A Convenient Synthesis of 1-Substituted 1,2,3-Triazoles via CuI/Et₃N Catalyzed ‘Click Chemistry’ from Azides and Acetylene Gas

Abstract

Copper(I)-catalyzed ‘click chemistry’ using acetylene gas was successfully explored under mild conditions. 1-Substituted-1,2,3-triazoles were conveniently synthesized from the corresponding aromatic and aliphatic azides.

Key words

azides - copper(I) catalysis - click chemistry - acetylene gas - 1,2,3-triazoles

References and Notes

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10

The present reaction exhibited strong solvent effect, which is greatly different from the typical ‘click chemistry’. The discrepancy was presumed to cause by the acetylene gas. In the reactions, abundant reddish-brown precipitate was formed.

11

Acetonitrile and DMSO-H₂O both gave excellent results in the template reaction. But when other azides used, the yields decreased significantly. In MeCN, 2b and 2c were obtained, respectively, in 52% and 63% after 24 h. In DMSO-H₂O (4:1), 4-methylphenyl azide was tried, but the yield was only poor 40%. Therefore, we chose DMSO as typical solvent in subsequent experiments. The reason of the discrepancy is unknown.

12

Typical Procedure for Compound 2.
To a 5 mL flask with Et₃N (0.4 mmol), azides 1 (1.0 mmol), and solvent (1.5 mL), CuI (0.1 mmol) was added into the mixture under N₂ atmosphere. The flask was purged with acetylene for several times. Then the mixture was stirred under a balloon pressure of acetylene at r.t. After the designed time, the mixture was diluted with 25 mL EtOAc, and washed by 10 mL H₂O for four times then by brine. The organic phase dried over anhyd Na₂SO₄. After removal of the solvent under reduced pressure, the residue was purified on SiO₂ with PE-EtOAc (4:1 to 1:2). Caution: Azides are potentially explosive compounds and should be handled with great care.

13

Analytical Data of Selected Products
Compound 2a: white solid, mp 51-53 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 7.71 (s, 1 H), 7.48 (s, 1 H), 7.37 (m, 3 H), 7.27 (m, 2 H), 5.57 (s, 2 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 134.6, 134.0, 128.9, 128.5, 127.8, 123.3, 53.7 ppm. MS (EI): m/z = 159 [M⁺], 130, 104, 91, 77.
Compound 2b: pale yellow solid, mp 52-53 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 8.04 (s, 1 H), 7.88 (s, 1 H), 7.77 (m, 2 H), 7.56 (m, 2 H), 7.47 (m, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 137.5, 135.7, 130.0, 129.0, 122.8, 121.0 ppm. MS (EI): m/z = 145 [M⁺].
Compound 2c: ^¹H NMR (400 MHz, CDCl₃): δ = 7.99 (s, 1 H), 7.80 (s, 1 H), 7.59 (d, J = 6.8 Hz, 2 H), 7.28 (d, J = 6.8 Hz, 2 H), 2.39 (s, 3 H) ppm. ^¹³C NMR (100 MHz, CDCl₃):
δ = 138.6, 134.5, 134.0, 130.0, 121.6, 120.2, 20.8 ppm.
MS (EI): m/z = 159 [M⁺].
Compound 2d: yellow oil. ^¹H NMR (400 MHz, CDCl₃): δ = 7.98 (s, 1 H), 7.79 (s, 1 H), 7.54 (s, 1 H), 7.47 (d, J = 8.0 Hz, 1 H), 7.35 (d, J = 7.6 Hz, 1 H), 7.20 (d, J = 7.2 Hz, 1 H), 2.40 (s, 3 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 139.8, 136.8, 134.2, 129.34, 129.33, 121.7, 121.1, 117.5, 21.2 ppm.
MS (EI): m/z = 159 [M⁺].
Compound 2f: white solid, mp 78-80 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 7.94 (s, 1 H), 7.85 (s, 1 H), 7.65 (dd, J ₁ = 6.9 Hz, J ₂ = 2.1 Hz, 2 H), 7.03 (dd, J ₁ = 6.9 Hz, J ₂ = 2.1 Hz, 2 H), 3.88 (s, 3 H) ppm. ^¹³C NMR (100 MHz, CDCl₃):
δ = 160.1, 135.7, 131.1, 123.0, 122.6, 115.1, 55.9 ppm.
MS (EI): m/z = 175 [M⁺].
Compound 2g: pale yellow solid, mp 111-113 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 8.01 (s, 1 H), 7.85 (s, 1 H), 7.70 (d, J = 8.8 Hz, 2 H), 7.50 (d, J = 8.8 Hz, 2 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 138.6, 134.5, 134.0, 130.0, 121.6, 120.2, 20.8 ppm. MS (EI): m/z = 179 [M⁺].
Compound 2h: pale yellow solid, mp 91-93 ˚C. ^¹H NMR (400 MHz, CDCl₃): δ = 8.05 (s, 1 H), 7.85 (s, 1 H), 7.79 (s, 1 H), 7.65 (d, J = 7.6 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.41 (d, J = 8.0 Hz, 1 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 137.7, 135.4, 134.6, 130.8, 128.7, 121.7, 120.7, 118.5 ppm. MS (EI): m/z = 179 [M⁺].