Synthesis and some transformations of 5-isoxazolylsulfonyl chlorides

The effect of the structure of 5-(benzylthio)isoxazoles on selectivity of the synthesis of 5-(chlorosulfonyl) isoxazoles has been determined. The chemical behavior in relation to amines has been described. Aim. To develop the methods for the synthesis of 5-(chlorosulfonyl)isoxazoles and 4-chloro-5-(chlorosulfonyl) isoxazoles as promising reagents for construction of prospective bioactive compounds. Results and discussion. The number of 5-(benzylthio)isoxazoles was obtained by cyclocondensation of N-hydroxyimidoyl chlorides or 2-chloro-2-(hydroxyimino) acetates with benzylethynylsulfide. Their oxidative chlorination with gaseous chlorine led to formation of the mixture of isoxazole-5-sulfonyl chlorides and 4-chloroisoxazole-5-sulfonyl chlorides. The ratio between these products in the mixture depended on the nature of the substitution group in position 3 of the isoxazole ring. For the synthesis of 4-chloro-5-(chlorosulfonyl)isoxazoles with acceptable yields the approach of an advance chlorination of 5-benzylthioisoxazoles by N-chlorosuccinimide with further oxidative chlorination was used. Experimental part. The synthesis of the starting and target compounds was performed in classic preparative conditions; flesh-chromatography; elemental analysis; LCMS; 1H and 13C NMR-spectroscopy were used. Conclusions. The reaction of oxidative chlorination of 5-(benzylthio)-3-isoxazoles has been studied. The synthetic approach for the previously unknown representatives of isoxazole-5-sulfonylchlorides has been developed.

The diversity of the titled reagents is limited, while methods of synthesis are not perfect. For example, for the synthesis of sulfonates I the cyclocondensation of α-bromopentafluorophenylvinyl sulfonate with aryl N-hydroxyimidoyl chlorides was suggested [6], and for the synthesis of sulfonyl chlorides II the oxidative chlorination of bis(isoxazol-5-yl)disulfides was proposed [12]. Thus, we have focused our attention on development of the preparative method of the synthesis of 5-isoxazolylsulfonyl chlorides that are universal reagents for sulfonylation.
Solutions of 3a-i in the mixture of water and chloroform were chlorinated with gaseous chlorine at 5-10 °C. The conversion of these mixtures finished in 3 h. The resulting mixtures were resoluted by column flesh-chromatography to obtain isoxazole-5-sulfonyl chlorides 4a-i and 4-chloroisoxazole-5-sulfonyl chlorides 5a,c-e (method a, Tab. 1, 2). The ratio between these products in the mixture depended on the nature of the substitution group in position 3 of the isoxazole ring. Compounds with electron donating alkyl and phenyl groups in 3 formed the corresponding products 4a,c-e with the yield of 5-20 %, while compounds with electron withdrawing groups formed the corresponding products 4b,f-і with the yield of 38-63 %. At the same time, the isolated yields of 4-chloroisoxazole-5-sulfonyl chlorides 5а,с-е were 16-39 %. We suppose that the sulfonyl chloride group deactivate the mobility of position 4 of the isoxazole ring. Thus, the increase of the chlorination period from 3 h up to 5 h did not affect the overall yield of products 5 (Scheme 2).
The problem of a direct process towards formation of sulfonyl chlorides 5a,c-e was solved by advance chlorination of compounds 3a,c-e with N-chloro succinimide. This allowed obtaining 4-chloro substituted derivatives 6a-d used for further oxidative chlorination with gaseous chlorine without additional purification. Such approach allowed obtaining the target compounds 5a,c-e with the yield of 46-68 % (method b, Tab. 1, 2, Scheme 3).
To display the synthetic potential of the derivatives obtained the bifunctional derivative 4h was selected as a convenient representative. Compound 4h is an interesting scaffold for design of new promising bioactive structures. It reacted with aqueous ammonia at -40 °C with formation of sulfonamide 7a. The same transformation with the ammonia excess at 0 °C finalized with carboxamide 8a. The reaction of 4h with morpholine at 0 °C led to compound 7b. Compounds 7a,b could be easily transformed into diamides 8a-c by the reaction with amines or ammonia. The carboxylic function in 7a,b could be transformed into synthetic promising derivatives with hydroxymethyl (compounds 9a,b) or bromomethyl (compounds 10a,b) group (Scheme 4).

Experimental Part
All chemicals and solvents were obtained from Enamine Ltd. and used without further purification. NMR spectra were recorded on a Bruker Advance 400 spectrometer ( 1 H NMR at 399.98 MHz and 13 C NMR at 125.7 MHz) in CDCl 3 [for compounds 7a,b, 9a,b, 10a,b in DMSO-d 6 ; for compounds 4a,b in C 6 D 6 ]. LC/MS spectra were recorded on an Agilent 1100 LCMSD SL instrument, column Zorbax SB C18 1.8 µm 4.6 × 15 mm, solvent DMSO, ionization at atmospheric pressure (70 eV). The melting points were measured with a Kohler melting point apparatus and were not corrected.

3-Substituted isoxazole-5-sulfonyl chlorides (4a-i) and 4-chloro-3-substituted isoxazole-5-sulfonyl chlorides (5a,c-e) (method a).
Place the mixture of compounds 3a-i (75 mmol) in dichloromethane (800 mL) and water (300 mL) in a glass flask. Then cool it with ice, and pass gaseous chlorine carefully    through the mixture while stirring vigorously for over the next 3 h, keeping the temperature of the reaction mixture below 10 ºC. Add crushed ice (500 g), then Na 2 SO 3 till discoloration of the organic layer keeping the temperature of the reaction below 10 ºC. Separate the organic layer, and wash the aqueous layer with dichloromethane (1 × 200 mL). Dry the combined organic layers over sodium sulfate and concentrate under reduced pressure on a water bath at the temperature of not more than 35 °C. Purify the residue by flash chromatography.

4-Chloro-3-substituted isoxazole-5-sulfonyl chlorides (5a,c-e) (method b).
To the solution of compounds 3a,c-e (16 mmol, 1 equiv.) in the appropriate solvent (CH 3 CN (30 ml) for 3a,c,e or DMF (30 ml) for 3d add N-сhlorosuccinimide (2.38 g, 18 mmol, 1.1 equiv), and stir the resulting mixture overnight at room temperature. Then dilute it with water (120 mL) and extract with ethyl acetate (2 × 70 ml). Wash the combined organic phases with brine (100 ml), dry over sodium sulfate, and concentrate under vacuum to obtain compounds 6a-d used without purification. Place the mixture of compounds 6a-d (75 mmol) in dichloromethane (800 mL) and water (300 mL) in a glass flask. Then cool it with ice, and pass gaseous chlorine carefully through the mixture while stirring vigorously for over the next 3 h, keeping the tempe-rature of the reaction mixture below 10 °C. Add crushed ice (500 g), then Na 2 SO 3 till discoloration of the organic layer keeping the temperature of the reaction below 10 °C. Separate the organic layer, and wash the aqueous layer with dichloromethane (1 × 200 mL). Dry the combined organic layers over sodium sulfate and concentrate under reduced pressure on a water bath at the temperature of not more than 35 °C. Purify the residue by flash chromatography.

Conclusions
1. The reaction of oxidative chlorination of 5-(benzylthio)-3-isoxazoles has been studied. The data obtained has been efficiently used for the synthesis of the previously unknown isoxazole-5-sulfonyl chlorides.
2. The synthetic potential of the resulting compounds has been demonstrated by the examples of the interaction of 5-(chlorosulfonyl)isoxazole-3-carboxylate with amines. The above products are reduced and brominated with formation of sulfonamides.
Conflicts of Interests: authors have no coflict of interests to declare.