Direct Guanylation of Amino Groups by Cyanamide in Water: Catalytic Generation and Activation of Unsubstituted Carbodiimide by Scandium(III) Triflate

Abstract

Guanylation proceeded efficiently upon treatment of the various amines with cyanamide in the presence of catalytic amounts of scandium(III) triflate under mild conditions. The method did not require the guanylation reagents to be preactivated, and the reaction proceeded efficiently in water. The method, therefore, has practical utility for substrates that dissolve only in aqueous solutions, for example, peptides or pharmacologically important compounds.

Key words

guanylation - Sc(OTf)₃ - cyanamide - activated carbodiimide

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• 18 General Procedure for the Guanylation of Amines: Preparation of N-(p-Methoxyphenyl)guanidine (2b) To a solution of p-methoxyaniline (1b, 61.6 mg, 0.50 μmol) and cyanamide (25.2 mg, 0.60 μmol) in H₂O (2.5 mL) was added Sc(OTf)₃ (24.6 mg, 50 nmol) at r.t. After the solution was stirred at 100 °C for 2 d, the resulting mixture was washed with CHCl₃ (3 × 10 mL). The aqueous layer was concentrated in vacuo, and the residue was purified by filtering through silica gel pad (CHCl₃–MeOH, 20:1) to give 2b as a purple solid (66.1 mg, 80%). IR (neat): 3353, 2158, 1673, 1513, 1244, 1028 cm^–1. ¹H NMR (400 MHz, CD₃OD, 25 °C): δ = 7.10 (d, J = 9.1 Hz, 2 H), 6.91 (d, J = 9.1 Hz, 2 H), 3.72 (s, 3 H). ¹³C NMR (100 MHz, CD₃OD, 25 °C): δ = 164.8, 160.9, 128.9, 128.1, 116.2, 56.0. ESI-MS: m/z calcd for C₈H₁₁N₃O [M + H]⁺: 166.1; found: 166.1.