Isohistamine' (2-(2-aminoethyl) imidazole) and related compounds.

As part of a programme to prepare structural analogues of histamine for pharmacological examination, the positional isomer, 2-(2-aminoethyl)- imidazole, (isohistamine) was required. The synthesis of this compound, published in 1949, involved the nucleophilic displacement of chlorine by cyanide ion in 1-benzyl-2-chloromethylimidazole. Repetition of this reaction has shown that a previously undetected rearrangement occurs and that a mixture of nitriles is obtained. The subsequent stages of the published synthesis led to 4(5)-aminomethyl-2-methylimidazole, and not isohistamine. This reformulation explains the anomalous properties of the compound previously thought to be isohistamine. A similar published synthesis of 2-(2-aminoethyl)-l-methylimidazole has been investigated and shown to be in error. When the cyanide ion displacement reaction on 1-benzyl-2-chloromethyl- imidazole was carried out in dimethylformamide, the expected 2-cyano- methyl compound was obtained together with a novel type of stable primary enamine, 1-amino-2-(1-benzylimidazol-2-y1)acrylonitrile. The homologues of isohistamine, 2-(3-aminopropyl)imidazole and 2-(4-aminobutyl)imidazole have been synthesised and the isothioureas and guanidines related to these amines have also been made for pharmacological examination. In order to provide alternative syntheses of the foregoing compounds, the preparation of 2-substituted imidazoles by cyclisation of the appropriate iminoethers has been investigated. The metalation of 1-substituted imidazoles with organo-lithium compounds, as another route to 2-substituted imidazoles, is discussed, and the reaction of these lithio derivatives has been investigated. The anomalous behaviour of ethylene oxide, which reacts with the lithio derivative of 1-benzylimidazole at the benzylic methylene group has been studied. The biological rationale for the synthesis of the compounds described in this work is briefly discussed.