Guanidines and Thioureas

Systematic NMR studies of a set of heterocycles containing guanidine and thiourea structural moiety have been published by an English team <1995MRC389>. In the frame of these investigations, some imidazo- and thiazolo-[l,2,4]triazinones having the general structure 50 have been analyzed by 13C and 1SN NMR spectroscopy. The chemical shifts of some derivatives are compiled in Table 3. 

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... 

It has already been stated that the guanidine and thiourea groups, used so successfully in the development of H2 antagonists, are polar and hydrophilic. This implies that... 

Sohtome, Y, Takemura, N., Takada, K.et al. (2007) Organocatalytic asymmetric nitroaldol reaction cooperative effects of guanidine and thiourea functional groups. Chemistry, an Asian Journal, 2, 1150-1160. 

Nagasawa et d. designed a novel bifunctional catalyst bearing both guanidine and thiourea functional groups (19), which effectively promoted the Henry reactions with aliphatic cyclic aldehydes and branched aldehydes in the presence of K1 as an additive to provide -nitroamine with high enantioselectivity. Use of a-substituted aldehyde improved the enantioselectivity to 95-99% (Scheme 2.60) [115]. 

Concerning the action of phenylhydrazine on these derivatives, Behrend and his students found that 6-methylisodialuric add gave a phenylhydrazine salt when treated in aqueous solution with phenylhydrazine. Levene found that isodialtuic acid was converted into 5,6-di-phenyl-hydrazinouracil (XX) by the action of a hot acetic acid solution of phenylhydrazine. This result becomes tmderstandable when we recall that Behrend, Koch, and von Vogd noticed that in hot acetic acid even bases like guanidine and thiourea isomerized isodialuric acid into dialuric acid (XIX). 

A synthesis of pyrimidine thiols in a yield of up to 60% from methoxybu-tenyne and thiourea has been described for the first time in (59JCS525). Later, a series of 2-amino-4-alkylpyrimidines (161) has been obtained in 25-27% yield from l-methoxyalk-l-en-3-ynes and guanidine (80°C, H, HoO, 2 h) (70ZOR2369). 

In a similar way, 1,3-dinitrogen systems such as diamines, amidines, guanidines, aminothiazoles, aminopyridines, ureas and thioureas react with alkynyl-carbene complexes generating the corresponding heterocycles. Of particular interest is the reaction with ureas, as the process can be applied to the easy synthesis of pyrimidine derivatives [88] (Scheme 41). 

Moreau and co-workers have also prepared (ll ,2K)-l,2-diaminocyclo-hexane amino-urea and thiourea derivatives [43]. Diphenylethylenediamine-substituted monothioureas are more stable than the cyclohexyldiamine counterpart, but they can also rearrange to guanidine derivatives, especially at high temperature or in the presence of metal [43]. Under the same conditions, thioureas also rearrange to guanidines in the presence of amines. Selective formation of substituted guanidines from thiourea derivatives of diaminocy-clohexane or diphenylethylenediamine were also reported in a recent paper from Ishikawa [44]. 

Preparation of guanidine from thioureas has been carried out. There are many ways to synthesize guanidines. Converting thioures and isothiourea moieties into guanidine is one of the most popular methods. 

The reaction of 113 with urea and thiourea (both compounds are weaker bases than guanidine) requires the presence of sodium ethoxide. With urea, uracil and with the thiourea, 2-thiouracil are obtained, respectively. 

Many of the most versatile and widely used syntheses of pyrimidines are straightforward examples of [3+3] condensations of amidines, guanidines, ureas and thioureas with 1,3-dielectrophiles, and clearly a considerable measure of control over the degree and nature of the substitution pattern in the final product is possible by appropriate choice of the two three-component units. Representative examples are given in equations (112)—(115), and the use of sulfamide in place of amidines, etc., allows the method to be extended to the synthesis of polyheteroatom systems e.g. equation 116). 

The combination of his-electrophilic and his-nucleophilic components is the basis of general pyrimidine synthesis. A reaction between an amidine (urea or thiourea or guanidine) and a 1,3-diketo compound produces corresponding pyrimidine systems. These reactions are usually facilitated by acid or base catalysis. 

On hydrolysis with dilute sulfuric acid it yields urea. On treatment with ammonium sulfide it prefers to react with the hydrogen sulfide part of the molecule to form thiourea, not with the ammonia part to form guanidine, and the reaction is the commercial source of many tons of thiourea for the rubber industry. On evaporation for crystals, the solution yields dicyandiamide which constitutes a convenient source for the preparation of guanidine nitrate. 

As already mentioned at the beginning of this chapter, one of the facile methods for the synthesis of dihydropyrimidine derivatives is the treatment of oc,(3-unsaturated carbonyls with urea and its analogues—thiourea, guanidine and amidines. However, the majority of the publications have dealt with syntheses involving thiourea. Most likely is the possibility of the modification of 3,4-dihydropyrimidine-2-thiones or their heteroaromatized analogues, which produces a diverse class of heterocycles. The reagent involved in this modification process can act like a,(3-unsaturated carbonyls [16] (Scheme 3.9). 

Interestingly, completely different types of organocatalyst have been found to have catalytic hydrocyanation properties. Among these molecules are chiral diketo-piperazine [4, 5], a bicydic guanidine [6], and imine-containing urea and thiourea derivatives [7-13]. All these molecules contain an imino bond which seems to be beneficial for catalyzing the hydrocyanation process. Chiral N-oxides also promote the cyanosilylation of aldimines, although stoichiometric amounts of the oxides are required [14]. 

Calcium Cyanamide (H2N-CN) is used as a fertilizer, herbicide, insecticide, a steel-making additive and an ore processing material. It can also be used to make thiourea, guanidine and ferrocyanides142. SKW Chemicals in Germany (now part of Degussa) claims to be the world leader in production of cyanamide and cyanamide-based chemical intermediates. 

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