Iodine-Driven Three-Component Reaction of Isocyanides, Amines, and TsNXNa (X = Br, Cl): A Facile, Metal-Free Approach towards N-Sulfonyl Guanidines

Abstract

This work illustrates an expeditious, highly efficient, metal-, base-, and oxidant-free approach towards synthesizing N-sulfonyl guanidines via a three-component reaction system comprising isocyanides, amines, and TsNXNa (X = Br, Cl). The reaction proceeds via the formation of an isolable carbodiimide intermediate. The synthetic protocol emerges as a promising route for a simple, efficient, and rapid transformation into a diverse range of N-sulfonyl guanidines under mild reaction conditions.

Key words

isocyanide - bromamine-T - carbodiimide - metal-free - guanidine

Publication History

Received: 26 February 2025

Accepted after revision: 07 April 2025

Accepted Manuscript online:
07 April 2025

Article published online:
20 May 2025

• References and Notes

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• 51 General Procedure for the Preparation of Bromamine-T ⁵⁰ To a vigorously stirred solution of NaOH (240 mg) in 1.5 mL of distilled water under ice-cold conditions, 1 g of TsNBr₂ was added in portions. The precipitate formed was filtered under suction and dried over anhydrous P₂O₅.
• 52 General Procedure for the Synthesis of N-Sulfonyl Guanidines and Characterization To a vigorously stirred solution of isocyanide (0.5 mmol, 1.0 equiv) in CHCl₃ (3 mL), iodine (15 mol%), TsNXNa (X = Br, Cl) (1.25 mmol, 2.5 equiv), and amine (0.5 mmol, 1 equiv) were added and allowed to stir continuously at room temperature for 1 h. After the completion of the reaction as monitored by TLC, the reaction mixture was extracted with ethyl acetate and washed with Na₂S₂O₃. The organic layer was dried over anhydrous Na₂SO₄, concentrated under reduced pressure, and purified by column chromatography on silica gel (230–400 mesh) using petroleum ether and ethyl acetate as eluent. N-[(tert-Butylamino)(dihexylamino)methylene]-4-methylbenzenesulfonamide (4d) White solid (81%, 177 mg); mp 50–52 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.74 (dd, J = 8.1, 1.4 Hz, 2 H), 7.17 (d, J = 7.2 Hz, 2 H), 5.36 (br s, 1 H), 3.31 (t, J = 7.6 Hz, 4 H), 2.33 (s, 3 H), 1.47 (s, 4 H), 1.25–1.17 (m, 21 H), 0.83 (t, J = 5.2 Hz, 6 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 158.0, 142.0, 141.0, 128.7, 125.8, 54.2, 49.9, 31.2, 29.8, 27.4, 26.3, 22.3, 21.2, 13.8. IR (KBr): ν = 3331, 2938, 2863, 1563, 1500, 1454, 1263, 1140, 1079, 951, 715, 537 cm^–1. HRMS (ESI): m/z calcd for C₂₄H₄₄N₃O₂S [M + H]⁺: 438.3149; found: 438.3159. N-(tert-Butyl)-N′-tosylazepane-1-carboximidamide (4i) White solid (68%, 128 mg); mp 62–64 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.76 (d, J = 8 Hz, 2 H), 7.19 (d, J = 8 Hz, 2 H), 4.91 (br s, 1 H), 3.59 (t, J = 6 Hz, 4 H), 2.35 (s, 3 H), 1.74 (s, 4 H), 1.56 (s, 4 H), 1.14 (s, 9 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 157.0, 142.5, 140.8, 128.7, 125.7, 53.4, 50.5, 29.6, 27.7, 27.5, 21.2. IR (KBr): ν = 3314, 2932, 2258, 1562, 1500, 1418, 1262, 1184, 1074, 863, 709, 543 cm^–1. HRMS (ESI): m/z calcd for C₁₈H₃₀N₃O₂S [M + H]⁺: 352.2053; found: 352.2056. Ethyl-1-[N-(tert-butyl)-N′-tosylcarbamimidoyl]piperidine-3-carboxylate (4j): White solid (65%, 133 mg); mp 98–100 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.76 (d, J = 8 Hz, 2 H), 7.19 (d, J = 8.4 Hz, 2 H), 6.51 (br s, 1 H), 4.23–4.10 (m, 2 H), 3.86–3.73 (m, 2 H), 3.51–3.38 (m, 2 H), 2.68 (p, J = 4.4 Hz, 1 H), 2.35 (s, 3 H), 2.13–2.09 (m, 1 H), 1.90–1.81 (m, 1 H), 1.66–1.62 (m, 1 H), 1.48–1.36 (m, 1 H), 1.25 (t, J = 6.8 Hz, 3 H), 1.12 (s, 9 H). ¹³C{¹H} NMR (100 MHz, CDCl₃): δ = 174.5, 156.9, 142.2, 140.9, 128.7, 125.7, 61.2, 52.4, 49.8, 40.1, 29.3, 26.6, 23.5, 21.2, 14.0. IR (KBr): ν = 3324, 2973, 2326, 1727, 1562, 1521, 1438, 1260, 1170, 1144, 1110, 1079, 1029, 964, 891, 858, 772, 709, 660, 582, 532 cm^–1. HRMS (ESI): m/z calcd for C₂₀H₃₂N₃O₄S [M + H]⁺: 410.2108; found: 410.2110.