Pyrimidine-4-thiones, 1,2-dihydro

Surprisingly, Kashima et al. (83TL209) reported the formation of individual 1,4-dihydro- and 1,6-dihydropyrimidines on desulfurization of the corresponding pyrimidine-2-thiones with Raney Ni and claimed that no tautomerization occurs under the reaction conditions (heating under reflux in MeOH). 

Other examples of CN/CC replacement are observed in reactions of l-phenyl-pyrimidin-2(l//)-one with active methylene compounds, such as diethyl malonate and benzoylacetate, giving in good yield 2-oxo-l,2-dihydro-3-pyridinecarboxylate and 3-benzoylpyridin-2(l H)-one, respectively (84CPB2942, 87H2223) (Scheme 8). In a similar way 4,6-dimethyl-1-phenylpyrimidin-2( 1 //)-one, 4,6-dimethyl-1 -phenylpyrimidine-2( 1 //)-thione and 4,6-dimethyl-1 -phenyl-2-phenylimino-1,2-dihydropyrimidine yield with malonitrile 2-amino-4,6-dimethyl-3-pyridinecarbonitrile. In a similar way 2,3-diarylpyrimidin-4(3//)-thiones give with malonitrile CN/CC replacement (84H763) (Scheme 8). The reaction takes a similar course as described in Scheme 7. 

Treatment of pyrimidine-2-thione 193 with AICI3 in PhN02 yielded 2-(4-benzylphenyl)-6-oxo-6,7-dihydro-4//-pyrido[6,l-a]isoquinolin-4-thione (194) (98MI47). Cyclization of l-(2-carboxyethyl)-l,2,3,4-tetrahydroquina-zoline-2,4-dione (195) in PPA afforded l,2,3,5,6,7-hexahydropyrimido[3,2, l-//]quinazoline-l,3,7-trione (196) (97CHE96). 

Reaction of 2-cyanomethylpyridine with iV-(l-aryl-l-chloro-2,2,2-trifluoroethyl)-iV -(4-methylphenyl)carbodiimides, and with (1,1,2,2,2-pentachloro- and l,l-dichloro-2,2,2-trifluoroethyl)isocyanates or A-methoxycarbonyl-l,2,2,2-tetrachloro-, — l-chloro-2,2-trifluoroacetaldehyde imines afforded 3-aryl-4-cyano-l-(4-methylphenyl)imino-3-trifluoromethyl-2,3-dihydro-17/-pyrido[l,2-f]pyrimidines and 4-cyano-3-trichloro-, 4-cyano-3-trifluoro-17/-pyrido[l,2-4pyrimidin-l-ones, respectively <2004CHE47>. Refluxing 2-cyanomethylpyridine and iV-(l-aryl-l-chloro-2,2,2-trifluoroethyl)isocyanates in benzene furnished l-aryl-4-cyano-l-trifluoromethyl-l,2-dihydro-3//-pyrido[l,2-4pyrimidin-3-ones. However, when the solution of the isocyanate was added dropwise to the solution of 2-cyanomethylpyridine, and the reaction mixture was then treated with NEt at room temperature, the isomeric 3-aryl-4-cyano-3-trifluoromethyl-2,3-dihydro-l//-pyr-ido[l,2-dpyrimidin-l-ones were obtained. Reaction of l-(acetyl- and benzoylmethylene)-6,7-dimethoxy-l,2,3,4-tetra-hydroisoquinolines with PhCONCS yielded 1-acetyl-, 1 -benzoyl-9,10-dime thoxy-3-pheny 1-6,7-dihydro-2//-pyrimido[6,l- ]isoquinoline-2-thiones <2003SL2369>. 

Reaction of 4-cyano-l -oxo-2,3-dihydro-l H-pyrido [1,2-c] pyrimidine-3-thione 72 with halogeno ketones 73 afforded tricyclic derivatives 74 (08MI2). 

Alkylation of l-aryl-4-cyano-l-trifluoromethyl-2,3-dihydro-lH-pyrido [l,2-c]pyrimidine-3-thiones with benzyl bromides, ethyl 2-broroacetate, and 2-chloroacetamides in the presence of K2C03 in DMF at ambient temperature gave 3-[(substituted methyl)thio)]-lH-pyrido[l,2-c]pyrimi-dines in 51-87% yields (07MI1). 

Cyclocondenzation of 2-pyridylacetonitrile and ethoxycarbonyl isothiocyanate in MeCN gave 4-cyano-l-oxo-2,3-dihydro-lH-pyrido[l,2-c]pyrimi-dine-3-thione in 18% yield (08MI2). 6-Endo-trig cyclization of anion, formed from 4-methylpyrimidine by LDA in THF at —78 °C, with methyl 3-propynoate provided 8-methyl-6H-pyrido[2,l-c]pyrimidin-6-one in 47% yield (06TL5063). 

Russian workers (82KGS118) reported the synthesis of 5,6-dihydro-thieno[2,3-d]pyrimidine 122 by brominating 5-allylpyrimidine-4(3//)-thione 121. 

Oxazines and 1,3-thiazines are commonly used as substrates in pyrimidine syntheses <1994HC(52)1, CHEC-III(8.02.10.1.3)227>. Rearrangement reactions involving 1,3-thiazines are often very easy. For example, reaction of 2-imino-4-phenyl-2//-l,3-thiazinium perchlorate 382 with NaOH at room temperature affords 4-phenylpyrimidine-2(l//)-thione 383 (Scheme 178) <2004CHE1595>, while treatment of 6-amino-2,3-dihydro- l,3-thiazin-4(l//)-ones 384 with KOH readily gives the potassium salt of the dihydropyrimidinone 385 (Scheme 179) <2005HAC426>. 

A derivative of a hitherto unknown nucleus was produced when 4-amino-5-aminomethyl-3-methyltriazole was refluxed with carbon disulfide and triethylamine in pyridine, which yielded 3-methyl-3,7-dihydro-l,2,3-triazolo-[4,5-d][l,3]thiazine-5-thione (98) (3 hr, 53%) the 3-benzyl analog was made similarly (63%) [80JCS(P1)2009]. Cyclization of 4-anilino-5-ethoxycarbonyltriazole with polyphosphoric acid produced 1 f/-triazolo-[4,5-h]quinol-4-one (99) [80EUP(A)2562]. Similarly, ring closure of 4-(2-pyridylamino)triazole-5-carboxylic acid (or its esters) gave l//-pyrido-[l,2-a]-l,2,3-triazolo[4,5-d]pyrimidin-4-one (100) (77GEP2757929). 4-Amino-5-formyl-3-methyltriazole and pentane-2,4-dione, set aside in 20% sulfuric acid, yielded 3,5-dimethyl-3//-l,2,3-triazolo [4,5-6] pyridin-6-yl... 

The base-catalyzed reaction of cycloalkanones with sulfur and cyanoace-tamide gave l,2-dihydro-2-spirothieno[2,3-d]pyrimidine-4(3//)-thiones 63 (90JPR223). 

The preparation of 9-niethyl and 9-butyl-2-hydroxy-8,9-dihydro-7H-purine-8-thione (XXVa Table 7) is somewhat unusual. Brown [45) has obtained these compounds from carbon disulfide and respectively f-methyl and 1 -butyl-5,6-diamino-1,2-dihydropyrimidin-2-one (XXIVa.). Evidently a shift of the alkyl group from the 3-N to the 9 N atom must occur during the ring closure. The structure of these two purines has been confirmed by their independent synthesis from 4-methylamino and 4-butylamino-5-amino-2-hydroxy pyrimidine. 

Yet another type of isomer formation has been discovered, the formation of a 1,2-dihydro-l,2,4-triazolo[l,5-a]pyrimidine-2-thione (XLVIII) from 2,3 - dihydro-1,2,4-triazolo[4,3-a]pj rimidine-3-thione (XLVII) during the cyclizations of carbon disulfide with 2-hydrazino-pyrimidine, 2-hydrazino-4-methylpyrimidine and 2-hydrazino-4.6-di-methylpyrimidine 316, 320). 

These isomers (XLVIII) are formed as side-products during the cycUzation reaction or when the 2,3-dihydro-l,2,4-triazolo[4,3-a]pyri-midine-3-thiones (XLVII) are heated either in water or water-pyridine mixtures. These isomerisations are probably proceeded by the hydrolysis of the (XLVII) first formed. The hydrolysis likely yields either the Schiff s base of 5-amino-2l4-l,2,4-triazoline-3-thione (XLIXa) or 5-amino-zl4-l,2,4-triazoline-3-thione (XLIXb) and the corresponding -dicarbonyl compound. These substances can now cyclize again either on the Nj or the nitrogen atom. This re-cyclization however will occur most readily on the more nucleophile nitrogen atom of the hydrazino function (Nj). Similar conversion reactions are known and have been studied in detail for the non-thioxo substituted l,2,4-triazolo[4,3-a] pyrimidines 3, 317, 318, 319, 383). 

Still another isomer, the 5-hydroxy-7-methyl-2,3-dihydro-l,2,4-triazolo[4,3-c]pyrimidine-3-thione (LI) is formed in the reaction of... 

A halogen atom in ortho-position to the amino group in a heterocyclic ring is also very reactive so much so in fact, that 4-chloro-5,6-diamino pyrimidines (CXX) react with carbon disulfide to give 7-amino-t,2-dihydrothiazolo[5,4-d]pyrimidine-2-thiones (XXVIa) (21) rather than 6-chloro-8,9-dihydro-7H-purine-8-thiones (XXV, Rg—Cl) (compare I.3.b). These products are listed in Table 17. 

Acyl-2,3-dihydro-lH-pyrido[l, 2-c]pyrimidin-4-ones were obtained when 2-vinylpyridine was reacted with acyl isocyanates (75IZV2608), Cyclocondensation of 3-methoxy-2-(2-oxopropyl)piperidine and phenyl isothiocyanate in boiling ethylene dichloride afforded 3-methyl-5-meth-oxy-2-phenyl-2,4a,5,6,7,8-hexahydro-l//-pyrido[l,2-c]pyrimidine-l-thione (55JOC136). 

Diamino-3,4-dihydro-2(l/7)-pyrimidine-2-one-4-thione with 1,3-dibromopropane gave (401)... 

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