Thiazolo 4,5- pyrimidine-7 -thiones

Another example of annelation was demonstrated by Hoffmann-La Roche at the thiazolo[4,5-d]pyrimidine scaffold synthesis and decoration. Under thionation with P2S5, the acylated 6-aminopyrimidine 195 gives the corresponding thioamide, which cyclised spontaneously into thiazolo[4,5-d]pyrimidine thione 196. Thione 196 was used further transformation for synthesis of key building block 197 applied for the preparation of the library 198 (Scheme 42) [185]. 

Treatment of 2-imino-3-phenyl-4-amino-(5-amido)-4-thiazoline with isocyanates or isothiocyanates yields the expected product (139) resulting from attack of the exocyclic nitrogen on the electrophilic center (276). Since 139 may be acetylated to thiazolo[4,5-d]pyrimidine-7-ones or 7-thiones (140). this reaction provides a route to condensed he erocycles (Scheme 92). 

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. ... 

The synthesis of thiazolo[3,2-a]-[l]benzothieno[2,3-d]pyrimidin-3(2/T)-ones (323) is accomplished in two ways. The first involves direct condensation of thione with a-chloroester, while the second, the cyclization of the acid through a mesoionic compound, is affected as illustrated in Scheme 76 [81IJC(B)538]. 3-Methyl(pheny )-4-oxo-5,6,7,8-tetrahydro[l]benzothi-eno[2,3-cf)pyrimidine-2-thiones (322a,b) react with ethyl a-chlorophe-... 

Structures comprising One Five-Membered and One Six—Membered Ring (5,6). - Thiazolon.2-al-. r3,4-al-, and 5,4-dlpyrimidines tC NS-C N ]. The reaction of 2-amino-2-thiazoline or thiazolidine with EtOOCCHRCOOEt/Na or R1R2NCH(C00Et)2[R1,R2=various] affords (252 R=alkyl,NR1R2 R3, R = H,bond)285 288. Other methods utilised include the preparation of thiazolo[3,2-a]pyrimidines by reaction of tetrahydropyrimidine-2-thione with broraoketones and... 

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... 

Thiazolo-[4,5-d]- and -[5,4-d]-pyrimidines [C3NS-C4N2]. The reaction of the A" -thiazoline (139) with NaSH or with H2S and pyridine gives the thiazolo-[4,5-i/]pyrimidine-7-thione (140 R = Ac, R = H, X = S), and with acetic anhydride and PPA yields (140 R = H, R = Me,X = O), whilst the readily available ethyl 2-methylmercapto-5-aminothiazole-4-carboxylate will react with formamide to give the thiazolo[5,4- f]pyrimidin-4-one (141). ... 

Cycloaddition and cyclization routes were used to access certain 1,3-diazines. The 4+2 cycloaddition reaction of 4-(N-allyl-N-aryl)amino-l,3-diaza-l,3-butadienes with vinyl-, isopropenyl-, and chloroketene led to pyrimidinone-fused pyrimidinones <97T13841>. Cis-cyclopenta[d]pyrimidines were derived from cis-2-amino-l-cyclopentanecarboxylates by cyclization with KOCN and KSCN <97JHC1211>. 2-Thioxopyrido[3, 2 4,5]thieno[3,2-r/]pyrimidin-4(3//)-ones 19 were prepared by cyclocondensation of 2-carbethoxy-3-amino-4-phenyl-6-substituted-thieno[2,3-/)]pyridines and isothiocyanates <97JHC937>. Thiazolyl-benzimidazoles derived from 2-cyanomethyl-l//-benzimidazole and 2,3-dihydrothiazole-2-(3//)-thiones were cyclized to the corresponding thiazolo[4,5-r/]pyrimidines <97PHA346>. Reductive cyclization of 6-cyanomethyl-5-nitropyrimidines afforded 7-alkyl-5//-pyrrolo[3,2-r/]pyrimidines and 6-amino-7,7-dialkyl-7//-pyrrolo[3,2-rf]pyrimidines <97T391>. 7-Methyl-5-alkyl-2-vinyl-pyrazolo[3,4-r/]pyrimidine-4,6(5//,7//)-diones arose from cyclization and alkylation of... 

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]. 

Diamino-l/f-pyrunidine-2-thione was coupled with aromatic aldehydes (At = Ph, d-Cl-CeHt) to give the corresponding SchiffhasQS 20. Treatment of 20 with chloroacetic acid gave thiazolo[3,2-a]pyrimidine 21, which was condensed with j>-chlorobenzaldehyde to give compound 22. Compound 22 was condensed with hydroxylamine to give isoxazolo[4,5-J]thiazolo[2,3-a]pyrimidine 23 as shown in Scheme 9 [27]. 

E)-2-(2,4-Dichlorobenzylidene)-6,7-dihydro-2H-thiazolo[3,2-a]pyrimidin-3(5H)-one 35 (Scheme 13) was synthesized by mixing 2,4-dichlorobenzaldehyde, ethyl chloroacetate and tetrahydropyrimidine-2-thione in ethanol [37],... 

Alkylation of l-methyltetrahydropyrimidine-2(lH)-thione (N-methylpropylenethiourea) with chloro- and bromoacetic acids and their esters gave 8-methyl-3-oxo-2,3,6,7-tetrahydro-5H-[l,3]thiazolo[3,2-a]pyrimidin-8-ium chloride or bromide 38 (Scheme 16). The former is readily hydrolyzed in 95% ethanol to 3-[(3-methylamino)propyl]-l,3-thiazolidine-2,4-dione hydrochloride 39 [40,41],... 

N-Aryl-3-oxobutanethioamides 74 reacted with 2-amino-1,3-thiazole or (2-amino-l,3-benzothiazole) 75 in acetic acid to give a mixture of thiazolo[3,2-a]pyrimidine-5-thiones 76 and 5-arylimino-7-methyl-5H-[l,3]thiazolo[3,2-ajpyrimidines 77 (Scheme 35) whose ratio depends on the nature of the aryl substituent in the initial butanethioamide [60],... 

Reaction of cycloalkenyl-1-diazenes 116 with tetrahydropyrimidine-2-thione (Scheme 52) in methanol at room temperature give thiazolo[3,2-a]pyrimidine]-2,3 -dione- 2-semicarbazones 118 via the intermediate 117 [78]... 

Amino-5-earboxamido-2,3-dihydrothiazole-2-thione 182 (Seheme 82) was prepared form eyanoaeetamide, sulphur and 4-fluorophenyl isothioeyanateisothioeyanate aeeording to the proeedure reported by Gewald. This eompound was eyelized to the thiazolo[4,5-d]pyrimidine 183 using a triethylorthoformate/aeetie anhydride mixture as deseribed [84], 7-... 

---