Patent GB-619659-A (GB)
Title: Improvements in and relating to processes for preparing substituted amidines
IPC: C07D215/50
Filed: 1946-12-19
Abstract: Amidines of the general formula <FORM:0619659/IV(b)/1> are prepared by reacting a nitrile RCN with a halo-magnesium derivative of a secondary amine <FORM:0619659/IV(b)/2> and hydrolysing the product, R being R DEG -(CH=CH)n, in which R DEG  is a monovalent isocyclic or heterocyclic aromatic radical containing from 1 to 3 rings and free of groups reactive with a Grignard reagent, or a derivative of such radical in which from 1 to 3 hydrogen atoms are replaced by alkyl, alkoxy, methylene-dioxy or dialkylamino groups or chlorine or bromine atoms, and n represents 0, 1 or 2; X is chlorine, bromine or iodine; R1 and R2 being groups nonreactive with a Grignard reagent, viz. alkyl, alkoxy alkyl, dialkylaminoalkyl, aralkyl, aryl, alkylaryl, alkoxyaryl, dialkylaminoaryl, or haloaryl, or together forming parts of a heterocyclic radical; R1 and R2 are not both aromatic and neither is identical with R.  The halo-magnesium secondary amine derivative is prepared from any Grignard reagent (ethyl magnesium bromide specified) and a slight excess of a secondary amine free from subsidiary groups which may react with the Grignard reagent such as hydroxy, carboxy, mercapto, unsubstituted amino or imino, carbonyl, thiono, ester, acid halide or amide groups; alkoxy, tertiary amino groups or ethylenic double bonds may be present.  The nitriles may be derived from aromatic compounds (e.g. benzene, naphthalene) or heterocyclic compounds free from active hydrogen atoms (e.g. pyridine, quinoline, acridine) and may carry further substituents as stated above.  The two reactants are refluxed together, the p halo-magnesium compound being in slight excess, either alone or in ethereal solution for 1/2 -4 hours, and the product decomposed with iced hydrochloric acid or ammonium chloride solution; the amidine is extracted with ether after optional addition of excess alkali, and may be separated by successive extractions with dilute hydrochloric acid.  Purification is effected by distillation of the base in vacuo or crystallisation as a salt.  A list is given of a number of amidines (some of which contain halogen atoms) prepared by the process of the invention. In the examples: (1) Di-n-butylamine is reacted with ethyl magnesium bromide and the product treated with benzonitrile to give N : N-Di-n-butyl benzamidine; similarly o-tolunitrile gives N : N-di-n-butyl-o-tolamidine; (2) the halo-magnesium derivative of n-butylaniline with benzonitrile yields N-n-butyl-N-phenyl benzamidine; (3) N-benzyl-piperazine is treated with ethyl magnesium bromide and the product reacted with benzonitrile to form N-benzyl-N1-benzimido-piperazine; (4) the product from D 1 : 2 : 3 : 4-tetrahydro-quinoline and ethyl magnesium bromide is treated with benzonitrile to give N-benzimido-tetrahydroquinoline; (5) the bromo-magnesium compound from di-n-butylamine with (a) 2 : 5-dimethoxy-benzaldehyde gives N : N-di-n-butyl-2 : 5-dimethoxy-benazmidine; (b) p-methoxy-benzonitrile gives N : N-di-n-butylanisamidine; (c) veratronitrile gives N : N-di-n-butyl-veratramidine; (d) piperonitrile gives N : N-di-n-butyl-piperonamidine; (e) p-dimethylamino-benzonitrile gives N : N-di-n-butyl-p-dimethylamino-benzamidine; (6) alpha-naphthonitrile with the bromomagnesium derivative of di-n-butylamine yields N : N-di-n-butyl-1-naphthamidine, and the corresponding compounds are obtained from 2- and 4-methoxy-1-naphthonitriles; (7) diethylamine and ethyl magnesium bromide give the bromo-magnesium compound which is treated with 4-cyano-quinoline to produce quinoline-4-(N : N-diethyl-)carboxamidine, and similar products are obtained from di-n-propylamine, di-n-butylamine and di-n-amylamine; also the bromomagnesium compound of di-n-butylamine reacts with nicotinonitrile to yield N : N-di-n-butyl-nicotinamidine; (8) the bromo-magnesium compound of di-n-butylamine with cinnamonitrile gives N - N-di-n-butyl-cinnamamidine.  The preparation of the hydrochlorides of the above amidines is described, except in the case of example (2).