Consecutive Tandem Cycloaddition between Nitriles and Azides; Synthesis of 5-Amino-1H-[1,2,3]-triazoles

Abstract

Novel 5-amino-1H-1,2,3-triazoles were synthesized by a new synthetic route that involves consecutive tandem cycloaddition between nitriles and azides.

Key words

triazoles - tandem cycloaddition - consecutive reaction - nitriles - azides

• References and Notes

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• 31 Preparation of Compounds 7a–h; General Procedure: To a solution of BuLi (2 mmol) in anhydrous THF (1.5 mL), was added a solution of the nitrile (acetonitrile or propionitrile; 2 mmol) in anhydrous THF (2 mL) at 0 °C and under an argon atmosphere. After 5 min, a solution of azide derivative 5 (2 mmol) in anhydrous THF (2 mL) was added. The reaction was allowed to warm to r.t. and monitored by TLC. Distilled H₂O (10 mL) was then added and the mixture was extracted with EtOAc. The organic layer was dried with sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with increasing polarity gradient mixture of hexane and EtOAc.
• 32 1-Phenyl-1H-1,2,3-triazole-5-amine (7a): Yield: 84%; white solid; mp 107.4–108.2 °C. IR (KBr): 3446 (N-H) cm^–1; ¹H NMR (CDCl₃–MeOD, 300 MHz): δ = 5.64 (br s, 2 H, NH₂), 6.75 (s, 1 H, H-4), 6.78–6.93 (m, 1 H, H-4′), 7.07–7.11 (m, 2 H, H-3′ and H-5′), 7.24–7.30 (m, 2 H, H2′–H-6′); ¹³C NMR (CDCl₃–MeOD, 75 MHz): δ = 128.8 (C-Ph), 120.0 (C-2′ and C-6′), 125.8 (C-4′), 130.1 (C-3′ and C-5), 134.60, 135.5; HRMS (ESI): m/z [M + H]⁺ calcd for C₈H₉N₄: 161.1833; found: 161.0924.4-Methyl-1-phenyl-1H-1,2,3-triazole-5-amine (7b): Yield: 61%; white solid; mp 127.5–128.9 °C. IR (KBr): 3381 (N-H) cm^–1; ¹H NMR (CDCl_3–MeOD, 300 MHz): δ = δ 2.23 (s, 3 H, CH₃), 3.82 (br s, 2 H, NH₂), 7.41–7.58 (m, 5 H, H-Ph); ¹³C NMR (CDCl_3–MeOD, 75 MHz): δ = 9.5 (CH₃), 123.8 (C-Ph), 126.0, 128.8 (C-Ph), 129.6 (C-Ph), 135.60, 137.5; HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₁₁N₄: 175.2099; found: 175.0977.1-(4-Chlorophenyl)-1H-1,2,3-triazole-5-amine (7c): Yield: 82%; brown solid; mp 118.6–119.7 °C. IR (KBr): 3297 (N-H), 831 (C-Cl) cm^–1; ¹H NMR (DMSO-d ₆, 500 MHz): δ = 5.78 (br s, 2 H, NH₂), 7.06 (s, 1 H, H-4), 7.75 (s, 4 H, H-2′, H-3′, H-5′ and H-6′); ¹³C NMR (CDCl₃, 125 MHz): δ = 116.97 (C-5), 125.31 (C-Ph), 128.55 (C-1′), 129.43 (C-Ph), 132.70 (C-6′), 134.58 (C-4′); HRMS (ESI): m/z [M + H]⁺ calcd for C₈H₈ClN₄: 195.6284; found: 195.0431.1-(4-Chlorophenyl)-4-methyl-1H-1,2,3-triazole-5-amine (7d): Yield: 76%; yellow solid; mp 139.6–140.3 °C; IR (KBr): 3340 (N-H), 834 (C-Cl) cm^–1; ¹H NMR (CDCl₃–MeOD, 300 MHz): δ = 2.25 (s, 3 H, CH₃), 7.51 (s, 2 H, H-3′ and H-5′), 7.52 (s, 2 H, H-2′ and H-6′); ¹³C NMR (CDCl₃–MeOD, 75 MHz): δ = 9.4 (CH₃), 124.9 (C-3′ and C-5′), 126.4 (C-5), 129.7 (C-2′ and C-6′), 134.0 (C-4), 134.6 (C-1′), 137.4 (C-4′); HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₁₀ClN₄: 209.6550; found: 209.0586.1-(1,2:3,4-Di-O-isopropylideno-α-d-galactopyranosyl)-1H-1,2,3-triazole-5-amine (7g): Yield: 82%; yellow solid; mp 179.0–181.4 °C; IR (KBr): 3410 (N-H), 2922 (C-C sugar unit), 2853 (C-C sugar unit), 1002–1212 (C-O-C sugar unit) cm^–1; ¹H NMR (CDCl₃–MeOD, 500 MHz): δ = 1.28 (s, 3 H, CH₃), 1.36 (s, 3 H, CH₃), 1.38 (s, 3 H, CH₃), 1.51 (s, 3 H, CH₃), 4.14–4.25 (m, 2 H, H-5′ and H-6′), 4.26–4.40 (m, 2 H, H-4′ and H-6′), 4.49 (dd, J = 2.5, 4.0 Hz, 1 H, H-2′), 4.64 (dd, J = 7.8, 2.5 Hz, 1 H, H-3′), 5.50 (d, J = 4.0 Hz, 1 H, H-1′), 7.04 (s, 1 H, H-4); ¹³C NMR (CDCl₃–MeOD, 125 MHz): δ = 24.4 (CH₃), 24.8 (CH₃), 25.9 (CH₃), 26.0 (CH₃), 49.6 (C-6′), 68.6 (C-5′), 70.4 (C-2′), 70.6 (C-3′), 71.1 (C-4′), 96.1 (C-1′), 109.3, 109.8; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₂₃N₄O₅: 327.3557; found: 327.1659.1-(1,2:3,4-Di-O-isopropylideno-α-d-galactopyranosyl)-4-methyl-1H-1,2,3-triazole-5-amine (7h): Yield: 54%; white solid; mp 204.2–205.6 °C; IR (KBr): 3450 (N-H), 2987 (C-C sugar unit), 2851 (C-C sugar unit), 1070–1237 (C-O-C sugar unit) cm^–1; ¹H NMR (CDCl₃–MeOD, 300 MHz): δ ¹H NMR (CDCl₃–MeOD, 300 MHz): δ = 1.36 (s, 3 H, CH₃), 1.49 (s, 3 H, CH₃), 1.55 (s, 3 H, CH₃), 1.57 (s, 3 H, CH₃), 2.34 (s, 3 H, CH₃), 4.15–4.20 (m, 1 H, H-5′), 4.45–4.55 (m, 2 H, H-6′), 4.31 (dd, J = 7.9, 1.9 Hz, 1 H, H-4′), 4.34 (dd, J = 5.0, 2.5 Hz, 1 H, H-2′), 4.65 (dd, J = 7.9, 2.6 Hz, 1 H, H-3′), 5.58 (d, J = 5.0 Hz, 1 H, H-1′′); ¹³C NMR (CDCl₃–MeOD, 75 MHz): δ = 24.3 (CH₃), 24.6 (CH₃), 25.6 (CH₃), 25.8 (CH₃), 44.4 (C-6′), 65.6 (C-5′), 70.4 (C-2′), 70.6 (C-3′), 70.8 (C-4′), 97.3 (C-1′), 107.9, 108.7; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₅H₂₅N₄O₅: 341.3823; found: 341.1695.
• 33 Preparation of 8a–c; General Procedure: To a solution of BuLi (2 mmol) in anhydrous THF (1.5 mL), was added a solution of the acetonitrile (4 mmol) in anhydrous THF (2.0 mL) at 0 °C under an argon atmosphere. After 5 min, a solution of azide derivative 5 (2 mmol) in anhydrous THF (2.0 mL) was added. The reaction was allowed to warm to r.t. with monitoring by TLC. Distilled water (10 mL) was then added, the mixture was extracted with EtOAc and the organic layer was dried with sodium sulfate, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel and eluted with increasing polarity gradient mixture of hexane and ethyl acetate.
• 34 4-Methyl-1-(5-amino-1-phenyl-1H-1,2,3-triazole-4-yl)ethanone (8a): Yield: 41%; white solid; mp 208.4–209.8 °C; IR (KBr): 3293 (N-H), 1664 (C=O) cm^–1; ¹H NMR (CDCl₃, 300 MHz): δ = 2.16 (s, 3 H, CH₃), 7.10 (t, J = 7.9 Hz, 1 H, H-4′), 7.30 (d, J = 7.9 Hz, 2 H, H-3′ and H-5′), 7.50 (d, J = 7.9 Hz, 2 H, H-2′ and H-6′), 7.60 (br s, 2 H, NH₂); ¹³C NMR (CDCl₃, 75 MHz): δ = 24.5 (CH₃), 119.9 (C-2′ and C-6′), 124.3 (C-4′), 128.9 (C-3′ and C-5′), 137.9, 168.5; HRMS (ESI): m/z [M + H]⁺ calcd for C₁₀H₁₁N₄O: 203.2200; found: 203.1021.1-[5-Amino-1-(4-chlorophenyl)-1H-1,2,3-triazole-4-yl]ethanone (8b): Yield: 30%; white solid; mp 210.7–211.2 °C; IR (KBr): 3359 (N-H), 1658 (C=O) cm^–1; ¹H NMR (CDCl₃, 500 MHz): δ = 2.64 (m, 3 H, COCH₃), 5.66 (s, 2 H, NH₂), 7.49 (d, J = 7.5 Hz, 2 H, H-3′ and H-5′), 7.56 (d, J = 7.5 Hz, 2 H, H-2′ and H-6′); ¹³C NMR (CDCl₃, 125 MHz): δ = 26.2 (CH₃), 125.0 (C3′ and C-5′), 129.6 (C-5), 130.3 (C-2′ and C-6′), 132.6 (C-4′), 135.7 (C-1′), 144.2 (C-4), 193.8 (C=O); HRMS (ESI): m/z [M + H]⁺ calcd for C₁₀H₁₀ClN₄O: 237.6651; found: 237.0536.1-[5-Amino-1-(4-methoxyphenyl)-1H-1,2,3-triazole-4-yl]ethanone (8c): Yield: 46%; brown solid; mp 206.4–207.8 °C; IR (KBr): 3324 (N-H), 1656 (C=O) cm^–1; ¹H NMR (CDCl₃, 300 MHz): δ = 2.66 (s, 3 H, CH₃), 3.88 (s, 3 H, OCH₃), 5.54 (br s, 2 H, NH₂), 7.07 (d, J = 9.0 Hz, 2 H, H-3′ and H-5′), 7.42 (d, J = 9.0 Hz, 2 H, H-2′ and H-6′); ¹³C NMR (CDCl₃, 75 MHz): δ = 26.2 (CH₃), 55.6 (OCH₃), 115.3 (C-3′ and C-5′), 125.8 (C-3′ and C-5′), 129.6, 144.5, 160.5 (C=O); HRMS (ESI): m/z [M + H]⁺ calcd for C₁₀H₁₃N₄O₂: 233.2460; found: 233.1031.