2- -l,3-thia

Electronic Structure of Benzo-2,l,3-thia- and -selena-diazoles 523... 

Anion radicals of benzo-2,l,3-thia(and selena)diazole have been produced by metal reduction in several solvents at low temperatures, and their electron spin resonance has been studied. The reductive desulphurization of substituted benzo-2,l,3-thiadiazoles by stannous chloride in concentrated hydrochloric acid gives o-phenylenediamines in 80—90% yields. The stability of the heterocyclics against reduction increases with the number of chlorine substituents. ... 

The by-products of these reactions are sulfides. The sulfide formed in the synthesis of 2-mercaptoethanol, 3-thia-l,5-pentanediol (thiodiglycol), has a variety of uses ranging from lubricant additive intermediates to textile finishing. 

Although derivatives of 2,1,3-benzoxadiazole have been used extensively to make quinoxalines (see Section 1.6.7), the corresponding selena and thia systems have been paid scant attention for that purpose. However, 5-chloro-4-nitro-2,l,3-benzoselenadiazole (456) has been used as a convenient source of 4-chloro-3-nitro-1,2-benzenediamine (457) (HCl + HI, 20°C, 2 h 88%), which was then converted into 6-chloro-5-nitro-2,3(l//,4//)-quinoxalinedione (458) (oxalic acid, 2M HCl, reflux, 2.5 h 23%). ° In addition, irradiation of 2,1,3-benzoselenadiazole (460, X = Se) or 2,1,3-benzothiadiazole (460, X = S) with dimethyl acetylenedicarboxy-late afforded, among other products, dimethyl 2,3-quinoxalinedicarboxylate (459)... 

At present there are seven NRTIs, which have been formally approved for the treatment of AIDS 3 -azido-2, 3 -dideoxythymidine (AZT, zidovudine), 2, 3 -dideoxyinosine (ddl, didanosine), 2, 3 -dideoxycytidine (ddC, zalcitabine), 2, 3 -didehydro-2, 3 -dideoxythymidine (d4T, stavudine), (—)-L-3 -thia-2, 3 -dideoxycytidine (3TC, lamivudine), cyclopentenyl V -cyclopropylaminopurine (abacavir, ABC), and (—)-L-5-fluoro-3 -thia-2, 3 -dideoxycytidine ((—)FTC, emtricitabine) (De Clercq 2004a) (Fig. 3). 

Irradiation of as-3,4-H-9-substituted 6-oxo-3,4-dihydro-2//,6//-pyrido[l,2-/d[l,3 thia/ine-4-carboxylates in benzene afforded tricyclic condensed cyclobutanone derivatives, sometimes as a diastereomeric mixture <2000J(P1)4373>. 

In a similar manner, 2,2,4-trimethyl-27/,677-pyrimido[2,T4][l,3]thiazines with 7-formyl, 7-acetyl, or 7-C02Me substituents were obtained in good to excellent yields by reacting Ar,Ar-dimethyl-Ar -(4,6,6-trimethyl-6//-l,3-thia-zin-2-yl)formamidine with acrolein, methyl vinyl ketone, or methyl acrylate, respectively <2002S403>. 

Ochiai, who reported in 1936 the first synthesis of the imidazo[2,l-h]thia-zole system (36CB1650), transformed ethyl 2-mercapto-5-methyl-imidaz-oIe-4-carboxylate with monochloroacetone into 2-(acylalkylthio)-imidazole 36. Refluxing 36 in phosphorus oxychloride yields ethyl 3,5-dimethylim-idazo[2,l-h]thiazole-6-carboxylate. No cyclization could be achieved by heating 36 in acetic anhydride because N-acylation (to 37) inhibited further reaction to the bicyclic system. 

A benzotriazole-assisted synthesis of ethyl 5-aminoimidazo[2,l-h]thia-zole-6-carboxylate 65 has been developed (96TL1787). Traces of compound 63 were isolated from 2-aminothiazole 23 using benzotriazole and freshly distilled ethyl glyoxylate in benzene, whereas by application of a-benzotria-zolyl-a-morpholino acetate with methyl iodide in THF, 63 was isolated in 40% yield. Subsequent treatment of 63 with potassium cyanide in ethanol at rt involves substitution of the benzotriazole moiety. Intramolecular cycli-zation of 64 yields 65, albeit in 10% yield. a-Ketoester 66 is also obtained (Scheme 3). 

X-ray structure determinations were performed for 6-phenylimidazo[2,l-bjthiazole (72CSC345), ethyl 3-phenyl-6-p-chlorophenylimidazo[2,l-b]thia-... 

Compound 185 can also be obtained by direct bromination of the corresponding thiazolo[3,2-ft][l,2,4]triazole (Bt2, acetie acid) (91AP49). Bromination at C-5 can also be affected by bromine/NBS in chloroform (72YZ935). Thiocyanation, which was possible in the imidazo[2,l-b]thia-zole and -[l,3,4]thiadiazole series (see Sections VI,B,l,a and VII,B,l) failed (72YZ935). 

Treatment of cycloadduct 287, obtained from a dibenzo thiazinylium intermediate and a diene, with base affords dibenzo[d,/]pyrrolo[2,l-lr][l,3]thia-zepine 290 in 58% yield. The proposed mechanism involves formation of ylide intermediate 288 which undergoes intramolecular rearrangement into dihydro derivative 289 and spontaneous oxidative aromatization (Scheme 62 (1999TL95)). 

Alkylation of W -(5-acetyl-67/-l,3-thiazin-2-yl)-WA -dimethylformamidine 113 with 2-bromo-l-(4-bromophenyl)etha-none resulted in attack at the nitrogen in the ring and formation of the N-alkylated salt (Scheme 4). The latter was not isolated but treated directly with 2 equiv of base to give, after loss of dimethylamine, the imidazo[2,l-/ ][l,3]thia-zine 114 <2003EJ0421>. 

The Rli2(OAc)4-catalysed reactions of ethyl diazoacetate with substituted benzalde-hydes yielded 1,3-dioxolanes via an initially formed carbonyl yhde. Catalyst-dependent diastereo-control was observed only when /rnitrobcnzaldchydc was used as catalyst.104 The intramolecular cycloaddition of carbonyl yhde dipoles with tethered alkenyl 71-bonds is greatly enhanced by placing an sp2 centre on the tethered side-chain.105 The thermal reaction of 3-phenyloxirane-2,2-carbonitrile and 2-phenyl-3-thia-l-azaspiro-[4,4]non-l-ene-4-thione yields cis- and /raw.v-cycloadducts via a regioselective 1,3-dipolar cycloaddition of an intermediate carbonyl yhde.106... 

Ethyl 9-ethoxycarbonyl- and 9-hydroxymcthyl-3-mcthyl-6-oxo-2//,6//-pyrido[2,l-ft][l,3]thia/inc-4-carhoxylates were isomerized into Ml fill-pyrido[2,l-b][l,3]thiazine-4-carboxylates by treatment with KOH overnight at room temperature and by treatment with NaOEt at 0 °C for 1 h and room temperature for 3h in EtOH, respectively. In another experiment, when the 9-hydroxymethyl derivative was treated with NaOEt in EtOH at —10 °C for 3h, a 2.5 1 mixture of ethyl 3,4-m-H-9-ethoxymethyl-3-methyl-6-oxo-3,4-dihydro-2//,6//-pyrido[2,1 -b 1,3]thiazine-4-carboxylate and the aforementioned 47/,6//-isomer were obtained (00JCS(P1)4373). 

Five-membered heterocycles with two vicinal chalcogen atoms in the ring system can be used as stable precursors for sulfur as well as for selenium-containing hetero-1,3-dienes in cycloaddition reactions. Consequently, 3//-1,2,4-thiaselenazoles have been used for the in situ formation of 4,4-bis(trifluoromethyl)-l-thia-3-azabuta-1,3-dienes, which exist at room temperature only as 4,4-bis(trifluoromethyl)-2//-l,3-thiazetes. This strategy was applied to the synthesis of the first stable selenophosphorane from bis(trifluoromethyl)-substituted 3//-diselenazol and 2-methoxy-1,3,2-dioxaphospholan [78AG(E)774] (Scheme 83). 

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