2.1- Benzothiazine 2,2-dioxides synthesis

An improved synthesis of 3,4-dihydro-2,l-benzothiazine 2,2-dioxide was reported by Togo and co-workers using photochemical conditions . Treatment of A-alkyl 2-(aryl)ethanesulfonamides 18 with (diacetoxyiodo)arenes under irradiation with a tungsten lamp at 20-30 °C afforded 2,1-benzothiazines 19 and 20. Chemical yields and selectivities were dependent upon the choice of solvents and the reactant s substituents 18 (Table 1). When THF and EtOH were used as solvents, the reactions failed to give the cyclized products, since their a-hydrogen was abstracted by the intermediate sulfonamidyl radical. Compound 20 was obtained as a major product when 1,2-dichloroethane was employed as a solvent. In contrast, in the case of EtOAc as solvent, compound 19 was obtained as the major product. 

The synthesis of 177-2,1-benzothiazine 2,2-dioxide was pioneered by Loer and coworkers <66JOC3531> and also by the Rossi group <66AC(R)728 66AC(R)741>. The general class of compounds is represented in Figure 4. 

An improved synthesis of li/-2,l-benzothiazine 4(3i/)-one 2,2-dioxide 33 that results in a relatively high overall yield was developed by Lombardino s group <710PP33 72JHC315>. This general method offered an easier entry into the 2,1-benzothiazine 2,2-dioxide heterocyclic system <67JHC403>. Treatment of methyl A-benzyl-A-methylsulfonylanthranilate 35 with sodium hydride led to 1-benzyl-4-oxo-l//-2,l-benzothiazine-4(3/7)-one 2,2-dioxide 36 in 68% yield. Reduction of 36 gave 4-oxo-17/-2,1 -... 

In order to study heterocyclic steroid analogues, such as the 7,11-dithiaazasteroid analogues, Fravolini developed the synthesis of new heterocyclic ring systems tri- and tetracyclic 2,1-benzothiazines <82JHC1045>. Intermediate 137 was prepared from 1-methyl-4-oxo-lH-2, -bcnzothiazinc-4(3f/)-onc 2,2-dioxide 37 and thioglycolic acid and could be converted into 6-methyl-4-oxo-3,4-dihydro-2//,6//-thiopyrano[3,2-c][2,l]benzothiazine 5,5-dioxide 138 by cyclization with polyphosphoric acid. The reaction of 138 with dimethyl... 

Piroxicam Piroxicam, 1,1 -dioxid-4-hydroxy-2-methyl-iV-2-pyradyl-2//-1,2-benzothiazine-3-carboxamide (3.2.78), is synthesized from saccharin (3.2.70). Two methods for saccharin synthesis are described. It usually comes from toluene, which is sulfonated by chlorosulfonic acid, forming isomeric 4- and 2-toluenesulfonyl chlorides. The isomeric products are separated by freezing (chilling). The liquid part, 2-toluenesulfonyl chloride (3.2.68) is separated from the crystallized 4-toluenesulfochloride and reacted with ammonia, giving 2-toluenesul-fonylamide (3.2.69). Oxidation of the product with sodium permanganate or chromium (VI) oxide in sulfuric acid gives saccharin—o-sulfobenzoic acid imide (3.2.70) [123-126]. 

For the synthesis of the benzosulfonamide subclass of 1,2-thiazines, introduction of the sulfonyl chloride has been effected by treatment of electron-rich aromatic compounds with chlorosulfonic acid. Such is the case for 1,2-benzothiazine 1,1-dioxides 181 which have been accessed from phenylethylamines 182 in 67-92% yields via intermediate 183 (Scheme 23) <1998SC2137>. 

Intramolecular methanesulfonamide anion alkylation and aldol condensation reactions have been employed for the synthesis of 2,1-benzothiazine 2,2-dioxides. For instance, Blondet and Pascal have utilized such a process for the formation of compounds 225 and 226 from ortV o-substituted aldehyde 227 and alkyl chloride 228, respectively (Scheme 30) <1994TL2911>. 

Directed ortV o-methyl lithiation/cyclization of AT-acyl-o-toluenesulfonamides 229 provides a second approach to the synthesis of 1,2-benzothiazine 1,1-dioxides 230 via creation of the bond between C-3 and C-4 (Scheme 31) <1999CPB1730>. The best yields of cyclization products are achieved when the R group on the amide 229 is bulky. In the case of substrates with small R groups (Me, Ph, etc.), products 231 and 232 are formed from attack of the Bu"Li on the carbonyl carbon. 

Synthesis The reaction of benzothiazolo-3(2H)-one-1,1-dioxide with methyl chloroacetate gives the methyl 2(3H) acetate derivative, which is isomerized with sodium methoxide in toluene/terf-butanol yielding methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate-1,1 -dioxide. The subsequent methylation with methyl iodide in methanol yields the 2-methyl compound. Finally this compound is treated with 2-amino-5-methylthiazole in xylene (Trummlitz et al. (Thomae GmbH), 1979 Trummlitz et al., 1989 Kleemann et al., 1999). 

The dioxopyrazolines are also acidic because of their enolic group (4,4-disubstituted analogues are inactive) and a recent example azapropazone (apazone) (184) inhibits prostaglandin synthesis. Its pharmacological properties are like those of phenylbutazone and it is also uricosuric. Anti-inflammatory 1,2-benzothiazine 1,1-dioxides such as piroxicam (185 R = 2-pyridyl) also have an acidic enolic group whose anion can be stabilized by... 

In the laboratory of R. Bihovsky, a series of peptide mimetic aldehyde inhibitors of calpain I was prepared in which the P2 and P3 amino acids were replaced with substituted 3,4-dihydro-1,2-benzothiazine-3-carboxylate-1,1-dioxides. The synthesis began with the diazotization of the substituted aniline substrate using sodium nitrite and hydrochloric acid. The aqueous solution of the corresponding diazonium chloride product was added dropwise to the solution of acrylonitrile in a water-acetone mixture, which contained catalytic amounts of copper(ll) chloride. This Meerwein arylation step afforded the chloronitrile derivative, which was subjected to sulfonation with chlorosulfonic acid, and the resulting sulfonyl chloride was treated with the solution of ammonia in dioxane to give the desired 3,4-dihydro-1,2-benzothiazine-2-carboxamide. 

Sianesi and co-workers39,40 utilized o-aminophenylacetonitrile (48) as starting material for a four-step synthesis of compounds related to 47. Thus, diazotization of aniline 48 and treatment of the diazonium salt with S02/Cu2Cl2 yielded the sulfonyl chloride 49 (Eq. 11). Treatment of 49 with primary amines produced the corresponding sulfonamides 50 which were cyclized by sulfuric acid to the 3-imino compounds 51. Finally, aqueous hydrolysis of the imine 51 produced the desired 1,2-benzothiazin-3 (2H)-one 1,1-dioxides (47) (R = H, Et, and Ph) (Eq. 11). 

Zenno and Mizutani55 extended this synthesis by treating N-(p-nitro-phenethyl)acetamide (73) with fuming sulfuric acid to give 3,4-dihydro-7-nitro-2W-1,2-benzothiazine 1,1-dioxide (74) in good overall yield (Eq. 17). After reduction and diazotization, the nitro group in 74 could be replaced with a variety of other functional groups (vide infra). 

The same workers153 extended a well-known carbostyril synthesis based on cyclization of -acylacetanilides to the corresponding /1-acylsulfanilides. Thus, when heated in phosphorus oxychloride, sulfanilide 240 gave 4-phenyl-7-methyl-IH-2,1 -benzothiazine 2,2-dioxide (241) (Eq. 48). However, the success of this reaction appears to be highly dependent on the substituents in the aniline starting material.153... 

An improved synthesis of 3,4-dihydro-lH-2,l-benzothiazin-4-one 2,2-dioxide (237) was reported by Lombardino and Treadway.154 N-Methyl-sulfonylanthranilic acid methyl ester (242) with benzyl bromide and sodium hydride gives the N-benzyl derivative (243) which directly cyclizes to l-benzyl-4-oxo-3,4-dihydro-IH-2,1 -benzothiazine 2,2-dioxide (244). Catalytic hydrogenation of 244 then gave 237 (Eq. 49). Lombardino155 prepared... 

Various other routes have been reported to give the 1,4-benzothiazine ring, some of which are summarized below. Synthesis of the 1,4-benzothiazine 1,1-dioxides (105) from benzaldimine and methylene sulfone ylide has been reported.147... 

A facile base-catalyzed cyclization can be induced in y-carboxamidosulfonates or y-carbo-alkoxysulfonamides, leading to the 3-oxo-l,2-thiazine 1,1-dioxide (134) (Scheme 25). These cyclization reactions leading to 1,2-thiazines are relatively general <91JOC3549>. A variation of this strategy has been successfully utilized in the synthesis of l,2-benzothiazin-3-ones (135) from... 

There are a few examples of 1,2-thiazine synthesis of this type which are of importance. The most noteworthy is the preparation of 4-hydroxy-2/f-l,2-benzothiazine 1,1-dioxides (199) from the benzisothiazolinone (200) <81AHC(28)73>. This general procedure can be extended to the preparation of 2-alkyl-4-hydroxybenzothiazines. The treatment of A-methylsaccharin (201) and an alkyl chloro-acetate with NaH in DMSO or DMF affords a 76% yield of the 1,2-benzothiazine (202) (Scheme 39) <83JOC3601, 86CCC 1113,86FES819>. 

Lombardino JG, Wiseman EH and McLamore WM, Synthesis and antiinflammatory activity of some 3-carboxamides of 2-alkyl-4-hydroxy-2H-l,2-benzothiazine-l,l-dioxide,/. Med. Chem., 14,1171-1175 (1971). NB This reference also reported apparent pJCa values for numerous analogues of piroxicam. 

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