Pyrimidin-2-thione derivatives, synthesis

The most common method for the preparation of thioureas is, however, based on the reaction of isothiocyanates with amines, and, not unexpectedly, the majority of papers deal with this particular reaction. 6-2 1 Among the N-substituent groups thus introduced into thiourea are 3-cyclo-pentenyl, 1-adamantyl, furfuryl, diphenylphosphinoyl, diphenyl-phosphinothioyl, AW-9,10-diacetyldihydro-2-phena2inyl, and variously substituted aryls. - If the isothiocyanate or the amine contains other reactive groups, cyclization to heterocyclic compounds containing the thiourea grouping may occur, either spontaneously or promoted by external influence, as recently demonstrated in the synthesis of thiones derived from imidazoline, pyrimidine, - and j-triazine. - ... 

Numerous examples of the synthesis of tricyclic systems based on indolizine derivative 232 have been reported <2000M959>. The product obtained from the reaction of 232 with carbon disulfide depends on the reaction medium. Thus, in aqueous potassium hydroxide the pyrimidine-dithione 233 is formed, whereas in pyridine the iminothiazine-thione 234 is obtained. In aqueous potassium hydroxide, compound 234 rearranges to 233 (Scheme 12) <2000M959>. 

Synthesis of 9-substituted tetrahydroazepinopurines as asmarine analogs has been described <03T6493>. In relation to adenosine receptor antagonists, new derivatives of pyrazolo[4,3-c][l,2,4]triazolo[l,5-c]pyrimidines have been synthesized <03IMC1229, 4287>. A one-pot synthesis of l,2,4-triazolo[l,5-c]quinazoline thiones 65, consisting of a domino cyclization of 2-isothiocyanatobenzonitrile 63 with hydrazides 64 has been published <03EJO182>. 

The availability of functionalized pyrimidines (cf. also Section 6.2.1.) gives the Traube synthesis great flexibility. The probability of ring closure during the Traube synthesis depends on the substituents of the pyrimidine-4,5-diamines, the condensation reagent and the reaction conditions. Problems are encountered with the ring closure of pyrimidine-6-thiols which can form thiazolo[5,4- f]pyrimidines 2. However, the 5-formamido derivative of 4,5-diaminopyrim-idine-6-thiol under alkaline conditions gives purine-6(li/)-thione 3. ... 

Another procedure for the synthesis of pyrimidines 119 involves alkylation of 5-ethoxycarbonylpyrimidine-4(3//)-thiones 121 with chloroacetic acid derivatives. In this case, thienopyrimidines 118 were prepared without isolation of intermediate pyrimidines 119 (1988GEP258012, 1988SL201, 1990SL75). 

The Wittig-type reactions of iminophosphoranes with isocyanates and related compounds have also been extensively used in heterocyclic synthesis. Examples include the preparations of the mesoionic [l,3,4]thiadiazolo[2,3-c][l,2,4]triazines (210) from (209), 0 bicyclic guanidines, e.g. (212), from (211), naphthypyridines (215), (216), and (217) from (213) and (214), 2 pyrido[l,2-f]pyrimido-[4,5-d)pyrimidines (218), 7H-pyrido-[4,3-c]- (219) and 10H-pyrido[3,4-b]- (220) carbazoles, tricyclic fused 2,4-diimino-l,3-diazetidines (222) from the bisiminophosphorane (221), benzotriazepines (225) from (223) and (224), 6 and mesoionic thiazolo-[2,3-b]-1,3,4-thiadiazoles (227) and N,N-bisheteroarylamines from the iminophosphorane (226), derived from 3-amino-4-phenylthiazole-2(3H)-thione. The carbodiimides (229), prepared from the iminophosphorane (228), can be converted into quinolines or a-carboline derivatives depending on the nature of the isocyanate used in the reaction with (228) and the reactions of iminophosphoranes (230) and (231) with aryl and styryl isocyanates provide one-pot syntheses of quinoline, a-carboline, and quinindoline derivatives. 9... 

Bis(methylthio)pyrimidines 40 have been obtained upon reaction of ketones with triflic anhydride (94MIS59]. Cycloaddition reactions of l,3-diaza-l,3-butadienes with haloketenes have been employed for the synthesis of pyrimidones [94T(50)7579). Reaction of 2-trimethylsilyloxy- and 2-trimethyI-silylthio-l,3-diazabutadienes (41) with enamines derived from aliphatic aldehydes (42) leads regio- and stereoselectiveiy to tetrahydropyri-midin-2(l -ones and thiones (43). This reaction type was also used for preparing quinazolines [94H(37)1109],... 

Numerous heterocyclic compounds can be oxidized with ozone to deliver derivatives useful in synthesis and the reaction products can be tuned according to the additives and conditions in the reaction medium. When treated with ozone, pyrimidine-2-thiones and 2-thiouracils react to give several p3Timidine derivatives (eq 57). Use of aprotic solvents or ozonolysis without an active nucleophile yields dimerization products, whereas ozonolysis in protic solvents or in the presence of a nucleophile leads to the sulfinic acid derivative that can then be converted to several products depending on workup conditions. The parent pyrimidine can be isolated when acid is introduced into the medium, and with an equal volume of water the pyrimidinone product is isolated. While a protic solvent, EtOH in the medium acts as a nucleophile to deliver the 2-ethoxypyrimidine. 

The reaction of dihydropyrimidine-2(lH)-thione (propylenethiourea) 1 with a-halocarboxylic acids gives only the bicyclic thiazolo[3,2-a]pyrimidine. The most convenient procedme for the synthesis of 3,4-dihydropyrimidine-2(l//)-thiones (known as the Biginelli reaction) is based on one-pot three-component condensation of aldehydes with P-keto esters and thiomea. Thiazolopyrimidine derivatives (3, Scheme 1) were obtained by a simple one-pot condensation reaction of 1 and 2-bromopropionic acid (2, R3 = H, bromoacetic acid (2, R3 = H, CH3) imder microwave irradiation and conventional conditions [12, 13]. 

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