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

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.

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

References

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<A NAME="RG21905ST-12">12</A>

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

<A NAME="RG21905ST-13A">13a</A> Michael JP. Nat. Prod. Rep.  2004,  21:  650 

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<A NAME="RG21905ST-14">14</A>

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.

<A NAME="RG21905ST-15">15</A>

Refer to publication 10a for general procedure.

<A NAME="RG21905ST-16">16</A> These compounds were isolated as a unique diastereomer, presumably cis, but this is not yet confirmed by NMR experiments

<A NAME="RG21905ST-17">17</A>

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

<A NAME="RG21905ST-18">18</A>

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⁺).