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Synthesis 2009(7): 1209-1219  
DOI: 10.1055/s-0028-1087990
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

1,2-Disubstituted 4-Quinolones via Copper-Catalyzed Cyclization of 1-(2-Halophenyl)-2-en-3-amin-1-ones

Roberta Berninia, Sandro Cacchi*b, Giancarlo Fabrizib, Alessio Sferrazzaa
a Dipartimento A.B.A.C., Università degli Studi della Tuscia e Consorzio Universitario ‘La Chimica per l’Ambiente’, Via S. Camillo De Lellis, 01100 Viterbo, Italy
b Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi ‘La Sapienza’, P.le A. Moro 5, 00185 Rome, Italy
Fax: +39(06)49912780; e-Mail: sandro.cacchi@uniroma1.it;
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Publication History

Received 28 November 2008
Publication Date:
06 March 2009 (online)

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Abstract

1,2-Disubstituted 4-quinolones have been prepared via copper-catalyzed heterocyclization of 1-(2-bromophenyl)- and 1-(2-chlorophenyl)-2-en-3-amin-1-ones, readily obtained from α,β-ynones and primary amines. The reaction tolerates a variety of useful functionalities including ester, keto, cyano, and chloro substituents. Quinolone derivatives can also be prepared via a sequential process from α,β-ynones and primary amines, omitting the isolation of the 1-(2-halophenyl)-2-en-3-amin-1-one intermediates.

Key words

copper - catalysis - enaminones - 4-quinolones - cyclizations

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16

In general, the use of copper catalysts proved superior to that of palladium catalysts in this reaction. For example, 2a was isolated in only 25% yield when 1a was subjected to Pd2(dba)3 (0.025 equiv), P(o-Tol)3 (0.1 equiv), and Cs2CO3 (2 equiv) in toluene at 80 ˚C for 8 hours.

18

The enaminone derivative containing a 4-bromophenyl substituent (instead of the 2-halophenyl group in 1), and with R¹ = n-Bu, R² = Ph was recovered essentially unchanged after 8 hours when it was subjected to standard cyclization conditions.