Synthesis 2004(17): 2825-2832  
DOI: 10.1055/s-2004-834862
PAPER
© Georg Thieme Verlag Stuttgart · New York

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

Taihei Yamane*, Hiroyuki Mitsudera, Takatsugu Shundoh
Chemical Development Laboratories, Pharmaceutical Production Division, Takeda Pharmaceutical Company Limited, Osaka, 532-8686, Japan
Fax: +81(6)63006251; e-Mail: Yamane_Taihei@takeda.co.jp;
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Publikationsverlauf

Received 29 June 2004
Publikationsdatum:
07. Oktober 2004 (online)

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.

    References

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  • 12a

    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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11

Unoptimized results.

13

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.

14

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