A New Approach to the Synthesis of 2-Aryl-4-halomethyl-5-methyl-1,3-oxa­zoles by Highly Regioselective Direct Halogenation with NBS or NCS/MeCN

Abstract

A simple and efficient method for the synthesis of 2-aryl-4-bromomethyl-5-methyl-1,3-oxazoles 2 and 2-aryl-4-chloromethyl-5-methyl-1,3-oxazoles 3 is described. The reaction of 2-aryl-4,5-dimethyl-1,3-oxazoles 1 with N-bromosuccinimide and N-chlorosuccinimide in acetonitrile under mild conditions provides 4-halomethyl isomers with exceptionally high regioselectivity in moderate to good yields.

oxazoles - halogenation - regioselectivity - heterocycles - drugs

References

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<A NAME="RF09604SS-11">11</A>

Unoptimized results.

<A NAME="RF09604SS-12A">12a</A>

The structures of 2 and 3 were confirmed by synthesizing the 2-aryl-5-halomethyl-4-methyloxazoles (the regioiso-mers of 2 and 3) according to a known procedure (Scheme [4] ) and comparing them with the help of ¹H/¹³C NMR spectroscopy and HPLC analysis. Compounds 2 or 3 and their regioisomers are distinguishable clearly by chemical shifts on ¹H/¹³C NMR and retention time on a HPLC analysis.

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<A NAME="RF09604SS-12C">12c</A> Chao EY.-H, Haffner CD, Lambert MH, Maloney PR, Sierra ML, Sternbach DD, Sznaidman ML, Willson TM, Xu HE, and Gellibert FJ. inventors; Patent WO  0100603. See also: ; Chem. Abstr. 2001, 134, 86235; and references cited therein

<A NAME="RF09604SS-13">13</A>

The regioselectivity was determined by HPLC analysis (HPLC conditions; YMC Pack-SIL A-002 column with 40:1-10:1 n-hexane-THF as the mobile phase). To investigate regioselectivity, we used HPLC with the normal phase, while the 5-halomethyl-4-methyl regioisomers easily decomposed during a HPLC analysis with the reverse phase.

<A NAME="RF09604SS-14">14</A>

One referee kindly suggested other plausible mechanisms (Schemes [5] and [6] ).