ORGANIC
LETTERS
2
002
Vol. 4, No. 4
59-661
Alkynenitriles: Chelation-Controlled
Conjugate Additions
6
Fraser F. Fleming,* Venugopal Gudipati, and Omar W. Steward
Department of Chemistry and Biochemistry, Duquesne UniVersity,
Pittsburgh, PennsylVania 15282-1530
Received December 21, 2001
ABSTRACT
Chelation between γ-hydroxybutynenitrile and Grignard reagents triggers a particularly facile anionic conjugate addition reaction. Structurally
diverse Grignard reagents add with equal efficiency, providing an intermediate anion that stereoselectively alkylates benzaldehyde in an
overall addition−alkylation reaction.
Anionic conjugate additions are among the most fundamental
of carbon-carbon bond forming reactions. Conjugate ad-
generates a transient alkylmagnesium alkoxide 2, triggering
a smooth conjugate addition. Protonation or alkylation of
the resulting chelate 3 efficiently provides substituted nitriles
with two new bonds and the controlled formation of up to
two new stereocenters.
1
ditions to unsaturated carbonyl compounds occur with
1
excellent chemo- and stereoselectivity for a diverse array
of stabilized and organometallic nucleophiles. Unsaturated
2
nitriles, in contrast, are recalcitrant Michael acceptors,
3
4
requiring activation or powerful nucleophiles to coax
otherwise difficult or impossible conjugate additions.
Scheme 1
A particularly expedient solution for conjugate addition
5
6
to alkenenitriles is to temporarily chelate the nucleophile
proximal to the Michael acceptor (Scheme 1). Deprotonating
1, followed by addition of a second Grignard reagent,
(
1) Perlmutter, P. In Conjugate Addition Reactions in Organic Synthesis;
Pergamon: New York, 1992.
2) Fleming, F. F.; Hussain, Z.; Weaver, D.; Norman, R. E. J. Org. Chem.
997, 62, 1305.
3) (a) Morales-Rios, M. S.; Suarez-Castillo, O. R.; Trujillo-Serrato, J.
(
1
(
J.; Joseph-Nathan, P. J. Org. Chem. 2001, 66, 1186. (b) Fleming, F. F.; Pu,
Y.; Tercek, F. J. Org. Chem. 1997, 62, 4883. (c) Wallenfels, K.; Friedrich,
K.; Rieser, J.; Ertel, W.; Thieme, H. K. Angew. Chem. 1976, 15, 261.
The enhanced Michael acceptor properties of alkynenitriles
suggested an analogous chelation-controlled addition as a
means of extending chelation strategies to encompass
(
(
(
4) Fleming, F. F.; Pak, J. J. J. Org. Chem. 1995, 60, 4299.
5) Fleming, F. F.; Wang, Q.; Steward, O. W. Org. Lett. 2000, 2, 1477.
6) (a) Fallis, A. G.; Forgione, P. Tetrahedron 2001, 57, 5899. (b)
Normant, J. F.; Alexakis, A. Synthesis 1981, 841.
7) Chelation-controlled conjugate additions to activated alkenes are
7
(
conjugate additions to activated alkynes. Particularly ap-
effective with several electron-withdrawing groups, with analogous additions
to activated alkynes appearing not to have been investigated: Hoveyda, A.
H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.
pealing is the possibility of intercepting the intermediate
chelate in a sequential addition-alkylation route to stereo-
defined, tetra-substituted alkenes that are otherwise difficult
(
8) Ojima, I.; Kumagai, M. Tetrahedron Lett. 1974, 4005.
(9) (a) Kleijn, H.; Westmijze, H.; Meijer, J.; Vermeer, P. J. Organomet.
8
to synthesize. Achieving this goal would extend current
Chem. 1981, 206, 257. (b) Westmijze, H.; Kleijn, H.; Vermeer, P. Synthesis
978, 454.
9
1
conjugate addition of organocopper reagents and alkyl-
1
0.1021/ol017286c CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/25/2002