Enantioselective Alkynylation Reactions to Substituted Benzaldehyde and Salicylaldehyde Derivatives: The Effect of Substituents upon the Efficiency and Enantioselectivity

Abstract

Asymmetric alkynylation reactions to mono-, di-, and trisubstituted aromatic aldehydes have been accomplished in good yields and with a range of selectivities. For salicylaldehyde derivatives both the yield and the enantioselectivity of the alkynylation reaction appears to depend not only upon the electron-donating/electron-withdrawing nature of substituents but also upon their position in the ring relative to the carbonyl. For benzaldehyde derivatives this observation is exemplified with nitrobenzaldehyde wherein asymmetric alkynylation with 3-nitrobenzaldehyde occurs in virtually quantitative yield and enantioselectivity. In contrast our attempts at asymmetric alkynylations with 4-nitrobenzaldehyde failed.

asymmetric alkynylation reaction - aromatic aldehydes - N-methylephedrine - substituent effects - position effects

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<A NAME="RP14606SS-14">14</A>

The effects of ortho substituents upon yield and enantiomeric excess has recently been highlighted.^4e With a dinuclear Zn catalyst and Me₂Zn a yield of 91% was recorded for the analogous reaction.

<A NAME="RP14606SS-15">15</A> This reaction was repeated 3 times with the same result. Interestingly, exposure of the same aldehyde to phenylethynylmagnesium bromide gave the racemic propargyl alcohol in a modest 30% yield

<A NAME="RP14606SS-16">16</A>

CCDC 628668 [(R)-10] and CCDC 628669 [(R)-15] contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

<A NAME="RP14606SS-17">17</A>

We have used both forms of N-methylephedrine in some selected examples in our studies in an attempt to obtain crystals suitable for X-ray analysis. We observed a significant difference in crystal morphology between enantiomeric propargyl alcohols.

<A NAME="RP14606SS-18">18</A>

In addition to the differences in the ¹H NMR spectra of these enantiomers, we observed differences in mp 90.5-90.7 °C (R -enantiomer) and 86.7-87.1 °C (S-enantiomer) and the corresponding HPLC retention time t _R = 9.69 (major), 14.31 min (minor) R-enantiomer and t _R = 61.35 (major), 9.80 min (minor) S-enantiomer.