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

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

References and Notes

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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).

9

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

15

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.

16

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.