4//-Benzo thiazin-3 -ones

As with five-membered heterocycles, phosphorus pentasulfide may replace a ring oxygen atom by sulfur, or it may effect replacement in an acyclic precursor and then bring about cyclization. Thus isochroman-l-one (99) is converted into thioisochroman-l-thione (100) under the same conditions a 3-arylisocoumarin( 101) produces a 3-ary 1-1-thioisocoumarin (102) only, with no replacement of the ring oxygen atom.122 A typical example of thiation, followed by cyclization, is the formation of 2-alkyl- or 2-aryl-3,l-benzo-thiazine-4-thiones (103) from /V-acylanthranilic acid esters (104) by treatment with phosphorus pentasulfide in boiling xylene.122... 

Similarly, nucleophilic substitution by thiourea of 2-bromo-4-hydroxy-2H-1,4-benzoxazin-3 (4//)-one, and 2-bromo-4-hydroxy-2/f-1,4-benzo-thiazin-3(4//)-one, gave rise to S-[4-hydroxy-2//-l,4-benzoxazin-3(4i )-on-2-yl]-isothiouronium bromide and S-[4-hydroxy-2fiM,4-benzothiazin-3(4/i/)-on-2-yl]-isothiouronium bromide, respectively. On alkaline cleavage the four isothiouronium bromides showed a different behaviour. 

A versatile synthetic approach to 4-hydroxy-1,2-benzothiazines was discovered by Abe and co-workers3-. 2-phenacyl-l,2-benzisothiazolin-3-ones (8 R = Ar) with strong base produce 3-benzoyl-4-hydroxy-2//-l,2-benzo-thiazine 1,1-dioxides (9 R = Ar) (Eq. 2). Yields up to 93% could be obtained using sodium ethoxide in ethanol. 

The benzisothiazoline ester 8 (R = OR ) is isomerized to a 1,2-benzo-thiazine-3-carboxylic ester (12) by sodium ethoxide in ethanol7,8 or by sodium methoxide in dimethyl sulfoxide.9 This rearrangement appears to be more sensitive to reaction conditions and solvent than the rearrangement of 2-phenacyl-l,2-benzisothiazolin-3-ones such as 8 (R = Ar) (Eq. 2), and two laboratories8,9 report unsatisfactory attempts to rearrange compound 8 (R = OMe) to 12 (R = Me) with sodium methoxide in methanol. 

Acylation and alkylation reactions of the enolic 4-hydroxy-1,2-benzo-thiazines have been studied. Zinnes et al.A O-alkylated compound 21 with isopropyl iodide (potassium carbonate in acetone) (see Scheme 1), and formed the 4-acetoxy compound 85 from 2-methyl-2f/-1,2-benzothiazin-4-one 1,1-dioxide (11) with acetyl chloride and sodium hydride (Eq. 19).6... 

The activated 4-methylene function of 3,4-dihydro-2-alkyl-l,2-benzo-thiazin-3(2ff )-one 1,1-dioxide (47) permits the formation of an anion. Treatment of the anion in DMSO14,38 or DMF74 with isocyanates yields the corresponding 4-carboxamides (116) (Eq. 28). 

Numerous spectra recorded for 1,2-benzothiazines include the 13CNMR of piroxicam (29),78 the electron spin resonance spectrum of the paramagnetic semidione obtained from base/oxygen oxidation of 3,4-dihydro-1,2-benzo-thiazin-4(2H)-one 1,1-dioxide 10,79 and the mass spectral fragmentations of 4-hydroxy-1,2-benzothiazines described in detail by Rasmussen8 and by Heyes et al.i0 The infrared, ultraviolet, and nuclear magnetic resonance spectra of various 1,2-benzothiazines are reported.4,6 8-10 17,21 34 66 Representative spectral data of 1,2-benzothiazines are presented in Table I. 

Trummlitz and co-workers126 also prepared derivatives of 150 by treatment of 2-methyl-2H-naphtho [2,1-c] [l,2]thiazin-4-(3H)-one 1,1-dioxide (151) with sodium hydride and an aryl isocyanate. The starting material (151) for this sequence was synthesized analogously to the related benzo-thiazine 11. 

The reaction of 2-mercaptobenzimidazole with pentafluorobenzoyl chloride forms 1,2,3,4-tetrafluoro-12//-benzimidazo[2,1 -b, 3]benzo-thiazin-1,2-one (yield 50%), whose structure was confirmed by X-ray data (94JOC7688) (Scheme 165). 

Similarly, N-arylsulfoximines and related species have been prepared by Pd-catalyzed coupling of a sulfoximine with aryl chlorides under the influence of microwave irradiation [72], Appropriately functionalized systems gave rise to benzo-thiazines directly in a one pot process. 

Benzo-l,3-thiazines.—Little work has been reported in this area. A new route to substituted 4/f-l,3-benzothiazines, e.g. (27), has been found in the acid-catalysed condensation of a nitrile with the carbinol (26), arising from the addition of Grignard reagents to 2-mercaptobenzoic esters. In view of the limitations of its applicability, and the low yields obtained, the synthetic value of this reaction is rather circumscribed. Condensation of cyanogen with 2-mercaptobenz-hydrazides results in ring-closure and formation of 3-amino-2-imino-l,3-benzo-thiazin-4-ones, but a similar reaction with 2-mercaptobenzoic acids gives predominantly the bis-l,3-benzothiazinones (28). 

Several thioureas have been synthesized by ring-opening reactions of heterocyclic compounds such as l,3-dithiolan-2-thiones, 5-arylimino-l,2,4-dithiazolidine-3-thiones, benzoxazole-2-thiones, and 3,1-benzo-thiazine-4-thione derivatives. Similarly, the action of triphenylphosphine on 5-amino-l,2,4-dithiazolo-3-thiones gave thiocarbamoyl isothiocyanates (304). Other thioureas have been obtained by thermolytic decarbonylation of 2-amino-5(4H)-thiazolones and by treatment of 4,5,6,7-tetrahydro-cyclopenta-l,3-dioxin-4-one" and 3-nitrophthalic anhydride with thiourea. ... 

Of the possible 16 pyridazino-, pyrimido-, and pyrazino-oxazines, 10 are known with 19 benzo-fused derivatives. Literature over the past 10 years reports 10 bicyclic and 9 tricyclic systems and these are shown in Table 2. Of the possible 16 N-bridgehead pyridazino-, pyrimido-, and pyrazino-thiazines, 7 are known along with 13 benzo-fused derivatives. In this review five bicyclic and four tricyclic systems are discussed and these are shown in Table 3. One bicyclic system has been reported with a Se heteroatom and this is shown in Table 4. 

A six-membered nitrogen-sulfur heterocycle, namely, a 2,3-dihydro-2-imino-4//-benzo[e thiazin-4-one, is produced on reaction of methyl 2-chloro-3,5-dinitrobenzoatc with thiourea in basic medium 373 furthermore, a tetrahydrospirobenzothiazine 213 is formed in addition to its hexahydrospiroquinazoline analog on interaction of cyclohexanone with thiourea in hydrochloric acid.329... 

R. E. Busby has written a chapter on thiadiazines containing adjacent sulfur and nitrogen ring atoms. This chapter complements one in Volume 44 which dealt with sulfamides of this type. H. Quiniou and O. Guilloton of Nantes have covered the chemistry of monocyclic 1,3-thiazines, a group that, surprisingly, has not been reviewed comprehensively for many years. Finally, E. V. Kuznetsov and I. V. Shcherbakova of Rostov collaborate with A. T. Balaban of Bucharest in a summary of the chemistry of benzo[c]pyrylium salts. This review complements the review by a group of authors under the leadership of Balaban who covered the chemistry of pyrylium salts in Supplement 2 of this series, which appeared in 1982. 

Recently, interest in the syntheses of polyheterocyclic systems containing fused l,3-thiazin-4-ones has been growing due to the search of new biologically active substances. The synthetic methods used for obtaining these compounds are the same as those used for benzo-TAs. 

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