Quaternized Chitosan as an Efficient Catalyst for Synthesis of N-alkylthio-phthalimides

The development of the N-alkylthio-phthalimides is of considerable interest because of the occurrence of many sulfur-containing compounds in many biologically important compounds (Tudge et al. 2006). Stable N-alkylthio-phthalimides have been used to prepare various N-(thioalkyl)amides (Ito et al. 2002; Ito et al. 2003), α-phenylthio-ketones (Wang et al. 2004), disulfides (Wang et al. 2003; Vigushin et al. 2003).

Different methods for preparation of N-alkylthio-phthalimides have been introduced.The synthesis of alkyl and aryl sulfenimides by the reaction of sulfenyl chlorides with imides in the presence of a tertiary amine was reported by Behforouz (Behforouz & Kerwood, 1969).Klose synthesized some N-alkylthio-phthalimides by the reactions of thiols or disulfides with phthalimides in the presence of bromine in pyridine-acetonitrile solution (Klose et al. 1997).
Chitosan (CS) is a very abundant biopolymer obtained by the alkaline deacetylation of chitin that is present in the exoskeletons of crustaceans, the cuticles of insects and the cell walls of most fungi.Chitosan has been not only extensively used as a support for the preparation of heterogeneous catalysts, but also itself has been used as a catalyst for some reactions.Owing to its biodegradability and non-toxicity, chitosan is considered as an environmentally friendly catalyst (Guibal, 2005).Recently, quaternary ammonium salts covalently bound to chitosan was used as a heterogeneous catalyst for the synthesis of dimethyl carbonate (Zhao et al. 2007;Zhao et al. 2008).We report here that the quaternized chitosan (QCS) can catalyze the reaction of N-chlorophthalimide with thiols under relatively mild conditions yielding N-alkylthio-phthalimides.

Results and discussion
The QCS catalyst was prepared as shown in Scheme 1. Reaction of CS with glycidyl trimethyl ammonium chloride at 85 o C for 10 h in water afforded QCS with the degree of substitution (DS) of 47%.The IR spectra of CS and QCS were shown in Figure 1.Because chitosan with degree of deacetylation of 90% was used as the starting materials for the quaternization reactions, both spectra of CS and QCS appeared the amide carbonyl signal at 1645 cm -1 .In the spectrum of QCS, the NH 2 -associated peak at 1595 cm -1 was weakened and a new peak at 1485 cm -1 (attributes to the methyl groups in the ammonium) appeared.The characteristic peaks of primary alcohol and secondary alcohol between 1083 and 1150 cm -1 did not change in QCS comparing with CS that showed the introduction of quaternary amino groups at NH 2 sites on chitosan chains.
The coupling of N-chlorophthalimide with benzyl mercaptan was studied to identify a suitable catalytic system.
Catalysts pyridine, CS and QCS were employed to search for the suitable catalyst (as shown in Table 1).It was found that QCS was effective (entry 3).It is noteworthy that QCS demonstrated a comparable activity to that of the homogeneous catalyst pyridine under the same reaction conditions (entries 1 and 3).However, there was only a trace amount of the corresponding products obtained in the presence of CS (entry 2).
The catalytic efficacy of QCS for general N-S bond formation between thiols and N-chlorophthalimide was further evaluated.As summarized in Table 2, the coupling reactions were performed under the condition of 10 mol% QCS in acetonitrile, the corresponding N-alkylthio-phthalimides 4 were obtained in moderate to good yields.These results demonstrated that QCS could be used as a good promoter for the coupling reactions between thiols and N-chlorophthalimide.
In summary, we have demonstrated that the quaternized chitosan can be used as an efficient and general catalyst for the coupling reactions between N-chlorophthalimide and thiols at relatively mild conditions, and a variety of N-alkylthio-phthalimides were prepared with moderate to good yields.

Experimental
Melting points were obtained on a B-540 Büchi melting-point apparatus and are uncorrected.FT-IR spectra were recorded on a PerkinElmer Spectrum 100 spectrometer from KBr pellets. 1 H NMR was measured with a Bruker 400 MHz spectrometer with tetramethylsilane (TMS) as an internal standard.LC-MS (ESI) spectra were recorded a Finnigan Mat LCQ mass Spectrophotometer 214 nm using a Betasil C 18 (3 μm, 100 Å, 3×50 mm) column.Chitosan with a degree of deacetylation of 90% was purchased from Shanghai Guoyao Biochemical Co. Ltd (China).Glycidyl trimethyl ammonium chloride was purchased from Dongying Guofeng Chemical Co.Ltd (China).N-chlorophthalimide was prepared according to the reported methods (Mintz & Walling, 1969;Zimmer & Audrieth, 1954).The thiols were purchased from Jiande Xingfeng Chemical Co., Ltd (China).Unless otherwise stated, all other chemicals and reagents used in this study were reagent grade.
General procedure for the coupling reaction of N-chlorophthalimide with benzyl mercaptan catalyzed by different catalysts N-chlorophthalimide (0.5 g, 2.75 mmol) was dissolved in acetonitrile (10 mL).The catalyst (0.25 mmol) was added under an argon atmosphere and the solution was stirred and heated to 80 o C. Benzyl mercaptan (2.5 mmol) in acetonitrile (5 mL) was added dropwise under an argon atmosphere.The mixture was kept at 80 o C for one hour.Then the reaction mixture was allowed to cool to room temperature.The resulting mixture was filtered and the residue was washed with acetonitrile.The filtrate was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel.
General procedure for the coupling reaction of N-chlorophthalimide with thiols catalyzed by QCS N-chlorophthalimide (0.5 g, 2.75 mmol) was dissolved in acetonitrile (10 mL).The QCS catalyst (0.055 g, 0.25 mmol) was added under an argon atmosphere and the solution was stirred and heated to 80 o C. Thiol (2.5 mmol) in acetonitrile (5 mL) was added dropwise under an argon atmosphere.The mixture was kept at 80 o C for one hour.Then the reaction mixture was allowed to cool to room temperature.The resulting mixture was filtered and the residue was washed with acetonitrile.The filtrate was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel.Compounds 4 were characterized by electrospray LC-MS and 1 H NMR.

Table 2 .
N-alkylthio-phthalimids prepared from N-chlorophthalimide and thiols catalyzed by QCS a