COMMUNICATION
Reversibility in the boron-mediated ketone–ketone aldol reaction{
Katie M. Cergol, Paul Jensen, Peter Turner and Mark J. Coster*
Received (in Cambridge, UK) 22nd November 2006, Accepted 10th January 2007
First published as an Advance Article on the web 22nd January 2007
DOI: 10.1039/b617094c
selectivity for equatorial attack of the enolate on conformationally
locked 4.
The boron-mediated ketone–ketone aldol reaction is demon-
strated, through 1H NMR studies, to be reversible, in contrast
to the strictly irreversible aldol reactions of boron enolates with
aldehydes.
The influence of a bulky substituent at the 4-position of the
starting cyclohexanone was also examined. Reaction of boron
enolate 7, derived from 4-tert-butylcyclohexanone (4), with
cyclohexanone (3), provided 8 with complete 1,3-cis stereocontrol
(. 97 : 3 dr by 1H NMR). Once again, 4-tert-butylcyclohexanone
(4) reacted as an acceptor in a similar manner, providing the 1,3-cis
product 9 with complete selectivity for equatorial attack on 4. The
stereochemistry of these four aldol products was assigned on the
basis of 2D NOESY experiments and coupling constant data, and
confirmed by single crystal X-ray diffraction on 6 and 9 (Figs. S2
and S3, Supplementary Information).{
In an effort to understand the somewhat surprising nature and
extent of diastereoselectivity in these reactions, we sought to
determine whether the boron-mediated ketone–ketone aldol
reaction is truly irreversible and under kinetic control, in contrast
to the well established irreversibility of the analogous reaction with
aldehyde acceptors.4–6
1H NMR studies of the boron-mediated ketone–ketone aldol
reaction were undertaken with a view to gaining information
about the nature of the boron aldolate forming step. Rapid
formation (, 10 min) of the dicyclohexylboron enolate 1 in d10-
diethyl ether was observed upon addition of ketone 2 to Chx2BCl–
Et3N, as indicated by the appearance of the olefinic boron enolate
proton signal at d 5.03 (app t, J = 3.7 Hz) (Fig. 1a).7 Formation of
the boron aldolate 10 between the pre-formed boron enolate 1,
and cyclohexanone (3) as the acceptor ketone (1.1 equiv.), was
The directed aldol reaction using boron enolates and aldehydes has
often been employed in stereoselective organic synthesis, including
the syntheses of several complex natural products, owing in large
part to the high levels of chemo-, regio- and stereoselectivity that
can be achieved.1 We have recently reported the first examples of
the directed, boron-mediated aldol reaction between non-activated,
cyclic aliphatic ketones.2 In an effort to further explore the utility
of this reaction for the stereoselective union of substituted
cyclohexanones, the aldol reactions of dicyclohexylboron enolate
1, derived from 2-tert-butylcyclohexanone (2) under standard
conditions (Chx2BCl, Et3N, Et2O, 0 uC),3 with cyclohexanone (3)
or 4-tert-butylcyclohexanone (4), were examined. Aldol adduct 5
was the sole isolated diastereomer (. 97 : 3 dr by 1H NMR), from
the reaction of 1 with 3, followed by oxidative treatment of the
intermediate boron aldolate (H2O2, MeOH, pH 7 buffer),
demonstrating that very bulky groups at the 2-position of the
starting cyclohexanone favour the formation of 1,3-trans products
(Scheme 1). The reaction of 1 with 4 similarly provided aldol
adduct 6 with 1,3-trans diastereoselectivity, and with complete
Scheme 1 Reagents and conditions: a. Chx2BCl, Et3N, Et2O, 0 uC, 1 h; b.
(i) cyclohexanone (3) or 4-tert-butylcyclohexanone (4), 0–5 uC, 24–40 h; (ii)
30% aq. H2O2, MeOH, pH 7 buffer, 0 uC to r.t., 2 h.
School of Chemistry (F11), The University of Sydney, NSW 2006,
Australia. E-mail: m.coster@chem.usyd.edu.au; Fax: +61 2 9351 3329;
Tel: +61 2 9351 2752
{ Electronic supplementary information (ESI) available: Experimental
section and NMR spectra. See DOI: 10.1039/b617094c
Fig. 1 1H NMR spectra (400 MHz, d10-diethyl ether, 273 K). (a) Boron
enolate 1; (b) cyclohexanone (3) added to enolate 1 at t = 0, and 278 K.
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 1363–1365 | 1363