4//-1,3-Thiazines, 4,4-bis

Although the dehydrogenation of dihydrothiazines of type lib, which are readily available compounds (Section V,B), may provide a useful route to thiazines, few examples have been reported. However, studies in the author s laboratory have shown that the compound 18a was converted into the thiazine 19 in good yield by lead tetraacetate in benzene. A further example is provided by the transformation, in boiling toluene, of the dihydrothiazine 18b into the bis(thiazine) 20 the product, however, was isolated only in 12% yield. The formation of the thiazinium chloride 23, from the reaction of the penicillin sulfoxide 21 with phenylacetyl chloride in acetone exposed to the air, constitutes a remarkable oxidative rearrangement. It seems likely that the dihydrothiazine 22, formed by the route suggested in Scheme 1,... 

The protons at position 2 of 2-unsubstituted 2//-l,4-thiazines resonate in the 5 136-3.40 region. " The chemical shift of the 3-proton of a 3-unsubstituted 2//-l,4-thiazine has not been reported, and the only example of a 5-unsubstituted 2ff-l,4-thiazine whose NMR spectrum is available is compound 19 its 5-proton absorbs at 5 8.43. The 6-protons of 3,5-diaryl-2//-l,4-thiazines appear in the S 6.30-6.53 region - a slight deshielding of the 6-proton (to S 6.13) is observed in the case of the bis(thiazine) 24. 

There are two reports of X-ray diffraction studies involving 1,4-thiazines. Thus the meso configuration of the bis(thiazine) 24 was established by the observation that the molecule possessed a center of symmetry. The crystal structiu-e of the thiazinium chloride 23 has also been described however. 

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. ... 

A 3,4,8,9-tetrahydropyrido[2,l-c][l,4]thiazine 336 and a benzo(A)-l,4-thiazine 335 was isolated from the reaction mixture of enaminone 334 and 2-(3-chlorobenzylidene)acetylacetate (99T7915). Reactions of enamines 334 and 337 with DMAD in MeOH yielded addition products 338 and 339 and bi- and tricyclic derivatives 340 and 341, respectively. The latters could be obtained in quantitative yields when the addition products 338 and 339 were heated in refluxing MeOH. 

Similarly, the reaction of ammonia with an excess of 539 produces bis-[2-(l-oxotetrahydro-l,4-thiazin)-ethyl] sulphoxide 541632 (equation 340). 

The bis[l,2]-dithiolo[l,4]thiazines prepared by Rees and co-workers are nonplanar, with the thiazine ring 34° out of plane for the W-ethyl compound. This gives a scorpion-like conformation with the N-substituent as the scorpion tail, seen in the crystal structure of this and other analogues <1998JOC2189>. 

The bis[l,2]dithiolo[5,4- ][5, 4 -< ][l,4]thiazine ring systems of Rees and co-workers easily extrude sulfur from the thiazine ring and undergo contraction to the fused pyrrole derivatives <1997CC879>. These tricycles generally have a nonplanar, scorpion-like solid-state structure <1998JOC2189> however, the dicarbonyl product of... 

Rees and co-workers have carried out extensive studies of the highly sulfurated bis[l,2]-dithiolo[l,4]thiazine ring system 469, formed by reaction of Hiinig s base 468 with S2C12 and l,4-diazabicyclo[2.2.2]octane (DABCO) (Equation 128) <1997AGE281>. 

The reaction of 1,4-diphenylbuta-l,3-diene (2) with trithiazyl trichloride (3) yields a bi(thiadiazole) (4), an isothiazoloisothiazole (5), a dithiazolothiazine (6), and two thiazin-odithiatriazepines (7) and (8) by 1,2-, 1,3-, and 1,4-cycloaddition reactions (Scheme 2). The bridged-mode (/3-tether) tandem inter-[4 -E 2]/intra-[3 -E 2] cycloaddition of (ii)-2-methyl-2-nitrostyrene (9) with 1-butoxypenta-1,4-diene (10) produces stable tricyclic nitroso acetals (11) which afford, after reduction and protection, highly functionalized aminocyclopentanedimethanol triacetates (12) (Scheme 3). ... 

Other bis[l,2]dithiolo[l,4]thiazines 75 and 76 can be also selectively obtained by the reaction of Hiinig s base with sulfur monochloride through the addition of oxygen donors such as cyclopentadienylacetic or formic acid (1998JOC2189 Scheme 38). 

In the reaction of salicylic acid thioamide 419 with 2-cyano-3,3-bis(methylsulfanyl)acrylate under acidic conditions, a 2-(o-hydroxyphenyl)-6-imino-l,3-thiazine derivative was obtained as a perchlorate salt 420 on treatment with phenacyl bromide, this underwent a ring transformation to yield 4-benzoylmethylthio-27/-l,3-benzoxazin-2-ylidene-substituted ethyl cyanoacetate 421 (Scheme 81) <2003H(60)2273, 2004H(63)2319>. 

Ring contraction with desulfurization occurs when the 4//-l,3-thiazines 131 are reacted with potassium /-butoxide (Scheme 7) <2004TL5913>. The bis(methoxycarbonyl)pyrroles 132 are not isolated but instead give the 4-oxo, 5 dihydro-2//-pyrrolo[3,4-c]quinolines 133 and 134. 

A variety of N,S-bis(nucleophiles) react with unsaturated 5(47/)-oxazolones to produce triazolo-l,3-thiazin -ones 570 and 1,3-thiazin-4-ones 572. Mechanistically, Michael addition of the bis(nucleophile) to 569 and 571 followed by ring opening with concomitant cyclization leads to the observed products. 

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. 

The condensation of 2-aminoethanethiol with a l,2-bis(electrophile) to give a mixture of perhydro-l,4-thiazino[3, 2-3][l,4]thiazine and 2,2 -bis(thiazolidine) was included in CHEC-II(1996) <1996CHEC-II(7)737>. The direct preparation of this target from glyoxal was not achieved, but this method has been used successfully for the preparation of 166 (Equation 192). 

Eine cyclisierende Hydroaminierung besonderer Art erfolgt bei der Reaktion von Bis-[2-phenyl-ethenyl]-sulfon mit N-Methyl-hydroxylamin. Es bildet sich 3,5-Diphenyl-4-me-thyl-tetrakydro-1,4-thiazin-1,1-dioxid (34%), moglicherweise fiber ein intermediates N-Oxid4. 

Similarly, 1,1-dioxides are formed either by the cyclodehydration of diacylsulfones and ammonia (Scheme 115) (720S(52)135) or through the action of sodamide on bis(2-chlorovinyl) sulfones (255) which are themselves obtained by a two-step sequence from alkynes (Scheme 116) (72S311). A less general route involves the addition of the thiirene sulfone (256) to the mesoionic oxazolone (257). In this example the initial adduct (258) eliminates carbon dioxide spontaneously, thus affording the 1,4-thiazine (259) (75CL1153). 

We also note the chemical shifts at C-2 and C-4 for two 2-aryl-4,4-bis(trifluoromethyl)-4//-thiazines (24) (83CC945) along with the chemical shifts of four carbons for twelve 4//-thiazine-4-ones (102) (86PS327). The chemical shifts of four carbons from two 4,6-diphenyl-2//-thiazine-2-thiones (103) [82JCS(P1)2149] and the chemical shifts of the carbons from 2-substituted-4-methyl-6//-thiazine-6-thiones (104) are also shown (81BSB75). (See structures 24,102-104.)... 

Group 3 volatiles, formed by further interactions, can reach even lower threshold values than those mentioned so far, particularly when sulfur is involved, usually derived by the break down of cysteine (bis(2-methyl-3-furyl) disulfide, 0.00002 2-methyl-3-furanthiol, 0.0004 2-furylmethanethiol, 0.005 dimethyl trisulfide, 0.01 dimethyl disulfide, 0.16 dimethyl sulfide, 0.3 hydrogen sulfide, 10). Into some volatile sulfur compounds other atoms as well as the sulfur of cysteine are incorporated (2-acetylthiazoline, 1 5-acetyl-2,3-dihydro-l,4-thiazine, 1.25 2-acetylthiazole, 10). Other volatiles are more likely to be derived from methionine (methanethiol, 0.2). 

Methylbenzo-1,4-thiazin-3(4//)-imine hydrochloride (132) with acetic anhydride gave the hexacyclic product (133) (neat reactants, reflux, 90 min 57%), which underwent desulfurization by Raney nickel to afford 4,5-dimethyl-2,7-bis(/V-methylanilino)-1,6-naphthyridine (134) (PhH, reflux, 12 h 20%).1032... 

---