TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 989–993
Reductive aldol reactions on aromatic heterocycles
a,∗
a
a
a,†
Timothy J. Donohoe, Karl W. Ace, Paul M. Guyo, Madeleine Helliwell and
Jeffrey McKenna b
a
Department of Chemistry, University of Manchester, Oxford Road, Manchester, M13 9PL, UK
b
Rhône-Poulenc Rorer, Dagenham Research Centre, Dagenham, RM10 3RX, UK
Received 27 October 1999; revised 24 November 1999; accepted 29 November 1999
Abstract
The Birch reduction of both pyrroles and furans can be quenched with an aldehyde electrophile, thus constituting
a reductive aldol reaction. Although the reaction was not stereoselective, the pyrrolines derived from reduction
of pyrroles could be oxidised and then reduced with NaBH4 to provide syn-aldol adducts with high levels of
stereoselectivity. The relative stereochemistry of two adducts was proven by X-ray crystallography. © 2000 Elsevier
Science Ltd. All rights reserved.
Keywords: Birch reduction; aldol; pyrrole; furan.
The aldol reaction is one of the most important carbon–carbon bond forming reactions used in
synthesis; one of the principal reasons for its success is that control of both relative and absolute
1
stereochemistry is possible. Normally, the enolate component of an aldol reaction is generated by
reaction of a carbonyl compound with base: however, other methods of enolate generation include
conjugate addition to unsaturated carbonyl compounds and reduction of, for example, α-halo carbonyl
compounds. There is another popular way of generating enolates, which involves reduction of aromatic
2
carboxylic acids with a group I metal in ammonia: however, to the best of our knowledge, reaction of
such enolates with carbonyl electrophiles (in what would then constitute a Birch reductive aldol reaction)
3
is unknown.
As part of a programme designed to study the partial reduction of heterocycles, we recently examined
4
5
the reductive alkylation of electron deficient pyrroles and furans: we believe that addition of two
electrons to such heterocycles generates a dianion and subsequently (after protonation at C-5 by
ammonia) an enolate, Scheme 1. This enolate is a willing partner in many alkylation reactions and in this
paper we wish to report on the use of aldehydes as electrophiles in the Birch reduction. Our study has
concentrated on the development of the reductive aldol reaction of pyrroles, as the products so produced
may have application in the synthesis of natural products such as lactacystin and oxazolamycin.
∗
†
Corresponding author. E-mail: t.j.donohoe@man.ac.uk (T. J. Donohoe)
Author to whom correspondence regarding the X-ray crystal structure should be addressed.
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