Copper-Catalysed Multicomponent Click Synthesis of 5-Alkynyl 1,2,3-Triazoles under Ambient Conditions

Dedicated to the memory of Professor Guy Solladié

Abstract

Copper(I) oxide has been found to effectively catalyse the multicomponent click synthesis of fully substituted 5-alkynyl 1,2,3-triazoles from organic halides, sodium azide, and terminal ­alkynes in methanol under ambient conditions.

Key words

alkynes - alkyl halides - azides - cycloaddition - copper - cross-coupling - heterocycles - multicomponent reaction

• References and Notes

• 1a Huisgen R, Knorr R, Moebius L, Szeimies G. Chem. Ber. 1965; 98: 4014
• 1b Huisgen R. Pure Appl. Chem. 1989; 61: 613
• 2 Tornøe CW, Christensen C, Meldal M. J. Org. Chem. 2002; 67: 3057
• 3 Rostovtsev VV, Green LG, Fokin VV, Sharpless KB. Angew. Chem. Int. Ed. 2002; 41: 2596
• 4 For a review, see: Kolb HC, Finn MG, Sharpless KB. Angew. Chem. Int. Ed. 2001; 40: 2004

For selected recent reviews and monographs, see:
• 5a Meldal M, Tornøe CW. Chem. Rev. 2008; 108: 2952
• 5b Appukkuttan P, Van der Eycken E. Eur. J. Org. Chem. 2008; 1133
• 5c Amblard F, Cho JH, Schinazi RF. Chem. Rev. 2009; 109: 4207
• 5d Click Chemistry for Biotechnology and Materials Science. Lahann J. John Wiley and Sons; Hoboken: 2009
• 5e Finn MG, Fokin VV In Catalysis Without Precious Metals . Morris Bullock R. Wiley-VCH; Weinheim: 2010: 235-260
• 5f For a special issue on applications of click chemistry, see: Chem. Soc. Rev. 2010, 39, issue 4.
• 5g Quin A, Lam JW. Y, Tang BZ. Chem. Soc. Rev. 2010; 39: 2522
• 5h Aragão-Leoneti V, Campo VL, Gomes AS, Field RA, Carvalho I. Tetrahedron 2010; 66: 9475
• 6 Boren BC, Narayan S, Rasmussen LK, Zhang L, Zhao H, Lin Z, Jia G, Fokin VV. J. Am. Chem. Soc. 2008; 130: 8923
• 7 For a perspective, including the synthesis of 5-halotriazoles, see: Ackermann L, Potukuchi HK. Org. Biomol. Chem. 2010; 8: 4503
• 8a Wu Y.-M, Deng J, Li Y, Chen Q.-Y. Synthesis 2005; 1314
• 8b Deng J, Wu Y.-M, Chen Q.-Y. Synthesis 2005; 2730
• 9 Gerard B, Ryan J, Beeler AB, Porco JA. Jr. Tetrahedron 2006; 62: 6405
• 10 Yang D, Fu N, Liu Z, Li Y, Chen B. Synlett 2007; 278
• 11 Brunner M, Maas G, Klärner F.-G. Helv. Chim. Acta 2005; 88: 1813
• 12a Alonso F, Moglie Y, Radivoy G, Yus M. Tetrahedron Lett. 2009; 50: 2358
• 12b Alonso F, Moglie Y, Radivoy G, Yus M. Eur. J. Org. Chem. 2010; 1875
• 12c Alonso F, Moglie Y, Radivoy G, Yus M. Adv. Synth. Catal. 2010; 352: 3208
• 12d Alonso F, Moglie Y, Radivoy G, Yus M. Org. Biomol. Chem. 2011; 9: 6385
• 12e Alonso F, Moglie Y, Radivoy G, Yus M. J. Org. Chem. 2011; 76: 8394
• 12f Alonso F, Moglie Y, Radivoy G, Yus M. Heterocycles 2012; 84: 1033
• 13a Stepanova NP, Orlova NA, Galishev VA, Turbanova ES, Petrov AA. Zh. Org. Khim. 1985; 21: 979 ; Chem. Abstr. 1985, 103, 123415
• 13b Bettison M, Hitchcock PB, Walton DR. M. J. Organomet. Chem. 1988; 341: 247
• 13c Domnin IN, Remizova LA, Starova GL, Rominger F. Russ. J. Org. Chem. 2009; 45: 1678
• 14 1,4-Disubstituted triazoles 4 are not formed, but only triazoles 3, when the organic halide 1 and the alkyne 2 are used in a 1:2 molar ratio. This fact is indicative of the high selectivity of the reaction.
• 15 Nolte C, Mayer P, Straub BF. Angew. Chem. Int. Ed. 2007; 46: 2101
• 16 See, for instance: Lam PY. S, Vincent G, Bonne D, Clark CG. Tetrahedron Lett. 2003; 44: 4927
• 17 For the recent observation of Cu(I)/Cu(III) redox steps in cross-coupling reactions, see: Casitas A, King AE, Parella T, Costas M, Stahl SS, Ribas X. Chem. Sci. 2010; 1: 326
• 18 General Procedure for the Synthesis of 5-Alkynyl 1,2,3-triazoles 3 The organic halide (1, 0.5 mmol), alkyne (2, 1.0 mmol), and NaN₃ (39.0 mg, 0.6 mmol) were added to a reactor tube containing a suspension of Cu₂O (1.4 mg, 0.01 mmol) in MeOH (2 mL). The reaction mixture was stirred at r.t. without the exclusion of air and monitored by TLC, GLC, and/or ¹H NMR spectroscopy until total conversion of the starting materials. H₂O (2 mL) was added to the mixture, followed by extraction with EtOAc (3 × 10 mL). The resulting organic phase was evaporated under vacuum, and the residue was purified by column chromatography (silica gel, hexane–EtOAc). 1-Benzyl-4-(p-tolyl)-5-(p-tolylethynyl)-1H-1,2,3-triazole (3ab) Starting from benzyl bromide (1a, 60 μL, 0.5 mmol), 1-ethynyl-4-methylbenzene (2b, 127 μL, 1.0 mmol), NaN₃ (39.0 mg, 0.6 mmol), and Cu₂O (1.4 mg, 0.01 mmol) in MeOH (2 mL), 3ab was isolated as a pale orange solid (145 mg, 80%); mp 81.9–84.0 °C; R_f = 0.66 (hexane–EtOAc = 7:3). IR (neat): ν = 3034, 2919, 1518, 1496, 1455, 1362, 1001, 815, 726, 692 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 8.07 (d, J = 8.1 Hz, 2 H), 7.42–7.30 (m, 7 H), 7.25 (d, J = 8.1 Hz, 2 H), 7.21 (d, J = 8.1 Hz, 2 H), 5.65 (s, 2 H), 2.39 (s, 3 H), 2.38 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 148.2, 140.2, 138.6, 134.9, 131.6, 129.6, 129.5, 128.9, 128.6, 128.2, 127.6, 126.2, 118.6, 117.2, 102.6, 77.4, 75.3, 53.0, 21.8, 21.5. MS (70 eV): m/z (%) = 364 (11) [M⁺ + 1), 363 (39) [M⁺], 334 (10), 245 (19), 244 (100), 203 (15), 127 (15), 91 (23). HRMS: m/z calcd for C₂₅H₂₁N₃: 363.1735; found: 363.1726.