Thiourea guanidine-based

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]. 

Figure 6.53 Structurai concept for the design of guanidine-based bifunctionai thiourea organocataiysts 179-189 and mode of bifunctionai substrate activation.

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

The described procedure is based on the methods of Johnson and Ambler 3 and Anderson et al.,4 as modified by Ulbricht and Price.5 This procedure is illustrative of a general method of preparing pyrimidines, wherein one condenses thiourea, guanidine, or an amidine with alkoxymethylenemalonic esters, alkoxy-methylenecyanoacetic esters, or alkoxymethylenemalononitrile. Kenner and Todd recently reviewed the synthesis of pyrimidines.6... 

Pyran-4-ones, chromones and flavones are converted into pyrimidines, usually under base catalysis, by reaction with compounds which contain the grouping N—C—N urea, thiourea, guanidine, aminoguanidine, acetamidine and dicyandiamide are examples of this type. Scheme 24 shows some typical examples (77BSF369, 81JHC619). 

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. 

Tertiary amides (and thioamides) with an a-proton react instead to give chloro enamines. These can undergo nucleophilic substitution (eq 15). CSiloro enamines are also intermediates in synthetically useful dehydrogenation reactions, using Pyridine N-Oxide or DMSO as oxidant (eq 16). Tertiary ureas and thioureas form related adducts which have been utilized in the synthesis of hindered guanidine bases by further reaction with amines (eq 17).33... 

Recent developments in organocatalytic pathways for the ROP of lactide and several lactones, without adverse transesterification creating polymers that are metal-free and therefore perfect candidates for biomedical and microelectronic applications, have been developed using N-heterocyclic carbenes, thiourea-tertiary amines, and amidine and guanidine bases. Here, the exquisite control, the absence of metal ions, the ready synthetic availability of the catalysts, and the mild reaction conditions are of major importance for tailor-made polyesters, and also have high potential for functional polycarbonates [91, 92]. 

Figure 14.1 Thioureas, amidines and guanidine bases for ROP. (a) Thiourea-amine (b) l-cyclohexyi-3-(3,5-bistrifiuoromethylphenyi)thiourea (c) (-)-Sparteine (d) DBU (e) MTBD (f) TBD.

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. 

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>. 

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. 

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 ). 

There are standard methods available for synthesis of amidines 10] and guanidines. In particular, reaction of an acylated thiourea with an amine, followed by removal of the acyl group(s) from the acylguanidine intermediate provides a mild and efficient synthesis [11]. When dihydroxyacetonc is treated with formamidine acetate in liquid ammonia, imidazole-4-methanol is isolated in 65-70% yield as its hydrochloride (3) (Scheme 4.3.2). This convenient synthesis is much less tedious than the old approach based on the reaction of fructose with ammonia [16]. 

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