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

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.

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.