Acylation 1,3-thiazines

The only known derivative, (495), was prepared by the ring closure of the A -acylated 1,3-thiazine-4-carboxylic acid (524) (Equation (123)). Diastereoisomers of (495) were separated <85H(23)889>. 

Acetylation of methylamino-2-thiazines (217) (65JOC2290) and imino-2-thiazines (226) (70JAP37529) occurs on the exocyclic NH (in the latter case, the endocyclic NH is not acylated). Thiazine-2-ones (228)... 

Indolo[2,3-d][l,3]thiazine-2,4-dithione formation, 4, 299 Indolothiazines synthesis, 4, 519 Indoloyl azides Curtius rearrangement, 4, 288 Indolyl anions acylation, 4, 232 alkylation, 4, 235 Michael-type additions, 4, 236 Indomethacin... 

In Corey and Chaykovsky s initial investigation, a cyclic ylide 79 was observed from the reaction of ethyl cinnamate with ylide 1 in addition to 32% of cyclopropane 53. In a similar fashion, an intermolecular cycloaddition between 2-acyl-3,3-bis(methylthio)acrylnitrile 80 and 1 furnished 1-methylthiabenzene 1-oxide 81. Similar cases are found in transformations of ynone 82 to 1-arylthiabenzene 1-oxide 83 and N-cyanoimidate 84 to adduct ylide 85, which was subsequently transformed to 1-methyl-lX -4-thiazin-l-oxide 86. ... 

Q, 9/3,9n/3)]-9-(Benzyloxycarbonylamino)-6-oxoperhydropyrido[2,l-Z)][l, 3]thiazine-4-carboxylic acid was obtained from the methyl ester by treatment with 2 N LiOH in MeOH at 0°C for 4.5 h. The carboxyl group was coupled with amino esters. The 9-(benzyloxycarbonylamino) group was deprotected by treatment with a 1 1 mixture of TFA and CH2CI2 at room temperature and the amino group was acylated with an amino acid (97MIP4, 98USP5710129). 

Treatment of alkyl 9-benzyloxycarbonyl-3-methyl-6-oxo-2/7,6//-pyr-ido[2,l-f ][l,3]thiazine-4-carboxylates with BBr3 in CH2CI2 at -70 °C for 0.5-1 h and at room temperature for 3h yielded 9-carboxyl derivatives. The decarboxylation of these acids was unsuccessful. Hydrolysis of diethyl cA-3,4-H-3,4-dihydro-3-methyl-6-oxo-2//,6//-pyrido[2,l-f ][l,3]thiazine-4,9-dicarboxylate in aqueous EtOH with KOH at room temperature for 3 days yielded 4-ethoxycarbonyl-3,4-dihydro-3-methyl-6-oxo-2//,6//-pyrido-[2,l-f ] [1,3]thiazine-9-carboxylic acid (00JCS(P1)4373). Alkyl 9-hydroxy-methyl-3-methyl-6-oxo-3,4-dihydro-2//,6//-pyrido[2,l-f ][l,3]thiazine-4-car-boxylates were O-acylated with AC2O and (PhC0)20 in pyridine at room temperature for 12-48h. 

There are cationic thiazine dyes (3 to 5) and neutral thiazinone dyes exemplified by Methylene Violet (6). Like leuco Methylene Blue, leuco Methylene Violet is too air sensitive to be isolated and therefore requires acylation. 

Phenazine leucos are generally more reactive and more susceptible to air oxidation than the thiazines and oxazines. Incorporation of electron-withdrawing groups on the acyl substituent at the 10-position of the leuco dye can provide a substantial improvement in the thermal and light stability of the leuco form and it is found that in general the stronger the electron-withdrawing character of the acyl substituents the more stable the leuco is.18... 

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. 

The majority of nonsteroidal antiinflammatory agents contain an acidic carboxyl group. A series of experimental agents in this class have been prepared in which the acidic proton is supplied by a highly enolizable proton from a function such as a p-dicarbonyl incorporated into a heterocyclic system. As an example, an acylated, highly oxidized isoquinoline moiety can fulfill this function (see also the benzo-thiazines below). Toward this end, reaction of... 

Moreover, there are several patents and reports on cephalosporins and 7-alkoxy derivatives thereof, which are characterized by a pyridazine-derived substituent attached to the thiazine ring. Some typical examples are given in formulae (126) [347-356], (127) [357], (128) [358], (129) [359, 360] and (130) [355, 361-363] in which R1 represents a variable acyl group. 

The reactions of 1,2-thiazine 1,1-dioxides with electrophiles can often lead to a mixture of products due to competing addition at C-4 and C-6. A selective Friedel-Grafts-type acylation of the C-6 position of the 1,2-thiazine 1,1-dioxo ring was observed in reaction of 3,5-dimethyl-1,2-thiazine 1,1-dioxide 71 with anhydrides, such as acetic anhydride, furnishing compound 45 (Equation 18) <1999JPR37>. 

The thiazin-2,6-diones 49 lose one molecule of COS in boiling dimethylformamide (DMF) to afford l-substituted-6-alkyl uracils 98 (Scheme 2) <2005RJC134,2003TL5279>. The same products are obtained when 5-acyl-4-hydroxy-3,6-dihydro-2//-l,3-thiazine-2,6-diones 61 are heated together with the corresponding primary amine in hoiling DMF. The dimeric compound 99 and the nitrophenyl hydroxylated example 100 are produced by the same route <2005RJC134>. 

N-Acylation of 2-methyl-5,6-dihydro-4/f-l,3-thiazine with cinnamoyl chloride in the presence of triethylamine furnishes ( )-l-(2-methylenetetrahydro-l,3-thiazin-3-yl)-3-arylprop-2-en-l-ones 122. These products undergo hydrolysis readily due to the j jA -ketene acetal-type bonds present in the molecules and are therefore not stable. Thus ( )-3-(3-(4-methoxyphenyl)acrylamido)propyl ethanethioate 123 is isolated in 92% yield from the corresponding thiazine after column chromatography on Si02 or AI2O3 <2001S135>. 

The nitrogen of 2/7-dihydrothiazines reacts readily with alkyl or acyl halides in the presence of a base. Table 8 contains a selection of N-alkylations and N-acylations performed on dihydro-1,4-thiazine derivatives. 

Reactions of pyrimido[4,5-3] [l,4]thiazines were discussed in CHEC-II(1996) <1996CHEC-II(7)737> more recently, reported reactions of this system involve nucleophilic substitution in a number of guises. Hemiaminals at C-3 react with ammonium acetate to form aminals (Equation 166) <1999CHE97>. The formation of acyl hydrazides from pyrimido[4,5-3][l,4]thiazine-2-carboxylic acids, along with their subsequent conversion to acyl azides and Curtius... 

Annulated forms of this system have been prepared by ring-closure of an annulated 2-acyl-l,4-thiazine-3-carboxylate with hydroxylamine one example is shown in Equation (191) <1988DEP3701737>, and another is included in CHEC-IK1996) <1996CHEC-II(7)737>. 

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... 

Treatment of 3-acylaminoperhydropyrido[2,l- >][1,3]thiazine-6-carboxy-late (109) with iodotrimethylsilane gave a 3-amino derivative (110). The amino group was acylated with (5)-2-(acetylthio)-3-phenylpropionic acid in the presence of benzotriazol-l-yloxitris(dimethylamino)phosphonium hexafluorophosphate and triethylamine in dichloromethane, and the product (111) was hydrolyzed to 112 (94EUP629627 96USP5508272). 

Two modes of dimerization of the 2-alkyl-6-methyl-4//-l,3-thiazine-4-one (249) have been observed (83CC56). One mode gave the linearly combined dimer 250, and the other led to a spiro compound (251). The structure of one of the spiro compounds was confirmed by X-ray crystallography (Scheme 101). The reactions occurred when the 2-alkyl group was methyl, ethyl, or n-propyl, but not when it was isopropyl. 4-Acyloxy-and 4-p-tosyloxy-l,3-thiazine-6-ones (253) have been prepared by acylation and sulfonylation starting from thiazine-4,6-diones (252), in a solvent, at temperatures from room temperature to reflux (Scheme 102) (79KGS44). 

TL2977 82IJC(B)765], Thiazine 361 and oxazines 267 and 297 form acyl derivatives in poor yield or not at all and cannot be alkylated (61BCJ146 83BCJ2756). 

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