Guanidine-based thiourea derivative

Figure 6.54 Structures of guanidine-based thiourea derivatives screened in the Henry reaction of nitromethane with cyclohexane carboxaldehyde under phase-transfer conditions.

However, initial attempts to use this strategy to prepare azapurine derivatives, by reaction of pentafluoropyridine and either guanidine or thiourea, led to 4-aminopyridine 25 and bispyridyl derivatives 26 respectively via base-induced elimination processes [46] (see Figure 11.9). 

Some bifunctional hydrogen-bond donor/Brpnsted base catalysts are shown in Figures 2.39 and 2.40. They comprise chiral amino alcohols and amino phenols, chiral amine-thiourea derivatives, and chiral guanidines, among others. In the absence of detailed experimental NMR or kinetic studies [179], most of our... 

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). 

Ethyl 2-ethylthio-4-chloro-5-pyrimidinecarboxylate (XXIIa), as well as the corresponding4-hydroxy-(XXIIb) and 4-amino-(XXIIIa) derivatives, possess-anti-cytogenic activity on Neurospora crassa [223, 224]. Compounds (XXIIIa, b and c) were found to inhibit the conversion of orotic acid to the uridine nucleotides [202]. Ethyl 2-methylthio-4-(halo-substituted anilino)-5-pyrimidinecarboxylates (XXIV), particularly the o-bromo- and the o-chloro- derivatives, substantially inhibit the growth of five experimental mouse tumours (Krebs-2 ascites carcinoma, Ehrlich carcinoma clone 2, leukaemia L-1210, carcinoma 755 and lymphocytic neoplasm P-288) [225]. Compounds of this type are usually prepared by the base catalysed condensation of ethoxymethylenemalonic esters or related derivatives with urea, thiourea, guanidine, or substituted amidine-type analogues [212, 225-237]. 

Other examples this type of quinazoline synthesis include the formation of the thione analog 752, by displacement of bromine from thiourea 751 <2003ARK(x)434>, and the imino compound 754, which could be formed by heating the guanidine derivative 753 in DMF, without the need for any added base <2005RJ01071>. 

Where R4 is a hydrogen or carbon atom, 10.15 is simply an amidine. However, urea 10.16, thiourea 10.17, or guanidine 10.18 and their derivatives may be used. These nucleophiles may be condensed with ester and nitrile functionalities as well as with aldehydes and ketones. Such condensations to afford pyridimidine derivatives are usually facilitated by acid or base catalysis, although certain combinations of reactive electrophilic and nucleophilic compounds require no catalyst at all. Some examples are shown below. 

The reaction of trichloromethanesulfenyl chloride 617 with amidines 616 and a mild base is a general preparation for 5-chloro-l,2,4-thiadiazoles 618 <1965AHC(5)119>. Iminochloromethanesulfenyl chlorides 620 (from RNCS + C12) react with amidines 619 to give 1,2,4-thiadiazolines 621 <1971T4117>. Chlorocarbonylsulfenyl chloride 623 (prepared from trichloromethanesulfenyl chloride and sulfuric acid) reacts with ureas, thioureas, and guanidines to give 1,2,4-thiadiazolidine derivatives 624 (Scheme 274) <1973CB3391> (see also ). 

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