Introduction

In the last decade, 1,2,3-triazoles have found wide application in many different fields.1,2,3,4,5,6 A large number of 1,2,3-triazoles have recently been discovered to have remarkable bioactivity, such as IDO1 inhibitors, antiviral agents, Src kinase and HDAC inhibitors.7 This review is devoted to the recent methods for NH-unsubstituted 1,2,3-triazole synthesis including catalytic, solid-phase, and microwave-assisted ones.

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CuAAC reaction followed by deprotection

Copper(I)-catalyzed azide–alkyne [3+2] cycloaddition (CuAAC) reaction is one of the most popular and frequently used methods for the synthesis of 1,2,3-triazoles.8N(1)H-Unsubstituted 1,2,3-triazoles were obtained in good yields via cycloaddition of acetylenes with azidomethyl pivalate under standard CuAAC conditions. The pivalate protecting group was then removed by treatment with bases, followed by acidification.9

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It has been shown that benzyl group at the first position of 1,2,3-triazole ring also can be removed by hydrogenation under various conditions.10,11

Hyojin Cha et al. recently developed new approach for the synthesis of 4-substituted NH-1,2,3-triazoles utilizing copper-catalyzed aerobic oxidative C–N bond cleavage reaction.12 This method is also based on the CuAAC reaction and requires the use of Cu(OAc)2 as a catalyst, pyridine as an additive, and trifluorotoluene as a solvent.

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Efimov Ilya V. received his engineer degree in 2010 from the Ural Federal University named after the first President of Russia B. N. Yeltsin in Yekaterinburg. He obtained PhD at the same university under supervision of Prof. Vasiliy Bakulev in 2015 and subsequently became a postdoctoral fellow. In 2018, he has started his postdoctoral fellowship at the RUDN University in the group of Prof. Leonid Voskressensky. His scientific interests include cycloaddition reactions of azides and enamines, as well as reactions of isoquinolines.

Solid-phase synthesis

Attractive method for the synthesis of NH-1,2,3-triazoles applying CuAAC reaction was reported by Katrine Qvortrup and Thomas E. Nielsen.13 The reaction of solid-supported photolabile azido linker and alkynes gave 4-substituted 1,2,3-triazoles which can easily release the desired NH-unsubstituted 1,2,3-triazoles upon UV irradiation under very mild conditions.

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New supported catalysts for the Huisgen's azide–alkyne [3+2] cycloaddition have been prepared by immobilization of copper species on commercially available polymeric matrices incorporating the 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) template.14 The use of this catalyst allowed to synthesize NH-unsubstituted 1,2,3-triazoles by the CuAAC reaction of trimethylsilyl azide and 1-alkynes. Since TMS ion is a good leaving group, the desired NH-unsubstituted 1,2,3-triazoles were efficiently obtained without any additional manipulations.

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Another solid-phase synthesis of NH-1,2,3-triazoles using 4,4'-(azidomethylene)bis(methoxybenzene) building block was developed by A. Emil Cohrt et al.15 The 4-(hydroxymethyl)-benzoic acid (HMBA) linker was coupled to the poly-[acryloylbis(aminopropyl)polyethylene glycol] (PEGA) resin using N,N,N',N'-tetramethyl-O-(benzotriazol-1-yl)-uronium tetrafluoroborate (TBTU) as the coupling reagent, followed by attachment of FmocGlyOH using 1-(2-mesitylenesulfonyl)-3-nitro-1H-1,2,4-triazole (MSNT) for the esterification. FmocPheOH and 4-pentynoic acid were subsequently attached to provide an alkyne handle for the CuAAC reaction.

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Three-component reaction of aldehydes, MeNO 2 , and NaN 3

Another attractive synthetic method toward NH-1,2,3-triazoles is based on the one-pot three-component reaction of aldehydes, nitromethane, and NaN3.16 The described approach is general and allows synthesis of 4-aryl-, 4-hetaryl-,and 4-alkenyl-1,2,3-triazoles.

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Reaction of alkenyl bromides with NaN 3

Palladium-catalyzed reaction of β-bromostyrenes with sodium azide provides NH-1,2,3-triazoles in high yields (up to 94%).17 The substituent on the aromatic ring had no influence on the reaction outcome. The reaction was tolerant to sensitive functional groups such as methoxycarbonyl or nitrile, as well as ortho substituent on the aromatic ring. The chemoselectivity of the reaction is noteworthy, as the presence of a halide (bromide or chloride) substituent on the aromatic ring provides the triazole as the sole reaction product.

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Reaction of enamines with TsN 3

Synthesis of rare 4-azolyl-1,2,3-triazoles was described by Ilya Efimov et al.18 It was shown that the reactions of β-azolylenamines with tosyl azide in acetonitrile provide 1H-4-(azol-5-yl)-1,2,3-triazoles in yields ranging from 50 to 93%. β-Benzoylenaminones and β-nitroenamine were also suitable reagents to form the corresponding products, thus showing the versatility and efficiency of the method. Acetylenes were not advisable dipolarophiles for similar transformation.

Another interesting protocol was developed by Wim Dehaen et al.19 Starting enamines were generated in situ from methyl ketones and DMF-DMA. Subsequent interaction of thus formed enamines with tosyl azide gave final NH-1,2,3-triazoles.

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