Greener and Expeditious Synthesis of 1,4-Disubstituted 1,2,3-Triazoles from Terminal Acetylenes and in situ Generated α-Azido Ketones

Abstract

A convenient and mild protocol for the one-pot regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles in aqueous PEG 400 has been reported. The methodology involves the one-pot reaction of α-bromo ketones, sodium azide, and terminal acetylenes catalyzed by Cu(I) in aqueous PEG 400 at room temperature. Prominent features of our approach are mild reaction conditions, use of readily available α-bromo compounds, aqueous PEG 400 as a benign reaction medium, avoiding the isolation of labile α-azido ketones, simple workup, and good yields.

1,2,3-triazoles - α-bromo ketones - click chemistry - α-azido ketones

References and Notes

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10

General Procedure
To a solution of α-halo compound 1 (1.0 mmol), NaN₃ (1.2 mmol), and terminal acetylene (1.0 mmol) in aq PEG 400 (2 mL) was added sodium ascorbate (19.8 mg, 10 mol%) and 1 M CuSO₄ (50 µL, 5 mol%) solution. The reaction mixture was allowed to stir at r.t. for 30 min. After the reaction was complete, as indicated by TLC, the solid product was filtered, washed, and dried to afford pure product.
Analytical Data for Selected Compounds Compound 2a:^7c IR (KBr): 1690 (CO) cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 8.04-8.00 (2 H, m), 7.95 (1 H, s), 7.89-7.84 (2 H, m), 7.73-7.65 (1 H, m), 7.59-7.31 (5 H, m), 5.91 (2 H, s). ^¹³C NMR (50 MHz, CDCl₃): δ = 195.0 (CO), 152.4, 139.0, 138.2, 134.5, 133.5, 133.2, 132.7, 132.5, 130.1, 126.4, 59.9. MS (EI): m/z calcd for C₁₆H₁₄N₃O [M + H]⁺: 264.1; found: 264.3.
Compound 2h: IR (KBr): 1680 (CO) cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.53 (1 H, s), 8.11 (2 H, d, J = 8.0 Hz), 7.88 (2 H, d, J = 8.0 Hz), 7.70 (2 H, d, J = 8.0 Hz), 7.48-7.45 (2 H, m), 7.37-7.35 (1 H, m), 6.27 (2 H, s). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 191.4 (CO), 146.3, 139.2, 132.8, 130.7, 130.1, 129.1, 128.9, 127.9, 125.1, 123.0, 56.0. MS (EI): m/z calcd for C₁₆H₁₃ClN₃O [M + H]⁺:298.0747; found: 297.9593. Compound 2l: IR (KBr): 1720 (CO) cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 8.56 (1 H, s), 7.85 (2 H, d, J = 8.0 Hz), 7.47-7.44 (2 H, m), 7.35-7.32 (1 H, m), 5.76-5.71
(1 H, m), 2.75-2.67 (1 H, m), 2.45-2.32 (3 H, m), 2.11-2.09 (1 H, m), 1.96-1.92 (2 H, m), 1.76-1.68 (1 H, m). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 204.1 (CO), 145.9, 130.8, 128.9, 127.8, 125.0, 121.3, 66.8, 40.4, 33.4, 26.4, 23.6. MS (EI):
m/z calcd for C₁₄H₁₆N₃O [M + H]⁺: 242.1293; found: 242.0473. Compound 2o: IR (KBr): 1685 (CO) cm^-¹. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 9.17 (1 H, s), 8.61 (1 H, s), 8.20 (2 H, d, J = 8.0 Hz), 8.15 (1 H, d, J = 8.0 Hz), 8.02 (1 H, d, J = 8.0 Hz), 7.90 (2 H, d, J = 8.0 Hz), 7.80-7.76 (1 H, m), 7.69-7.65 (2 H, m), 7.49-7.33 (5 H, m), 6.26 (2 H, s). ^¹³C NMR (100 MHz, DMSO-d ₆): δ = 187.9 (CO), 146.3, 136.3, 135.4, 134.8, 133.9, 130.7, 130.2, 128.9, 127.9, 127.3, 126.8, 126.2, 125.2, 125.1, 123.2, 122.0, 117.5, 113.1, 56.0. MS (EI): m/z calcd for C₂₄H₁₉N₄O₃S [M + H]⁺: 443.1178; found: 443.0073.
Compound 2p: IR (KBr): 1759 (CO) cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 7.92-7.82 (3 H, m), 7.42-7.27 (3 H, m), 5.21 (2 H, s), 3.80 (3 H, s). ^¹³C NMR (75 MHz, CDCl₃): δ = 166.8 (CO), 148.2, 130.4, 128.9, 128.3, 125.8, 121.1, 53.0, 50.8. MS (EI): m/z calcd for C₁₁H₁₂N₃O₂ [M + H]⁺: 218.1; found: 218.3.
Compound 2q: IR (KBr): 1651 (CO) cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 8.03 (1 H, s), 7.85-7.83 (2 H, m), 7.44-7.39 (2 H, m), 7.39-7.30 (1 H, m), 5.23 (2 H, s), 3.46-3.39 (4 H, m), 1.25 (3 H, t, J = 7.15 Hz), 1.15 (3 H, t, J = 7.10 Hz). ^¹³C NMR (75 MHz, CDCl₃): δ = 164.0 (CO), 148.0, 130.7, 128.8, 128.1, 125.8, 121.4, 50.9, 42.0, 41.0, 14.4, 12.8. MS (EI): m/z calcd for C₁₄H₁₉N₄O [M + H]⁺: 259.2; found: 259.3.
Compound 2r: IR (KBr): 2286 (CN) cm^-¹. ^¹H NMR (200 MHz, CDCl₃): δ = 8.00 (1 H, s), 7.86-7.81 (2 H, m), 7.51-7.38 (3 H, m), 5.40 (2 H, s). ^¹³C NMR (50 MHz, CDCl₃):
δ = 149.6, 129.9, 129.4, 129.3, 126.3, 120.3, 113.1, 38.0. MS (EI): m/z calcd for C₁₀H₉N₄ [M + H]⁺: 185.1; found: 185.2.
Compound 2s: IR (KBr): 1693 (CO) cm^-¹. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 7.86 (2 H, d, J = 8.49 Hz), 7.68 (2 H, d, J = 8.49 Hz), 7.51 (1 H, s), 5.79 (2 H, s), 3.65-3.58 (2 H, m), 2.96-2.91 (2 H, m), 2.24-2.15 (2 H, m). ^¹³C NMR (75 MHz, CDCl₃): δ = 189.7 (CO), 146.8, 132.7, 132.6, 130.0, 129.6, 123.0, 55.3, 44.2, 31.8, 22.7. MS (EI): m/z calcd for C₁₃H₁₄BrClN₃O [M + H]⁺: 342.0; found: 342.0.

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