Substituted Biguanides

Aryl-substituted biguanides (c.g. 1) can be condensed with 1-benzoylacetone to provide 1,3,5-triazocine derivatives,13 Two isomers of product 2 can be isolated upon recrystallization from ethanol. The isomers, probably tautomers 2A and 2B, exhibit the same melting point and rapidly interconvert in solution, thereby giving identical NMR spectra in deuteriochloroform at room temperature. 

The structure of a single example of a chloro-substituted biguanide [Cu(clbg)2]Cl2 2H20 (clbg=2-chlorobiguanide),has been reported [34]. Chlorine substitution leads to a reduction in the number of N-H donors from seven to six. Five are involved in the construction of a 2-D architecture (Fig. 15). Two pairs of N-H donors form R2(4) assemblies with separate chlorine atoms the fifth forms a N-H 0 contact to the water molecule which also uses its O-H donors to link two chloride anions (Fig. 15). The resultant 2-D sheet architecture lies parallel to the (2 -1 1) plane. The sixth forms a N-H -Cl contact to a chloride anion in an adjacent sheet. 

The method is normally limited to the production of s unmetrically substituted biguanides by the stepwise addition of unlike amines, biguanides bearing different 1- and 5-substituents (e.g. isoCsHisNH ... 

The interaction of guanidinomagnesium halides (XLV) with disubsti-tuted cyanamides (XLVI), for example, affords substituted biguanides (XLVIII) [59). The variation in 3nelds (7 to 48%) is attributed [59) to differences in solubility in ether of the guanidinomagnesium halides and the resultant complexes, and to the electronic effects of the substituents. 

Aminomagnesium halides (XLIX) may also serve as a source of the same substituted biguanides (XLVIII) by reaction with substituted cyanoguanidines (L), but 3delds are again low and variable. The possible mechanism of this group of reactions has been discussed [59), but the studies are as yet incomplete. 

Salts of substituted biguanides with N-acylsulphonamides, of general structure [RS0zN-C0R ] [R NH2C( NH)NH-C( NH)NH2] have been prepared (JSO), as have addition complexes with 2-hydroxy-4,6-dimethylpyrimidine (477). 

In contrast, 1-substituted biguanides are hydrolysed to N-amidino-N -substituted ureas (LXXVII) (498), the structure of which is confirmed by the unequivocal s mthesis of their isomers (LXXVIII) by acid hydrolysis of the appropriate cyanoguanidine. 

Esters of aromatic (instead of aliphatic) acids react rapidly at room temperature (701). but the addition of a condensing agent is still desirable when 1-substituted biguanides are used. 

Heterocyclic carboxylic esters (708) are as reactive as formate and acetate esters. Extended to 1-substituted biguanides, the reaction is promoted by metal alkoxides. Since the heterocyclic ring must be five-or six-membered and contains a conjugated system of double bonds, the reaction resembles formally that involving a,p-unsaturated esters (see below). Several successful examples are on record (599, 606). 

Methyl acetoacetate is reported (696) to yield the triazine (XCV R = H) as main product (85%), the pyrimidine being the by-product, of probable structure (XCIX) rather than (XCIV R = H). However, in view of the opposite conclusion in the case of the condensation of ethyl acetoacetate and substituted biguanides (see above), this formulation requires careful confirmation. 

The condensation of diethyl formylsuccinate with amidines is an established p3mmidine synthesis (16, 714). Extended to 1-substituted biguanides, the reaction yields 2-guanidino-4-hydroxy-5-carbethoxy-methylpyrimidines as follows (684) ... 

Table 9. Interaction of substituted biguanides with acetone...

Studies have recently become available concerning the kinetics and mechanism of the isomerisation, in dilute aqueous solution, of dihydrotriazines of this type (e.g. 4,6-diamino-l-(3,5-dichlorophenyl)-l,2-dihydro-2,2-dimethyl-l,3,5-triazine), and of their degradation to substituted biguanides 683). 

A number of well-defined crystalline complexes of silver(III) have been described.496 In particular, biguanides, substituted biguanides, ethylenebis(biguanide) and piperazine dibiguan-ide have been found to complex and stabilize silver(lll). 

The bivalent metals, as usual, combine with two molecules of biguanide to form 4-coordinated planar complexes, while the trivalent cobalt and chromium combine with three molecules of the ligand to produce a 6-coordinated octahedral configuration. The only exception is the trivalent silver which yields, however, a 4-coordinated planar complex. The preparation of the free tris(biguanidato) chromium, Cr(C2N5H6)s, in the anhydrous state,6 as well as of the corresponding anhydrous cobalt(III),8 copper(II), cobalt(II), palladium(II), and nickel(II) compounds, provides indisputable evidence for the structure proposed. Similar anhydrous metallic complexes with numerous substituted biguanides also have been included in the above-mentioned studies. 

In order to increase the efficiency of the catalysts, stronger bases are required such as the highly N-substituted biguanides of type 4 or 5 (Figure.2). 

There seem to be no unsubstituted complexes of biguanide with osmium, though a few tris species of substituted biguanides have been reported. 

Beyond the 3+ oxidation state, rhodium forms a limited number of complexes in the 4+, 5+ and 6+ oxidation states. A recent review1221 gives an excellent summary of the chemistry of the higher oxidation state chemistry of Rh (as well as Ru, Os, Ir, Pd and Pt). For the 4+ oxidation state, the hexafluoro, hexachloro and trioxo dianions are well characterized. The known neutral species include RhF4 and some oxides. There are also scattered reports of Rhlv complexes containing substituted biguanides and Schiff base chelates. 

Structure-Activity. The available data on the relationship of structure to hypoglycemic activity for substituted biguanides result from a very limited number of studies, generally in healthy animals (135-137). Alkyl substitution (structure ll)at Ri increases ac-... 

Substituted biguanides (19) also react with benzil on heating in alcohol in the absence of any catalyst to give 2-substituted guanilydene-5,5-diphenylhydantoins (20), whose formation involves an anionotropic migration of a phenyl group.41 N-Amidino-O-alkylisoureas and 1-aryl- or 1-alkyl-3-amidino-2-thioureas behave similarly.42... 

Phenylbiguanide-p-sulfonic acid is prepared by the usual reaction for the synthesis of Af-substituted biguanides the addition of dicyanodiamide (cyanoguanidine) to... 

Cyclocondensation of substituted biguanides 81 with methyl trifluoroacetate in the presence of catalytic amounts of sodium ethylate gave 2-amino-4-(substituted amino)-6-trifluoromethyl 5ym-ttiazines 82 (Scheme 35) [66-72], A rapid and efQcient synthesis under microwave irradiation has been developed for various substituted l.S.S-biazines that can serve as versatile building blocks for both supramolecular and medicinal chemistry [61, 73],... 

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