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Synlett 2005(18): 2786-2790  
DOI: 10.1055/s-2005-918953
LETTER
© Georg Thieme Verlag Stuttgart · New York

Efficient Base-Catalyzed 5-exo-dig Cyclization of Carbonyl Groups on Unactivated Alkynyl-Quinolines: An Entry to Versatile Oxygenated Heterocycles Related to the Furoquinoline Alkaloids Family

Thomas Godet, Johann Bosson, Philippe Belmont*
Université Claude Bernard Lyon I, UMR CNRS 5181, Méthodologie de Synthèse et Molécules Bioactives, Bâtiment CPE, 43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Fax: +33(4)72432963; e-Mail: belmont@cpe.fr;
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Publication History

Received 4 August 2005
Publication Date:
21 October 2005 (online)

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Efficient Base-Catalyzed 5-exo-dig Cyclization of Carbonyl Groups on Unactivated Alkynyl-Quinolines: An Entry to Versatile Oxygenated Heterocycles Related to the Furoquinoline Alkaloids FamilySynlett 2005; 2005(19): 3018-3018
DOI: 10.1055/s-2005-921903

Abstract

An efficient 5-exo-dig cyclization was observed when TMS-protected alkynyl-quinolines bearing a carbonyl group were submitted to a mixture of an alcohol (alkyl-OH, diol, amino alcohol) with an inorganic base (K2CO3). The cyclization process seems to go through the deprotection of the TMS group prior to the ­cyclization step. The dihydrofuroquinoline derivatives formed are structurally related to the well-known furoquinoline alkaloids family. The scope and limitations of this reaction have also been studied with diverse bases and various alkynyl and carbonyl derivatives.

Key words

quinoline - 5-exo-dig cyclization - 1,3-dihydrofuro[3,4-b]quinoline - base-catalyzed cyclization

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The exo-methylene J(CH2) coupling constant was in accordance with geminal coupling value, i.e. 2.3 Hz and in the 13C NMR DEPT experiments, a signal was found for the exo-methylene CH2 carbon center which could not exist in a 6-endo-dig product (Scheme [4] ).

Scheme 4

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The 3-D structure was confirmed by comparison with the NMR data from the non-deuterated derivative 3. The silyl species D3C-OSi(CH3)3 was also identified by 1H NMR from a sample of commercially available H3C-OSi(CH3)3, in CD3OD.

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Refer to publication 10a for general procedure.

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Column chromatography was performed on silica gel (mixture of cyclohexane-EtOAc) adding 0.6% of Et3N. If care is not taken during purification, we have observed for compounds derived from aldehyde 1, the formation of a quinoline bearing an aldehyde function in position 3 and a methyl ketone in position 2 (see Scheme [5] below). This compound results from the hydrolysis of the hemiacetal. The presence of the methyl ketone confirms the formation of a 5-exo-dig product in all cases since a 6-endo-dig cyclization would have produced the formation of a quinoline bearing two aldehyde groups.

Scheme 5

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Typical Experimental Conditions for the Cyclization.
To a 0.1 M solution of alkynyl-quinoline in the appropriate solvent was added 0.05 equiv of anhyd K2CO3. The mixture was stirred overnight at r.t. The crude was purified by flash chromatography on silica gel, eluting with an appropriate mixture of cyclohexane-EtOAc with 0.6% of Et3N.
Typical analytical data are given for compound 5 (Entry 2, Table 2):
Yield: 99%; yellow oil.
R f = 0.3 (cyclohexane-EtOAc, 9:1)
1H NMR (300 MHz, CDCl3): δ = 8.19 (s, 1 H), 8.15 (d, J = 8.3 Hz, 1 H), 7.86 (dd, J = 8.3, 1.1 Hz, 1 H), 7.75 (td, J = 7.2, 1.5 Hz, 1 H), 7.53 (td, J = 7.9, 1.1 Hz, 1 H), 6.53 (s, 1 H), 5.79 (d, J = 2.3 Hz, 1 H), 5.35 (d, J = 2.3 Hz, 1 H), 3.80 (m, 2 H), 1.65 (m, 2 H), 1.41 (m, 2 H), (s, J = 5.3 Hz, 2 H), 0.94 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): δ = 157.1 (C), 153.6 (C), 149.9 (C), 131.4 (CH), 130.5 (CH), 129.6 (CH), 129.5 (C), 128.4 (CH), 127.8 (C), 126.9 (CH), 103.6 (CH), 83.9 (CH2), 68.2 (CH2), 31.7 (CH2), 30.1 (CH2), 13.8 (CH3).
MS: m/z = 256 (MH+).