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Variation in site of lithiation with ring substituent of N′-aryl-N,N-dimethylureas: application in synthesis

Smith, Keith, El-Hiti, Gamal A. and Shukla, Amba P. 1999. Variation in site of lithiation with ring substituent of N′-aryl-N,N-dimethylureas: application in synthesis. Journal of the Chemical Society, Perkin Transactions 1 (16) , pp. 2305-2313. 10.1039/A903464A

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Abstract

Lithiation of various N′-aryl-N,N-dimethylureas takes different courses depending on the substituent in the aryl ring. N′-(4-Chlorophenyl)-, N′-(4-fluorophenyl)- and N′-(4-trifluoromethylphenyl)-N,N-dimethylureas are doubly lithiated, on nitrogen and on the carbon at position 2, with n-butyllithium or tert-butyllithium at 0 °C. The lithium reagents thus obtained react with a variety of electrophiles (iodomethane, D2O, benzophenone, benzaldehyde, phenyl isocyanate and phenyl isothiocyanate) to give the corresponding 2-substituted derivatives, in very good yields for the chloro and fluoro derivatives. Reaction of the dilithio reagent of N′-(4-chlorophenyl)-N,N-dimethylurea with 2-chlorocyclohexanone gives an 82% isolated yield of 4a-hydroxy-N-(dimethylaminocarbonyl)-1,2,3,4,4a,9a-hexahydrocarbazole, which on treatment with trifluoroacetic acid affords N-(dimethylaminocarbonyl)-1,2,3,4-tetrahydrocarbazole in 97% yield. Double lithiation of N′-phenyl- and N′-(4-methylphenyl)-N,N-dimethylureas is achieved using tert-butyllithium at –20 °C, and takes place on nitrogen and predominantly on one of the two methyl groups of the urea. The lithium reagents so produced also react with a range of electrophiles to give the corresponding N-methyl-substituted compounds in very good yields. Lithiation of the N′-(4-methoxyphenyl)-analogue with tert-butyllithium at 0 °C or at –20 °C takes place on nitrogen, and then partially on carbon at position 3 but primarily on a methyl group of the urea, leading to a mixture of ring substitution, methyl substitution and disubstitution (in the ring and on the methyl group) on reaction with representative electrophiles. However, disubstituted derivatives are obtained in very good yields when 3 molar equivalents of tert-butyllithium are used to form a trianion. Attempted lithiation of the N′-(4-nitrophenyl) analogue was not successful under various reaction conditions.

Item Type: Article
Status: Published
Schools: Chemistry
Subjects: Q Science > QD Chemistry
Publisher: RSC Publishing
ISSN: 0300-922X
Last Modified: 04 Jun 2017 02:51
URI: http://orca-mwe.cf.ac.uk/id/eprint/12697

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