Nucleophilic substitution of 2,2'-disulfanediyldianiline by β -keto esters and 1,3-diketones in the presence of triethylamine

The nucleophilic substitution at the S–S-bond of 2,2'-disulfanediyldianiline acting as an electro-phile by β -keto esters, dimethyl malonate, and 1,3-diketones in the presence of triethylamine is followed by cyclization providing 4 H -benzo[ b ][1


Introduction
2][3] The synthesis of heterocyclic systems is of continuing interest, at least in part as a result on the large number of biologically active molecules that contain heterocyclic rings. 4,5A relatively unexplored heterocyclic ring system with respect to both its synthesis and its biological activity is 4H-benzo[b] [1,4]thiazine.Various benzothiazine derivatives have been patented as therapeutic agents having calcium-antagonistic properties 6,7 and anti inflammatory. 8It has been long known that pheomelanins, the distinctive pigments of red hair and celtic skin, arise by the oxidative cyclization of cysteinyldopas via 1,4-benzothiazines. 9Benzothiazines bearing a nitrooxyethyl group show anti-ischemic properties for heart diseases and for their control of hypertension. 10The importance and utility of benzothiazine derivatives have led to the development of numerous synthetic routes.One of the most widely methods employed for the preparation of 1,4-benzothiazines involves the reaction of 2-aminothiophenol with alkynes, 11 αbromocarbonyl compounds, 12 and 1,3-ketones. 13,14

Scheme 2
In this context it should be noted that in the presence of a trace of p-toluenesulfonic acid the reaction of ethyl acetoacetate (1a; R = Et) with disulfide 2 leads to the formation of ethyl 3methyl-4H-benzo[b] [1,4]thiazine-2-carboxylates (3a) and ethyl 2-(2-methyl-2,3-dihydrobenzo [d]thiazol-2-yl)acetate (8) in about equal amounts (Scheme 2). 18any useful and interesting reactions of disulfides are known. 19,20 isulfides, especially diaryl disulfides, are commonly used as electrophiles in the sulfenylation of enolates anions; 21,22 sulfenamides and sulfenylimines have been prepared by nucleophilic substitution of the S-Sbond of disulfides with amines 23 and ketimines, 24 respectively.Recently, Munde et al. have reported an in situ synthesis of 1,4-benzothiazines from 2-aminobenzenethiols and 1,3dicarbonyl compounds under oxidative conditions involving the formation of disulfide 2 under solvent free conditions. 25Although the mechanism of these reactions have not yet been established, Trapani and his colleagues have reported an intermediate A, which was formed from the initial attack of amine at the ester group. 17

B
In this investigation, the reaction of 1,3-diketones 9a-f with disulfide 2 was carried out in boiling ethanol in the presence of triethylamine, and products 10a and 11b-f were isolated in high yields and characterized spectroscopically (Scheme 3).

Scheme 3
Since β-diketone 9c is capable of forming two isomeric enol tautomers both reacting as nucleophiles, the formation of 11c (R 1 = Me, R 2 = Ph) and/or the isomeric 1-(3-phenyl-4Hbenzo[b] [1,4]thiazin-2-yl)ethanone (11; R 1 = Ph, R 2 = Me) has to be considered.However, only one product was isolated; its mass spectrum exhibiting the base peak at 105 (PhCO + ) is taken as evidence for structure 11c.In addition, the isolated product 11c did not give a positive iodoform test as would be expected for the isomer product with an acetyl group.
Attempts to clarify the mechanism of the reaction by isolation of an intermediate were unsuccessful.The isolated product of the reaction of 1,3-diphenyl-1,3-propandione (9a) with disulfide 2 was characterized as 2-[(2-aminophenyl)sulfanyl]-1,3-diphenyl-1,3-propanedione (10a).On the basis of the formation of 10a we assume that products 11b-f result from the initial attack of the nucleophilic β-carbon atom of the enol tautomer of 1,3-diketones 9 at the electrophilic S-S-bond of disulfide 2, followed by intramolecular nucleophilic addition of the 2-amino group to the carbonyl group of intermediate 10.Similarly, enol tautomers of β-keto esters 1 and dimethyl malonate (5) give rise to the formation of products 3a,b and 6, respectively.Since the by-product 2-aminobenzenethiol is easily oxidized by oxygen (air) and reverted to disulfide 2, only 0.5 equivalents of disulfide 2 is needed (Scheme 4).
Experimental Section

General Procedures
Melting points were measured on a calibrated Gallenkamp melting point apparatus.IR spectra were measured with a Mattson 1000 FT-IR spectrometer. 1 H and 13 C NMR spectra were measured with a BRUKER DRX-500 AVANCE spectrometer at 500 and 125.77MHz, respectively.Mass spectra were recorded on a MS-QP2000A Shimadzu mass spectrometer operating at an ionization potential of 70 eV.
Munde et al. proposed a possible pathway with B as the suggested intermediate.Neither of these intermediates have been trapped or characterized.