Review

. 2020 Oct 27;25(21):4970.

doi: 10.3390/molecules25214970.

Recent Developments in Transition-Metal Catalyzed Direct C-H Alkenylation, Alkylation, and Alkynylation of Azoles

Su Chen¹, Prabhat Ranjan¹, Leonid G Voskressensky², Erik V Van der Eycken^{1

2}, Upendra K Sharma¹

Affiliations

¹ Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001 Leuven, Belgium.
² Organic Chemistry Department, Science Faculty, Peoples' Friendship University of Russia (RUDN University), Miklukho-Maklaya street 6, RU-117198 Moscow, Russia.

PMID: 33121108
PMCID: PMC7662665
DOI: 10.3390/molecules25214970

Review

Recent Developments in Transition-Metal Catalyzed Direct C-H Alkenylation, Alkylation, and Alkynylation of Azoles

Su Chen et al. Molecules. 2020.

. 2020 Oct 27;25(21):4970.

doi: 10.3390/molecules25214970.

Authors

Su Chen¹, Prabhat Ranjan¹, Leonid G Voskressensky², Erik V Van der Eycken^{1

2}, Upendra K Sharma¹

Affiliations

¹ Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001 Leuven, Belgium.
² Organic Chemistry Department, Science Faculty, Peoples' Friendship University of Russia (RUDN University), Miklukho-Maklaya street 6, RU-117198 Moscow, Russia.

PMID: 33121108
PMCID: PMC7662665
DOI: 10.3390/molecules25214970

Abstract

The transition metal-catalyzed C-H bond functionalization of azoles has emerged as one of the most important strategies to decorate these biologically important scaffolds. Despite significant progress in the C-H functionalization of various heteroarenes, the regioselective alkylation and alkenylation of azoles are still arduous transformations in many cases. This review covers recent advances in the direct C-H alkenylation, alkylation and alkynylation of azoles utilizing transition metal-catalysis. Moreover, the limitations of different strategies, chemoselectivity and regioselectivity issues will be discussed in this review.

Keywords: C–H activation; C–H functionalization; alkenylation; alkylation; alkynylation; azoles; transition metal-catalysis.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Scheme 1**
Direct Pd-catalyzed alkenylation of azoles with bromoalkenes.

**Scheme 2**
Pd/Cu-catalyzed direct alkenylation of azole heterocycles with alkenyl bromides.

**Scheme 3**
Direct alkenylation of azoles with phosphates.

**Scheme 4**
Pd-catalyzed direct functionalization of benzoxazoles with alkenyl iodides.

**Scheme 5**
Direct C–H fluoroalkenylation of 2-phenyl-1,3,4-oxadiazole.

**Scheme 6**
Nano CuO-catalyzed C–H functionalization of azoles with bromoalkenes.

**Scheme 7**
Ni-catalyzed alkenylation of azoles with (a) enol derivatives and (b) carbamate.

**Scheme 8**
Direct C2-alkenylation of oxazoles with alkenyl tosylates.

**Scheme 9**
CuCl-catalyzed direct C–H alkenylation of benzoxazoles with allyl halides.

**Scheme 10**
Ni-catalyzed direct alkenylation of azole derivatives with alkenyl bromides.

**Scheme 11**
Pd-catalyzed direct oxidative alkenylation of azoles.

**Scheme 12**
Pd-catalyzed C4-olefination of oxazoles.

**Scheme 13**
Pd-catalyzed reaction of 1,3,5-trisubstituted pyrazoles with *gem*-difluoromethylenated acetonide.

**Scheme 14**
Pd(II)-catalyzed oxidative Heck coupling of thiazole-4-carboxylates.

**Scheme 15**
Pd/Cu-catalyzed dehydrogenative alkenylation of caffeine derivatives.

**Scheme 16**
Pd-catalyzed dehydrogenative alkenylation of azole motifs.

**Scheme 17**
Pd-catalyzed C2-selective olefination of thiazoles.

**Scheme 18**
Pd-catalyzed direct alkenylation of thiazolo[3,2-b]-1,2,4-triazoles.

**Scheme 19**
Synthesis of multifunctionalized thiazole derivatives via regioselective and programmed C–H activation.

**Scheme 20**
Pd-catalyzed site-selective C–H alkenylation of imidazo[2,1-b]thiazoles.

**Scheme 21**
Ni-catalyzed functionalization of imidazoles with allenes.

**Scheme 22**
Rh (III)-catalyzed selective direct olefination of imidazoles.

**Scheme 23**
Regioselective C–H alkenylation for (a) C2-unsubstituted and (b) C2-substituted imidazoles.

**Scheme 24**
Catalyst control in positional-selective C–H alkenylation of isoxazoles.

**Scheme 25**
Pd-catalyzed template-directed C-5 selective olefination of thiazoles.

**Scheme 26**
Co-catalyzed addition of benzoxazoles to alkynes.

**Scheme 27**
Co-catalyzed alkenylation of thiazoles with alkynes.

**Scheme 28**
Ni-catalyzed alkenylation of triazolopyridines.

**Scheme 29**
C–H alkenylation of imidazo[1,5-a]pyridine with alkynes.

**Scheme 30**
Rh(III)-catalyzed cyclization reaction of azoles with alkynes.

**Scheme 31**
Rh/Cu-catalyzed highly trans-selective 1,2-diheteroarylation of alkynes with azoles.

**Scheme 32**
Pd-catalyzed *syn*-hydroarylation reaction of diaryl alkynes with azoles.

**Scheme 33**
Pd-catalyzed trisallylation of benzoxazoles with an alkyne.

**Scheme 34**
Ni-catalyzed decarbonylative C–H alkenylation of various azoles.

**Scheme 35**
Decarboxylative/direct C–H monofluoroalkenylation with fluoroacrylic acids.

**Scheme 36**
Pd-catalyzed α-carboxyenol ether formation with various azoles via direct decarboxylative cross-coupling and proposed mechanism.

**Scheme 37**
The Ni/Cu-catalyzed direct alkylation of heterocyclic C–H bonds.

**Scheme 38**
Pd-catalyzed direct C–H alkylation of benzoxazoles with various alkyl halides.

**Scheme 39**
Benzylations on oxazol(in)es with a Pd- catalyst of a secondary phosphine oxide.

**Scheme 40**
Rh- catalyzed alkylation by the addition of azoles to alkenes.

**Scheme 41**
Amino-NHC mediated C–H activation of benzimidazole via Ni-Al synergistic catalysis.

**Scheme 42**
Rh(I)−bisphosphine catalyzed asymmetric, intermolecular hydroheteroarylation of α-substituted acrylate derivatives with benzoxazoles.

**Scheme 43**
Pd-catalyzed C–H allylation and benzylation of pyrazoles.

**Scheme 44**
NHC-Pd(II) complex-catalyzed benzylation of (benz)oxazoles with benzyl chlorides.

**Scheme 45**
DDQ-promoted direct C5-alkylation of oxazoles with alkylboronic acids.

**Scheme 46**
Pd-catalyzed C–H benzylation of (benz)oxazoles with benzylic quaternary ammonium triflates and a plausible mechanism.

**Scheme 47**
[Ni]-catalyzed alkylation of benzannulated azoles with alkylbromides.

**Scheme 48**
Ni/IMes-catalyzed hydroheteroarylation of azoles with styrene.

**Scheme 49**
Cu-catalyzed direct benzylation or allylation of 1,3-azoles with N-tosylhydrazones.

**Scheme 50**
Cu-catalyzed allylic alkylation of electron-deficient heteroarenes with internal secondary allylic phosphates.

**Scheme 51**
Ni- and Co-catalyzed direct alkylation of azoles with N-tosylhydrazones bearing unactivated secondary alkyl groups. (a) Ni-catalyzed; (b) Co-catalyzed.

**Scheme 52**
Cu-catalyzed direct secondary C–H alkylation of azoles.

**Scheme 53**
Cu-catalyzed direct cross-coupling of 1,3,4-oxadiazoles with N-tosylhydrazones.

**Scheme 54**
Pd-catalyzed C−H/C−O coupling of oxazoles and diarylmethanol derivatives.

**Scheme 55**
Cu-catalyzed cross-coupling of ferrocenyl ketone-derived N-tosylhydrazones with benzoxazoles.

**Scheme 56**
Pd catalyzed cyclopropylation of benzoxazoles with cyclopropyl halides.

**Scheme 57**
Rh(I)-catalyzed branched alkylation of benzimidazoles.

**Scheme 58**
Pd-catalyzed desulfonative cross-coupling reaction of benzylic sulfone derivatives with 1,3-oxazoles.

**Scheme 59**
N-heterocyclic carbene and Ni(COD)₂-catalyzed hydroheteroarylation of vinylarenes with benzoxazole.

**Scheme 60**
Ni-catalyzed hydroarylation of vinylarenes with benzothiazoles.

**Scheme 61**
Cu(I)-catalyzed reaction of bis(trimethylsilyl)diazomethane with benzoxazoles and oxazoles.

**Scheme 62**
Palladium-catalyzed functionalization of azoles with a quaternary carbon center.

**Scheme 63**
Transition metal-catalyzed direct alkynylation of azoles with 1,1-dihalo-1-alkenes.

**Scheme 64**
Ni-catalyzed direct alkynylation of azoles with terminal alkynes.

**Scheme 65**
Pd-catalyzed decarboxylative C–H alkynylation of benzoxazoles with *α,β*-ynoic acids.

**Scheme 66**
Direct alkynylation of arenes with Cu acetylides.

**Scheme 67**
Dehydrogenative and decarboxylative C–H alkynylation of heteroarenes, catalyzed by a Pd(II)–carbene complex.

**Scheme 68**
Palladium-catalyzed cross-coupling of nitropyrazoles with terminal alkynes.

**Scheme 69**
Ni (II)-catalyzed C–H bond alkynylation of benzothiazoles and related azoles.

See this image and copyright information in PMC

References

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Recent Developments in Transition-Metal Catalyzed Direct C-H Alkenylation, Alkylation, and Alkynylation of Azoles

Affiliations

Recent Developments in Transition-Metal Catalyzed Direct C-H Alkenylation, Alkylation, and Alkynylation of Azoles

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources