Disubstituted Biguanides

In the preparation of 1,5-disubstituted biguanides by this method, alcoholic ammonia at 100° in a closed vessel is used (755). Thiourea is an effective desulphurising agent (755). 

Under the influence of desulphurising agents, guanidines and thioureas combine to form biguanides (XIX), albeit in low yields (722, 575). In their re-examination of this reaction. Curd, Rose et al. (24, 57, 754) synthesised 1,5-disubstituted biguanides however, the yields did not... 

The sulphur atoms in dithiobiuret can be successively alkylated. It is therefore possible to synthesise 1,5-disubstituted biguanides carrying unlike substituents by the stepwise alkylation and replacement of the alkylthio-groups of dithiobimet, as has been described (295) for Paludrine (XXVIII, R = p-ClCeH4). 

The 1,5-disubstituted biguanides have been described in detail (748). They are generally low-melting solids which are sparingly soluble in cold water. The lower members are sufficiently soluble to give strongly alkaline solutions.They rapidly absorb atmospheric carbon dioxide and are best characterised as their stable and crystalline acid salts (748,749,752,753,232). 

In contrast, sulphonyl hahdes acylate biguanides in the expected manner, the parent compound, for example, being convertible into 1- -nitro-benzenesulphonylbiguanide. The reaction has been extended to 1,1-disubstituted biguanides 548) and to several other examples 167, 521). 

In the general reaction, 1,1-disubstituted biguanides (95) (e.g. 1-p-chlorophenyl-l-methylbiguanide) afford the same product (CXXXIII) under both acidic and basic conditions. The phenyl analogue gave similar results (95). Independent studies by Modest et al. (443) confirmed the assigned structure (CXXXIII). 

The interaction of 1,2-disubstituted biguanides and acetone has provided particularly significant results (95). l-p-Chlorophenyl-2-methylbiguanide and acetone reacted in the expected manner, under acidic or basic conditions respectively, to yield the isomers (CXXXIV) or (CXXXV). 

Guanidines react with equimolar amounts of carbodiimides to give disubstituted biguanids 577.549... 

Synthesis was accomplished of the s-triazine derivatives from uronic and polyuronic acids.5(R)-(2-Amino-4-di-methylamino-l,3,5-triazin-6-yl)-L-arabinopyranose and its methyl glucoside were prepared from gaiact-uronic acid. 5(R)-(2-amino-4-dimethylamino-l,3,5-triazin-6-yl)-p-d-xylo-pyranose was prepared from glucuronolactone. Methyl 5(R)-(2-Amino-4-di-methyl-amino-1,3,5-triazin-6-yl)-a-D-lyxopyranoside was prepared from mannuronolactone by ring closure with N,N-disubstituted biguanide. s-Triazine derivatives of polyuronic acids, such as pectin and alginic acid, were prepared similarly. 

With N,N -disubstituted guanidines the problem arises whether 1,2,5- (XXXV) or 1,3,5-trisubstituted biguanides (XXXVI) are produced, or a mixture of both. Relevant experiments (5) show that the former (XXXV) are in fact obtained to the exclusion of the latter. 

The reaction between biguanides and carbodiimides in dimethyl-formamide provides a general route to substituted melamines (375). Thus, biguanide or its 1-mono- or 1.2-disubstituted homologues afford, respectively, satisfactory yields of mono- or 2.4-disubstituted melamines (CXLVIII) or 1.2.6-trisubstituted isomelamines (CXLIX). In each case, the reaction probably involves primary addition of the reactants, followed by the cydisation of the resulting intermediate labile triguanide, with loss of amine (375) ... 

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