Synthesis of Multisubstituted Guanidines through Palladium-Catalyzed Insertion of Isonitriles

Abstract

A new method for the synthesis of multisubstituted guanidines through tandem intermolecular insertion of isonitriles with un­activated amides has been developed. In this study, isonitriles could be used not only as reaction materials but also as the source of amines.

Key words

insertion of isonitriles - unactivated amides - cascade transformation - palladium

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• 13 Typical Procedure: To a round-bottom flask was added amide 1 (0.3 mmol), tert-butyl isocyanide 2 (0.72 mmol), PdCl₂, and Cs₂CO₃, and MeCN (2.0 mL) was added under air. The reaction mixture was stirred at 70 °C for ca. 2 h, and the progress of the reaction was monitored by TLC. The reaction mixture was evacuated under vacuum, and the residue was further purified by silica gel column chromatography (petroleum ether and ethyl acetate) to afford the product 3.
• 14a Representative Analytical Data for 3b: White solid; mp 137–139 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.94 (d, J = 7.4 Hz, 1 H), 7.25–7.14 (m, 3 H), 2.63 (s, 3 H), 1.46 (s, 18 H). ¹³C NMR (100 MHz, CDCl₃): δ = 179.55 (s), 158.43 (s), 139.81 (s), 137.54 (s), 130.84 (s), 129.46 (s), 128.83 (s), 124.86 (s), 50.92 (s), 29.87 (s), 21.39 (s). HRMS (ESI): m/z [M+H]⁺ calcd for C₁₇H₂₈N₃O: 290.2227; found: 290.2215.