In a previous communication the formation of 5-dialkylaminotetrazoles by the interaction of dialkylcyanamides and hydrazoic acid vas described (1). Since Hantzsch and Vagt had shown that cyanamide and hydrazoic acid react readily to form 5-aminotetrazole ( 2 ) , it was of interest to investigate the behavior of the monosubstituted cyanamides toward hydrazoic acid.1 Based on a thesis submitted to the School of Graduate Studies a t Michigan State College in 1952 by William L. Garbrecht in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

Three series of 6-methylergoline-8-carboxylic acid esters with various alkyl substituents in the N1-position were prepared and their 5HT2 receptor affinities measured. Some overlap occurred in the 5HT2 receptor affinities of the different ester series, indicating that both the ester side chain and the indole substituent influenced 5HT2 receptor affinity. While 5HT2 receptor affinity was affected by the structure of the ester side chain, the N1-substituent played a more crucial role in determining 5HT2 receptor affinity. When the ester side chain was held constant, maximal 5HT2 receptor affinity for that series of esters was obtained when the N1-substituent was isopropyl. Smaller substituents in the N1-position resulted in reduced 5HT2 receptor affinity. Groups C4 or larger in the N1-position resulted in a further decline in 5HT2 receptor affinity. The importance of the N1-substituent in determining 5HT2 receptor affinity was further substantiated when several 2-methyl-3-ethyl-5-(dimethylamino)indoles with various N1-substituents were tested. Again, maximal 5HT2 receptor affinity was obtained when the N1-substituent was isopropyl.

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While 5-aminotetrazole has been known for many years (1), its derivatives in which amino hydrogens are replaced by alkyl groups are not, in general, known. A study of this class of compounds, the 5-monoand 5-di-alkylaminotetrazoles, is of interest for several reasons. Since the parent substance, 5-aminotetrazole, possesses both an acidic and a basic function, it would be interesting to know the effect of substituents on these functions. Furthermore, alkylation of 5-aminotetrazole leads to a mixture of products (2) and there is need for a direct, unequivocal synthesis of these derivatives. The possibility that this class of compounds might have useful pharmacological activity also seemed attractive.The synthesis of 5-aminotetrazole and some of its substituted derivatives has been accomplished by a number of methods. The parent compound was first obtained by Thiele (1) through the action of nitrous acid on aminoguanidine. The reaction involved the initial formation of guanyl azide which readily cyclized to form 5-aminotetrazole. Busch and Bauer (3) have applied an analogous reaction to N,N,-diaryl-Nv,-aminoguanidines and have reported the formation of 1 -aryl-5-arylaminotetrazoles. Recently a similar sequence of reactions has been applied to N-nitro-N'-aminoguanidine for the preparation of 5-nitraminotetrazole (4).The direct formation of 5-aminotetrazole by the addition of hydrazoic acid to cyanamide was observed by Hantzsch and Vagt (5). It was suggested that the reaction involved the formation of guanyl azide through addition of hydrazoic acid to the cyanide group followed by immediate cyclization of the intermediate. Stollé (6) has applied the same type of reaction to several phenylalkylcyanamides and has described the formation of the corresponding 5-aminotetrazoles in which the amino hydrogens were replaced by a phenyl and an alkyl group.The formation of 5-substituted tetrazoles by addition of hydrazoic acid to the cyano group of nitriles has become recognized as a general procedure through the studies of Dimroth and Fester with hydrocyanic acid (7), Oliveri-Mandalá with cyanogen, cyanogen bromide, and ethyl cyanoformate (8), and Mihina and Herbst with an extensive group of alkyl and aryl cyanides (9). In an attempt to prepare 5-alkyltetrazoles from nitriles by interaction with hydrazoic acid in the presence of concentrated sulfuric acid von Braun and Keller (10) observed the 1 Based on a thesis submitted to the School of Graduate Studies at Michigan State College in 1952 by William L. Garbrecht in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

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