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Synlett 2009(8): 1245-1250  
DOI: 10.1055/s-0029-1216734
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Polysubstituted Quinolines from 2-Alkynylanilines and α,β-Ynones through a Sequential Conjugate Addition-Cyclization Process

Roberta Berninia, Sandro Cacchi*b, Giancarlo Fabrizib, Eleonora Filistib, 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 3 February 2009
Publication Date:
17 April 2009 (online)

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Abstract

Polysubstituted quinolines have been prepared, usually in good to high yields, from readily available 2-alkynylanilines and α,β-ynones through a sequential process that omits the isolation of the enaminone intermediates. The reaction tolerates several useful functionalities including ether, cyano, ester, and chloro substituents.

Key words

enaminones - cyclization - quinolines - α,β-ynones - 2-alkynylanilines

3

Bernini R., Cacchi S., Fabrizi G., Sferrazza A.; Synthesis; 2009, in press

4

Bernini, R.; Cacchi, S.; Fabrizi, G.; Filisti, E.; Sferrazza, A. Synlett 2009, submitted.

8

Conjugate additions of 2-(alkynyl)anilines to 1,3-diphenyl-propynones (MeOH, 120 ˚C) were carried out using a Carousel Tube Reaction (Radley Discovery).

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Enaminones 3 can also be prepared by treating the conjugate addition products derived from 2-iodonilines and 1,3-diaryl-propynones with terminal alkynes. Using this procedure, 3a, 3q, and 3r were isolated in 77%, 74%, and 70% overall yields, respectively. This protocol, however, appeared less suited for the development of a sequential process that would omit the isolation of the enaminone intermediates (Scheme  [4] ).

Scheme 4

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Typical Procedure for the Cyclization of Enaminones 3 to Quinolines 4 To a stirred solution of 3a (80 mg, 0.2 mmol) in anhyd DMSO (1.5 mL), Cs2CO3 (66 mg, 0.2 mmol) was added at r.t. The reaction mixture was warmed at 35 ˚C and stirred for 2 h. After cooling, the reaction mixture was diluted with EtOAc, washed with 2 N HCl and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 [n-hexane-EtOAc, 85:15] to afford 64 mg (92% yield) of 4a.
Light brown solid; mp 137-139 ˚C. IR (KBr): 3059, 2924, 1662 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 8.31-8.29 (m, 1 H), 8.11-8.08 (m, 1 H), 7.80-7.78 (m, 1 H), 7.63-7.54 (m, 5 H), 7.38-7.36 (m, 1 H), 7.29-7.13 (m, 10 H), 4.49-4.41 (m, 2 H). ¹³C NMR (100.6 MHz, CDCl3): δ = 198.0, 156.4, 148.1, 144.4, 140.0, 138.6, 137.4, 133.3, 133.2, 130.4, 130.1, 129.3, 128.6, 128.5, 128.4, 128.21, 128.17, 127.2, 126.3, 126.0, 125.0, 35.3. Anal. Calcd for C29H21NO: C, 87.19; H, 5.30. Found: C, 87.25; H, 5.36.

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Typical Procedure for the Preparation of Quinolines 4 from 2-(Alkynyl)anilines 1 and α,β-Ynones 2 To a stirred solution of 1b (45.5 mg, 0.2 mmol) in anhyd MeOH (0.5 mL), 2b (47.3 mg, 0.2 mmol) was added at r.t. The reaction mixture was warmed at 120 ˚C and stirred for 48 h. After that period the volatile materials were evaporated at reduced pressure, Cs2CO3 (65.2 mg, 0.2 mmol) and anhyd MeCN (1.5 mL) were added. The resulting reaction mixture was warmed at 60 ˚C and stirred for 1.5 h. After cooling, the reaction mixture was diluted with EtOAc, washed with 2 N HCl and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 [n-hexane-EtOAc, 85:15] to afford 71.0 mg (76% yield) of 4b.
White solid; mp 167-169 ˚C. IR (KBr): 3072, 2943, 1664 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 8.30-8.28 (m, 1 H), 8.02-8.00 (m, 1 H), 7.82-7.78 (m, 1 H), 7.63-7.56 (m, 3 H), 7.29-7.28 (m, 3 H), 7.17-7.09 (m, 6 H), 7.03-7.01 (m, 1 H), 6.96-6.94 (m, 1 H), 4.43-4.32 (m, 2 H), 3.73 (s, 3 H). ¹³C NMR (100.6 MHz, CDCl3): δ = 197.8, 159.5, 156.4, 148.1, 143.7, 139.9, 138.7, 137.1, 133.2, 132.2, 130.6, 130.2, 129.8, 129.31, 129.28, 128.7, 128.6, 128.2, 127.4, 125.7, 124.7, 122.5, 120.1, 113.0, 55.3, 34.7. Anal. Calcd for C30H22ClNO2: C, 77.66; H, 4.78. Found: C, 77.52; H, 4.70.