1.3- Thiazin-6-ones, 2-amino

As in the case of thiazine and oxazine leuco dyes described earlier, the reductive acylation of the phenazine dye 52 results in the acylation of the exocyclic amino group.18 The phenazine leuco obtained 53 retains the exocyclic amide group on oxidation resulting in the acylated phenazine dye 54, the color of which is different from the one intended. 

Dihydro-4//,8//-pyrimido[2,l-3][l,3]thiazine-7-carboxylic esters and amides exhibited high activity on antiinflammatory and antipyretic tests <1996EJM663>. 8-(Benzoylbenzyloxy) and (benzoylbenzylthio)-7-methyl-3,4-dihydro-2//,6//-pyrimido[2,l-3][l,3]thiazin-6-ones exhibit antitumor activity <1996EPP0733633>. 9-Amino- or 9-methyl-3.4-dihydro-2//,6//-pyrimido[2,l -3, 1,3]thiazin-6-oncs have anticorrosive effect <2003RUP2198245>. 

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>. 

Reaction of isothiocyanate with amine gives the corresponding thioureas. Many reports are appeared.102 111 The thiourea derivatives have been prepared by reactions of isothiocyanates with arylamines (Scheme 39) and reacted with some substrates to afford heterocyclic compounds, such as 2-amino-4//-ben-zothiazine, 1,3-thiazine, 1,3-thiazinone and l,3-thiazolidin-4-one.112 115... 

Amino-4//- 1,3-thiazines have been obtained from a three-component one-pot condensation using alkynes, thiourea and aryl aldehydes (Scheme 67).156... 

Alicyclic 2-isocyanato-l-carboxylic acids 214 synthesized from alicyclic trimethylsilyl 2-amino-l-carboxylates 213 were cyclized to the unstable 2-thioxoperhydro-l,3-oxazin-4-ones, which isomerize to the thermodynamically more stable perhydro-l,3-thiazine-2,4-diones 215 (cm, X = CH2 — CH2, CH = CH trans, X = CH2-CH2) (74MI2). 

Rearrangement reactions involving 1,3-thiazines are often very facile. For example, reaction of 2-imino-4-phenyl-2/7-1,3-thiazinium perchlorate 957 with NaOH at room temperature gave 4-phenylpyrimidine-2(l//)-thione 958 <2004CHE1595>, while treatment of 6-amino-2,3-dihydro-l,3-thiazin-4(l// )-ones 959 with KOH readily gave the potassium salt of the dihydropyrimidinone 960 <2005HAC426>. 

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>. 

A series of 4-heteroaryl-5,6-di(2,5-dimethyl-3-thienyl)-2-phenyM//-l,6-thiazines 54 with photochromic properties was prepared by reacting 3-(2-(2,5-dimethylthiophen-3-yl)ethynyl)-2,5-di ethylthiophene with thiobenzamide and aldehydes <2005CHE86, 2005PS1503>. The acid-catalyzed cyclocondensation of cyclopentanone, aromatic aldehydes, ArCHO, and thiourea affords the cyclopenta[t ]l,3-thiazines 37 <2006PS1655>. Two equivalents of the aldehyde are required. The same products are isolated when 2,5-dibenzylidenecyclopentanones are treated with thiourea under the same conditions. 2-Amino-4i/-l,3-thiazines 184 are easily synthesized in one pot by the reaction of aromatic alkynes, R feCH, aromatic aldehydes, R CHO, and thiourea in the presence of TFA/acetic acid <2005OL3797>. 

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. 

Stirring a chloroform solution of 9a-amino-2-fm-butyl-4,6,7,8,9,9a-hexahy-dropyrido[2,l-b][l,3]thiazin-4-one at 35°C for 64 h afforded 2-tert-butyl-6,7,8,9-tetrahydro-4H-pyrido[l,2-fl]pyrimidin-4-one in 95% yield [89JCS(P1)1231]. 

Examples of the preparation of oxazines and thiazines on insoluble supports are listed in Table 15.34. 3,l-Benzoxazin-4-ones can be prepared by intramolecular O-acy-lation of /V-aminocarbonyl anthranilic acids (Entry 1, Table 15.34). The resulting ben-zoxazinones are sufficiently stable towards acids to enable TFA-mediated cleavage from a Wang linker [410]. 1,3-Oxazines have also been obtained by acidolytic cleavage of functionalized 3-amino-l-propanols from Wang resin (Entry 4, Table 3.30). 

The reaction between thioacylformamidines and ketenes leads to thiazine-6-ones (29) (Scheme 16) (75T3055). 4-Amino-4//-thiazines (30) are obtained by condensation of thioacylformamidines with acetylenic compounds (Scheme 17) (85JOC1545). Thiobenzoyl-1 and )V,A/-diethylami-nothiocarbonyl isocyanates and isothiocyanates have been reacted with enaminoketones and ynamines. Enaminoketones and ynamines reacted with thiobenzoyl isocyanate give thiazine-4-ones 31 and 32, respectively (Scheme 18) (76BCJ2828 85ZC324). 

For 4//-thiazine-4-ones (78), two maxima are generally noted one between 233 and 258 nm and the other between 278 and 298 nm [66TL3225 77LA1249 78JCS(P1)1428]. The differences in the long-wave maxima between amino and imino structures in the UV spectra are not usually substantial, with the exception of the dirnethylamino derivative (79) (82CCC3268). This compound (X max = 330 nm) shows a bathochromic shift of 60-80 nm compared to all other thiazine derivatives, probably due... 

The pKd of 2-amino-4-methyl-6//-l,3-thiazine-6-one has been spectro-photometrically determined and is high (13.30) similar to that of disodium sulfide (80CCC732). 

Reaction of 4-benzylidene-l-phenylpyrrolidine-2,3,5-trione 56 with thiourea 28 occurs with hydrolysis of the amino group and leads to the formation ofl,4-dihydropyrrolo[3,4-J][l,3]thiazine-2,5,7-trione 57 [65] (Scheme 3.17). There is just one reference to the formation of a dihydrothiazine derivative 59 in the reaction of thiourea with an unsaturated ketone 58 under basic catalysis [68] (Scheme 3.18). 

The analogous condensation of methyl acetylenedicarboxylate with substituted thiosemicarbazides leads to 2-imino-3-amino-6-carbomethoxyl-l,3-thiazin-4-ones (67CJC953). 

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... 

Halo- or 7,7-dihalopyrazino[2,3-A][l,4]thiazin-6-ones (222) can be converted into the 7-amino or 7,7-diamino compounds (223) by treatment with aliphatic, aromatic, or heterocyclic amines in an organic solvent and in the presence of Et3N <72MI 719-01). 

The reaction of 2-chloro-3-(7V-substituted amino)pyrazines (233) with thioglycolates gives 2,3-dihydro-4-substituted-(4//)-pyrazino[2,3-6][ 1,4]thiazin-3-ones (234) <71JAP32670, 74JAP(K)49041397> with analgesic properties (Equation (34)). 

The 3-amino-2-chloropyrazines (235) can be transformed into the thiols (236) by NaSH and cyclization with 2-chloroacetic acid or 2-chloropropionic acid gives 2,3-dihydro-(4//)-pyrazino[2,3-b][, 4]thiazin-3-ones (237) <71KGS230>. 

Some 7-amino derivatives of 5//-pyrimido[4,5-6][l,4]thiazin-6-ones (283) have been reported to have antitumor activity <82Mi 719-01). 

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>. 

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