Preparation and Utility of N-Alkynyl Azoles in Synthesis

Abstract

Heteroatom-substituted alkynes have attracted a significant amount of interest in the synthetic community due to the polarized nature of these alkynes and their utility in a wide range of reactions. One specific class of heteroatom-substituted alkynes combines this utility with the presence of an azole moiety. These N-alkynyl azoles have been known for nearly 50 years, but recently there has been a tremendous increase in the number of reports detailing the synthesis and utility of this class of compound. While much of the chemistry of N-alkynyl azoles mirrors that of the more extensively studied N-alkynyl amides (ynamides), there are notable exceptions. In addition, as azoles are extremely common in natural products and pharmaceuticals, these N-alkynyl azoles have high potential for accessing biologically important compounds. In this review, the literature reports of N-alkynyl azole synthesis, reactions, and uses have been assembled. Collectively, these reports demonstrate the growth in this area and the promise of exploiting N-alkynyl azoles in synthesis.

Keywords: alkynes; carbenes; cyclizations; natural products; polymers.

Figure 1

Examples of N-alkynyl azoles.

Scheme 1

Kundu and Okamoto’s synthesis of N-ethynylcarbazole.

Scheme 2

Pielichowski and Chrzaszcz’s phase-transfer synthesis of N-ethynylcarbazole.

Scheme 3

Burger and Dreier’s synthesis of an N-alkynyl pyrrole.

Scheme 4

Paley and coworkers’ targeted synthesis of N-ethynylpyrrole.

Scheme 5

Zemlicka’s synthesis of N⁹-alkynyl purines.

Scheme 6

Katritzky’s ‘Corey-Fuchs’ approach to various N¹-alkynyl benzotriazoles.

Scheme 7

Anderson’s synthesis of N-alkynyl amides and N-alkynyl azoles.

Scheme 8

Zhao’s transition-metal free one-step synthesis of N-alkynyl amides.

Scheme 9

Katritzky’s Shapiro-type synthesis on an N-alkynyl pyrrole.

Scheme 10

Katritzky’s N¹-alkynyl benzotriazole synthesis.

Scheme 11

Mechanism of alkynyliodonium salts as alkyne-transfer reagents.

Scheme 12

Kitamura’s synthesis of N¹-alkynyl benzotriazoles.

Scheme 13

Kitamura’s synthesis of N²-alkynyl benzotriazoles.

Scheme 14

Kerwin’s synthesis of N-alkynylimidazoles using alkynyliodonium reagents.

Scheme 15

Bisai’s synthesis of an N-alkynylindole.

Scheme 16

Toriumi and Uchiyama’s synthesis of N-alkynyl azolium salts.

Scheme 17

Hsung’s copper-catalyzed synthesis of various N-alkynyl azoles.

Scheme 18

Competing alkynylation in tryptamine derivatives.

Scheme 19

Kerwin’s copper-catalyzed synthesis of N-alkynyl imidazoles.

Scheme 20

Kerwin’s copper-catalyzed synthesis of N-alkynyl pyrroles.

Scheme 21

Peters and Fu’s photoinduced-copper-catalyzed synthesis of N-alkynyl carbazole.

Scheme 22

Burley’s microwave-promoted copper-catalyzed synthesis of N-alkynyl azoles.

Scheme 23

Das’s ligand-free copper-catalyzed synthesis of N-alkynyl azoles.

Scheme 24

Wu’s copper-catalyzed N-alkynylation of Boc-protected indoles.

Scheme 25

Pale’s copper-zeolite-catalyzed synthesis of N-alkynyl amides.

Scheme 26

Zhang’s iron-catalyzed synthesis of N-alkynyl amides.

Scheme 27

Das’s [Cu(Phen)PPh₃Br]–catalyzed synthesis of N-alkynyl azoles.

Scheme 28

Stahl’s oxidative copper-catalyzed synthesis of N-alkynyl indoles.

Scheme 29

Bhattacharjee’s oxidative copper-catalyzed synthesis of N-alkynyl pyrazoles.

Scheme 30

Jiao’s copper-catalyzed decarboxylative synthesis of N-alkynyl indoles.

Scheme 31

Brown’s flash vacuum pyrolysis synthesis of N-alkynyl pyrazole.

Scheme 32

Synthesis of diacetylenes of N-alkynyl azoles.

Scheme 33

Zemlicka’s synthesis of carbinols of N⁹-alkynyl adenine.

Scheme 34

Wolf’s enantioselective addition of N-alkynyl indole to various aldehydes.

Scheme 35

Huang’s low-yielding Sonogashira coupling of an N-alkynyl purine.

Figure 2

Polarization of the N-alkynyl azole triple bond.

Scheme 36

Addition of acids and thiophenol to various N-alkynyl azoles.

Scheme 37

Neuenschwander’s rearrangement of 5-substituted 5-aminopentadienals.

Scheme 38

Regio- and stereoselective iodobromination of N-alkynylindoles.

Scheme 39

Zhu’s sulfenylchloride-mediated addition of DMSO to N-alkynyl amides.

Scheme 40

Zhu’s iodoamination of N-alkynyl amides and indole.

Scheme 41

Iodocyclizations of N-alkynyl azoles.

Scheme 42

Zhu’s iodine-mediated oxidation of N-alkynyl amides and indoles.

Scheme 43

Hwang’s photochemical oxidation of N-alkynyl carbazoles.

Scheme 44

Additions to N-alkynyl azoles under basic conditions.

Scheme 45

Kerwin’s regiocontrolled cyclization to imidazoazines and imidazoazoles.

Scheme 46

Kerwin’s synthesis of several imidazo-fused heterocycles.

Scheme 47

Kerwin’s synthesis of pyrrole[2,1-c]oxazin-1-ones.

Scheme 48

Balci’s intramolecular addition of hydrazide to N-alkynyl pyrrole.

Scheme 49

Gillaizeau’s cyclization of ortho-ynamidyl benzoate esters to 3-aminoisocoumarins.

Scheme 50

Clavier and Buono’s regioselective addition of cyclic 1,3-diones to N-alkynyl amides.

Scheme 51

Katritzky’s synthesis of disubstituted alkynes from N-alkynyl benzotriazole.

Scheme 52

Reddy’s hydroalkynylation of N-alkynyl amides.

Scheme 53

Park’s regiodivergent cyclization of N-alkynylindoles.

Scheme 54

Park’s hydroalkynylation/cyclization approach to pentacyclic heterocycles.

Scheme 55

Zhu’s (Z)-stereoselective boronic acid coupling to N-alkynyl amides and azoles.

Scheme 56

Shin’s Bronsted acid catalyzed oxygenative Friedel-Crafts coupling of an N-alkynlindole.

Scheme 57

Addition of hydrogen and deuteride to N-alkynyl azoles.

Scheme 58

Zhu’s copper-catalyzed reduction of N-alkynyl amides.

Scheme 59

Zhu’s stereoselective hydroboration of N-alkynyl amides and indoles.

Scheme 60

Pirrung’s [2 + 1] cycloaddition with N-ethynyl pyrrole.

Scheme 61

Clavier and Buono’s [2 + 1] cycloadditions of N-alkynyl amides/azoles.

Scheme 62

Alcaide’s Ficini cycloaddition of N-alkynylindoles, -carbazoles, and indazoles.

Scheme 63

Watson and Burley’s click reaction with N-alkynyl benzimidazole.

Scheme 64

Watson and Burley’s orthogonal click-cycloaddition scheme.

Scheme 65

Metal-catalyzed formal [3 + 2] additions of N-alkynylindoles.

Scheme 66

Li’s cobalt-catalyzed synthesis of 5-azole-oxazoles.

Scheme 67

Zhou’s selenium π-acid catalyzed synthesis of 2-methylozazoles.

Scheme 68

Gandon and Blanchard’s [4 + 2] cycloaddition of N-substituted alkynes.

Scheme 69

Goswami’s [2 + 2 + 2] route to N-arylindoles and tri-indolylbenzenes.

Scheme 70

Saito’s [3 + 2 + 2] cycloaddition with N-alkynyl pyrrole.

Scheme 71

Saito’s nickel-catalyzed [4 + 3 + 2] cycloaddition with N-alkynyl pyrrole.

Scheme 72

Other annulations of N-alkynylindoles.

Scheme 73

Kerwin’s aza-Bergman cyclization-based rearrangements of dialkynylimidazoles.

Scheme 74

Kerwin’s dialkynylimidazole route to cyclopentapyrazines.

Scheme 75

Rabasso’s [2,3]-sigmatropic rearrangement of N-alkynyl indole.

Scheme 76

Zhao and Gagosz’s gold-catalyzed hydride shift of N-alkynyl azoles.

Scheme 77

Functionalization of N-alkynyl indoles.

Scheme 78

Beaudry’s synthesis of the bis-indole alkaloids from Arundo donax.

Scheme 79

Pale and Beneteau’s zeolite strategy towards acortatarin A.

Scheme 80

Application of N-alkynyl azoles in polymerization reactions.