Conversion of alcohols into the corresponding Trimethylacetyl chloride is one of the most important and commonly used transformation in organic synthesis and development of such a procedure is still desirable in academia as well as in industrial research. A number of reagents have been employed to carry out this transformation. Some of the methods developed for this purpose utilize reagents such as thionyl chloride, PCL, Vilsmeier–Haack salt, benzothiazolium salts,2-chlo-robenzoxazolium salts, Vieche salts, polymer-supported triphenyl phosphine, dimethylammoni-umchloride or a filterable phosphine source such as 1,2-bis(diphenylphosphino)ethane.
More recently, halide based ionic liquids and complex of TCT–DMF have been reported to effect this transformation. During our recent endeavor with HKR (hydrolytic kinetic reso-lution) mediated synthesis of biologically active compounds, werequired to convert a diol into the required epoxide through piva-late via a three step-sequence reaction. Interestingly, we observed an efficient chlorination of alcohol instead of its protection as piv-alate when reaction was performed in DMF. This could probably be attributed to the generation of a new reactive species responsible for chlorination and this observation prompted us to initiate a sys-tematic investigation of pivaloyl chloride/DMF reagent system for chlorination of alcohol. Herein we wish to disclose our results for a very mild and efficient conversion of alcohol to chloride.
In a typical experimental procedure, when alcohols were trea-ted with a pre-formed complex of DMF and pivaloyl chloride in dichloromethane, it gave the corresponding chloro compounds in moderate to good yields.
The present procedure is quite general as a wide range of struc-turally varied alcohols such as primary, secondary, allylic, homoal-lylic, and benzylic ones underwent smooth conversion with pivaloyl chloride/DMF into their corresponding Trimethylacetyl chloride(CAS NO:3282-30-2) under mild reaction conditions in moderate to good yields of the corre-sponding chloride. It should be mentioned here that insome cases small amount (5–15% yield) of the pivaloyl ester of the corresponding alcohol was also obtained as a side product.
The superiority of this procedure can be clearly visualized in chlo-rination of b-amino alcohol leading to the corresponding chloro compound in good yield without formation of any side product. The cleavage of acetonide group under the reac-tion conditions employed was not observed. It should be men-tioned here that the amino acid based azide thus prepared could serve as a useful building block to synthesise a new class of unnat-ural C-glycosyl amino acid featuring a triazole moiety between the sugar and amino acid entities.
PMBCl, an important protecting group in organic synthesis was also synthesized from the corre-sponding alcohol. Our method yielded the prod-uct free from any acidic impurities while the conventional method of its synthesis using hydrochloric acid generally affords the prod-uct contaminated with acidic impurities.
The measurement of optical rotation and its com-parison with literature values indicated that the reaction occurs with inversion of configuration via SN2 displacement leading to the corresponding chloro product in enantiomerically pure form. The involvement of Vilsmeier–Haack type complex as a possible reactive intermediate is invoked which adds on the hy-droxyl group of the alcohol to form the cationic species followed by subsequent nucleophilic attack of chloride ion in SN2 fashion to produce the corresponding chloride.
Some of the crude chloro compounds which were found to be volatile and unstable were subsequently treated with sodium azide in DMF at 60 C to afford the corresponding azide in good yield.
In conclusion, a mild, general and efficient conversion of alco-hols into Trimethylacetyl chloride has been developed. The noteworthy feature of the present method is the use of pivaloyl chloride/DMF as a mild, non-toxic and inexpensive reagent coupled with simple operation and ease of work-up. We believe this will present a better and more practical alternative to the existing methodologies.
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