Paper
An Efficient Synthesis of 3-Chloromethyl-1,2-benzisoxazoles via Modified Boekelheide Rearrangement.
Published May 3, 2011 · V. Arava, Laxminarasimhulu Gorentla, Udaya Bhaskara Rao Siripalli
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Abstract
Isoxazole and benzisoxazole are important classes of nitrogen-oxygen containing heterocycles. They have extensive applications as structural units of various biologically important molecules and as useful intermediates in medicinal chemistry 1 . Among them, 3-substituted-1,2-benzisoxazole and their derivatives are emerging as potential antipsychotic compounds 2 . For example, 1,2-benzisoxazole-3-methanesulfonamide, also known as Zonisamide, 1 (Figure 1), is an efficient antiseizure agent available in the market. It has been reported that it blocks the repetitive firing of voltage-sensitive sodium channels and reduces voltage-sensitive T-type calcium currents. With its extensive use as a drug for epilepsy, its cost-effective synthesis still remained as a great challenge for synthetic organic chemists. Various synthetic schemes for synthesizing 1 have been reported in the literature. However, it is often synthesized from 3-halomethylbenzisoxazole by the reaction of sodium sulfite followed by phosphorus oxychloride and ammonia 3 . 3-Bromomethylbenzisoxazole is in turn prepared from o-hydroxyacetophenone 4 . However, the main drawbacks of above reactions, i.e. low yields and harsh reaction conditions, limit the practical applicability of the above synthetic methods. On the other hand, Boekelheide rearrangement, i.e. [3,3]-sigmatropic rearrangement of N-oxide to corresponding alcohols or halides has been used for the synthesis of various heterocyclic derivatives 5,6 . Acetic anhydride or trifluoroacetic anhydrides are commonly used in the above reactions. Although Boekelheide rearrangement was reported with various N-oxides, to the best of our knowledge, there is no report on the halogen transfer to 3-position of N-oxide of benzisoxazole. Hence, we report for the first time the synthesis of 3-cholomethylbenzisoxazole via Boekelheide rearrangement using phosphorus oxychloride in the presence of organic bases. The required benzisoxazole and their N-oxides are prepared using sodium hypochlorite as an oxidizing agent 7 . And the oximes are prepared according to reported literature methods in good yields (70-98%) from ketones. Initial attempts to halogenate 3 with different halogenating agents such as elemental bromine, NBS, DDH, NCS and chlorine (gas) are unsuccessful. The direct halogenation reactions mainly resulted in the formation of a mixture of mono halogenated and dihalogenated derivatives. Furthermore, the reactions did not proceed to completion. The usefulness of Boekelheide reaction is investigated in the synthesis of 3-chloro or 3-bromomethylbenzisoxazole using acetic anhydride. It is surprising to observe that the reaction of 3-methylbezisoxazole-N-oxide 2a with acetic anhydride did not lead to the formation of the required product 5 but mainly formed 3 and 4 as shown in the Scheme I. It is reported that when acetic anhydride or trifluoro acetic anhydride is used in Boekelheide reaction, the acetate group (or hydroxy group) will be transferred to the adjacent carbon atom and when POCl3 is used, it will lead to the formation of halogen derivatives instead of acetate or hydroxy derivatives 6 . Therefore, POCl3 is used in the presence of organic bases such as triethylamine (TEA) or diisopropyl-
This study demonstrates an efficient synthesis of 3-cholomethyl-1,2-benzisoxazole using phosphorus oxychloride in the presence of organic bases, offering a cost-effective alternative to traditional methods.
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