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Synthesis 1990; 1990(4): 295-299
DOI: 10.1055/s-1990-26856
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Metallation of N-(Pivaloyl)- and N-(tert-Butoxycarbonyl)difluoroanilines : Regiocontrol by Fluorine in the Synthesis of 4-Methoxycarbonyl Derivatives

Timothy J. Thornton* , Michael Jarman
  • *Chemistry-Drug Metabolism Team, Section of Drug Development, 15 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, England
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Publication Date:
17 September 2002 (online)

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Methyl 2,6-difluoro-4-(pivaloylamino)benzoate (3) and the corresponding 4-(tert-butoxycarbonylamino)-analogue 6 have been synthesised by reacting the appropriate 3,5-difluoroaniline derivatives with butyllithium followed by methyl chloroformate. N-(tert-Butoxycarbonyl)-2,3-difluoroaniline (9) required the "super-basic" butyllithium/potassium tert-butoxide mixture to convert it into methyl 4-(tert-butoxycarbonylamino)-2,3-difluorobenzoate (14): the 2,5-difluoro-analogue was formed in a similar manner. In all cases the regiocontrol of metallation was directed by fluorine rather than by the amide substituent.

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