A novel benzothiazole synthesis by cyclization of ketenimines bearing sulfenylimine fragments. Unexpected sulfur to carbon migration of an imino group

Transient ketenimines containing sulfenylimine fragments in which both functionalities are linked by an ortho-phenylene scaffold through their nitrogen and sulfur atoms respectively, underwent intramolecular cyclization yielding 2-(iminomethyl)benzothiazoles. These processes involve the formation of a new C–S bond and the concomitant migration of the imino group from the sulfur atom of the sulfenylimine fragment to the terminal carbon atom of the ketenimine function


Introduction
N-Sulfenylimines (N-alkylidenesulfenamides, sulfenimines) are important organic compounds, structurally characterized by a divalent sulfur atom binding an imine function by means of the nitrogen atom [R 1 -S-N=CR 2 R 3 ].The N-sulfenylimine functional group is the key constituent of some biologically active compounds.Smyth has recently demonstrated that penicillins and cephalosporins bearing an S-aminosulfenylimine side chain at the 6-and 7-positions respectively, are prototypical examples of novel classes of β-lactamase-dependent prodrugs, wherein enzyme-catalyzed cleavage of the β-lactam ring triggers a rapid expulsion of the Samino moiety. 1 N-Sulfenylimines can be prepared by a variety of synthetic methods 2 that involve the use as starting materials of various types of sulfur-containing compounds such as sulfenamides, 3 disulfides, 4 sulfenyl halides, 5 thioketenes, 6 thioamides, 7 and other less common substrates. 8N-Sulfenylimines are compounds with very rich chemistry which can be explained on the following grounds: a) the oxidation of the divalent sulfur atom; 9 b) the nucleophilic character of the nitrogen and sulfur atoms, thus allowing reactions with electrophilic species; 10 c) the electrophilic nature of the iminyl carbon, which is responsible for the addition of a variety of nucleophiles to that carbon; 9e,11 and d) the reaction of N-sulfenylimines as enolate equivalents with electrophiles.3a,12 However, to the best of our knowledge, there are no reports describing the participation of sulfenylimines in cycloaddition reactions, with the sole exception of the cycloaddition of the hexafluoroisopropylideneamidosulfenyl system (CF 3 ) 2 C=N-S-F with the CF 3 NO diradical. 13ver the last few years, we have studied several modes of intramolecular cyclization of imino-ketenimines in which the two reactive functionalities are connected through their nitrogen atoms by different tethers.We have found that such intramolecular [2+2] cycloadditions take place efficiently when the imine and ketenimine functions are supported on an ortho-benzylic scaffold, as in the imino-ketenimines 1 14 (Scheme 1).The same selective mode of cyclization was found with imino-ketenimines 3, 15 in which the N=C double bond involved in the cycloaddition is part of an N-acylimino group (Scheme 1).
Based on these results, we decided to explore whether an N-sulfenylimine function could participate in analogous [2+2] cycloadditions involving its iminic N=C double bond.To this end we selected as substrates sulfenylimino-ketenimines of general structure I (structural analogs of compounds 1 and 3 in which the benzylic sp 3 or sp 2 carbon atom has been replaced by a sulfur atom), which, by intramolecular [2+2] cycloaddition, could provide new heterocyclic compounds II, bearing an azetidine ring fused to a benzothiadiazine system (Scheme 2).Herein we describe the results obtained in attempts to prepare some sulfenyliminoketenimines of structure I.These compounds proved to be transient intermediates in cyclization processes that take place by nucleophilic addition of the sulfur atom of the sulfenylimine function into the sp-hybridized carbon atom of the ketenimine fragment, instead of through the planned intramolecular [2+2] cycloaddition of the sulfenylimine with the ketenimine.The products so obtained are 2-substituted benzothiazoles.

Results and Discussion
The readily available bis-(2-azidophenyl) disulfide 5, in solution in methanol, was treated sequentially with silver nitrate and diphenylketimine or bis-(4-methylphenyl)ketimine-this last step in the presence of triethylamine-to provide the sulfenylimines 6a-b, which are disubstituted at the iminic carbon atom (Scheme 3).A different synthetic method was necessary for preparing the sulfenylimines 6c-e, monosubstituted at the imine carbon atom.For the preparation of compounds 6c-e a solution of bis-(2-azidophenyl) disulfide 5 in methanol was treated first with silver nitrate, and then gaseous ammonia was bubbled through the resulting suspension to produce 2-azidobenzenesulfenamide 7 which, in the same reaction flask, reacts with aromatic aldehydes to yield the sulfenylimines 6c-e (Scheme 3).
MeO H, r.t., 12 h Scheme 3. Methods for the preparation of the 2-azidobenzenesulfenamides 6. 6a: R 1 Staudinger reactions 16 of the 2-azidobenzenesulfenamides 6 with trimethylphosphine, in toluene solution at room temperature, gave the trimethylphosphazenes 8, which were used in the following step without isolation, because of the hydrolytic sensitivity of the phosphazene group.The conversion 6→8 could be followed by IR and 31 P-NMR.Thirty minutes after the addition of trimethylphosphine to the toluene solution of the azide 6, the IR spectra of the reaction mixtures showed two strong absorptions at 1438 cm -1 and 1121 cm -1 corresponding to the phosphazene grouping, and the band corresponding to the azide group (near 2100 cm -1 ) of the starting material did not appear.The 31 P-NMR spectra of compounds 8, obtained by removing the solvent from a small fraction of the reaction mixture, showed one signal around 10 ppm attributable to the N-aryltrimethylphosphazene grouping.The toluene solutions of compounds 8 were subsequently treated at room temperature with disubstituted ketenes (diphenylketene and methylphenylketene).In less than one hour, IR analyses of the reaction mixtures showed no cumulenic absorptions in the 1900-2100 cm -1 range, and after chromatographic purification the 2-substituted benzothiazoles 10 were isolated in moderate to good yields (Scheme 4, Table 1). 17he E/Z configuration of the N=C bond in compounds 10d-g (in which R 1 ≠ R 2 ) has not been elucidated, although they were apparently obtained as single diastereoisomers.
Scheme 4. Synthetic sequence leading to the benzothiazoles 10.The structural elucidation of the benzothiazoles 10 was achieved from their analytical and spectral data, and was eventually confirmed by an X-ray structure determination of 10a (R 1 1). 18The IR spectra of the benzothiazoles 10 show strong absorptions in the region 1627-1652 cm -1 , attributable to the imine function on the side chain.In the 1 H-NMR spectra of compounds 10d,f,g (R 1 = H; R 3 = C 6 H 5 ) the proton at the iminic carbon resonates at δ = 7.65-7.71,whereas for 10e (R 1 = H; R 3 = CH 3 ) the same proton is observed at δ = 8.13.In the 13 C-NMR spectra of the benzothiazoles 10 the aliphatic quaternary carbon atom linked to C2 resonates at δ = 68.1-78.2ppm.For compounds 10d-g (R 1 = H) the signal of the methine carbon of the imine function appeared at δ = 159.2-161.8.
In the crystal structure of 10a, the benzothiazole ring is planar, with a mean deviation of only 0.01Å.The S-C and the N-C bonds of the benzothiazole ring are in the normal range.
A reasonable mechanism for explaining the conversion 8→10 is shown in Scheme 5: an aza-Wittig 19 reaction between the trimethylphosphazenes 8 and the ketenes should give the transient sulfenylimino-ketenimines 9, which probably undergo cyclization to the zwitterionic intermediate 11 by nucleophilic addition of the sulfur atom of the sulfenylimine function onto the electrophilic central carbon atom of the ketenimine moiety.Next, the intramolecular 1,3migration of the imino group from the sulfur atom of the zwitterionic intermediate 11 to the carbon atom linked to carbon C2 of the benzothiazole ring should lead to compounds 10.Thus, the formation of the benzothiazoles 10 from the sulfenylimino-ketenimines 9 involves an electrophilic intramolecular migration of the imino group 20 from the sulfur atom of the sulfenylimine function to the terminal carbon atom of the ketenimine fragment.
The benzothiazole nucleus is of particular interest, especially in the field of medicinal chemistry, because many useful therapeutic agents contain this heterocyclic system.For example, benzothiazoles bearing a 2-(4-aminophenyl) substituent at the 2-position represent a novel class of potent and selective antitumor agents. 21Benzothiazoles are commonly synthesized by sequential or simultaneous formation of one S-C and one N-C bond starting from 2aminoarenethiols. 22

Experimental Section
General Procedures.All melting points were determined on a Kofler hot-plate melting point apparatus and are uncorrected.IR spectra were recorded as films or Nujol emulsions on a Nicolet Impact-400 spectrophotometer.NMR spectra were recorded on a Bruker AC-200 or a Varian Unity-300.Chemical shifts (δ in ppm) are given from internal SiMe 4 (0.0 ppm) for 1 H-NMR and CDCl 3 (77.1 ppm) for 13 C-NMR.Mass spectra were recorded on a Hewlett-Packard 5993 instrument.Microanalyses were performed on a Carlo Erba EA-1108 instrument.The crystal structure of 10a was determined by single crystal X-ray diffraction.Measurements were recorded using a Bruker Smart 1000 CCD diffractometer with monochromated Mo-Kα radiation in the ω-scan mode.The structure was solved by direct methods and refined anisotropically on F 2 (program system SHELXL-97, G.M. Sheldrick, University of Göttingen, Germany).Hydrogen atoms were included using a riding model.

General procedure for the preparation of the 2-azidobenzenesulfenamides 6a-b
A suspension of bis-(2-azidophenyl) disulfide 5 (0.3 g, 1 mmol) and silver nitrate (0.17 g, 1.01 mmol) in methanol (5 ml) was heated at reflux for 1 hour.After cooling at room temperature, a solution of the corresponding ketimine (0.75 mmol) and triethylamine (0.079 g, 0.078 mmol) in the same solvent (2 ml) was added.The resulting heterogeneous mixture was stirred at room temperature for 20 hours.Then dichloromethane (20 ml) was added, and the solids were separated by filtration and washed with more dichloromethane (2 x 10 ml).The combined organic extracts were washed with water (2 x 20 ml) and dried over anhydrous magnesium sulfate.After filtration, the solvent was removed under reduced pressure and the resulting material was chromatographed on a silica gel column using hexanes/diethyl ether [9:1, (v/v)] as eluent.

General procedure for the preparation of the 2-azidobenzenesulfenamides 6c-e
A suspension of bis-(2-azidophenyl) disulfide 5 (0.3 g, 1 mmol) and silver nitrate (0.17 g, 1.01 mmol) in methanol (5 ml) was refluxed for 1 hour.After cooling the reaction mixture at 0°C in an ice bath, ammonia was bubbled through the solution for nearly 15 minutes.The aldehyde (1.2 mmol) was added and the heterogeneous reaction mixture was stirred at room temperature for 12 hours.Then dichloromethane (20 ml) was added, and the solids were separated by filtration and washed with more dichloromethane (2 x 10 ml).The combined organic phase was washed with water (2 x 20 ml) and dried over anhydrous magnesium sulfate.After filtration, the solvent was removed under reduced pressure and the resulting material was chromatographed on a silica gel column using hexanes/diethyl ether [9:1, (v/v)] as eluent.

General procedure for the preparation of the 2-(iminomethyl)benzothiazoles 10
Trimethylphosphine (1.5 mmol, 1.5 ml of a 1 M toluene solution) was added to a solution of the corresponding 2-azidobenzenesulfenamide 6 (1.5 mmol) in dry toluene (10 ml), and the reaction mixture was stirred at room temperature until the evolution of nitrogen ceased (15-30 minutes).Then diphenylketene or methylphenylketene (1.5 mmol) was added, and the mixture was allowed to stir at room temperature for 1 hour.The solvent was removed under reduced pressure and the crude material purified by column chromatography.