Efficient Ring-Closure Approach via Copper-Catalyzed Reactions of Sulfonyl Azide, Terminal Alkynes and Alcohols/Amines

Abstract

We have developed a general and efficient method for synthesis of medium- and large-sized heterocycles via copper-catalyzed reactions of sulfonyl azide, terminal alkynes (or bisalkyne) and alcohols/amines (diamines) at room temperature, and the highly practical method provides an entry toward diverse medium- and large-sized heterocycles.

Key words

heterocycle - ring closure - copper-catalyzed - sulfonyl azide - synthetic method

References and Notes

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14

Preparation of Compounds 4 and 10a-d
Et₃N (1.2 mmol) was slowly added to a stirred mixture of p-methylbenzenesulfonyl azide (1.2 mmol), 3 or 9 (1 mmol) and CuI (0.1 mmol) in CHCl₃ (3 mL) at r.t. under an N₂ atmosphere. Later (8-10 h), the solvent was removed in vacuo, and the crude residue was purified by flash column chromatography on silica gel with an appropriate eluting solvent system (CH₂Cl₂-MeOH 15:1 to 20:1) to give the target product 4 or 10. Compound 10a: eluent: CH₂Cl₂-MeOH (15:1); white solid, yield 76%. ¹H NMR (300 MHz, DMSO-d ₆): δ = 7.93 (br s, 2 H), 7.29-7.71 (m, 8 H), 3.97 (t, 2 H, J = 2.40 Hz), 3.50 (d, 2 H, J = 2.73 Hz), 3.39 (d, 2 H, J = 2.40 Hz), 2.83 (t, 2 H, J = 2.73 Hz), 2.27 (s, 3 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 175.1, 169.2, 168.9, 143.6, 139.6, 136.9, 136.5, 130.1, 130.0, 129.8, 127.8, 127.2, 126.7, 67.7, 37.2, 36.9, 34.4, 21.5. HRMS: m/z calcd for C₂₀H₂₂N₃O₅S [M + H]⁺: 416.1280; found: 416.1287.
Preparation of Compounds 14a-d
Et₃N (2.4 mmol) was slowly added to a stirred mixture of p-methylbenzenesulfonyl azide (1.2 mmol), 13 (1 mmol) and CuI (0.1 mmol) in CHCl₃ (3 mL) at r.t. under an N₂ atmosphere. Later (9-12 h), the solvent was removed in vacuo, and the crude residue was purified by flash column chromatography on silica gel with an appropriate eluting solvent system (CH₂Cl₂-MeOH, 15:1 to 20:1) to give the target product 14. Compound 14b: eluent: CH₂Cl₂-MeOH (20:1); white solid, yield 73%, ¹H NMR (300 MHz, DMSO-d ₆): δ = 8.40 (br s, 2 H), 8.22 (br s, 1 H), 7.28-7.68 (m, 8 H), 3.52 (m, 2 H), 3.27 (m, 4 H), 2.82 (m, 2 H), 2.32 (s, 3 H), 1.67 (m, 2 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 168.9, 168.7, 166.6, 142.1, 136.6, 135.6, 130.5, 130.2, 129.8, 128.4, 128.0, 126.2, 42.5, 36.6, 34.9, 27.7, 21.4. HRMS: m/z calcd for C₂₁H₂₅N₄O₄S [M + H]⁺: 429.1597; found: 429.1605.
Preparation of Compounds 17a,b
A solution of diamine (1.2 mmol) in CHCl₃ (1 mL) was slowly added to a stirred mixture of p-methylbenzene-sulfonyl azide (2.4 mmol), 15 (1 mmol) and CuI (0.2 mmol) in CHCl₃ (3 mL) at r.t. under an N₂ atmosphere. After a 5-7 h stirring, the solvent was concentrated in vacuo. The crude residue was purified by flash column chromatography on silica gel with an appropriate eluting solvent system to give 17.
Compound 17a: eluent: CH₂Cl₂-MeOH (20:1); white solid, yield 77%. ¹H NMR (300 MHz, DMSO-d ₆): δ = 8.78 (br t, 2 H), 8.62, (br t, 2 H), 7.32-7.70 (m, 12 H), 3.58 (m, 4 H), 3.07 (m, 4 H), 2.90 (m, 4 H), 2.34 (s, 6 H), 1.38 (m, 4 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 169.2, 167.2, 142.2, 142.0, 136.1, 130.2, 129.7, 128.2, 126.1, 41.5, 37.5, 34.1, 26.0, 21.4. HRMS: m/z calcd for C₃₂H₃₉N₆O₆S₂ [M + H]⁺: 667.2372; found: 667.2376.