Tetramethylguanidinium Azide (TMGA) - A Versatile Azidation Agent

Abstract

Organic azides have been widely used in synthesis, especially for the construction of heterocyclic systems, and as precursors of the primary amino group. [1] One method to incorporate the azide moiety into organic compounds is to use tetramethylguanidinium azide as the azidation agent. Tetramethylguanidinium azide (TMGA, TMGN3) introduced by Papa [2] is commercially available, stable, non-toxic, and safe in use. [3] TMGA is a colorless hygroscopic solid, which is soluble in organic solvents (chloroform, dichloromethane, acetonitrile, nitromethane, DMF, acetone) and water; it is insoluble in diethyl ether and THF. The standard procedure for the preparation of TMGA involves the action of hydrazoic acid (HN3) on tetramethylguanidine in ether. [2] The use of TMGA allows the introduction of the azido group under very mild non-aqueous conditions; however, it is not recommended to use halogenated solvents because explosive azidomethane species may be formed during the reaction. [3] [4] TMGA is frequently used as a source of azide, in nucleophilic addition, substitution, azidolysis of epoxides, and heterocyclic ring formation. [5] It has been successfully used for the synthesis of alkyl, [2] alkenyl, [6] propargyl, [7] heteroaryl, [8] acyl, [9] phosphinic, [10] and sulfonyl azides [11] as well as for the preparation of tert-butyl azidoformate, [12] tetrazoles, [13] β-azido alcohols, [14] α-azido ketones [15] and α-amino acid derivatives. [16]