CuAAC reaction was performed using hex-1-yne
202 and 4-azidobenzonitrile (Scheme 85). Mediated with CuSO4∙5H2O and Na ascorbate, the reaction proceeded smoothly to afford the 1,4-disubstituted 1,2,3- triazole product in a high yield (92%).
· CuSO4 5H2O (2 mol%) H Na ascorbate (10 mol%) N N N 343g NC N3 (1 equiv.)
344 NC t 345a H2O: BuOH (2:1) 92% RT, 5h
Scheme 85. CuAAC reaction of hex-1-yne and 4-azidobenzonitrile
103
The product of the zipper reaction, before it is quenched, is a potassium acetylide. It was proposed that cycloaddition could proceed on this reactive intermediate without the aid of additional transition metal catalyst (Scheme 86).
Unfortunately upon addition to the unquenched KAPA solution the azide immediately degraded. This suggested that the azide was incompatible with the strong base present in the reaction mixture, and therefore that the KAPA must be quenched before the click reaction can take place.
Concurrently, an experiment to see if the copper-catalysed cycloaddition was compatible with the unquenched KAPA solution was performed (Scheme 86).
This would simplify the methodology since the reagents could all be charged at the start of the experiment. As discussed above, the azide reacted immediately with the KAPA to give the aniline.
KH (30% in mineral oil, 1.4 equiv.) 1,3-diaminopropane · CuSO4 5H2O (2 mol%) Na ascorbate (10 mol%)
NH2
NC N3 (1 equiv.) NC 344 t 346 H2O: BuOH (2:1) RT, 5 h C8H17 H 343b 342b KH (30% in mineral oil, 1.4 equiv.) other degradation 1,3-diaminopropane, RT, 5h products not determined
NC N3 (1 equiv.)
344
Scheme 86. Attempted one-pot zipper-cycloaddition reactions
104
The sequential zipper-click reaction was then performed in a one-pot fashion, but including the quenching of the KAPA reagent after a long enough time that all the alkyne was likely to have completed the migration. KAPA is quenched with ice-water, and thanks to the extremely robust nature of the CuAAC reaction200,201 this would be compatible with the cycloaddition step it precedes. The reaction was then carried out using common copper “click” reaction conditions (Table
199 t 20). The reaction did not proceed in H2O: BuOH (2:1) or THF, affording only the re-isolated azide and the aniline degradation by-product. In TBME the
reaction was successful, albeit in low yield. Pleasingly in CH2Cl2 the reaction proceeded smoothly to give the product in 71% yield with few competing side products.
Table 20. Solvent screen for the combined zipper-click reaction
1) KH (30% in mineral oil, 1.4 equiv.) 1,3-diaminopropane, RT, 16 h 2) H2O quench C8H17 · 3) CuSO4 5H2O (2 mol%) N N Na ascorbate (10 mol%) N
NC N3 (1 equiv.) 342b NC 344 345b solvent, RT, 16 h
solvent Yield (%) H O:tBuOH 1 2 0 (2:1) 2 THF 0
3 TBME 32
4 CH2Cl2 71
a azide and aniline (degradation by-product) isolated 105
This reactivity may be explained by the water-immiscibility of the solvents in the successful reactions. It has been shown by Sharpless and others that CuAAC reactions often react better when they take place “on water”.229 On water reactions occur when reagents are not soluble in water, but instead react at the surface; some mechanistic studies suggest that interaction between the reagents and the water can increase the rate of the reaction, possibly by inducing
230,231 mechanisms which benefit from hydrogen-bonding. Both CH2Cl2 and
TBME are highly immiscible with water; as such the organic reagents are likely to remain in the organic phase to react with one another, with the catalyst in the aqueous phase to promote the reaction at the surface.
The scope of the reaction with respect to the azide was investigated (Scheme 87).
The reaction was tolerant of a number of different functionalities, including electron withdrawing and donating groups. Yields were higher for electron withdrawing groups on the aryl ring. Substituents with groups in the para- or ortho-positions also reacted well. Having a benzyl, rather than phenyl, group on the azide had a deleterious effect on the yield.
106
1) KH (30% in mineral oil, 1.4 equiv.) RT, 16 h 1,3-diaminopropane, 2n+1 2) H2O quench n n N · N 3) CuSO4 5H2O (2 mol%) N n = ascorbate 2 342a 2 Na (10 mol%) R 342b n = 3 R-N3 (1 equiv.) CH2Cl2 345 RT, 16 h
C8H17 C6H13 C6H13
N N N N N N N N N
NC I Cl 345b 345c 345d 71% 75% 61%
C6H13 C6H13 C6H13 N N N N N N N N N
Br EtO2C F
CN 345e 345f 345g 35% 15%* 63%
C6H13 C6H13
N N N N N N
OH
345h 345i 67% 66% a azides prepared by Dr. Christopher D. Smith, with the exception of 344; *detected in mixture with starting azide and aniline by product, inseparable.
Scheme 87. Substrate scope with respect to the azidea
107
The scope of the reaction with respect to the alkyne was examined. As mentioned previously, the KAPA promoted zipper reaction does not tolerate many functional groups. In accordance with this observation, using alkynes bearing alcohol, ester or aldehyde moieties resulted in none of the desired product or terminal alkyne being produced (Scheme 88). Sodium-mediated zipper reactions have been shown to be effective for acetylenic alcohols,182 and although these conditions were not attempted in conjunction with the CuAAC reaction this could be an avenue of research for extending the substrate scope of this reaction.
108
1) KH (30% in mineral oil, 1.4 equiv.) 1,3-diaminopropane, RT, 16 h R 2) H2O quench n+1 · 3) CuSO4 5H2O (2 mol%) R Na ascorbate (10 mol%) N n N N 343 NC N3 (1 equiv.) NC 344 346 CH2Cl2 RT, 16 h
O O HO H 5 O 5 2 N N N N N N N N N
NC NC NC 346a 346b 346b 0% 0% 0%
HO HO 4 4
N N N N N N
NC NC 346d 346e 0% 0%
Scheme 88. Attempted substrate scope with respect to the alkyne
In 2003, Balova disclosed a method of using Li to perform the zipper reaction on
1,3-diynes sequentially followed by a Sonogashira cross-coupling (Scheme 89).189
In this work Balova reports the use of lithium 2-aminoethylamide (LAETA) to effect the rearrangement of the internal diyne to the terminal position. In all cases, both alkyne groups moved to the same end of the chain. The products of the LAETA zipper were treated with water, to release the diyne from the salt,
109 followed by an aryl iodide, palladium(II) acetate, PPh3, triethylamine and CuI to accomplish the Sonogashira cross-coupling. The cross-coupling products were all isolated in good to excellent yields, although the homocoupling product was observed.
X Ar n LAETA ArI
0 Pd , Et3N, CuI n 2n+1 2n+1
n = = 263 261a 2 347 X Li 261b n = 3 262 X = H 72-95%
I I I
NH 2 O2N O
348a n = 2, 87% 349 n = 3, 72% 350 n = 3, 86% 348b n = 3, 95%
NH 2 I I H
O NO2
351a n = 2, 88% 352 n = 2, 77% 351b n = 3, 92%
Scheme 89. Balova’s LAETA mediated zipper-Sonogashira reaction
Symmetrical diynes can be prepared using a Glaser-Hay coupling reaction
(Scheme 90, 1).232 This method employs the use of copper(I) and oxygen to form the alkynyl radical, which then reacts with another to form the homocoupled product. An alternative to this is the Hay coupling, using the TMEDA complex of CuCl, which is more soluble and therefore can be more versatile.233 The
Eglinton reaction employs Cu(OAc)2 and pyridine to afford the homocoupled
110 product.234 Balova reported in a later paper that non-symmetrical alkynes such as those in Scheme 90 (2) can be synthesised using an alkynyl bromide through a modified Cadiot-Chodkiewicz method.235 This reaction, while also proceeding via a copper(I) acetylide, differs from the Glaser reaction in that it involves a cycle of oxidative addition and reductive elimination, rather than a radical mechanism. For use in this research, diyne dodeca-5,7-diyne was synthesised using a variation of the Glaser conditions.236 The acid derivative could not be isolated.
CuCl O2 2 R H 2 R Cu R R (1) NH OH NH OH 309 4 353 4 261 EtOH EtOH
CuCl R H R Br R R' (2) NEt 309 354 3 261
Scheme 90. The Glaser (1) and Cadiot-Chodkiewicz (2) couplings to form diynes
· Cu(OAc)2 H2O (10 mol%) n n n Bu Bu 2 Bu H piperidine (1 eq.) 261b 309a CH2Cl2, RT, 5 h 69%
Scheme 91. Synthesis of dodeca-5,7-diyne
Using these substrates and under the LAETA-mediated zipper conditions described by Balova, the rearrangement products were isolated in moderate yields. It is likely that the yields were lower than expected due to loss of product during purification resulting from high volatility. These compounds were
111 unstable, and decomposed to brown oils after time and in the presence of light.
They must be used immediately after purification and analysis.
Combining the LAETA zipper with the CuAAC method in the same fashion as above, several triazoles were successfully isolated in moderate to good yields
(Scheme 92). Both electron withdrawing and electron donating groups were tolerated well in the reactions, as well as para-, ortho-, and meta-substitution on the phenyl ring. Disubstituted aryl azides were also well tolerated.
112
Li 1) (3 equiv.) C8H17 ethylene diamine (3 equiv.) THF, hexane, toluene RT, 16 h 2) H2O quench N · N 3) CuSO4 5H2O (2 mol%) N ascorbate Na (10 mol%) R 261b R-N3 (1 equiv.) CH2Cl2 RT, 16 h 355
C8H17 C8H17 C8H17 C8H17
N N N N N N N N N N N N
NC MeO Cl EtO2C 355a 355b 355c 355d 40% 37% 84% 65% C H C8H17 C8H17 8 17 C8H17
N N N N N N N N N N N N
CO2Me Br O 355e 355f 355g 355h 66% 64% 35% 21% C8H17 C8H17
N Cl N N N N N
Cl
355i 355j 31% 77%
Scheme 92. Substrate scope of LAETA zipper-click reaction with respect to
azide
113
Overall, both the KAPA-zipper and LAETA-zipper were combined with a
CuAAC reaction in one-pot with few side reactions or by-products, often in good yields.
Although we were able to combine two different zipper methods with a copper- catalysed click reaction, these methods are harsh and employ difficult to handle alkali metals or their hydrides. The key to the zipper reaction is the stability of the terminal acetylide salt, so as the research moved forward, we decided an important goal would be to see if we could exploit other methods that could produce a stable acetylide using milder conditions.
2.1.2. Other one-pot zipper reactions
In an attempt to broaden the scope of this research, other ways to exploit the acetylide anion were investigated. The initial research was inspired by the
CuAAC click reaction, and as such it was though that a Ru-catalysed
1,5-disubstituted-1,2,3-triazole synthesis might be possible. As discussed in the introduction to this chapter, Ru-catalysed cycloadditions are generally performed
220–223,237 using RuCp*Cl(PPh3)2 as a catalyst. This method has been the most successful synthesis of 1,5-disubstituted-1,2,3-triazoles and was first disclosed in
2005 by Jia and Fokin, who used 1 mol% RuCp*Cl(PPh3)2 in dioxane or toluene at 80 °C to afford the triazoles in good yields (Scheme 93).220
114
N3 N N N mol%) 356 Cp*RuCl(PPh3)2 (1 R toluene or dioxane, 80 °C R
357 358 81-94%
Scheme 93. RuAAC reaction reported by Jia and Fokin220
The mechanism of this reaction is different to that of the copper-catalysed cycloaddition, which guides the orthogonal selectivity of the reaction (Scheme
94).222,223,237,238 Suggested first by Fokin,222 the mechanism underwent further studies by Nolan in 2012.238 The reaction proceeds via the ruthenium catalyst precursor 359, followed by alkyne π-coordination to the ruthenium centre.
Dissociation of a phosphine ligand, and ligation of the azide through an internal nitrogen leads to complex 362, which now has both reagents in place to undergo the cycloaddition. Nucleophilic attack by the terminal acetylene onto the terminal azide nitrogen, followed by C–N oxidative coupling gives the Ru- ligated triazole 365. The catalyst is regenerated by co-ordination of another acetylene molecule, and release of the triazole 311. The formation of the triazole is exothermic, and therefore likely drives the reaction; the reductive elimination is the rate limiting step. Since the acetylene moiety is ligated through π-co- ordination, rather than σ-coordination as seen in the copper mediated cycloaddition, the substrates used can not only be internal alkynes, but also unsymmetrical; regioselectivity has been reported.222,223,237
115
Cl Ru *Cp P(Ph)3 359
R1 H 309 R1 Cl Ru *Cp P(Ph)3 R1 360 N N N N N 2 2 N R R R1 311 310 Cl Ru R1 1 *Cp R1 R 361 Cl Ru N Cl N Ru N N R2 N N *Cp *Cp R2 366 362
1 R H R1 309 1 R Cl Cl N Ru Ru N N R2 N N *Cp N *Cp R2 365 R2 R1 363 Cl N Ru N N *Cp 364
Scheme 94. Nolan’s RuAAC mechanism238
It is known that the RuAAC reaction is more sensitive than the copper variant with respect to functional group tolerance and compatibility with reaction conditions,239 as several deactivation pathways are feasible that do not occur in the copper mediated variant (Scheme 95). For example, in the absence of alkyne, organic azides react with the ruthenium catalyst to form stable tetraazadiene
116 complexes. The reaction is also sensitive to atmospheric oxygen so must be run under an inert atmosphere.
R
R R 370
R 309 * Cp Cp* Cp* R RN3 R u R N R 310 Ru 309 Ru Cl Cl Cl N N N R R 367 368 369 " " O2
ox a ve ca a s ea id ti t ly t d th
Scheme 95. Potential deactivation pathways in the RuAAC239
As such it was not known if the conditions of the zipper, or indeed the quenched zipper reaction would be compatible with this cycloaddition. The zipper-click was attempted using common literature RuAAC conditions, and the results are shown in the table below (Table 21). Unfortunately the reaction was found to be incompatible with the zipper conditions; this may be due to oxygen present or the water added to the reaction mixture. However, if the reaction is not quenched the azide degrades.
117
Table 21. Attempted Zipper-RuAAC one-pot reactions
1) KH (30% in mineral oil, 1.4 equiv.) RT, 16 h 1,3-diaminopropane, C8H17 H O quench 2) 2 N N N 3) RuCp*Cl(PPh3)2 (2 mol%)
R N3 (1 equiv.) R
342a = 344 311a R CN solvent 311b R = I RT, 16 h
quench azide solvent Yield
1 H2O R = CN CH2Cl2 0
2 H2O R = CN 1,3-dioxane 0
3 H2O R = I CH2Cl2/TBME 0
a 4 none R = CN CH2Cl2 <10%
5 none R = CN 1,3-dioxane 0b
a 6 none R = I CH2Cl2/TBME <10% a Yield by NMR; mostly aniline (degradation product); bdegradation to aniline
Moving forward, research focussed on a simpler reaction system: nucleophilic attack by the acetylide onto a carbonyl group. By adding an aldehyde or ketone, it was hoped that the reaction with the potassium acetylide would furnish a propargylic alcohol in high yield and with few by-products, akin to the similar reactions known using sodium, lithium, copper and zinc reagents.240 The reaction of an acetylide ion as a nucleophile is well known, with examples of the enantioselective reaction as early as the 1970s.241
118
O O OH R3 R3 R2 R3 H+ R2 R2 372 R1 R1 R1 373 374 371
Scheme 96. General mechanism for the nucleophilic addition of an acetylide ion
to a carbonyl group
In this research a number of aldehydes and ketones were screened against the
KAPA-zipper reaction, with addition after at least an hour (Scheme 97). No desired product was isolated. Only degradation or undesired by-products were observed. This was most probably due to incompatibility of the reactants with the harsh conditions of this type of zipper reaction. At this point research was paused, although further investigation could be done into combining this idea with milder zipper conditions, or using the potassium acetylide as a nucleophile in other transformations, such as the reaction with alkyl halides.
119
1) KH (30% in mineral oil, 1.4 equiv.) 1,3-diaminopropane, RT, 16 h OH R1 C H C H 4 9 4 9 X R2 O 342a R1 2) , then H2O R1 R2 374 372
O O O O H H H H H
375 376 377 378 O O O
379 380 381
Scheme 97. Attempted nucleophilic addition of the intermediate acetylide anion
with aldehydes or ketones, with examples used
2.1.3. Alternative zipper conditions
Other conditions for the zipper reaction used in the literature generally still require the use of alkali metals or their hydrides. In order to make the reaction compatible with more functionality and other reaction conditions, new conditions for the migration are required. Alkynes can be transformed to allenes using CuH or ZrH synthons242 and can migrate alkenes from internal to terminal positions.153
Use of the CuH synthon in modern chemistry is reported to have begun with
Stryker’s reagent in 1988.243 In this paper, Stryker describes the use of a phosphine
244 stabilised hexamer [(PPh3)CuH]6 to perform conjugate reductions of carbonyls. The reaction quickly became popular due to the mild conditions, and
120 the high functional group compatibility; this CuH source was named Reagent of the Year in 1991.243 Alternatives to the phosphine hexamer have emerged in the last 20 years. The most popular employ the use of cheap and environmentally benign silanes as a hydride source, including polymethylhydrosiloxane (PMHS) and tetramethyldisiloxane (TMDS).
Stryker reported in 2000 the reduction of alkynes selectively to Z-alkenes via
245 hydrocupration (Scheme 98). Using [(PPh3)CuH]6, terminal alkynes were reduced at room temperature, and internal alkynes at higher temperatures. More recently, Deutsch and Krause reported246 the NHC-CuH-promoted reduction of propargyl carbonates to allenes. The ligand IBiox12 was used to afford the desired allenes in high yields, and the reaction was highly tolerant to functional groups in the substrates. In both of these cases, no further isomerisation was seen.
[(Ph3P)CuH]6 (0.5 equiv.) 1 2 H2O (5 equiv.) R R R1 R2 benzene, RT or 80 °C 51 54 42-96%
Scheme 98. Schwartz’s reduction of alkynes to alkenes
121
1) CuCl (3 mol%) · IBiox12 HOTf mol%) (3 H OCOMe t NaO Bu (9 mol%) 1 • R1 R H 2 PMHS equiv.) R (2 R2 382 toluene, RT, 14-40 h 383 2) NaHCO3 59-95% O O
N N
OTf
384 · IBiox12 HOTf
Scheme 99. NHC-CuH-catalysed propargylic carbonate SN2’-reduction
In the same year Ito and Sawamura reported a catalytic CuH reduction of internal propargylic carbonates to give various di- and tri-substituted allenes in good yields (Scheme 100).242 The work was a follow-up to a similar borylation reported by the same group,247 and was inspired by catalytic conditions for the
CuH reductions of carbonyls.243,246,248 There is little published in this area as the methods are usually stoichiometric.249 In this method, the CuH source used is
Cu(OAc)2 with a Xantphos ligand 387 and PMHS as the hydride source. The reaction is proposed to go via syn-addition of the CuH over the triple bond, followed by anti-elimination of the Cu and carbonyl group.
122
PPh PPh 2 2 mol%) OCO2Me Cu(OAc)2 (2 R1 R3 O Xantphos (3 mol%) R3 C R2 R2 H R3 PMHS (4 equiv.) 385 THF (0.5 M), 50 °C 386 387 Xantphos
Scheme 100. Ito and Sawamura’s allene synthesis
Hydrozirconation has been used as a method for functionalising alkene, alkynes
and dienes. The applications of Schwartz’s reagent, Cp2ZrHCl, in this field were developed in the mid 1970’s by Jeffery Schwartz.152–154 The complex was first isolated by Wailes and Weigold in 1970250, but it was Schwartz who brought to attention the use of the compound in organic synthesis. Once formed the organozirconium intermediates can react with a variety of electrophiles. Of
particular interest is the ability of Cp2ZrHCl to migrate an internal double bond to a terminal position (Scheme 101); an internally metallated alkylzirconium
153 complex rapidly isomerises via β-hydride elimination/reinsertion. Cp2ZrHCl will also react with an alkyne to afford a cis-substituted organozirconium complex (Scheme 102).152
389
Cp Zr Cp ZrCl 2 2 2 Cl 390 392
391
Scheme 101. Synthesis and rearrangement of alkylzirconium complexes
123
Cl Cl Cp Zr H Cp Zr H R1 R2 Cp2ZrClH 2 2 51 R1 R2 R2 R1 393 394
Scheme 102. Synthesis of vinylzirconium complexes
Thus, dec-5-yne was subjected to a series of conditions attempting to exploit the nature of the reactivity of CuH and ZrH reagents (Table 22). The source of CuH
used was Stryker’s reagent, as described above, using Cu(OAc)2, PPh3 and the stoichiometric hydride source PMHS. The source of ZrH used was Schwartz’s reagent, available commercially.
Table 22. Attempted alkyne migration using CuH or ZrH sources
[CuH] source additive
THF 343b 50 °C 342a
CuH source Additive Yield
1 [CuH(PPh3)] (1 equiv.) - 0
2 [CuH(PPh3)] (0.1 equiv.) - 0
3 [CuH(xantphos)] (0.1 equiv.) - 0
4 [CuH(PPh3)] (1 equiv.) I2 0
5 [CuH(PPh3)] (1 equiv.) 1,3-DAP 0
124
Cp2ZrClH (1.1 equiv.) X benzene, RT 343b 342a
Scheme 103. Attempted alkyne migration using Schwartz’s reagent
Using CuH promoted conditions known to produce the allene from the alkyne, the substrate was left overnight. No desired terminal alkyne was observed, and the starting material was re-isolated in good yield. The reaction also yielded a film, possibly polymeric material that may have been produced by the PMHS or the alkyne itself. In previous work a leaving group was necessary to afford the
allene (for example, a carbonate which releases CO2) and as such this might be an avenue for further research to see if after producing the allene, migration could be promoted.
2.1.4. Conclusions
To compendiate, in this research a one-pot reaction combining the acetylene zipper and a copper-catalysed click reaction has been reported. 1,4-Disubstituted
1,2,3-triazoles with long alkyl chains were isolated in moderate to good yields, with little purification needed. Two variants of the zipper reaction were used, applied to different substrates- potassium hydride-promoted conditions for the mono-alkyne substrate, and Li-mediated conditions for the diynes. The reaction was generally not tolerant of functionality in the zipper step, which is an area for further development. If milder conditions can be found, the scope of this reaction would be greatly extended.
125
Other reactions attempted in conjunction with the zipper were not successful, including the Ru-catalysed azide-alkyne cycloaddition and the reaction between the alkyne and a carbonyl. In the case of the RuAAC reaction, this may be due to the sensitivity of the reaction to water; it is much less robust than the CuAAC method to form 1,4-disubstituted triazoles.239 If the reaction could be carried out in such a way that did not necessitate the use of an aqueous quench, this reaction may be possible.
For the synthesis of the propargyl alcohol, the reaction was only attempted with the KAPA-conditions, which probably degraded the carbonyl-containing substrates or products if they were formed. Again, milder conditions would favour this transformation.
Research into a milder set of conditions for the zipper reactions was begun; however no positive results were gained, with no conversion to the terminal acetylene seen nor any other isomers of the alkynes. It may yet be possible for the reaction to be performed when mediated by transition metals. However research into this subject was inconclusive. Other avenues of interest include using a leaving group to promote the initial allene formation, which may then initiate the migration.
2.1.5. Future Work
Continuing the work set out in the latter part of this chapter into transition metal–mediated isomerisation of the triple bond would be feasible future work in this area. This could then be used to make useful substrates which could be used 126 in, for example, the synthesis of triazole-containing macrocycles.251,252 Milder conditions might also allow for the combination of other reactions with the zipper reaction, to exploit the acetylide salt or (upon quenching) the terminal alkyne. The unsuccessful reactions attempted within this chapter might then be possible. These reactions should be attempted using the LAETA or Na conditions initially to test for compatibility. In addition, using the acetylide ion as a nucleophile in other reactions would be a good line of research to expand the uses of the zipper reaction.
127
3. Experimental
3.1. General methods
IR spectra were recorded for neat thin films using Perkin-Elmer FT-IR Spectrum
RX1 or BX spectrometers. 1H, 19F and 13C NMR spectra were recorded on
Bruker Avance 400 or 500 instruments and calibrated to residual solvent peaks:
1 proton (CHCl3 7.26 ppm) and carbon (CHCl3 77.2 ppm). The H data is presented as follows: chemical shift (in ppm on the δ scale), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), the coupling constant
(J, in Hertz, Hz) and integration. The 13C data is recorded as ppm on the δ scale.
NMR spectra were assigned with the aid of 2-D correlation and DEPT-135 spectra where appropriate. Reactions were monitored by LC-MS on an Agilent
1200 series fitted with a 3.0 x 20 mm, C18, 3.0 µm column, and mass analysis performed by a single quadrupole Agilent 6100, with ESI ionisation. TLC was performed on Merck 60F254 silica plates and visualised by UV light (254 nm) and/or potassium permanganate stains.
Reactions were routinely carried out under nitrogen. Most reagents and solvents were used as supplied commercially, including anhydrous
N,N-dimethylacetamide (DMA; Sigma Aldrich 271012). Anhydrous THF was distilled from sodium/benzophenone ketyl immediately before use. Preparative column (flash) chromatography was carried out on 60H silica gel (Merck 9385) using the flash technique. Compositions of solvent mixtures are quoted as ratios of volume. 'Ether' refers to diethyl ether. 'Petrol' refers to a fraction of light
128 petroleum, b.p. 60-80 ˚C, unless indicated otherwise. Other than
4-azidobenzonitrile, all azides were prepared by Dr. Christopher Smith.
3.2. C–H activation for alkyne insertion
General Procedure A for the synthesis of N-substituted indoles
To the indole (20 mmol, 1 equiv.) was added K2CO3 (5.5 g, 40 mmol, 2 equiv.)
113 and Cu2O (2.86 g, 2 mmol, 0.1 equiv.). The flask was evacuated and back- filled with nitrogen three times. To the flask was added DMF (20 mL), then iodobenzene or 2-bromopyridine (40 mmol, 2 equiv.) under nitrogen. The reaction was heated to 150 °C and left to stir under nitrogen for 18 h. The reaction mixture was filtered through celite using EtOAc as an eluent. The solution was then washed with water (2 x 100 mL) and brine (50 mL) and the organic layer concentrated in vacuo. The reaction was purified by flash column chromatography (eluent 9:1 Hex:EtOAc) and the product recrystallised from ether (5 mL/g) to give the N-arylated product.
129
1-Phenyl-1H-indole-3-carbaldehyde, 139
CHO
N
Chemical Formula: C15H11NO Molecular 221.26 Weight:
1-Phenyl-1H-indole-3-carbaldehyde was prepared using general procedure A, from 1H-indole-3-carbaldehyde (2.9 g, 20 mmol) to give the product as red
-1 crystals (3.0 g, 14 mmol, 68%); m.p. 87 °C; νmax/cm (neat) 3103, 3052, 2786,
1 1656, 1616; Rf 0.28 (EtOAc-hexane, 1:4); H NMR (400 MHz, CDCl3) δ = 10.13
(s, 1 H, CHO), 8.40 (d, J = 7.1 Hz, 1 H, ArH), 7.94 (s, 1 H, ArH), 7.63 - 7.57 (m,
2 H, ArH), 7.59 - 7.51 (m, 1 H, ArH), 7.54 - 7.47 (m, 3 H, ArH), 7.39 - 7.32 (m,
13 2 H, ArH); C NMR (101 MHz, CDCl3) δ = 185.0 (CHO), 138.2 (CH), 138.2
(C), 137.5 (C), 130.0 (2 CH), 128.3 (CH), 125.6 (C), 124.9 (C), 124.6 (2 CH),
123.5 (CH), 122.3 (CH), 119.7 (C), 111.1 (CH); m/z (ES+) 222 ([M + H]+, 100%);
+ + HRMS (TOF MS ES ) m/z calculated for C15H12NO [M + H] 222.0919, found
222.0917. Data was consistent with the literature.253
130
1-Phenyl-1H-indole-3-carbonitrile, 141
CN
N
Chemical Formula: C15H10N2 Molecular 218.26 Weight:
1-Phenyl-1H-indole-3-carbonitrile was prepared using general procedure A, from
3-cyanoindole (2.9 g, 20 mmol) to give the product as off white needles (2.8 g,
-1 13 mmol, 64%); m.p. 99 °C; νmax/cm (neat) 3123, 2222, 1598; Rf 0.31
1 (EtOAc-hexane, 1:4); H NMR (300 MHz, CDCl3) δ = 7.85 (d, J = 7.2 Hz, 1 H,
ArH), 7.82 (s, 1 H, ArH), 7.62 - 7.56 (m, 2 H, ArH), 7.54 (d, J = 6.1 Hz, 1 H,
ArH), 7.52 - 7.47 (m, 3 H, ArH), 7.39 - 7.33 (m, 2 H, ArH); 13C NMR (75 MHz,
CDCl3) δ = 137.8 (C), 135.6 (C), 134.6 (CH), 130.0 (2 CH), 128.4 (CH), 127.9
(C), 124.9 (2 CH), 124.5 (CH), 122.8 (CH), 120.0 (CH), 115.5 (C≡N), 111.5
(CH), 88.1 (C); m/z (ES+) 219 ([M + H]+, 100%); HRMS (TOF MS ES+) m/z
+ calculated for C15H11N2 [M + H] 219.0922, found 219.0924. Data was consistent with the literature.254
131
3-Methyl-1-phenyl-1H-indole, 170
Me
N
Chemical Formula: C15H13N Molecular 207.28 Weight:
3-Methyl-1-phenyl-1H-indole was prepared using general procedure A, from
3-methyl indole (1.3 g, 10 mmol) to give the product as a pale yellow oil (1.5 g,
-1 7.2 mmol, 71%); νmax/cm (neat): 3050, 2914, 1598; Rf 0.29 (EtOAc-hexane,
1 1:9); H NMR (300 MHz, CDCl3) δ = 7.67 (d, J = 7.9 Hz, 1 H, ArH), 7.61 (d, J
= 8.1 Hz, 1 H, ArH), 7.53 (s, 1 H, ArH), 7.52 - 7.51 (m, 2 H, ArH), 7.40 - 7.31
(m, 2 H, ArH), 7.28 - 7.19 (m, 2 H, ArH), 7.19 - 7.17 (m, 1 H, ArH), 2.43 (s, 3
13 H, CH3); C NMR (75 MHz, CDCl3) δ = 140.0 (C), 135.9 (C), 129.7 (C), 129.5
(2 CH), 125.9 (CH), 125.4 (CH), 124.0 (2 CH), 122.3 (CH), 119.7 (CH), 119.2
+ + (CH), 112.8 (C), 110.3 (CH), 9.6 (CH3); m/z (ES ) 208 ([M + H] , 100%);
+ + HRMS (TOF MS ES ) m/z calculated for C15H14N2 [M + H] 208.1126, found
208.1125. Data was consistent with the literature.253
132
1-Phenyl-1H-indole, 171a
N
Chemical Formula: C14H11N Molecular 193.25 Weight:
1-Phenyl-1H-indole was prepared using general procedure A, from indole (1.1 g,
10 mmol) to give the product as a dark brown oil (1.3 g, 6.7 mmol, 67%);
1 H NMR (400 MHz, CDCl3) δ = 7.79 - 7.76 (m, 1H, ArH), 7.66 - 7.64 (m, 1H,
ArH), 7.57 (m, 4H, ArH), 7.47 - 7.38 (m, 2H, ArH), 7.33 - 7.24 (m, 2H, ArH),
13 6.79 - 6.77 (m, 1H, ArH); C NMR (101 MHz, CDCl3) δ = 140.0 (C), 136.0 (C),
129.8 (C), 129.5 (CH), 128.1 (CH), 126.6 (CH), 124.5 (CH), 122.5 (CH), 121.32
(CH), 120.5 (CH), 110.7 (CH), 103.7 (CH); m/z (ES+) 194 ([M + H]+, 100%);
+ + HRMS (TOF MS ES ) m/z calculated for C14H12N [M + H] 194.0970, found
194.0971. Data was consistent with the literature.255
133
Methyl 1-phenyl-1H-indole-3-carboxylate, 172a
O O
N
Chemical Formula: C H NO 16 .13 2 Molecular Weight: 251 2799
Methyl 1-phenyl-1H-indole-3-carboxylate was prepared using general procedure
A, from methyl 1H-indole-3-carboxylate (1.8 g, 10 mmol) to give the product as
-1 off white crystals (2.0 g, 7.9 mmol, 79%); m.p. 83-84 °C; νmax/cm (neat) 3128,
1 2989, 1728, 1596; Rf 0.30 (EtOAc-hexane, 1:4); H NMR (400 MHz, CDCl3) δ =
8.27 (d, J = 7.8 Hz, 1 H, ArH), 8.05 (s, 1 H, ArH), 7.60 - 7.50 (m, 5 H, ArH),
7.48 - 7.43 (m, 1 H, ArH), 7.37 - 7.27 (m, 2 H, ArH), 3.96 (s, 3 H, CO2Me);
13 C NMR (101 MHz, CDCl3) δ = 165.4 (CO2Me), 138.4 (C), 136.6 (C), 134.1
(C), 129.8 (2 CH), 127.8 (CH), 126.8 (CH), 124.8 (2 CH), 123.4 (CH), 122.5
+ (CH), 121.8 (CH), 111.0 (C), 109.0 (CH), 51.2 (CO2Me); m/z (ES ) 252 ([M +
+ + + H] , 100%); HRMS (TOF MS AP ) m/z calculated for C18H14NO2 [M + H]
252.1025, found 252.1023. Data was consistent with the literature.254
134
1-(Pyridin-2-yl)-1H-indole-3-carbaldehyde, 140
CHO
N
N
Chemical Formula: C14H10N2O Molecular 222.25 Weight:
1-(Pyridin-2-yl)-1H-indole-3-carbaldehyde was prepared using general procedure
A, from 1H-indole-3-carbaldehyde (1.5 g, 10 mmol) to give the product as a
-1 yellow powder (1.8 g, 8.1 mmol, 82%); m.p. 112 °C; νmax/cm (neat) 3101, 3050,
1 2821, 1648; Rf 0.12 (EtOAc-hexane, 1:9); H NMR (300 MHz, CDCl3): δ =
10.14 (s, 1 H, CHO), 8.64 (d, J = 4.8 Hz, 1 H, ArH), 8.41 - 8.37 (m, 1 H, ArH),
8.36 (s, 1 H, ArH), 8.07 - 7.98 (m, 1 H, ArH), 7.94 (m, 1 H, ArH), 7.62 (d, J =
13 8.2 Hz, 1 H, ArH), 7.43 - 7.31 ppm (m, 3 H, ArH); C NMR (75 MHz, CDCl3)
δ = 185.4 (CHO), 150.9 (C), 149.5 (CH), 138.9 (C), 136.9 (CH), 136.1 (CH),
126.3 (C), 125.0 (CH), 123.8 (CH), 122.3 (CH), 122.1 (CH), 120.5 (C), 115.8
(CH), 112.6 (CH); m/z (ES+) 223 ([M + H]+, 100%); HRMS (TOF MS ES+) m/z
+ calculated for C14H11N2O [M + H] 223.0871, found 223.0871. Data was consistent with the literature.113
135
1-(Pyridin-2-yl)-1H-indole-3-carbonitrile, 142
CN
N
N
Chemical Formula: C14H9N3 Molecular 219.25 Weight:
1-(Pyridin-2-yl)-1H-indole-3-carbonitrile was prepared using general procedure
A, from 3-cyanoindole (2.9 g, 20 mmol) to give the product as yellow needles
-1 (1.8 g, 8.3 mmol, 69%); m.p. 153 °C; νmax/cm (neat): 3050, 3010, 2222, 1592;
1 Rf 0.31 (EtOAc-hexane, 1:9); H NMR (500 MHz, CDCl3) δ = 8.64 (ddd, J =
0.8, 1.9, 4.9 Hz, 1 H, ArH), 8.24 (s, 1 H, ArH), 8.11 (d, J = 8.2 Hz, 1 H, ArH),
7.95 (ddd, J = 1.9, 7.4, 8.2 Hz, 1 H, ArH), 7.84 (d, J = 7.9 Hz, 1 H, ArH), 7.58
(ddd, J = 0.8, 0.9, 8.2 Hz, 1 H, ArH), 7.45 - 7.34 (m, 2 H, ArH), 7.36 (ddd, J =
13 0.9, 4.9, 7.4 Hz, 1 H); C NMR (126 MHz, CDCl3) δ = 158.6 (C), 150.7 (CH),
149.4 (C), 139.0 (CH), 134.3 (C), 133.2 (CH), 128.6 (CH), 125.1 (CH), 123.3
(CH), 122.2 (CH), 120.0 (C≡N), 115.5 (CH), 113.3 (CH), 89.8 (C); m/z (ES+)
+ + 220 ([M + H] , 100%); HRMS (TOF MS ES ) m/z calculated for C14H10N3 [M +
H]+ 220.0875, found 220.0883. Data was consistent with the literature.113
136
3-Methyl-1-(pyridin-2-yl)-1H-indole, 171b
Me
N
N
Chemical Formula: C14H12N2 Molecular 208.26 Weight:
3-Methyl-1-(pyridin-2-yl)-1H-indole was prepared using general procedure A, from 3-methyl indole (1.3 g, 10 mmol) to give the product as a pale yellow oil
-1 (1.4 g, 7 mmol, 69%); νmax/cm (neat): 3046, 2914, 1588; Rf 0.26 (EtOAc-
1 hexane, 1:9); H NMR (300 MHz, CDCl3) δ = 8.55 (ddd, J = 0.8, 1.9, 4.9 Hz, 1
H, ArH), 8.23 (d, J = 8.3 Hz, 1 H, ArH), 7.79 (ddd, J = 1.9, 7.3, 8.3 Hz, 1 H,
ArH), 7.61 (d, J = 7.7 Hz, 1 H, ArH), 7.53 (d, J = 1.1 Hz, 1 H, ArH), 7.45 (ddd,
J = 0.8, 0.9, 8.3 Hz, 1 H, ArH), 7.37 - 7.28 (m, 2 H, ArH), 7.12 (ddd, J = 0.9,
13 4.9, 7.3 Hz, 1 H, ArH), 2.39 (d, J = 1.1 Hz, 3 H, CH3); C NMR (75 MHz,
CDCl3) δ = 152.5 (C), 148.7 (CH), 138.3 (CH), 135.3 (C), 131.0 (C), 123.2 (CH),
123.1 (CH), 120.8 (CH), 119.3 (CH), 119.0 (CH), 118.1 (C), 113.9 (CH), 113.0
+ + + (CH), 9.6 (CH3); m/z (ES ) 209 ([M + H] , 100%); HRMS (TOF MS ES ) m/z
+ calculated for C14H13N2 [M + H] 209.1079, found 209.1080.
137
1-(Pyridin-2-yl)-1H-indole, 171b
N
N
Chemical Formula: C13H10N2 Molecular 194.24 Weight:
1-(Pyridin-2-yl)-1H-indole was prepared using general procedure A, from indole
(1.1 g, 10 mmol) to give the product as a dark brown oil (1.5 g, 7.5 mmol,
1 75%); H NMR (400 MHz, CDCl3) δ = 8.59 (ddd, J = 0.8, 1.8, 4.8 Hz, 1 H,
ArH), 8.21 (d, J = 8.2 Hz, 1 H, ArH), 7.84 (ddd, J = 1.8, 7.4, 8.3 Hz, 1 H, ArH),
7.75 (d, J = 3.6 Hz, 1 H, ArH), 7.70 (d, J = 7.8 Hz, 1 H, ArH), 7.52 (ddd, J =
0.8, 0.9, 8.3 Hz, 1 H, ArH), 7.35 - 7.15 (m, 3 H, ArH), 6.74 (d, J = 3.6 Hz, 1 H,
13 ArH); C NMR (101 MHz, CDCl3) δ = 152.4 (C), 149.0 (CH), 138.4 (CH),
135.1 (C), 130.5 (C), 125.9 (CH), 123.3 (CH), 121.2 (CH), 121.0 (CH), 120.0
(CH), 114.6 (CH), 112.9 (CH), 105.7 (CH); m/z (ES+) 195 ([M + H]+, 100%);
+ + HRMS (TOF MS ES ) m/z calculated for C13H11N2 [M + H] 195.0922, found
195.0922. Data was consistent with the literature.99
138
1-(1-(Pyridin-2-yl)-1H-indol-3-yl)ethan-1-one, 173b
O
N
N
Chemical Formula: C15H12N2O Molecular Weight: 236.27
1-(1-(pyridin-2-yl)-1H-indol-3-yl)ethan-1-one was prepared using general procedure A, from 1-(1H-indol-3-yl)ethanone (1.59 g, 10 mmol) to give the
-1 product as off white crystals (1.2 g, 5.1 mmol, 51%); m.p. 112 °C; νmax/cm
1 (neat): 3011, 2899, 1679, 1589; Rf 0.34 (EtOAc-hexane, 1:9); H NMR
(400 MHz, CDCl3) δ = 8.65 (d, J = 4.9 Hz, 1 H, ArH), 8.52 - 8.47 (m, 1 H,
ArH), 8.41 (s, 1 H, ArH), 8.01 - 7.96 (m, 1 H, ArH), 7.96 - 7.91 (m, 1 H, ArH),
7.65 (d, J = 8.2 Hz, 1 H, ArH), 7.41 - 7.36 (m, 2 H, ArH), 7.34 (dd, J = 4.9, 7.5
13 Hz, 1 H, ArH), 2.63 (s, 3 H, COMe); C NMR (101 MHz, CDCl3) δ = 193.8
(COMe), 151.1 (C), 149.6 (CH), 138.9 (C), 135.7 (CH), 133.3 (CH), 127.5 (C),
124.5 (CH), 123.6 (CH), 123.0 (CH), 121.9 (CH), 119.5 (C), 116.0 (CH), 112.1
(CH), 27.8 (COMe); m/z (ES+) 237 ([M + H]+, 100%); HRMS (TOF MS ES+)
+ m/z calculated for C15H13N2O [M + H] 237.1028, found 237.1032.
139
Methyl 1-(pyridin-2-yl)-1H-indole-3-carboxylate, 172b
O O
N
N
Chemical Formula: C15H12N2O2 Molecular Weight: 252.27
Methyl 1-(pyridin-2-yl)-1H-indole-3-carboxylate was prepared using general procedure A, from methyl 1H-indole-3-carboxylate (1.75 g, 10 mmol) to give the
-1 product as off white crystals (1.9 g, 7.7 mmol, 77%); m.p. 118-119 °C; νmax/cm
1 (neat): 3101, 3048, 2991, 1729, 1598; Rf 0.32 (EtOAc-hexane, 1:9); H NMR
(400 MHz, CDCl3) δ = 8.63 (ddd, J = 0.7, 1.9, 4.9 Hz, 1 H, ArH), 8.42 (s, 1 H,
ArH), 8.23 - 8.29 (m, 1 H, ArH), 8.18 - 8.11 (m, 1 H, ArH), 7.91 (ddd, J = 1.9,
7.4, 8.2 Hz, 1 H, ArH), 7.58 (ddd, J = 0.7, 0.9, 8.2 Hz, 1 H, ArH), 7.40 - 7.34
(m, 2 H, ArH), 7.31 (ddd, J = 0.9, 4.9, 7.4 Hz, 1 H, ArH), 3.96 (s, 3 H,
13 CO2Me); C NMR (101 MHz, CDCl3) δ = 165.2 (CO2Me), 151.4 (C), 149.2
(CH), 138.8 (C), 135.6 (CH), 132.5 (CH), 127.6 (C), 124.0 (CH), 123.0 (CH),
121.8 (CH), 121.6 (CH), 115.6 (CH), 113.0 (CH), 110.4 (C), 51.3 (CO2Me); m/z
(ES+) 253 ([M + H]+, 100%); HRMS (TOF MS ES+) m/z calculated for
C15H12N2O2Na
[M + Na]+ 275.0796, found 275.0806.
140
1-(Pyrazin-2-yl)-1H-indole-3-carbaldehyde, 174
CHO
N
N N
Chemical Formula: C13H9N3O Molecular 223.23 Weight:
1-(Pyrazin-2-yl)-1H-indole-3-carbaldehyde was prepared using general procedure
A, from 1H-indole-3-carbaldehyde (1.5 g, 10 mmol) to give the product as off
-1 white crystals (1.2 g, 5.2 mmol, 52%); m.p. 161 °C; νmax/cm (neat): 3099, 2828,
1 1689, 1595; Rf 0.26 (EtOAc-hexane, 1:9); H NMR (400 MHz, CDCl3) δ = 10.19
(s, 1 H, CHO), 9.07 (br. s., 1 H, ArH), 8.63 (br. s., 2 H, ArH), 8.43 - 8.39 (m, 1
H, ArH), 8.39 (s, 1 H, ArH), 8.13 - 8.09 (m, 1 H, ArH), 7.50 - 7.38 (m, 2 H,
13 ArH); C NMR (101 MHz, CDCl3) δ = 185.4 (CHO), 147.8 (C), 143.3 (CH),
142.3 (C), 137.2 (CH), 135.9 (CH), 135.8 (CH), 126.4 (C), 125.6 (CH), 124.4
(CH), 122.5 (CH), 121.5 (C), 112.7 (CH); m/z (ES+) 224 ([M + H]+, 100%);
+ + HRMS (TOF MS ES ) m/z calculated for C13H10N3O [M + H] 224.0824, found
224.0821.
141
Methyl 1-(pyrazin-2-yl)-1H-indole-3-carboxylate, 172c
O O
N
N N
Chemical Formula: C14H11N3O2 Molecular Weight: 253.26
Methyl 1-(pyrazin-2-yl)-1H-indole-3-carboxylate was prepared using general procedure A, from methyl 1H-indole-3-carboxylate (1.8 g, 10 mmol) to give the
-1 product as off white crystals (1.4 g, 5.5 mmol, 55%); m.p. 147 °C; νmax/cm
1 (neat): 3112, 3025, 2987, 1726, 1595; Rf 0.32 (EtOAc-hexane, 1:9); H NMR
(500 MHz, CDCl3) δ = 9.01 (d, J = 1.4 Hz, 1 H, ArH), 8.61 (dd, J = 1.4, 2.5 Hz,
1 H, ArH), 8.59 (d, J = 2.5 Hz, 1 H, ArH), 8.45 (s, 1 H, ArH), 8.28 - 8.32 (m, 1
H, ArH), 8.20 - 8.24 (m, 1 H, ArH), 7.43 - 7.38 (m, 2 H, ArH), 4.00 (s, 3 H,
13 CO2Me); C NMR (126 MHz, CDCl3) δ = 164.8 (CO2Me), 148.2 (C), 143.0
(CH), 141.7 (C), 137.0 (CH), 135.4 (CH), 131.4 (CH), 127.7 (C), 124.7 (CH),
+ 123.7 (CH), 122.0 (CH), 113.1 (C), 112.0 (CH), 51.5 (CO2Me); m/z (ES ) 254
+ + ([M + H] , 100%); HRMS (TOF MS AP ) m/z calculated for C14H12N3O2 [M +
H]+ 254.0930, found 254.0927.
142
Methyl 1-(pyridin-3-yl)-1H-indole-3-carboxylate, 172d
O O
N
N
Chemical Formula: C15H12N2O2 Molecular Weight: 252.27
Methyl 1-(pyridin-3-yl)-1H-indole-3-carboxylate was prepared using general procedure A, from methyl 1H-indole-3-carboxylate (1.8 g, 10 mmol) to give the
-1 product as off white crystals (1.2 g, 4.9 mmol, 49%); m.p. 116 °C; νmax/cm
1 (neat): 3119, 3020, 1729, 1599; Rf 0.31 (EtOAc-hexane, 1:9); H NMR
(500 MHz, CDCl3) δ = 8.86 (s, 1 H, ArH), 8.73 (d, J = 4.7 Hz, 1H, ArH), 8.28
(d, J = 7.6 Hz, 1 H, ArH), 8.03 (s, 1 H, ArH), 7.88 (ddd, J = 1.6, 2.5, 8.0 Hz, 1
H, ArH), 7.54 (dd, J = 4.7, 8.0 Hz, 1 H, ArH), 7. (d, J = 8.3 Hz, 1 H, ArH), 7.40
13 - 7.31 (m, 2 H, ArH), 3.97 (s, 3 H, CO2Me) ppm; C NMR (126 MHz, CDCl3) δ
= 165.1 (CO2Me), 146.1 (CH), 145.0 (C), 137.8 (CH), 133.6 (C), 132.1 (CH),
127.0 (C), 124.0 (CH), 123.0 (CH), 122.1 (CH), 119.8 (CH), 117.7 (CH), 110.5
+ + (CH), 110.3 (C), 51.3 (CO2Me); m/z (ES ) 253 ([M + H] , 100%); HRMS (TOF
+ + MS AP ) m/z calculated for C15H13N2O2 [M + H] 253.0977, found 253.0973.
143
Methyl 1-(thiophen-2-yl)-1H-indole-3-carboxylate, 172e
O O
N S
Chemical Formula: C14H11NO2S Molecular 257.31 Weight:
Methyl 1-(thiophen-2-yl)-1H-indole-3-carboxylate was prepared using general procedure A, from methyl 1H-indole-3-carboxylate (1.8 g, 10 mmol) to give the
-1 product as off white crystals (0.5 g, 2.1 mmol, 21%); m.p. 90-91 °C; νmax/cm
1 (neat): 3159, 3020, 1729, 1594; Rf 0.34 (EtOAc-hexane, 1:9); H NMR
(500 MHz, CDCl3) δ = 8.27 - 8.22 (m, 1 H, ArH), 7.99 (s, 1 H, ArH), 7.58 - 7.53
(m, 1 H, ArH), 7.37 - 7.31 (m, 2 H, ArH), 7.29 (dd, J = 1.4, 5.7 Hz, 1 H, ArH),
7.17 (dd, J = 1.4, 3.7 Hz, 1 H, ArH), 7.10 (dd, J = 3.7, 5.7 Hz, 1 H, ArH), 3.96
13 (s, 3 H, CO2Me); C NMR (126 MHz, CDCl3) δ = 165.1 (CO2Me), 139.6 (C),
137.7 (C), 135.2 (CH), 126.5 (CH), 126.2 (C), 123.8 (CH), 123.1 (CH), 122.9
+ (CH), 122.1 (CH), 121.7 (CH), 111.0 (CH), 109.6 (C), 51.3 (CO2Me); m/z (ES )
+ + 258 ([M + H] , 100%); HRMS (TOF MS AP ) m/z calculated for C14H12NO2S
[M + H]+ 258.0589, found 258.0590.
144
1-Phenyl-1H-pyrrole, 197
N
Chemical Formula: C10H9N Molecular 143.19 Weight:
1-Phenyl-1H-pyrrole was prepared using general procedure A, from pyrrole
(0.7 g, 10 mmol) to give the product as a dark brown oil (1.2 g, 8.3 mmol,
1 83%); H NMR (400 MHz, CDCl3) δ = 7.48 - 7.41 (m, 4H, ArH) 7.31 - 7.26 (m,
1H, ArH), 7.15 (t, J = 2.3 Hz, 2H, ArH), 6.39 (t, J = 2.3 Hz, 2H, ArH); 13C
NMR (101 MHz, CDCl3) δ = 140.8 (C), 129.3 (2 CH), 125.9 (CH), 120.7 (2
CH), 119.5 (2 CH), 110.6 (2 CH); m/z (ES+) 144 [M + H]+. Data was consistent with the literature.255
145
2-(1H-Pyrrol-1-yl)pyridine, 198
N N
Chemical Formula: C9H8N2 Molecular 144.18 Weight:
2-(1H-Pyrrol-1-yl)pyridine was prepared using general procedure A, from pyrrole
(0.7 g, 10 mmol) to give the product as a dark brown oil (1.0 g, 7.2 mmol,
1 72%); H NMR (300 MHz, CDCl3) δ = 8.47 (dd, J = 0.9, 3.0 Hz, 1H, ArH), 7.79
- 7.73 (m, 1H, ArH), 7.56 (t, J = 2.3 Hz, 2H, ArH), 7.35 - 7.29 (m, 1H, ArH),
7.14 - 7.09 (m, 1H, ArH), 6.39 (t, J = 2.3 Hz, 2H, ArH); 13C NMR (75 MHz,
CDCl3) δ = 151.4 (C), 148.8 (CH), 138.4 (CH), 120.2 (CH), 118.1 (2 CH), 111.4
(CH), 109.7 (2 CH); m/z (ES+) 145 [M + H]+. Data was consistent with the literature.256
General procedure B for the attempted palladium-catalysed alkyne insertion (see results and discussion for specific reagents and equivalents)
To a vial was added the indole (0.2 mmol), Pd(OAc)2 (4.5 mg, 0.02 mmol), oxidant (0.4 mmol), base (0.4 mmol) and alkyne (0.26 mmol). The vial was sealed, evacuated and back-filled with nitrogen. To the sealed vial was added the solvent (1 mL) and the reaction was stirred at 120 °C overnight under nitrogen.
The reaction mixture was diluted with water (10 mL) and extracted with EtOAc
146
(3 x 10 mL). The organic layers were combined, concentrated under reduced pressure and purified by column chromatography (eluent 9:1 Hex:EtOAc). The reactions were monitored by LC-MS.
General procedure C for the Fujiwara alkenylation (see results and discussion for specific reagents and equivalents)
The indole (2 mmol, 2 equiv.) was added to a carousel tube along with Pd(OAc)2
(11.3 mg, 0.05 mmol, 0.05 equiv.), methyl 3-phenylpropiolate (160 mg, 0.15 mL,
1 mmol, 1 equiv.) and AcOH (1 mL).114 The vessel was evacuated and back-filled with nitrogen. The reaction was stirred at room temperature overnight. The products were purified by flash column chromatography (eluent 9:1
Hex:EtOAc). Stereochemistry was determined by analogy with the literature, where differential NOE 1H NMR experiments were used.
Methyl (E)-3-(3-methyl-1H-indol-2-yl)-3-phenylacrylate, 150a
Ph
N CO Me H 2
Chemical Formula: C19H17NO2 Molecular 291.35 Weight:
Methyl (E)-3-(3-methyl-1H-indol-2-yl)-3-phenylacrylate was prepared using general procedure C, from 3-methyl indole (262 mg, 2 mmol) to give the product as white crystals (367 mg, 1.26 mmol, 63%); m.p. 116-118 °C; 1H NMR (300
147
MHz, CDCl3) δ = 10.16 (s, 1 H, NH), 7.36 - 7.20 (m, 9 H, ArH), 6.21 (s, 1 H,
13 vinyl CH), 3.80 (s, 3 H, CO2Me), 1.87 (s, 3 H, Me); C NMR (75 MHz, CDCl3)
δ = 166.9 (CO2Me), 148.2 (vinyl C), 141.2 (C), 136.1 (C), 130.3 (C), 129.0 (2
CH), 128.8 (2 CH), 128.7 (CH), 128.4 (CH), 125.7 (C), 123.6 (CH), 119.2 (CH),
+ 117.7 (C), 115.8 (vinyl CH), 111.2 (CH), 51.1 (CO2Me), 10.2 (Me); m/z (ES )
292 ([M +H]+, 100%). Data was consistent with the literature.114
Methyl (E)-3-(3-cyano-1H-indol-2-yl)-3-phenylacrylate, 150b
CN Ph
N CO Me H 2
Chemical Formula: C19H14N2O2 Molecular 302.33 Weight:
Methyl (E)-3-(3-cyano-1H-indol-2-yl)-3-phenylacrylate was prepared using general procedure C, from 1H-indole-3-carbonitrile (284 mg, 2 mmol) to give the product as an off-white solid (230 mg, 0.76 mmol, 38%); m.p. 134-135 °C;
-1 νmax/cm (neat): 3219, 3058, 2981, 2205, 1735, 1658, 1526; Rf 0.19 (EtOAc-
1 hexane, 1:9); H NMR (400 MHz, CDCl3) δ = 8.94 (br. s, 1 H, NH), 7.79 (d, J =
7.3 Hz, 1 H, ArH), 7.72 (d, J = 2.8 Hz, 1 H, ArH), 7.62 - 7.57 (m, 5 H, ArH),
13 7.35 - 7.30 (m, 2 H, ArH), 6.29 (s, 1 H, vinyl CH), 3.76 (s, 3 H, CO2Me); C
NMR (101 MHz, CDCl3) δ = 167.1 (CO2Me), 148.8 (vinyl C), 140.9 (C), 137.4
(C), 129.8 (C), 128.9 (2 CH), 128.9 (2 CH), 128.5 (CH), 128.3 (CH), 124.4 (C),
123.7 (CH), 119.0 (CH), 118.0 (C≡N), 115.6 (vinyl CH), 110.8 (CH), 70.2 (C),
148
+ + + 51.1 (CO2Me); m/z (ES ) 303 ([M + H] , 100%); HRMS (TOF MS ES ) m/z
+ calculated for C19H15N2O2 [M + H] 303.1134, found 303.1136.
Methyl (E)-3-(3-cyano-1-phenyl-1H-indol-2-yl)-3-phenylacrylate, 150c
CN Ph
N CO2Me
Chemical Formula: C25H18N2O2 Molecular Weight: 378.4310
Methyl (E)-3-(3-cyano-1-phenyl-1H-indol-2-yl)-3-phenylacrylate was prepared using general procedure C, from 1-phenyl-1H-indole-3-carbonitrile (436 mg,
2 mmol) to give the product as an off-white solid (159 mg, 0.42 mmol, 21 %);
-1 m.p. 165-166 °C; νmax/cm (neat): 3020, 2959, 2206, 1732, 1658, 1524; Rf 0.38
1 (EtOAc-hexane, 1:9); H NMR (400 MHz, CDCl3) δ = 7.91 - 7.73 (m, 2 H,
ArH), 7.61 - 7.36 (m, 12 H, ArH), 6.29 (s, 1 H, vinyl CH), 3.75 (s, 3 H,
13 CO2Me); C NMR (101 MHz, CDCl3) δ = 167.0 (CO2Me), 148.7 (vinyl C),
140.9 (C), 140.1 (C), 137.4 (C), 129.8 (C), 129.7 (2 CH), 128.9 (2 CH), 128.8 (2
CH), 128.6 (CH), 124.6 (2 CH), 124.5 (C), 123.9 (CH), 123.7 (CH), 122.8 (CH),
119.2 (CH), 118.1 (C≡N), 115.7 (vinyl CH), 110.8 (CH), 70.5 (C), 51.1
+ + + (CO2Me); m/z (ES ) 379 ([M + H] , 100%); HRMS (TOF MS ES ) m/z
+ calculated for C25H19N2O2 [M + H] 379.1447, found 379.1450.
149
Procedure for the synthesis of neopentylmagnesium bromide, 398
MgBr
Chemical Formula: C5H11BrMg Molecular Weight: 175.35
A 3-neck RBF fitted with an addition funnel and condenser and charged with magnesium turnings (1 g, 41 mmol) was evacuated, flame-dried, cooled and
116 back-filled with N2. The magnesium turnings were stirred vigorously at room temperature in THF for 1h. Iodine was added and the addition funnel was charged with neopentyl bromide (4.30 mL, 34 mmol) in THF (20 mL). The neopentyl bromide was added dropwise over an hour and the reaction left for 16 h. The solution was transferred via cannula to a flame-dried Schlenk flask under nitrogen. An aliquot was titrated with iodine (1 mL of Grignard solution with
130 mg of iodine in 2 mL THF). This gave a solution of neopentylmagnesium bromide in THF (0.7 M, 82%), which was used directly in the next step.
General procedure D for the cobalt-catalysed hydroarylation reaction
(see results and discussion for specific reagents and equivalents)
To the indole (0.3 mmol, 1 equiv.) was added alkyne (0.45 mmol, 1.5 equiv.),
cobalt(II) (either CoBr2 (6.6 mg, 0.03 mmol, 0.1 equiv.) or Co(acac)2 (7.7 mg,
0.03 mmol, 0.1 equiv.)).116 The vial was evacuated and back-filled with nitrogen.
THF (1 mL) was added, and the Grignard reagent (0.18 mmol, 0.5-0.7 M). The reaction was left to stir at room temperature for 16 h. The reaction was quenched
with NH4Cl (aq., sat.) and extracted with ethyl acetate (3 x 25 mL).
150
Stereochemistry was determined by analogy with the literature, where X-ray crystallography was used.
(E)-2-(1,2-Diphenylvinyl)-1-(pyridin-2-yl)-1H-indole-3-carbonitrile, 155
CN Ph
N Ph
N
Chemical Formula: C28H19N3 Molecular Weight: 397.48
(E)-2-(1,2-Diphenylvinyl)-1-(pyridin-2-yl)-1H-indole-3-carbonitrile was prepared using general procedure D, from 1-(pyridin-2-yl)-1H-indole-3-carbonitrile
(66 mg, 0.3 mmol) to give the product as off white crystals (78 mg, 0.2 mmol,
-1 66%); m.p. 187-188 °C; νmax/cm (neat): 3055, 3025, 2218, 1589; Rf 0.36
1 (EtOAc-hexane, 1:9); H NMR (500 MHz, CDCl3) δ = 8.39 (d, J = 4.9 Hz, 1 H,
ArH), 7.78 (d, J = 6.6 Hz, 1 H, ArH), 7.59 - 7.51 (m, 2 H, ArH), 7.38 - 7.32 (m,
2 H, ArH), 7.27 - 7.22 (m, 5 H, ArH), 7.21 - 7.13 (m, 5 H, ArH), 7.08 (d, J = 8.2
Hz, 2 H, ArH), 7.03 (d, J = 7.9 Hz, 1 H, vinyl CH); 13C NMR (126 MHz,
CDCl3) δ = 160.5 (C), 152.0 (CH), 149.4 (C), 149.2 (C), 140.0 (CH), 137.8 (vinyl
C), 136.0 (C), 135.0 (CH), 130.0 (vinyl CH), 128.8 (CH), 128.4 (2 CH), 128.4
(C), 128.2 (CH), 128.1 (CH), 127.5 (CH), 127.1 (2 CH), 124.8 (C), 123.1 (CH),
122.6 (CH), 120.4 (CH), 119.8 (CH), 116.6 (C≡N), 112.2 (CH), 109.5 (CH), 90.4
(CH), 69.7 (C); m/z (ES+) 398 ([M + H]+, 100%); HRMS (TOF MS ES+) m/z
+ calculated for C28H20N3 [M + H] 398.1657, found 398.1658.
151
General Procedure E for the rhodium-catalysed alkyne insertion (see results and discussion for specific reagents and equivalents)
To a vial was added the indole (0.15 mmol, 1 equiv.), the alkyne (0.3 mmol, 2
-3 equiv.), [Cp*RhCl2]2 (2.3 mg, 3.75 x 10 mmol, 5 mol% [Rh]), Cu(OAc)2∙H2O
119–121 (30 mg, 0.15 mmol, 1 equiv.) and Na2CO3 (15 mg, 0.15 mmol, 1 equiv.).
The vial was sealed, evacuated and back filled with nitrogen. Xylene (1 mL) was added and the reaction stirred at 150 °C overnight. The reaction was cooled to room temperature and the product purified by flash column chromatography
(eluent 8:2 Hex:EtOAc).
152
5,6-Diphenylindolo[1,2-a][1,8]naphthyridine-7-carbonitrile, 146a
CN Ph
N Ph
N
Chemical Formula: C28H17N3 Molecular Weight: 395.47
5,6-Diphenylindolo[1,2-a][1,8]naphthyridine-7-carbonitrile was prepared using general procedure E, from 1-(pyridin-2-yl)-1H-indole-3-carbonitrile (33 mg,
0.15 mmol) to give the product as a yellow/green solid (25 mg, 0.06 mmol,
-1 39%); m.p. >250 °C; νmax/cm (neat): 2921, 2851, 2206, 1580; Rf 0.52 (EtOAc-
1 hexane, 1:9); H NMR (300 MHz, CDCl3) δ = 9.62 (d, J = 8.1 Hz, 1 H, ArH),
8.82 (d, J = 4.6 Hz, 1 H, ArH), 7.92 (d, J = 7.5 Hz, 1 H, ArH), 7.79 (d, J = 8.0
Hz, 1 H, ArH), 7.51 - 7.63 (m, 2 H, ArH), 7.25 - 7.39 (m, 9 H, ArH), 7.16 - 7.20
13 (m, 2 H, ArH); C NMR (75 MHz, CDCl3) δ = 148.4 (CH), 141.9 (C), 140.6
(C), 140.2 (C), 136.2 (C), 135.6 (C), 132.8 (C), 131.1 (CH), 131.1 (CH), 130.6 (2
CH), 130.4 (2 CH), 129.4 (CH), 128.8 (CH), 128.3 (2 CH), 128.2 (2 CH), 127.9
(CH), 124.7 (CH), 124.7 (CH), 120.1 (C), 119.2 (C), 118.8 (C≡N), 118.2 (C),
109.6 (CH), 97.6 (C); m/z (ES+) 396 ([M + H]+, 100%); HRMS (ESI) m/z
+ calculated for C28H18N3 [M + H] 396.1501, found 396.1501.
153
Crystals suitable for X-ray diffraction were grown from ethanol.
Summary of X-ray data
Compound reference s3836ma
Chemical formula C28H17N3 Formula mass 395.45 Crystal system Monoclinic a/Å 9.6090(2) b/Å 20.4722(5) c/Å 10.0073(3)
/° 90.00
αβ/° 92.517(2) γ/° 90.00 Unit cell volume/Å3 1966.71(9) Temperature/K 296(2) Space group P2(1)/c No. of formula units per unit cell, Z 4 No. of reflections measured 9175 No. of independent reflections 3626
Rint 0.0499
Final R1 values (I > 2σ(I)) 0.0424 Final wR(F2) values (I > 2σ(I)) 0.0961
Final R1 values (all data) 0.0654 Final wR(F2) values (all data) 0.1046
154
5,6-Dipropylindolo[1,2-a][1,8]naphthyridine-7-carbonitrile, 146b
CN
N
N
Chemical Formula: C22H21N3 Molecular Weight: 327.43
5,6-Dipropylindolo[1,2-a][1,8]naphthyridine-7-carbonitrile was prepared using general procedure E, from 1-(pyridin-2-yl)-1H-indole-3-carbonitrile (33 mg,
0.15 mmol) to give the product as a yellow/green crystals (32 mg, 0.10 mmol,
-1 65%); m.p. 170 °C; νmax/cm (neat): 3054, 2976, 2207, 1581; Rf 0.35 (EtOAc-
1 hexane, 1:9); H NMR (400MHz, CDCl3) δ = 9.58 - 9.42 (m, 1 H, ArH), 8.74 (d,
J = 4.6 Hz, 1 H, ArH), 8.19 (d, J = 8.0 Hz, 1 H, ArH), 7.98 - 7.91 (m, 1 H, ArH),
7.56 - 7.48 (m, 2 H, ArH), 7.44 (dd, J = 4.6, 8.0 Hz, 1 H, ArH), 3.30 - 3.16 (m, 2
H, CH2), 3.00 - 2.88 (m, 2 H, CH2), 1.90 - 1.77 (m, 2 H, CH2), 1.77 - 1.63 (m, 2
13 H, CH2), 1.23 (t, J = 7.3 Hz, 3 H CH3), 1.16 (t, J = 7.3 Hz, 3 H, CH3); C NMR
(CDCl3, 101 MHz) δ = 147.4 (CH), 146.7 (C), 140.7 (C), 134.9 (C), 133.1 (C),
132.5 (C), 130.0 (CH), 129.5 (CH), 124.5 (CH), 124.1 (CH), 119.9 (CH), 118.8
(C≡N), 118.7 (C), 118.7 (C), 117.5 (CH), 79.6 (C), 30.7 (CH2), 29.7 (CH2), 23.7
+ + (CH2), 23.6 (CH2), 14.6 (CH3), 13.7 (CH3); m/z (ES ) 328 ([M + H] , 100%);
+ + HRMS (TOF MS ES ) m/z calculated for C22H22N3 [M + H] 328.1814, found
328.1824.
155
5,6-Dibutylindolo[1,2-a][1,8]naphthyridine-7-carbonitrile, 146c
CN
N
N
Chemical Formula: C24H25N3 Molecular Weight: 355.49
5,6-Dibutylindolo[1,2-a][1,8]naphthyridine-7-carbonitrile was prepared using general procedure E, from 1-(pyridin-2-yl)-1H-indole-3-carbonitrile (33 mg,
0.15 mmol) to give the product as a yellow/green crystals (37 mg, 0.10 mmol,
-1 69%); m.p. 169 °C; νmax/cm (neat): 3050, 2969 2206, 1582; Rf 0.43 (EtOAc-
1 hexane, 1:9); H NMR (400 MHz, CDCl3) δ = 9.51 (d, J = 7.7 Hz, 1 H, ArH),
8.74 (dd, J = 1.5, 4.5 Hz, 1 H, ArH), 8.20 (dd, J = 1.5, 8.1 Hz, 1 H, ArH), 7.94
(d, J = 8.7 Hz, 1 H, ArH), 7.56 - 7.48 (m, 2 H, ArH), 7.44 (dd, J = 4.5, 8.1 Hz, 1
H, ArH), 3.24 (t, J = 7.8 Hz, 2 H, CH2), 2.97 (t, J = 7.8 Hz, 2 H, CH2), 1.82 -
13 1.58 (m, 8 H, CH2), 1.05 (t, J = 7.2 Hz, 6 H, CH3); C NMR (101 MHz, CDCl3)
δ = 147.4 (CH), 146.7 (C), 140.7 (C), 135.0 (C), 133.0 (C), 132.5 (C), 130.1
(CH), 129.6 (CH), 124.5 (CH), 124.1 (CH), 120.0 (CH), 118.8 (C≡N), 118.7 (C),
118.7 (C), 117.5 (CH), 79.5 (C), 32.4 (2 CH2), 28.6 (CH2), 27.4 (CH2), 23.2
+ + (CH2), 22.4 (CH2), 14.1 (CH3), 13.9 (CH3); m/z (ES ) 356 ([M + H] , 100%);
+ + HRMS (TOF MS ES ) m/z calculated for C24H26N3 [M + H] 356.2127, found
356.2116.
156
7-Methyl-5,6-diphenylindolo[1,2-a][1,8]naphthyridine, 175
Me Ph
N Ph
N
Chemical Formula: C28H20N2 Molecular Weight: 384.48
7-Methyl-5,6-diphenylindolo[1,2-a][1,8]naphthyridine was prepared using general procedure E, from 3-methyl-1-(pyridin-2-yl)-1H-indole (31 mg,
0.15 mmol) to give the product as green/yellow crystals (21 mg, 0.06 mmol,
-1 37%); m.p. 217 °C; νmax/cm (neat): 3052, 2859, 1598; Rf 0.29 (EtOAc-hexane,
1 1:9); H NMR (300 MHz, CDCl3) δ = 7.72 (d, J = 7.9 Hz, 1 H, ArH), 7.65 (d, J
= 7.9 Hz, 1 H, ArH), 7.61 - 7.53 (m, 5 H, ArH), 7.52 - 7.51 (m, 2 H, ArH), 7.40 -
7.31 (m, 5 H, ArH), 7.25 - 7.19 (m, 2 H, ArH), 7.17 - 7.15 (m, 1 H, ArH), 2.41 (s,
13 3 H, CH3); C NMR (75 MHz, CDCl3) δ = 140.0 (CH), 135.9 (C), 135.1 (C),
134.0 (C), 133.5 (C), 130.3 (CH), 129.7 (CH), 129.5 (5 CH), 128.2 (C), 127.5 (C),
125.9 (2 CH), 125.5 (2 CH), 124.0 (CH), 123.7 (CH), 122.3 (C), 119.7 (C), 119.2
+ (CH), 113.1 (CH), 112.8 (CH), 110.3 (C), 108.7 (C), 9.6 (CH3); m/z (ES ) 385
+ + + ([M + H] , 100%); HRMS (TOF MS ES ) m/z calculated for C28H21N2 [M + H]
385.1705, found 385.1698.
157
1-(5,6-Diphenylindolo[1,2-a][1,8]naphthyridin-7-yl)ethan-1-one, 176
O
Ph
N Ph
N
Chemical Formula: C H N O 29 2.0 2 Molecular Wei ht: 412 4 g 9
1-(5,6-Diphenylindolo[1,2-a][1,8]naphthyridin-7-yl)ethan-1-one was prepared using general procedure E, from 1-(1-(pyridin-2-yl)-1H-indol-3-yl)ethanone
(35 mg, 0.15 mmol) to give the product as green/yellow crystals (36 mg, 0.09
-1 mmol, 58%); m.p. >250 °C; νmax/cm (neat): 3010, 2898, 1680, 1579; Rf 0.27
(EtOAc-hexane, 1:9); 1H NMR (400 MHz, CDCl3) δ = 9.65 (d, J = 8.4 Hz, 1 H,
ArH), 8.75 (d, J = 4.6 Hz, 1 H, ArH), 7.95 (d, J = 7.9 Hz, 1 H, ArH), 7.72 (d, J
= 7.9 Hz, 1 H, ArH), 7.59 - 7.46 (m, 2 H, ArH), 7.35 - 7.28 (m, 3 H, ArH), 7.26 -
13 7.20 (m, 6 H, ArH), 7.13 (d, J = 7.4 Hz, 2 H, ArH), 1.73 (s, 3 H, CH3); C NMR
(101 MHz, CDCl3) δ = 199.6 (COMe), 147.9 (C), 147.2 (C), 137.8 (C), 136.0
(C), 135.6 (C), 135.3 (C), 134.9 (CH), 132.5 (CH), 131.1 (CH), 130.7 (CH),
130.7 (CH), 128.6 (CH), 128.3 (CH), 128.2 (CH), 127.8 (CH), 127.5 (CH), 126.4
(CH), 124.0 (CH), 123.9 (CH), 122.1 (CH), 119.7 (CH), 119.7 (C), 119.3 (C),
118.3 (CH), 116.2 (C), 115.4 (CH), 115.3 (C), 31.9 (COMe); m/z (ES+) 413 ([M
+ + + H] , 100%); HRMS (ESI) m/z calculated for C29H20N2ONa [M + Na]
435.1473, found 435.1482.
158
Methyl 5,6-diphenylindolo[1,2-a][1,8]naphthyridine-7-carboxylate, 177
O O Ph
N Ph
N
Chemical Formula: C29H20N2O2 Molecular 428.49 Weight:
Methyl 5,6-diphenylindolo[1,2-a][1,8]naphthyridine-7-carboxylate was prepared using general procedure E, from methyl 1-(pyridin-2-yl)-1H-indole-3-carboxylate
(38 mg, 0.15 mmol) to give the product as green/yellow crystals (46 mg,
-1 0.11 mmol, 72%); m.p. >250 °C; νmax/cm (neat): 3052, 3039, 2989, 1738, 1587;
1 Rf 0.35 (EtOAc-hexane, 1:9); H NMR (400 MHz, CDCl3) δ = 9.65 (d, J = 8.4
Hz, 1 H, ArH), 8.76 (dd, J = 1.6, 4.6 Hz, 1 H, ArH), 8.10 (d, J = 7.6 Hz, 1 H,
ArH), 7.71 (dd, J = 1.6, 7.9 Hz, 1 H, ArH), 7.59 - 7.48 (m, 2 H, ArH), 7.33 - 7.24
(m, 5 H, ArH), 7.23 - 7.16 (m, 4 H, ArH), 7.14 - 7.08 (m, 2 H, ArH), 3.14 (s, 3
13 H, CO2Me); C NMR (101 MHz, CDCl3) δ = 165.8 (CO2Me), 147.9 (CH),
137.9 (C), 137.2 (C), 136.1 (C), 136.0 (C), 135.9 (C), 135.6 (C), 132.6 (C), 132.4
(CH), 131.1 (CH), 131.0 (CH), 130.6 (CH), 129.7 (CH), 128.9 (CH), 128.1 (CH),
127.7 (CH), 127.4 (CH), 127.1 (CH), 124.0 (CH), 123.9 (CH), 119.9 (CH), 119.7
(C), 119.5 (CH), 119.3 (C), 118.3 (CH), 104.9 (CH), 103.8 (C), 51.4 (CO2Me);
+ + m/z (ES ) 429 ([M + H] , 100%); HRMS (ESI) m/z calculated for C29H21N2O [M
+ H]+ 429.1603, found 429.1607.
159
5,6-Diphenylpyrimido[5',4':5,6]pyrido[1,2-a]indole-7-carbaldehyde, 178
O H Ph
N Ph
N N
Chemical Formula: C H N O 27 1.7 3 o ecu ar e t: M l l W igh 399 44
5,6-Diphenylpyrimido[5',4':5,6]pyrido[1,2-a]indole-7-carbaldehyde was prepared using general procedure E, from 1-(pyrazin-2-yl)-1H-indole-3-carbaldehyde
(33 mg, 0.15 mmol) to give the product as orange crystals (21 mg, 0.05 mmol,
-1 35%); m.p. >250 °C; νmax/cm (neat): 3058, 2840, 1671, 1595; Rf 0.32 (EtOAc-
1 hexane, 1:9); H NMR (400 MHz, CDCl3) δ = 9.48 (d, J = 7.3 Hz, 1 H, ArH),
8.84 (s, 1 H, CHO), 8.77 (d, J = 6.5 Hz, 1 H, ArH), 8.75 (s, 2 H, ArH), 7.67 -
7.53 (m, 2 H, ArH), 7.40 - 7.27 (m, 8 H, ArH), 7.19 ppm (d, J = 7.5 Hz, 2 H,
13 ArH); C NMR (101 MHz, CDCl3) δ = 187.5 (CHO), 143.6 (CH), 141.7 (CH),
141.3 (C), 140.5 (C), 139.3 (C), 137.2 (C), 136.5 (C), 135.7 (C), 134.4 (C), 133.7
(CH), 130.6 (CH), 129.7 (CH), 129.1 (CH), 128.8 (CH), 128.3 (CH), 128.2 (CH),
127.9 (CH), 127.7 (CH), 127.7 (CH), 126.0 (CH), 125.5 (CH), 123.2 (C), 117.6
(CH), 116.9 (C), 116.7 (CH), 113.7 (C); m/z (ES+) 400 ([M + H]+, 100%); HRMS
+ + (TOF MS ES ) m/z calculated for C27H18N3O [M + H] 400.1444, found
400.1446.
160
Methyl 5,6-diphenylpyrazino[2',3':5,6]pyrido[1,2-a]indole-7-carboxylate, 179a
O O Ph
N Ph
N N
Chemical Formula: C28H19N3O2 Molecular Weight: 429.48
Methyl 5,6-diphenylpyrazino[2',3':5,6]pyrido[1,2-a]indole-7-carboxylate was prepared using general procedure E, from methyl 1-(pyrazin-2-yl)-1H-indole-3- carboxylate (38 mg, 0.15 mmol) to give the product as yellow/orange crystals
-1 (59 mg, 0.14 mmol, 91%); m.p. >250 °C; νmax/cm (neat): 3058, 2980, 1741,
1 1595; Rf 0.29 (EtOAc-hexane, 1:9); H NMR (400 MHz, CDCl3) δ = 9.44 (d, J =
8.3 Hz, 1 H, ArH), 8.67 - 8.61 (m, 2 H, ArH), 8.08 (d, J = 8.0 Hz, 1 H, ArH),
7.62 - 7.50 (m, 4 H, ArH), 7.37 - 7.34 (m, 2 H, ArH), 7.25 - 7.22 (m, 4 H, ArH),
13 7.16 - 7.12 (m, 2 H, ArH), 3.15 (s, 3 H, CO2Me); C NMR (101 MHz, CDCl3) δ
= 160.9 (CO2Me), 145.5 (CH), 140.8 (CH), 140.2 (C), 137.6 (C), 137.3 (C),
136.6 (C), 135.5 (C), 133.9 (C), 131.6 (C), 131.0 (2 CH), 129.6 (2 CH), 128.3 (2
CH), 128.2 (CH), 127.9 (CH), 127.6 (2 CH), 127.3 (CH), 124.7 (CH), 123.2 (C),
+ 120.5 (CH), 118.4 (C), 117.6 (CH), 113.3 (C), 51.6 (CO2Me); m/z (ES ) 430 ([M
+ + + + H] , 100%); HRMS (TOF MS ES ) m/z calculated for C28H20N3O2 [M + H]
430.1556, found 430.4773.
161
Methyl 5,6-dipropylpyrazino[2',3':5,6]pyrido[1,2-a]indole-7-carboxylate, 179b
O O
N
N N
Chemical Formula: C22H23N3O2 Molecular 361.44 Weight:
Methyl 5,6-dipropylpyrazino[2',3':5,6]pyrido[1,2-a]indole-7-carboxylate was prepared using general procedure E, from methyl
1-(pyrazine-2-yl)-1H-indole-3-carboxylate (38mg, 0.15 mmol) to give the product
-1 as yellow/green crystals (23 mg, 0.06 mmol, 42%) m.p. 217 °C; νmax/cm (neat):
1 3035, 2998, 1732, 1596; Rf 0.32 (EtOAc-hexane, 1:9); H NMR (400 MHz,
CDCl3) δ = 8.89 - 8.81 (m, 1 H, ArH), 8.37 (s, 2 H, ArH), 8.18 (d, J = 6.3 Hz, 1
H, ArH), 7.39 - 7.33 (m, 2 H, ArH), 4.03 (s, 3 H, CO2Me), 3.24 - 3.13 (m, 4 H),
1.74 - 1.59 (m, 4 H), 1.11 (t, J = 7.3 Hz, 3 H, CH3), 1.05 (t, J = 7.3 Hz, 3 H,
13 CH3); C NMR (101 MHz, CDCl3) δ = 165.7 (CO2Me), 144.5 (CH), 140.5
(CH), 140.1 (C), 137.1 (C), 136.6 (C), 135.2 (C), 134.6 (C), 127.8 (CH), 124.2
(CH), 124.0 (CH), 123.8 (C), 121.5 (C), 115.6 (CH), 105.9 (C), 51.3 (CO2Me),
31.2 (CH2), 28.9 (CH2), 23.6 (CH2), 22.9 (CH2), 14.7 (CH3), 14.3 (CH3); m/z
(ES+) 362 ([M + H]+, 100%); HRMS (TOF MS ES+) m/z calculated for
+ C22H24N3O2 [M + H] 362.1863, found 362.1866.
162
General procedure F for the synthesis of 395 and 396
To a solution of either 3-(p-tolyl)propiolic acid (310 mg, 2 mmol, 1 equiv.) or 3-
(2-chlorophenyl)propiolic acid (360mg, 2 mmol, 1 equiv.) in acetonitrile (10 mL)
was added K2CO3 (304 mg, 2.2 mmol, 1.1 equiv.). Methyl iodide (315 mg, 0.14 mL, 2.2 mmol, 1.1 equiv.) was added dropwise. The reaction was stirred at room
temperature for 3 h. The reaction was then diluted with Et2O (20 mL) and extracted with water (2 x 50 mL). The organic layers were dried over MgSO4 and the solvent removed in vacuo.
Methyl 3-(p-tolyl)propiolate, 395
O
O
Chemical Formula: C H O 11 .10 2 Molecular Weight: 174 20
Methyl 3-(p-tolyl)propiolate was prepared using general procedure F, from 3-(p- tolyl)propiolic acid (310 mg, 2 mmol) to give the product as a yellow oil (141
1 mg, 0.81 mmol, 42%); H NMR (500 MHz, CDCl3) δ = 7.49 (d, J = 7.1 Hz, 2 H,
ArH), 7.19 (d, J = 7.1 Hz, 2 H, ArH), 3.85 (s, 3 H, CO2Me), 2.39 (s, 3 H,
13 CH3); C NMR (101 MHz, CDCl3) δ = 154.7 (CO2Me), 141.4 (C), 132.9 (2
CH), 129.3 (2 CH), 116.4 (C), 87.3 (alkynyl C), 80.2 (alkynyl C), 52.8 (CO2Me),
+ + 21.7 (CH3); m/z (ES ) 175 ([M + H] , 100%). Data was consistent with the literature.257
163
Methyl 3-(2-chlorophenyl)propiolate, 396
O
O
Cl
Chemical Formula: C10H7ClO2 Molecular Weight: 194.61
Methyl 3-(2-chlorophenyl)propiolate was prepared using general procedure F, from 3-(2-chlorophenyl)propiolic acid (360 mg, 2 mmol) to give the product as a
1 yellow oil (138 mg, 0.70 mmol, 35%); H NMR (400 MHz, CDCl3) δ = 7.62 (dd,
J = 1.5, 7.9 Hz, 1 H, ArH), 7.45 (dd, J = 1.1, 7.9 Hz, 1 H, ArH), 7.39 (td, J =
1.5, 7.6 Hz, 1 H, ArH), 7.28 (td, J = 1.1, 7.6 Hz, 1 H, ArH), 3.87 (s, 3 H,
13 CO2Me); C NMR (101 MHz, CDCl3) δ = 154.2 (CO2Me), 137.3 (CH), 134.6
(C), 131.6 (CH), 129.6 (CH), 126.7 (CH), 119.8 (C), 84.5 (alkynyl C), 82.6
+ 35 + (alkynyl C), 52.9 (CO2Me); m/z (ES ) 195 ([M + H, Cl] , 100%), 197 ([M +
H, 37Cl]+, 30%). Data was consistent with the literature.258
164
Procedure for the synthesis of 1-acetyl-1H-indole-3-carbaldehyde, 180
CHO
N
O
Chemical Formula: C11H9NO2 Molecular Weight: 187.20
A solution of 1H-indole-3-carbaldehyde (145 mg, 1 mmol, 1 equiv.), acetyl chloride (113 mg, 0.1 mL, 1.5 mmol, 1.5 equiv.) and NaOH (44 mg, 1.1 mmol,
1.1 equiv.) in CH2Cl2 (2 mL) was stirred vigorously overnight. The reaction was washed thoroughly with water and the organic layers dried over MgSO4. The solvent was removed in vacuo and the product purified by recrystallisation from methanol (5 mL) to give the product as pink crystals (76 mg, 0.41 mmol,
1 41%); H NMR (400 MHz, CDCl3) δ = 10.18 (s, 1H, CHO), 8.42 (d, J = 7.6 Hz,
1H, ArH), 8.30 (dd, J = 6.6 Hz, 1.9 Hz, 1H, ArH), 8.09 (s, 1H, ArH), 7.52–7.37
13 (m, 2H, ArH), 2.79 (s, 3H, CH3); C NMR (101 MHz, CDCl3) δ = 185.9
(CHO), 168.4 (COMe), 136.5 (C), 135.2 (C), 126.9 (CH), 126.2 (CH), 125.6
+ + (CH), 122.8 (CH), 121.9 (CH), 116.5 (C), 24.1 (CH3); m/z (ES ) 188 (M + H) .
Data was consistent with the literature.259
165
General procedure G for the synthesis of N-phenylacetyl indoles
To a solution of 1H-indole-3-carbaldehyde (145 mg, 1 mmol, 1 equiv.), triethylamine (202 mg, 0.3 mL, 2 mmol, 2 equiv.) and 4-dimethylaminopyridine
(DMAP, 12.2 mg, 0.1 mmol, 0.1 equiv.) in CH2Cl2 (15 mL) was added the phenylacetyl chloride (1.5 mmol, 1.5 equiv.) at 0 °C. The reaction was warmed to room temperature and stirred overnight. The reaction was washed thoroughly
with water and the organic layers dried over MgSO4. The solvent was removed in vacuo and the product purified by column chromatography (9:1 hexane:ethyl acetate) and recrystallised from methanol (5 mL).
1-(2-(4-Methoxyphenyl)acetyl)-1H-indole-3-carbaldehyde, 181
CHO
N
O
OMe
Chemical Formula: C18H15NO3 Molecular 293.32 Weight:
1-(2-(4-Methoxyphenyl)acetyl)-1H-indole-3-carbaldehyde was prepared using general procedure G, from 1H-indole-3-carbaldehyde (145 mg, 1 mmol) as off
-1 white crystals (226 mg, 0.77 mmol, 77%); m.p. 129 °C; νmax/cm (neat): 3131,
1 3012, 2950, 2927, 2831, 1728, 1668, 1585; Rf 0.03 (EtOAc-hexane, 1:9); H
NMR (400 MHz, CDCl3) δ = 10.11 (s, 1 H, CHO), 8.47 (d, J = 8.3 Hz, 1 H,
ArH), 8.28 (d, J = 7.5 Hz, 1 H, ArH), 8.15 (s, 1 H, ArH), 7.51 - 7.39 (m, 2 H, 166
ArH), 7.26 (d, J = 8.8 Hz, 2 H, ArH), 6.94 (d, J = 8.8 Hz, 2 H, ArH), 4.29 (s, 2
13 H, CH2), 3.82 (s, 3 H, OMe); C NMR (101 MHz, CDCl3) δ = 185.6 (CHO),
169.8 (phenylacetyl C=O), 159.1 (C), 134.8 (C), 130.1 (2 CH), 127.0 (C), 125.9
(C), 125.5 (CH), 124.2 (CH), 122.8 (CH), 121.9 (CH), 116.6 (C), 114.6 (2 CH),
+ + 114.0 (CH), 55.3 (OMe), 42.1 (CH2); m/z (ES ) 294 ([M + H] , 100%); HRMS
+ + (TOF MS ES ) m/z calculated for C18H16NO3 [M + H] 294.1130, found
294.1130.
1-(2-(4-Chlorophenyl)acetyl)-1H-indole-3-carbaldehyde, 182
CHO
N
O
Cl
Chemical Formula: C17H12ClNO2 Molecular 297.74 Weight:
1-(2-(4-Chlorophenyl)acetyl)-1H-indole-3-carbaldehyde was prepared using general procedure G, from 1H-indole-3-carbaldehyde (145 mg, 1 mmol) as an off
-1 white solid (241 mg, 0.81 mmol, 81%); m.p. 134 °C; νmax/cm (neat): 3100,
1 2999, 2927, 1725, 1669, 1584; Rf 0.04 (EtOAc-hexane, 1:9); H NMR (400 MHz,
CDCl3) δ = 10.09 (s, 1 H, CHO), 8.46 (d, J = 8.3 Hz, 1 H, ArH), 8.28 (d, J = 7.5
Hz, 1 H, ArH), 8.14 (s, 1 H, ArH), 7.62 (d, J = 8.8 Hz, 2 H, ArH), 7.53 (d, J =
13 8.8 Hz, 2 H, ArH), 7.50 - 7.39 (m, 2 H, ArH), 4.38 (s, 2 H, CH2); C NMR (101
MHz, CDCl3) δ = 185.6 (CHO), 169.8 (phenylacetyl C=O), 135.0 (C), 134.8 (C),
167
134. 5 (C), 130.5 (2 CH), 125.9 (C), 125.5 (CH), 124.2 (CH), 122.8 (CH), 121.9
+ (CH), 121.6 (2 CH), 116.6 (C), 114.0 (CH), 42.1 (CH2); m/z (ES ) 298 ([M +
H, 35Cl]+, 100%), 300 ([M + H, 37Cl]+, 30%); HRMS (TOF MS ES+) m/z
35 + calculated for C17H12ClNO2Na [M + Na, Cl] 320.0454, found 320.0460.
General procedure H for the attempted ruthenium-catalysed alkyne insertion (see results and discussion for specific reagents and equivalents)
To a 10 mL RBF was added the indole (0.5 mmol), [Ru(p-cymene)Cl2]2 (15 mg,
0.025 mmol), and Cu(OAc)2·H2O (10 mg, 0.05 mmol). The solvent (2 mL) was added, followed by the alkyne (1 mmol).95–97,126–137 The reaction was heated at 100
°C under air or nitrogen overnight. The reaction mixture was cooled to room temperature and filtered through celite (eluent EtOAc). The solvent was removed in vacuo and the mixture analysed by LC-MS.
168
Procedure for the synthesis of complex 194
O O Cl Rh N N
Chemical Formula: C25H26ClN2O2Rh Molecular Weight: 524.85
To a dried schlenk flask under N2 was added the indole (76 mg, 0.30 mmol, 2.1 equiv.), [RhCp*Cl2]2 (87 mg, 0.14 mmol, 1.0 equiv.) and NaOAc (69 mg, 0.84 mmol, 6.0 equiv.). Dry CH2Cl2 (8 mL) was added and the reaction stirred at room temperature overnight.138 The reaction mixture was then filtered and the
solvent removed in vacuo. The residue was washed with Et2O (5 x 5 mL) and
recrystallised from CHCl3 (25 mL/g) to furnish the product as orange crystals
-1 (143 mg, 0.27 mmol, 97%); m.p. >250 °C; νmax/cm (neat): 3068, 2948, 2917,
1 2224, 1700, 1608, 1593; H NMR (400 MHz, CDCl3) δ = 8.41 (dd, J = 1.7, 6.0
Hz, 1 H, ArH), 8.20 (dd, J = 1.4, 8.0 Hz, 1 H, ArH), 7.77 (dd, J = 1.0, 8.3 Hz, 1
H, ArH), 7.70 (ddd, J = 1.7, 7.3, 8.3 Hz, 1 H, ArH), 7.68 (dd, J = 0.7, 8.2 Hz, 1
H, ArH), 7.26 (ddd, J = 0.7, 7.1, 8.0 Hz, 1 H, ArH), 7.15 (ddd, J = 1.4, 7.1, 8.2
Hz, 1 H, ArH), 6.85 (ddd, J = 1.0, 6.0, 7.3 Hz, 1 H, ArH), 3.95 (s, 3 H, CO2Me),
13 1.63 (s, 15 H, 5 x Cp* Me); C NMR (101 MHz, CDCl3) δ = 184.2 (Rh–C, d,
JRh–C = 42.6 Hz), 167.4 (CO2Me), 154.9 (C), 151.9 (CH), 140.1 (CH), 136.3 (C),
133.2 (C), 122.7 (CH), 121.3 (CH), 120.5 (CH), 119.4 (CH), 117.2 (C), 110.9
(CH), 110.2 (CH), 97.8 (5 x Cp*–Rh, d, JRh–C = 5.9 Hz), 51.1 (CO2Me), 9.3 (5 x
169
Cp* Me); m/z (ES+) 489 ([M – Cl]+, 100%); HRMS (TOF MS ES+) m/z
+ calculated for C25H26N2O2Rh [M – Cl] 489.1049, found 489.1041.
Crystals suitable for X-ray diffraction were grown from CHCl3.
Summary of X-ray data Compound reference s4261na
Chemical formula C27H28Cl7N2O2Rh Formula mass 763.57 Crystal system Triclinic a/Å 11.0913(4) b/Å 11.6852(5) c/Å 14.8597(6) /° 97.629(2)
βα/° 105.933(2) γ/° 117.933(2) Unit cell volume/Å3 1556.79(11) Temperature/K 100(2) Space group P-1 No. of formula units per unit cell, Z 2 No. of reflections measured 12350 No. of independent reflections 5832
Rint 0.0265
Final R1 values (I > 2σ(I)) 0.0458 Final wR(F2) values (I > 2σ(I)) 0.1119
Final R1 values (all data) 0.0476 Final wR(F2) values (all data) 0.1132
170
Procedure for the complex 194-catalysed alkyne insertion
To a vial was added methyl 1-(pyridin-2-yl)-1H-indole-3-carboxylate (50 mg, 0.2 mmol, 1.0 equiv.), diphenyl acetylene (43 mg, 0.24 mmol, 1.2 equiv.), complex
194 (5.3 mg, 0.01 mmol, 5 mol%), Cu(OAc)2∙H2O (80 mg, 0.4 mmol, 2 equiv.)
119–121 and Na2CO3 (40 mg, 0.4 mmol, 2 equiv.). The vial was sealed, evacuated and back filled with nitrogen. Xylene (1 mL) was added and the reaction stirred at 150 °C overnight. The reaction was cooled to room temperature and the product purified by flash column chromatography (eluent 8:2 Hex:EtOAc). 177 was isolated as yellow/green crystals (38 mg, 0.09 mmol, 44%).
171
3.3. One-pot zipper-click reaction
General procedure A for the KAPA acetylene zipper reaction174,176
To a vial was added KH (200 mg, 1.4 mmol, 1.4 equiv., 30% in mineral oil). The vial was sealed under nitrogen and the oil removed by washing with pentane (3 x
3 mL). To this was added 1,3-DAP (1.2 mL) and the mixture stirred at 40 °C for
30 min. This furnished a yellow suspension to which was added the alkyne (1 mmol, 1 equiv.). The reaction was left between 1-18 h, after which the insoluble potassium acetylide could be observed as an off white precipitate, which was quenched with ice water (1 mL). The organic components were extracted with
CH2Cl2, filtered through silica and the solvent was removed in vacuo.
Dec-1-yne, 343b
Chemical Formula: C10H18 Molecular Weight: 138.25
Dec-1-yne was prepared using general procedure A, from dec-5-yne (138 mg,
0.18 mL, 1 mmol) to give the product as a colourless oil (115 mg, 0.83 mmol,
1 83%); H NMR (400 MHz, CDCl3) δ = 2.18 - 2.15 (2 H, m, HC≡C–CH2–), 1.90
(t, J = 2.2, 1 H, –C≡CH), 1.57−1.31 (m, 12 H, CH2), 0.91 (t, J = 6.9, 3 H,
13 CH3); C NMR (101 MHz, CDCl3) δ = 84.6 (–C≡CH), 68.0 (–C≡CH), 31.8
(HC≡C–CH2–), 29.1 (CH2), 29.1 (CH2), 28.8 (CH2), 28.6 (CH2), 22.7 (CH2),
+ 18.3 (CH2), 14.1 (CH3); m/z (EI) 138 [M] . Data was consistent with the literature.260
172
Procedure for the synthesis of 4-azidobenzonitrile, 344228
NC N3
Chemical Formula: C7H4N4 Molecular 144.14 Weight:
CAUTION: Azides are both shock sensitive and toxic. The use of acids in the presence of the azide ion is advised against due to the possible release of
hydrazoic acid gas, a known poison. Furthermore, the useof CH2Cl2 in the presence of the azide ion may lead to the formation of diazidomethane
(N3CH2N3) which is known to self-detonate. No incidents occurred during the synthesis or use of azides but for these reasons the reactions were not performed on scales greater than 5g.
To a dry round-bottomed flask was added 4-aminobenzonitrile (6.2 g, 52 mmol,
1 equiv.) and acetonitrile (100 mL). The flask was flushed with N2 and cooled to
0 °C. Azidotrimethylsilane (8.2 mL, 62 mmol, 1.2 equiv.) was added by syringe and the reaction stirred for 5 min. tBuONO was added dropwise over 45 minutes at 0 °C. The reaction was warmed to room temperature and stirred overnight.
The solvent was removed in vacuo to give 4-azidobenzonitrile as an orange solid
1 (7.2 g, 50 mmol, 96%); 60-61 °C; H NMR (400 MHz, CDCl3) δ = 7.64 (d, J =
13 8.4 Hz, 2 H, ArH), 7.11 (d, J = 8.4 Hz, 2 H, ArH); C NMR (101 MHz, CDCl3)
δ = 145.1 (C), 134.2 (2 CH), 119.9 (2 CH), 118.5 (C≡N), 108.5 (C); m/z (EI) 144
+ + 215 ([M] , 60%) , 116 ([M – N2] , 100%). Data was consistent with the literature.
173
Procedure for the CuAAC reaction for the synthesis of
4-(4-hexyl-1H-1,2,3-triazol-1-yl)benzonitrile, 345a
C6H13
N N N
NC
Chemical Formula: C15H18N4 Molecular 254.34 Weight:
To the azide (144 mg, 1 mmol, 1 equiv.) was added CuSO4∙5H2O (5 mg, 0.02 mmol, 0.02 equiv.), and sodium ascorbate (20 mg, 0.1 mmol, 0.1 equiv.) in
t H2O: BuOH (2:1, 1 mL). Oct-4-yne (110 mg, 0.15 mL, 1 mmol) was added. The
reaction was stirred at RT overnight. The reaction was washed with CH2Cl2, the organic layers combined and the solvent removed in vacuo; the product was isolated using flash column chromatography (hexane:ethyl acetate
9:1). 4-(4-Hexyl-1H-1,2,3-triazol-1-yl)benzonitrile was isolated as a yellow solid
-1 (234 mg, 0.92 mmol, 92%); m.p. 94-96 °C; νmax/cm (neat): 3083, 2960, 2930,
1 2867, 2220, 1602, 1577; Rf 0.09 (EtOAc-hexane, 1:9); H NMR (400 MHz,
CDCl3) δ = 7.90 (d, J = 8.8 Hz, 2 H, ArH), 7.83 (s, 1 H, triazole ArH), 7.80 (d, J
= 8.8 Hz, 2 H, ArH), 2.77 (t, J = 7.7 Hz, 2 H, CH2), 1.70 (m, 2 H, CH2), 1.39 -
13 1.21 (m, 6 H, CH2), 0.84 (t, J = 6.7 Hz, 3 H, CH3); C NMR (101 MHz, CDCl3)
δ = 149.9 (C), 139.8 (triazole C), 133.7 (2 CH), 120.2 (2 CH), 118.4 (triazole
CH), 117.7 (C≡N), 111.8 (C), 31.6 (CH2), 29.3 (CH2), 29.0 (CH2), 25.6 (CH2),
+ + + 22.5 (CH2), 14.2 (CH3); m/z (ES ) 255 ([M + H] , 100%); HRMS (TOF MS ES )
+ m/z calculated for C15H18N4 [M + H] 255.1610, found 255.1612.
174
General procedure B for the one-pot Zipper-click reaction (KAPA method)
To a vial was added KH (200 mg, 1.4 mmol, 1.4 equiv., 30% in mineral oil). The vial was sealed under nitrogen and the oil removed by washing with pentane (3 x
3 mL). To this was added diaminopropane (1.2 mL) and the mixture was stirred at 40 °C for 30 mins. This furnished a yellow suspension to which was added the alkyne (1 mmol, 1 equiv.). The reaction was left between 1 and 18 h, after which the insoluble potassium acetylide could be observed as an off white precipitate, which was subsequently quenched with ice water (1 mL). To the reaction was
added CuSO4∙5H2O (5 mg, 0.02 mmol, 0.02 equiv.), sodium ascorbate (20 mg,
0.1 mmol, 0.1 equiv.) and the azide (1 mmol, 1 equiv.) in CH2Cl2 (1 mL), and the reaction was stirred overnight. The organic layers were washed with aq.
NH4Cl and the solvent removed in vacuo; the product was isolated using flash column chromatography (hexane:ethyl acetate 9:1).
175
4-(4-Octyl-1H-1,2,3-triazol-1-yl)benzonitrile, 345b
C8H17
N N N
NC
Chemical Formula: C17H22N4 Molecular 282.39 Weight:
4-(4-Octyl-1H-1,2,3-triazol-1-yl)benzonitrile was prepared using general procedure B, from dec-5-yne (138 mg, 0.18 mL, 1 mmol) and 4-azidobenzonitrile
(144 mg, 1 mmol) to give the product as a yellow solid (201 mg, 0.71 mmol,
-1 71%); m.p. 105-106 °C; νmax/cm (neat): 3125, 3081, 2956, 2931, 2860, 2236,
1 1609, 1586; Rf 0.07 (EtOAc-hexane, 1:9); H NMR (400 MHz, CDCl3) δ = 7.90
(d, J = 8.8 Hz, 2 H, ArH), 7.83 (s, 1 H, triazole ArH), 7.80 (d, J = 8.8 Hz, 2 H,
ArH), 2.77 (t, J = 7.6 Hz, 2 H, CH2), 1.70 (m, 2 H, CH2), 1.39 - 1.21 (m, 10 H,
13 CH2), 0.84 (t, J = 6.6 Hz, 3 H, CH3); C NMR (101 MHz, CDCl3) δ = 149.9
(C), 139.9 (triazole C), 133.7 (2 CH), 120.2 (2 CH), 118.4 (triazole CH), 117.7
(C≡N), 111.8 (C), 31.7 (CH2), 29.2 (CH2), 29.1 (CH2), 29.1 (CH2), 29.0 (CH2),
+ + 25.5 (CH2), 22.5 (CH2), 14.0 (CH3); m/z (ES ) 283 ([M + H] , 100%); HRMS
+ + (TOF MS ES ) m/z calculated for C17H23N4 [M + H] 283.1923, found
283.1920.
176
1-(4-Iodophenyl)-4-octyl-1H-1,2,3-triazole, 345c
C6H13
N N N
I
Chemical Formula: C14H18IN3 Molecular 355.22 Weight:
1-(4-Iodophenyl)-4-octyl-1H-1,2,3-triazole was prepared using general procedure
B, from oct-4-yne (110 mg, 0.15 mL, 1 mmol) and 1-azido-4-iodobenzene (245 mg, 1 mmol) to give the product as a yellow solid (287 mg, 0.75 mmol, 75%);
-1 m.p. 81 °C; νmax/cm (neat): 3079, 2959, 2901, 1592; Rf 0.18 (EtOAc-hexane,
1 1:9); H NMR (400 MHz, CDCl3) δ = 7.84 (d, J = 8.8 Hz, 2 H, ArH), 7.70 (s, 1
H, triazole ArH), 7.50 (d, J = 8.8 Hz, 2 H, ArH), 2.79 (t, J = 7.6 Hz, 2 H, CH2),
1.73 (quin, J = 7.6 Hz, 2 H, CH2), 1.43 - 1.31 (m, 6 H, CH2), 0.90 (t, J = 6.7 Hz,
13 3 H, CH3); C NMR (101 MHz, CDCl3) δ = 138.7 (2 CH), 138.7 (triazole C),
121.8 (2 CH), 121.0 (C), 118.4 (triazole CH), 93.1 (C), 31.5 (CH2), 29.3 (CH2),
+ + 28.9 (CH2), 25.6 (CH2), 22.5 (CH2), 14.1 (CH3); m/z (ES ) 356 ([M + H] ,
+ + 100%); HRMS (ES ) m/z calculated for C14H19IN3 [M + H] 356.0624, found
356.0656.
177
1-(4-Chlorophenyl)-4-hexyl-1H-1,2,3-triazole, 345d
C6H13
N N N
Cl
Chemical Formula: C14H18ClN3 Molecular 263.77 Weight:
1-(4-Chlorophenyl)-4-hexyl-1H-1,2,3-triazole was prepared using general procedure B, from oct-4-yne (110 mg, 0.15 mL, 1 mmol) and
1-azido-4-chlorobenzene (153 mg, 1 mmol) to give the product as a yellow solid
(160 mg, 0.61 mmol, 61%); m.p. 75 °C; νmax/cm-1 (neat): 3123, 3084, 2947,
1 2926, 2846, 1595, 1554; Rf 0.20 (EtOAc-hexane, 1:9); H NMR (400 MHz,
CDCl3) δ = 7.71 - 7.67 (m, 3 H, ArH), 7.49 (d, J = 8.8 Hz, 2 H, ArH), 2.80 (t, J
= 7.7 Hz, 2 H, CH2), 1.74 (quin, J = 7.7 Hz, 2 H, CH2), 1.46 - 1.37 (m, 2 H,
13 CH2), 1.37 - 1.30 (m, 4 H, CH2), 0.90 (t, J = 6.9 Hz, 3 H, CH3); C NMR (101
MHz, CDCl3) δ = 135.5 (C), 138.8 (triazole C), 134.8 (C), 130.1 (2 CH), 121.7 (2
CH), 118.5 (triazole CH), 31.6 (CH2), 29.2 (CH2), 28.9 (CH2), 25.7 (CH2), 22.6
+ 35 + 37 + (CH2), 14.1 (CH3); m/z (ES ) 263 ([M + H, Cl] , 100%), 265 ([M + H, Cl] ,
+ + 30%); HRMS (TOF MS AP ) m/z calculated for C14H18ClN3Na [M + Na]
286.1087, found 286.1092.
178
Ethyl 4-(4-hexyl-1H-1,2,3-triazol-1-yl)benzoate, 345e
C6H13
N N N
EtO2C
Chemical Formula: C17H23N3O2 Molecular 301.39 Weight:
Ethyl 4-(4-hexyl-1H-1,2,3-triazol-1-yl)benzoate was prepared using general procedure B, from oct-4-yne (110 mg, 0.15 mL, 1 mmol) and ethyl 4-azidobenzoate (191 mg, 1 mmol) to give the product as a yellow solid
-1 (105 mg, 0.35 mmol, 35%); m.p. 71 °C; νmax/cm (neat): 2982, 2953, 2934, 2859,
1 1712, 1602, 1519; Rf 0.41 (EtOAc-hexane, 1:9); H NMR (400 MHz, CDCl3) δ =
8.20 (d, J = 8.8 Hz, 2 H, ArH), 7.84 (d, J = 8.8 Hz, 2 H, ArH), 7.79 (s, 1 H,
triazole ArH), 4.42 (q, J = 7.1 Hz, 2 H, –CO2CH2CH3), 2.81 (t, J = 7.7 Hz, 2 H,
CH2), 1.75 (quin, J = 7.7 Hz, 2 H, CH2), 1.43 (t, J = 7.1 Hz, 3 H, –
13 CO2CH2CH3), 1.39 - 1.32 (m, 6 H, CH2), 0.90 (t, J = 6.9 Hz, 3 H, CH3); C
NMR (101 MHz, CDCl3) δ = 165.3 (CO2Et), 139.6 (C), 137.7 (triazole C), 132.7
(C), 131.3 (2 CH), 119.8 (2 CH), 118.4 (triazole CH), 61.5 (CH3CH2O–), 31.8
(CH2), 29.2 (CH2), 28.9 (CH2), 25.6 (CH2), 22.6 (CH2), 14.3 (CH3CH2O–), 14.1
+ + + (CH3); m/z (ES ) 302 ([M + H] , 100%); HRMS (TOF MS ES ) m/z calculated
+ for C17H24N3O2 [M + H] 302.1896, found 302.1897.
179
1-(2-Bromo-4-fluorophenyl)-4-octyl-1H-1,2,3-triazole, 345g
C6H13
N N N
Br F
Chemical Formula: C14H17BrFN3 Molecular 326.21 Weight:
1-(2-Bromo-4-fluorophenyl)-4-octyl-1H-1,2,3-triazole was prepared using general procedure B, from oct-4-yne (110 mg, 0.15 mL, 1 mmol) and
1-azido-2-bromo-4-fluorobenzene (216 mg, 1 mmol) to give the product as a
-1 yellow solid (205 mg, 0.63 mmol, 63%); m.p. 79 °C; νmax/cm (neat): 3018,
1 3052, 2984, 2940, 1594; Rf 0.21 (EtOAc-hexane, 1:9); H NMR (400 MHz,
CDCl3) δ = 8.01 - 7.93 (m, 2 H, ArH), 7.73 (s, 1 H, ArH), 7.38 (t, J = 9.1 Hz, 1
H, ArH), 2.80 (t, J = 7.7 Hz, 2 H, CH2), 1.74 (quin, J = 7.7 Hz, 2 H, CH2), 1.41
13 (m, 2 H, CH2), 1.37 - 1.29 (m, 4 H, CH2), 0.90 (t, J = 6.7 Hz, 3 H, CH3); C
NMR (101 MHz, CDCl3) δ = 162.7 (d, J = 256.0 Hz, CF), 138.4 (triazole C),
132.6 (d, J = 3.6 Hz, C), 130.7 (d, J = 9.6 Hz, CH), 122.4 (d, J = 10.3 Hz, C),
121.1 (d, J = 25.6 Hz, CH), 118.4 (triazole CH), 115.9 (d, J = 22.0 Hz, CH), 31.6
+ (CH2), 29.2 (CH2), 28.9 (CH2), 25.7 (CH2), 22.6 (CH2), 14.1 (CH3); m/z (ES )
326 ([M + H, 79Br]+, 100%), 328 ([M + H, 81Br]+, 100%); HRMS (TOF MS ES+)
+ m/z calculated for C14H17BrFN3Na [M + Na] 348.0488, found 348.0493.
180
1-([1,1'-Biphenyl]-2-yl)-4-hexyl-1H-1,2,3-triazole, 345h
C6H13
N N N
Chemical Formula: C20H23N3 Molecular 305.43 Weight:
1-([1,1'-Biphenyl]-2-yl)-4-hexyl-1H-1,2,3-triazole was prepared using general procedure B, from oct-4-yne (110 mg, 0.15 mL, 1 mmol) and
2-azido-1,1'-biphenyl (195 mg, 1 mmol) to give the product as a yellow oil (204
-1 mg, 0.67 mmol, 67%); νmax/cm (neat): 3049, 2978, 2856, 1599; Rf 0.16
1 (EtOAc-hexane, 1:9); H NMR (400 MHz, CDCl3) δ = 7.65 (d, J = 8.4 Hz, 1 H,
ArH), 7.59 - 7.47 (m, 3 H, ArH), 7.32 - 7.25 (m, 3 H, ArH), 7.14 - 7.05 (m, 2 H,
ArH), 6.89 (s, 1 H, ArH), 2.61 (t, J = 7.4 Hz, 2 H, CH2), 1.51 (quin, J = 7.4 Hz,
13 2 H, CH2), 1.32 - 1.14 (m, 6 H, CH2), 0.87 (t, J = 6.9 Hz, 3 H, CH3); C NMR
(101 MHz, CDCl3) δ = 148.0 (C), 137.5 (C), 136.9 (triazole C), 135.3 (CH),
130.9 (CH), 129.6 (CH), 128.5 (2 CH), 128.5 (CH), 128.4 (2 CH), 127.8 (CH),
126.5 (C), 122.9 (triazole CH), 31.5 (CH2), 29.2 (CH2), 28.5 (CH2), 25.3 (CH2),
+ + + 22.5 (CH2), 14.1 (CH3); m/z (ES ) 306 ([M + H] , 100%); HRMS (TOF MS ES )
+ m/z calculated for C20H24N3 [M + H] 306.1970, found 306.1974.
181
(2-(4-Hexyl-1H-1,2,3-triazol-1-yl)phenyl)methanol, 345i
C6H13
N N N
OH
Chemical Formula: C15H21N3O Molecular 259.35 Weight:
(2-(4-Hexyl-1H-1,2,3-triazol-1-yl)phenyl)methanol was prepared using general procedure B, from oct-4-yne (110 mg, 0.15 mL, 1 mmol) and
(2-azidophenyl)methanol (149 mg, 1 mmol) to give the product as a yellow solid
-1 (171 mg, 0.66 mmol, 66%); m.p. 60 °C; νmax/cm (neat): 3290, 3062, 2924, 2870,
1 1582; Rf 0.11 (EtOAc-hexane, 1:9); H NMR (400 MHz, CDCl3) δ = 7.67 (s, 1
H, triazole ArH), 7.62 (dd, J = 1.8, 7.2 Hz, 1 H, ArH), 7.53 - 7.43 (m, 2H, ArH),
7.37 (dd, J = 1.6, 7.5 Hz, 1 H, ArH), 4.53 - 4.40 (m, 2 H, benzyl CH2), 3.73 (br.
s., 1 H, OH), 2.82 (t, J = 7.7 Hz, 2 H, CH2), 1.76 (quin, J = 7.6 Hz, 2 H, CH2),
13 1.46 - 1.31 (m, 6 H, CH2), 0.91 (t, J = 6.9 Hz, 3 H, CH3); C NMR (101 MHz,
CDCl3) δ = 148.8 (C), 136.2 (triazole C), 135.6 (CH), 131.6 (CH), 129.7 (CH),
129.0 (CH), 124.1 (C), 122.0 (triazole CH), 61.9 (CH2OH), 31.5 (CH2), 29.2
+ (CH2), 28.9 (CH2), 25.6 (CH2), 22.5 (CH2), 14.0 (CH3); m/z (ES ) 282 ([M +
+ + Na] , 100%); HRMS (TOF MS ES ) m/z calculated for C15H21N3NaO [M +
Na]+ 282.1582, found 282.1583.
182
Procedure for the synthesis of dodeca-5,7-diyne, 261b236
Chemical Formula: C12H18 Molecular Weight: 162.28
A mixture of hex-1-yne (1.15 mL, 10 mmol, 1 equiv.), Cu(OAc)2∙H2O (182 mg,
1 mmol, 0.1 equiv.) and piperidine (1 mL, 10 mmol, 1 equiv.) in CH2Cl2 (20 mL) was stirred at room temperature overnight. The reaction mixture was then filtered through silica and the solvent removed in vacuo. Dodeca-5,7-diyne was isolated as a colourless oil (561 mg, 3.5 mmol, 69%); 1H NMR (400 MHz,
CDCl3) δ = 2.26 (t, J = 6.9 Hz, 4 H, 2 –C≡C–CH2–), 1.56 - 1.35 (m, 8 H, 4
13 CH2), 0.90 (t, J = 7.2 Hz, 6 H, 2 CH3); C NMR (101 MHz, CDCl3) δ = 77.5 (2 alkynyl C), 65.1 (2 alkynyl C), 30.3 (2 CH2), 21.9 (2 CH2), 18.9 (2 CH2), 13.5 (2
+ 236 CH3); m/z (EI) 162 ([M] , 100%). Data was consistent with the literature.
General procedure C for the LAETA acetylene zipper reaction187,190
To a solution of ethylene diamine (EDA) (0.2 mL, 3 mmol, 3 equiv.) in THF
(0.75 mL) was added lithium metal (21 mg, 3 mmol, 3 equiv.) with stirring at
room temperature under a stream of N2. The reaction mixture was stirred under
N2 at 40 °C until it formed a grey suspension. The reaction was cooled to room temperature and hexane (0.75 mL) followed by toluene (0.75 mL) was added.
The reaction was cooled to 15 °C and the alkyne (1 mmol, 1 equiv.) was added, and the reaction stirred at 15 °C for 1 h. The mixture was then poured into ice 183 water (5 mL) and extracted with diethyl ether. The organic layers were washed
with aq. NH4Cl, H2O, and brine, then dried over MgSO4 and the solvent removed in vacuo.
Dodeca-1,3-diyne, 397
Chemical Formula: C12H18 Molecular 162.28 Weight:
Dodeca-1,3-diyne was prepared using general procedure C, from dodeca-5,7- diyne (162 mg, 1 mmol) to give the product as a colourless oil (125 mg, 0.77
1 mmol, 77%); H NMR (500 MHz, CDCl3) δ = 2.25 (t, J = 7.3 Hz, 2 H,
HC≡C≡C–CH2–), 1.96 (s, 1 H, HC≡C≡C–CH2–), 1.56 - 1.50 (m, 2 H, CH2), 1.41
- 1.30 (m, 2 H, CH2), 1.29 - 1.25 (m, 8 H, CH2), 0.88 (t, J = 6.8 Hz, 3 H,
13 CH3); C NMR (126 MHz, CDCl3) δ = 78.7 (alkynyl C), 68.6 (alkynyl C), 64.7
(alkynyl C), 64.5 (alkynyl CH), 31.9 (CH2), 29.3 (CH2), 29.1 (CH2), 28.8 (CH2),
+ 28.2 (CH2), 22.7 (CH2), 19.1 (CH2), 14.1 (CH3); m/z (EI) 147 ([M – Me] ,
100%). Data was consistent with the literature.261
184
General procedure D for the one-pot Zipper-click reaction (LAETA method)
To a solution of ethylene diamine (EDA) (0.2 mL, 3 mmol, 3 equiv.) in THF
(0.75 mL) was added lithium metal (21 mg, 3 mmol, 3 equiv.) with stirring at
room temperature under a stream of N2. The reaction mixture was stirred under
N2 at 40 °C until it formed a grey suspension. The reaction was cooled to room temperature and hexane (0.75 mL) followed by toluene (0.75 mL) was added.
The reaction was cooled to 15 °C and the diyne (1 mmol, 1 equiv.) was added, and the reaction stirred at 15 °C for 1 h. Ice water (1 mL) was added to the
reaction, followed by CuSO4∙5H2O (5 mg, 0.02 mmol, 2 mol%), sodium ascorbate (20 mg, 0.1 mmol, 10 mol%) and the azide (1 mmol, 1 equiv.) in
CH2Cl2 (1 mL), and the reaction was stirred overnight. The organic layers were washed with aq. NH4Cl and the solvent removed in vacuo; the product was isolated using flash column chromatography (hexane: ethyl acetate 9:1).
185
4-(4-(Dec-1-yn-1-yl)-1H-1,2,3-triazol-1-yl)benzonitrile, 355a
C8H17
N N N
NC
Chemical Formula: C19H22N4 Molecular Weight: 306.41
4-(4-(Dec-1-yn-1-yl)-1H-1,2,3-triazol-1-yl)benzonitrile was prepared using general procedure D, from dodeca-5,7-diyne (162 mg, 1 mmol) and 4-azidobenzonitrile
(144 mg, 1 mmol) to give the product as a yellow solid (201 mg, 0.66 mmol,
-1 66%); m.p. 90 °C; νmax/cm (neat): 3151, 3048, 2927, 2857, 2230, 1602, 1548; Rf
1 0.10 (EtOAc-hexane, 1:9); H NMR (400 MHz, CDCl3) δ = 8.05 (s, 1 H, triazole
ArH), 7.91 (d, J = 8.9 Hz, 2 H, ArH), 7.86 (d, J = 8.9 Hz, 2 H, ArH), 2.47 (t, J =
7.2 Hz, 2 H, –C≡C–CH2–), 1.64 (quin, J = 7.2 Hz, 2 H, CH2), 1.46 (quin, J = 7.2
13 Hz, 2 H, CH2), 1.35 - 1.27 (m, 8 H, CH2), 0.89 (t, J = 6.9 Hz, 3 H, CH3); C
NMR (101 MHz, CDCl3) δ = 139.4 (C), 134.0 (2 CH), 133.1 (triazole C), 122.7
(triazole CH), 120.5 (2 CH), 117.6 (C≡N), 112.6 (C), 95.9 (alkynyl C), 68.9
(alkynyl C), 31.8 (–C≡C–CH2–), 29.2 (CH2), 29.1 (CH2), 28.9 (CH2), 28.3
+ + (CH2), 22.6 (CH2), 19.4 (CH2), 14.1 (CH3); m/z (ES ) 329 ([M + Na] , 100%),
+ + 307 ([M + H] , 50%); HRMS (TOF MS ES ) m/z calculated for C19H22N4Na [M
+ Na]+ 329.1742, found 329.1754.
186
4-(Dec-1-yn-1-yl)-1-(4-methoxyphenyl)-1H-1,2,3-triazole, 355b
C8H17
N N N
MeO
Chemical Formula: C19H25N3O Molecular Weight: 311.43
4-(Dec-1-yn-1-yl)-1-(4-methoxyphenyl)-1H-1,2,3-triazole was prepared using general procedure D, from dodeca-5,7-diyne (162 mg, 1 mmol) and
1-azido-4-methoxybenzene (149 mg, 1 mmol) to give the product as a yellow
-1 solid (115 mg, 0.37 mmol, 37%); m.p. 87 °C; νmax/cm (neat): 3060, 3028, 2952,
1 2926, 2056, 2122, 2088, 1596; Rf 0.15 (EtOAc-hexane, 1:9); H NMR (500 MHz,
CDCl3) δ = 7.91 (s, 1 H, triazole ArH), 7.63 (d, J = 8.9 Hz, 2 H, ArH), 7.04 (d, J
= 8.9 Hz, 2 H, ArH), 3.89 (s, 3 H, OMe), 2.47 (t, J = 7.4 Hz, 2 H, –C≡C–CH2–),
1.65 (quin, J = 7.4 Hz, 2 H, CH2), 1.51 - 1.44 (m, 2 H, CH2), 1.36 - 1.29 (m, 8 H,
13 CH2), 0.91 (t, J = 6.9 Hz, 3 H, CH3); C NMR (126 MHz, CDCl3) δ = 158.6
(C), 132.4 (triazole C), 128.7 (C), 123.8 (triazole CH), 120.6 (2 CH), 115.7 (2
CH) 95.3 (alkynyl C), 69.2 (alkynyl C), 52.6 (OMe), 31.8 (–C≡C–CH2–), 29.2
(CH2), 29.1 (CH2), 28.9 (CH2), 28.3 (CH2), 22.6 (CH2), 19.4 (CH2), 14.1 (CH3); m/z (ES+) 312 ([M + H]+, 100%); HRMS (TOF MS ES+) m/z calculated for
+ C19H26N3O [M + H] 312.2076, found 312.2077.
187
1-(4-Chlorophenyl)-4-(dec-1-yn-1-yl)-1H-1,2,3-triazole, 355c
C8H17
N N N
Cl
Chemical Formula: C18H22ClN3 Molecular Weight: 315.84
1-(4-Chlorophenyl)-4-(dec-1-yn-1-yl)-1H-1,2,3-triazole was prepared using general procedure D, from dodeca-5,7-diyne (162 mg, 1 mmol) and
1-azido-4-chlorobenzene (153 mg, 1 mmol) to give the product as a yellow solid
-1 (265 mg, 0.84 mmol, 84%); m.p. 85 °C; νmax/cm (neat): 3103, 3079, 2950, 2926,
1 2105, 1595; Rf 0.28 (EtOAc-hexane, 1:9); H NMR (500 MHz, CDCl3) δ = 7.97
(s, 1 H, triazole ArH), 7.68 (d, J = 8.8 Hz, 2 H, ArH), 7.52 (d, J = 8.8 Hz, 2 H,
ArH), 2.46 (t, J = 7.2 Hz, 2 H, –C≡C–CH2–), 1.63 (quin, J = 7.2 Hz, 2 H, CH2),
1.47-1.45 (m, 2 H, CH2), 1.34 - 1.26 (m, 8 H, CH2), 0.89 (t, J = 6.5 Hz, 3 H,
13 CH3); C NMR (101 MHz, CDCl3) δ = 135.1 (C), 134.7 (C), 132.6 (triazole C),
130.0 (2 CH), 123.1 (triazole CH), 121.7 (2 CH), 95.3 (alkynyl C), 69.2 (alkynyl
C), 31.8 (–C≡C–CH2–), 29.2 (CH2), 29.1 (CH2), 28.9 (CH2), 28.3 (CH2), 22.6
+ 35 + (CH2), 19.4 (CH2), 14.1 (CH3); m/z (ES ) 316 ([M + H, Cl] , 100%), 318 ([M +
37 + + H, Cl] , 30%); HRMS (TOF MS AP ) m/z calculated for C18H22N3NaCl [M +
Na, 35Cl]+ 338.1400, found 338.1412.
188
Ethyl 4-(4-(dec-1-yn-1-yl)-1H-1,2,3-triazol-1-yl)benzoate, 355d
C8H17
N N N
EtO2C
Chemical Formula: C21H27N3O2 Molecular 353.47 Weight:
Ethyl 4-(4-(dec-1-yn-1-yl)-1H-1,2,3-triazol-1-yl)benzoate was prepared using general procedure D, from dodeca-5,7-diyne (162 mg, 1 mmol) and ethyl 4- azidobenzoate (191 mg, 1 mmol) to give the product as a yellow solid (230 mg,
-1 0.65 mmol, 65%); m.p. 98-99 °C; νmax/cm (neat): 3133, 3060, 2925, 2855, 2239,
1 1717, 1607, 1516; Rf 0.14 (EtOAc-hexane, 1:9); H NMR (500 MHz, CDCl3) δ =
8.21 (d, J = 8.8 Hz, 2 H, ArH), 8.05 (s, 1 H, triazole ArH), 7.82 (d, J = 8.8 Hz, 2
H, ArH), 4.42 (q, J = 7.2 Hz, 2 H, CO2CH2CH3), 2.46 (t, J = 7.3 Hz, 2 H, –
C≡C–CH2–), 1.64 (quin, J = 7.3 Hz, 2 H, CH2), 1.46 (quin, J = 7.3 Hz, 2 H,
CH2), 1.43 (t, J = 7.2 Hz, 3 H, CO2CH2CH3), 1.36 - 1.25 (m, 8 H, CH2), 0.89 (t,
13 J = 7.1 Hz, 3 H, CH3); C NMR (126 MHz, CDCl3) δ = 165.3 (CO2Et), 139.6
(C), 132.7 (C), 131.3 (2 CH), 130.8 (triazole C), 123.0 (triazole CH), 119.8 (2
CH), 95.4 (alkynyl C), 69.2 (alkynyl C), 61.5 (CH3CH2O–), 31.8 (–C≡C–CH2–),
29.2 (CH2), 29.1 (CH2), 28.9 (CH2), 28.3 (CH2), 22.6 (CH2), 19.4 (CH2), 14.3
+ + (CH3CH2O–), 14.1 (CH3); m/z (ES ) 354 ([M + H] , 100%); HRMS (TOF MS
+ + AP ) m/z calculated for C21H28N3O2 [M + H] 354.2182, found 354.2169.
189
1-([1,1'-Biphenyl]-2-yl)-4-(dec-1-yn-1-yl)-1H-1,2,3-triazole, 355e
C8H17
N N N
Chemical Formula: C24H27N3 Molecular 357.50 Weight:
1-([1,1'-Biphenyl]-2-yl)-4-(dec-1-yn-1-yl)-1H-1,2,3-triazole was prepared using general procedure D, from dodeca-5,7-diyne (162 mg, 1 mmol) and 2-azido-1,1'- biphenyl (195 mg, 1 mmol) to give the product as a yellow oil (234 mg, 0.66
-1 mmol, 66%); νmax/cm (neat): 3049, 2923, 2123, 2089, 1601; Rf 0.25 (EtOAc-
1 hexane, 1:9); H NMR (500 MHz, CDCl3) δ = 7.64 - 7.56 (m, 2 H, ArH), 7.55 -
7.50 (m, 2 H, ArH), 7.35 - 7.29 (m, 3 H, ArH), 7.22 (s, 1 H, ArH), 7.13 - 7.08 (m,
2 H, ArH), 2.37 (t, J = 7.3 Hz, 2 H, –C≡C–CH2–), 1.58 (quin, J = 7.3 Hz, 2 H,
CH2), 1.40 (quin, J = 7.3 Hz, 2 H, CH2), 1.33 - 1.23 (m, 9 H, CH2), 0.89 (t, J =
13 6.9 Hz, 3 H, CH3); C NMR (101 MHz, CDCl3) δ = 147.9 (C), 137.4 (C), 135.5
(CH), 133.5 (triazole C), 130.8 (C), 129.7 (CH), 128.5 (2 CH), 128.4 (CH), 128.4
(2 CH), 127.8 (CH), 126.6 (CH), 122.9 (triazole CH), 95.1 (alkynyl C), 68.9
(alkynyl C), 31.8 (–C≡C–CH2–), 29.2 (CH2), 29.1 (CH2), 28.9 (CH2), 28.4
+ + (CH2), 22.6 (CH2), 19.4 (CH2), 14.1 (CH3); m/z (ES ) 358 ([M + H] , 100%);
+ + HRMS (TOF MS ES ) m/z calculated for C24H28N3 [M + H] 358.2283, found
358.2283.
190
Methyl 2-(4-(dec-1-yn-1-yl)-1H-1,2,3-triazol-1-yl)benzoate, 355f
C8H17
N N N
CO2Me
Chemical Formula: C20H25N3O2 Molecular 339.44 Weight:
Methyl 2-(4-(dec-1-yn-1-yl)-1H-1,2,3-triazol-1-yl)benzoate was prepared using general procedure D, from dodeca-5,7-diyne (162 mg, 1 mmol) and methyl 2- azidobenzoate (177 mg, 1 mmol) to give the product as a yellow oil (217 mg,
-1 0.64 mmol, 64%); νmax/cm (neat): 3120, 3058, 2925, 2185, 1716, 1601, 1584; Rf
1 0.12 (EtOAc-hexane, 1:9); H NMR (500 MHz, CDCl3) δ = 8.03 (dd, J = 1.6,
7.7 Hz, 1 H, ArH), 7.85 (s, 1 H, triazole ArH), 7.69 (dt, J = 1.6, 7.8 Hz, 1 H,
ArH), 7.62 (dt, J = 1.1, 7.7 Hz, 1 H, ArH), 7.47 (dd, J = 1.0, 7.8 Hz, 1 H, ArH),
3.74 (s, 3 H, CO2Me), 2.45 (t, J = 7.2 Hz, 2 H, –C≡C–CH2–), 1.64 (quin, J = 7.2
Hz, 2 H, CH2), 1.46 (quin, J = 7.2 Hz, 2 H, CH2), 1.34 - 1.25 (m, 8 H, CH2),
13 0.89 (t, J = 6.7 Hz, 3 H, CH3); C NMR (126 MHz, CDCl3) δ = 165.0 (CO2Me),
139.1 (C), 135.2 (C), 133.7 (triazole C), 132.4 (CH), 132.2 (CH), 131.4 (CH),
130.1 (CH), 122.4 (triazole CH), 95.3 (alkynyl C), 69.2 (alkynyl C), 52.4
(CO2Me), 31.8 (–C≡C–CH2–), 29.2 (CH2), 29.1 (CH2), 28.9 (CH2), 28.3 (CH2),
+ + 22.6 (CH2), 19.4 (CH2), 14.1 (CH3); m/z (ES ) 340 ([M + H] , 100%); HRMS
+ + (TOF MS AP ) m/z calculated for C20H26N3O2 [M + H] 340.2025, found
340.2026.
191
1-(3-Bromophenyl)-4-(dec-1-yn-1-yl)-1H-1,2,3-triazole, 355g
C8H17
N N N
Br
Chemical Formula: C H BrN 18 2.2 3 Molecular Weight: 360 30
1-(3-Bromophenyl)-4-(dec-1-yn-1-yl)-1H-1,2,3-triazole was prepared using general procedure D, from dodeca-5,7-diyne (162 mg, 1 mmol) and
1-azido-3-bromobenzene (198 mg, 1 mmol) to give the product as a yellow solid
-1 (126 mg, 0.35 mmol, 35%); m.p. 65 °C; νmax/cm (neat): 3135, 3079, 2955, 2918,
1 2853, 2243, 1682, 1589; Rf 0.28 (EtOAc-hexane, 1:9); H NMR (400 MHz,
CDCl3) δ = 7.98 (s, 1 H, triazole CH), 7.93 (t, J = 1.9 Hz, 1 H, ArH), 7.67 (ddd,
J = 1.0, 1.9, 8.1 Hz, 1 H, ArH), 7.59 (ddd, J = 1.0, 1.9, 8.1 Hz, 1 H, ArH), 7.41
(t, J = 8.1 Hz, 1 H, ArH), 2.46 (t, J = 7.2 Hz, 2 H, –C≡C–CH2–), 1.66 - 1.62 (m,
2 H, CH2), 1.51 - 1.41 (m, 2 H, CH2), 1.34 - 1.27 (m, 8 H, CH2), 0.89 (t, J = 7.1
13 Hz, 3 H, CH3); C NMR (101 MHz, CDCl3) δ = 137.5 (triazole C), 132.6 (CH),
131.9 (CH), 131.1 (C), 123.6 (triazole CH), 123.4 (C), 123.1 (CH), 118.9 (CH),
95.4 (alkynyl C), 69.2 (alkynyl C), 31.8 (–C≡C–CH2–), 29.2 (CH2), 29.1 (CH2),
+ 28.9 (CH2), 28.3 (CH2), 22.6 (CH2), 19.4 (CH2), 14.1 (CH3); m/z (ES ) 360 ([M
192
+ H, 79Br]+, 100%), 362 ([M + H, 81Br]+, 100%); HRMS (TOF MS ES+) m/z
+ calculated for C18H22BrN3Na [M + Na] 382.0895, found 382.0902.
1-(3-(4-(Dec-1-yn-1-yl)-1H-1,2,3-triazol-1-yl)phenyl)ethan-1-one, 355h
C8H17
N N N
O
Chemical Formula: C H N O 20 2.5 3 Molecular Weight: 323 44
1-(3-(4-(Dec-1-yn-1-yl)-1H-1,2,3-triazol-1-yl)phenyl)ethan-1-one was prepared using general procedure D, from dodeca-5,7-diyne (162 mg, 1 mmol) and
1-(3-azidophenyl)ethanone (161 mg, 1 mmol) to give the product as a yellow oil
-1 (68 mg, 0.21 mmol, 21%); νmax/cm (neat): 3021, 2925, 2855, 2102, 1684, 1583;
1 Rf 0.16 (EtOAc-hexane, 1:9); H NMR (400 MHz, CDCl3) δ = 8.27 (t, J = 1.7
Hz, 1 H, ArH), 8.08 (s, 1 H, triazole ArH), 8.04 - 7.97 (m, 2 H, ArH), 7.66 (t, J =
8.1 Hz, 1 H, ArH), 2.70 - 2.65 (s, 3 H, COMe), 2.46 (t, J = 7.1 Hz, 2 H,
–C≡C–CH2–), 1.66 - 1.62 (m, 2 H, CH2), 1.50 - 1.40 (m, 2 H, CH2), 1.35 - 1.26
13 (m, 8 H, CH2), 0.89 (t, J = 6.7 Hz, 3 H, CH3); C NMR (101 MHz, CDCl3) δ =
196.6 (COMe), 140.9 (C), 138.6 (C), 132.7 (CH), 130.3 (triazole C), 128.6 (CH),
124.7 (CH), 123.2 (triazole CH), 119.7 (CH), 95.4 (alkynyl C), 69.2 (alkynyl C),
31.9 (–C≡C–CH2–), 29.2 (CH2), 29.1 (CH2), 29.0 (CH2), 28.3 (CH2), 26.7
+ + (COMe), 22.7 (CH2), 19.4 (CH2), 14.1 (CH3); m/z (ES ) 324 ([M + H] , 100%);
193
+ + HRMS (TOF MS ES ) m/z calculated for C20H26N3O [M + H] 324.2076, found
324.2079.
4-(Dec-1-yn-1-yl)-1-(2,6-dichlorophenyl)-1H-1,2,3-triazole, 355i
C8H17
Cl N N N
Cl
Chemical Formula: C18H21Cl2N3 Molecular Weight: 350.29
4-(Dec-1-yn-1-yl)-1-(2,6-dichlorophenyl)-1H-1,2,3-triazole was prepared using general procedure D, from dodeca-5,7-diyne (162 mg, 1 mmol) and
2-azido-1,3-dichlorobenzene (188 mg, 1 mmol) to give the product as a yellow
-1 oil (109 mg, 0.31 mmol, 31%); νmax/cm (neat): 3059, 2924, 2854, 2105, 1570; Rf
1 0.16 (EtOAc-hexane, 1:9); H NMR (400 MHz, CDCl3) δ = 7.74 (s, 1 H, triazole
ArH), 7.55 - 7.50 (m, 3 H, ArH), 2.47 (t, J = 7.1 Hz, 2 H, –C≡C–CH2–), 1.69 -
1.59 (m, 2 H, CH2), 1.52 - 1.43 (m, 2H, CH2), 1.35 - 1.27 (m, 8 H, CH2), 0.89 (t,
13 J = 6.7 Hz, 3 H, CH3); C NMR (101 MHz, CDCl3) δ = 134.7 (2 C), 133.9 (2
CH), 131.9 (triazole C), 129.1 (CH), 128.9 (C), 127.4 (triazole CH), 95.0
(alkynyl C), 69.2 (alkynyl C), 31.9 (–C≡C–CH2–), 29.2 (CH2), 29.1 (CH2), 29.0
+ (CH2), 28.4 (CH2), 22.7 (CH2), 19.5 (CH2), 14.1 (CH3); m/z (ES ) 350 ([M +
H, 35Cl]+, 100%), 352 ([M + H, 37Cl]+, 60%); HRMS (TOF MS ES+) m/z
+ calculated for C18H21Cl2N3Na [M + Na] 372.1010, found 372.1016.
194
4-(Dec-1-yn-1-yl)-1-(2,6-diisopropylphenyl)-1H-1,2,3-triazole, 355j
C8H17
N N N
Chemical Formula: C H N 24 .35 3 Molecular Wei ht: 365 57 g
4-(Dec-1-yn-1-yl)-1-(2,6-diisopropylphenyl)-1H-1,2,3-triazole was prepared using general procedure D, from dodeca-5,7-diyne (162 mg, 1 mmol) and 2-azido-1,3- diisopropylbenzene (203 mg, 1 mmol) to give the product as a yellow oil (282
-1 mg, 0.77 mmol, 77%); νmax/cm (neat): 3058, 2962, 2927, 2869, 2856, 2122,
1 1473; Rf 0.25 (EtOAc-hexane, 1:9); H NMR (400 MHz, CDCl3) δ = 7.64 (s, 1
H, triazole ArH), 7.50 (t, J = 7.9 Hz, 1 H, ArH), 7.29 (d, J = 7.9 Hz, 2 H, ArH),
2.48 (t, J = 7.2 Hz, 2 H, –C≡C–CH2–), 2.23 (spt, J = 6.8 Hz, 2 H,
2 –CH(CH3)2), 1.68 - 1.64 (m, 2 H, CH2), 1.52 - 1.44 (m, 2 H, CH2), 1.40 - 1.29
(m, 8 H, CH2), 1.28 (d, J = 6.8 Hz, 12 H, 2 –CH(CH3)2), 0.90 (t, J = 6.8 Hz, 3
13 H, CH3); C NMR (101 MHz, CDCl3) δ = 146.1 (2 C), 143.1 (C), 130.9
(triazole C), 128.0 (CH), 126.8 (triazole CH), 123.8 (2 CH), 94.7 (alkynyl C),
69.6 (alkynyl C), 31.8 (–C≡C–CH2–), 29.2 (CH2), 29.1 (CH2), 29.0 (CH2), 28.4
(2 –CH(CH3)2), 28.3 (CH2), 24.1 (2 –CH(CH3)2), 24.0 (2 –CH(CH3)2), 22.6
195
+ + (CH2), 19.5 (CH2), 14.1 (CH3); m/z (ES ) 366 ([M + H] , 100%); HRMS (TOF
+ + MS ES ) m/z calculated for C24H36N3 [M + H] 366.2909, found 366.292.
196
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