1.3- Thiazin-6-ones synthesis

Similar ring systems were prepared <97JHC1693> by Coppo and Fawzi from the reaction of substituted ethyl 5-[methyl(methylsulfonyl)amino]-l 7/-pyrazole-4-carboxylates 119 with sodium hydride. This gave the 7-substitued 1,7-dihydro-l-methylpyrazolo[3,4-c][l, 2]thiazin-4(37/)-one 2,2-dioxides 120 in fair to good yield (Scheme 30). They also extended this synthesis by treating methyl 2-[methyl(methylsulfonyl)amino]-6-(trifluoromethyl)-3-pyridinecarboxylate 121 with sodium hydride in dimethylformamide to yield l-methyl-7-(trifhioromethyl)-l//-pyrido[2,3-c][l,2]thiazin-4(3//)-one 2,2-dioxide 122 in 79% yield (Scheme 31) <98JHC499>. 

Oxazines and 1,3-thiazines have been used quite extensively as substrates in pyrimidine syntheses <1994HC(52)1>, and an improved procedure for the synthesis of 6-trifluoromethyluracil derivatives 956 from 2-dimethylamino-4-trifluoromethyl-l,3-oxazine-6-one 955 has been developed using DBU in xylene <2000USP6140270, 2002USP6355796>. 

One notable advance in this chemistry since the publication of CHEC-II(1996) is the use of enantiomerically enriched 3,6-dihydro-l,2-thiazine 1-oxides in the rearrangement sequence. For instance, iV-Cbz-protected bicyclic 1,2-dihydrothiazine 44 undergoes ring opening upon treatment with phenylmagnesium bromide (Scheme 16). The synthesis of allylic amino alcohol 129 is completed in excellent yield upon exposure of the intermediate sulfoxide 130 to trimethyl phosphite and methanol at 80 °C <2002TA2407, 2000TL3743>. 

The following section provides an update to the synthesis of the title ring systems covering material published from 1996 to 2006. Similar to CHEC-II(1996), this information is organized by the type of disconnection, beginning with the one-bond disconnections A-F, followed by [4-1-2] and [3-1-3] two-bond disconnections (Figure 23). There have been several notable advancements in the synthesis of 1,2-thiazines since the publication of CHEC-II(1996). For one,... 

One failed synthesis using this method was also reported instead of the thiazine ylide its thermolysis products (see Scheme 11) were obtained, even if the reaction was performed at —78°C. The synthesis was also extended from benzothiazines to 277-1,4-thiazines, but these products were unstable <1991J(P1)2249>. 

The one-step synthesis of further tri- and tetracyclic pteridine derivatives from 2-aminopyrazine 153 has also been described <2001JHC1173>. Cyclic analogues of A -[bis(methylthio)methylene]amino reagents such as 2-(methylthio)-2-thiazoline, 5,6-dihydro-2-(methylthio)-4//-l,3-thiazine, 2-(methylthio)-2-imidazoline, 2-(methylthio)-l,4,5,6-tetrahydro-pyrimidine, 2-(methylthio)-2-pyrazine, and 2-chloropyrimidine reacted with aminopyrazine 153 to afford thiazolo/thia-zino[2,3-3]- 159 ( = 1 (53%), n = 2 (42%)), imidazo/pyrimidino[2,l-/ ]- 160 ( = 1 (53%), = 2 (57%)), pyrazino[2,l-/ ]-161 (21%), and pyrimido[2,l-/ ]-pteridine 162 (42%) derivatives, respectively. 

We have described (88TL4855) a simple synthesis of pyridin-2-ones by a two-step annulation of 2 with aliphatic acid chlorides (Scheme 27). The acylation of aminoazadienes 2 in pyridine furnished 4-amidoyl-l-azabutadienes 107 in high yields (85JOC802) lithium diisopropylamide-catalyzed aldol-type cyclization of 107 afforded pyridin-2-ones 108 in 83-94% yield. Extension of this reaction to methanesulfonyl chloride permitted preparation of open-chain derivatives 109 in 88-90% yield, which in turn cyclized in the presence of lithium diisopropylamide to 2//-l,2-thiazines 110 in 82-92% yield (89TL4705). Earlier work by the Komatsu-Ohshiro group showed that the reaction of simple 1-azadienes... 

Other preparations of 2-iminothiazolidin-4-ones which are discussed in the review by Brown139 utilize the reactions of thiourea with a-hydroxy acids,146 ethyl diazoacetate,73 glycidic esters,74,147 cinnamic acid,148 unsaturated diacids (fumaric, maleic, and citraconic) or their esters or imides,149-152 and propiolic esters.153,154 There has been considerable controversy in the literature surrounding the propiolic ester synthesis since many workers have proposed that the products are 1,3-thiazines (see Section IV, B, 1). The pertinent papers in this controversy have been summarized by Cain and Warrener.155 Nagase158 has recently settled the argument in favor of the 2-iminothiazolidin-4-... 

H,3 H-Oxazolo[4,3-c][ 1,4]thiazine-6-carboxylic acid, 8,8a-dihydro-3,3-dimethyl-methyl ester X-ray diffraction, 6, 647 Oxazolo[2,3-h]thiazol-3(2H) -one 1,1-dioxide synthesis, 6, 1005... 

The synthesis of 2,3-dihydrothieno[3,2-e]-l,3-thiazin-4-ones 184, in which the orientation of the thiophene ring toward the 1,3-thiazine ring is different, is based on a reaction between mercaptoamide 183 and various ketones (72KGS909) (Scheme 63). 

Another approach to the synthesis of simultaneously b- and e-fused heterosystems containing l,3-thiazin-4-one fragments is based on the use of a thiazinone ring prepared in advance. Thus, 2-imino-3-amino-TA 79, obtained from hydrazide 198, was applied to the syntheses of triazolobenzo-TAs 199,200, and 201 (75MI1). Amine 201 may be obtained from hydrazide... 

The third chapter in the present volume is by Drs. Ryabukhin, Korzha-vina, and Suzdalev (Rostov University, Russia), who have provided the first specialized review of l,3-thiazin-4-ones. Professor Varvounis and Dr. Giannopoulos (Ioannina, Greece) cover recent developments in the synthesis, chemistry, and biological properties of the thienopyrimidines in the fourth chapter of this volume. 

The described synthesis of l,4-thiazino[3,2-6][l,4]thiazine (305) <87JA4308> starts with the reaction of aqueous glyoxal (302) with iV-methylguanidinium chloride (303) in water (pH 8). The resulting 2-amino-4,5-dihydro-4,5-dihydroxy-l-methylimidazolium chloride (304) is treated with 2-amino-ethane thiol in H20 (pH 8-9) to give either (305) or (306). The NMR spectrum of the product supports both of the structures (305) and (306) there is only one diastereomer <87JA4308>. 

A method involving the facile addition of mercaptoacetic acid across the double bond of an azomethine for the one-step preparation of 4-thiazolidinones has been used in the synthesis of thiazolo[2,3-c][l,4]thiazine-3(2//)-one. Thus, 2f/-3,4-dihydro-1,4-thiazines (138) react with alkyl mercaptoacetic acid at 100°C under nitrogen to give thiazolo[2,3-c][l,4]thiazin-3(2//)-ones (139) Similarly, 7/f-hexahydro-l,4-benzothia-zine[138, RR = (CH2)4] condenses with mercaptoacetic acid to yield 139 [RR = (CH2)4, R = R = H] (64M1335) (Scheme 30). 

The search for dopamine antagonists has led to the synthesis of compounds of type 427. The diester 425, prepared by treatment of methyl (3-thiomorpholino) acetate (424) with ethyl bromoacetate on Dieckmann cyclization, gave perhydropyrrolo[2,l-c][l,4]thiazin-6-one (426). This was converted to the oxime, which was then reduced and acylated to 427 (82EUP57536). 

The majority of syntheses of 1,4-thiazines involve the elimination of HL from species of type 11. Precursors of type 11a are not usually isolable compounds but are generated as intermediates. Two methods for the formation of such intermediates have been described one utilizes tetrahydro-1,4-thiazine-3,5-diones as starting materials, and the other requires diacyl sulfides and ammonia. Thus the synthesis of 2/f-l,4-thiazine (6), reported in 1948, was achieved by heating compound 16 at 450°C in the presence of powdered aluminum. Potentially, the procedure may be applied to the preparation of thiazines variously substituted at positions 2 and 6 however, the low yield (13%) achieved for the parent compound is a detraction. It was initially claimed that the reaction of diphenacyl sulfide with ammonia gave 3,5-diphenyl-4H-l,4-thiazine subsequent studies, however, revealed that the product was the 2//-tautomer 3,5-Diaryl-2/f-l,4-thiazines and... 

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