Al-Isopropoxydiisobutylalane: A Study of
the Effect of Solvent on the Rate and
Stereoselectivity of Cyclic Ketone
Reduction
Perdip S. Bahia, Matthew A. Jones, and John S. Snaith*
FIGURE 1. Diastereofacial attack on cyclohexanones.
School of Chemistry, The University of Birmingham,
Edgbaston, Birmingham, B15 2TT, United Kingdom
aluminum trichloride complex,9 and the use of very bulky
aluminum Lewis acids in conjunction with Grignard
reagents.10
Received April 27, 2004
Cha and Kwon recently published a new method for
reducing cyclic ketones to the thermodynamically more
stable alcohols using Al-isopropoxydiisobutylalane
(DIBAiOPr) in diethyl ether;11 the reagent is readily
prepared from diisobutylaluminum hydride and 2-pro-
panol. The authors postulate that the reduction proceeds
through a Meerwein-Ponndorf-Verley-type mechanism,
supported by the fact that the relative proportion of the
thermodynamically more stable alcohol increases over the
course of the reduction.
Stereocontrol with this reagent is good to excellent, but
a significant drawback is that long reaction times are
required to achieve this, typically between 5 and 7 days.
In an effort to reduce the reaction times and improve the
stereoselectivity, we undertook an investigation into the
solvent dependency of the reaction.
Results and Discussion. The reduction of a number
of cyclic ketones was examined in a range of solvents
varying in polarity from DMF to toluene. No reaction
occurred in DMF and acetonitrile, but reduction was
rapid in THF, dichloromethane, and toluene. The results
for the latter three solvents are presented in Table 1.
The stereoselectivity of the reduction clearly shows a
remarkable dependency on the solvent. Reaction in THF
is essentially unselective, typically yielding approxi-
mately equal amounts of axial and equatorial alcohols
after 6 h. Extending the reaction time improved the ratio
in favor of the thermodynamically more stable alcohol.
Thus, in the reduction of 4-tert-butylcyclohexanone, the
ratio increased from 50:50 axial:equatorial after 6 h to
92:8 in favor of the axial product after 24 h.
By contrast, the reductions performed in dichlo-
romethane generally gave good-to-excellent ratios in
favor of the thermodynamically less stable alcohol.
Particularly noteworthy are the ketones bearing bulky
groups at the 2-position, 2-tert-butylcyclohexanone and
menthone, and 2-methylcyclopentanone, all of which
afforded the thermodynamically less stable alcohol es-
sentially exclusively. These results suggest that in this
solvent DIBAiOPr behaves as a bulky reducing agent,
Abstract: The effect of solvent on the rate and stereo-
selectivity of cyclic ketone reduction by Al-isopropoxydi-
isobutylalane (DIBAiOPr) has been investigated. In dichlo-
romethane, DIBAiOPr behaves as a bulky reducing agent,
approaching the carbonyl group along an equatorial trajec-
tory to produce the axial alcohol with >10:1 stereoselectivity.
In sharp contrast, reduction in toluene gives the comple-
mentary outcome, affording the thermodynamically more
stable isomer with >99:1 stereoselectivity.
The stereoselective reduction of cyclic ketones is an
extremely important reaction in organic synthesis. In
general, bulky reducing agents favor approach to the
carbonyl group via an equatorial trajectory, resulting in
formation of the axial alcohol, while small nucleophiles
attack from the axial position to yield the equatorial
alcohol (Figure 1).1 Reductions that proceed through the
establishment of an equilibrium will usually favor forma-
tion of the equatorial alcohol.
The thermodynamically less stable alcohol products
(with an axial hydroxyl group) can often be prepared with
extremely good stereocontrol, with the Selectride re-
agents developed by Brown most notable among the
methods used to achieve this conversion.2 Reagents for
the preparation of the thermodynamically more stable
alcohols (with an equatorial hydroxyl group) are not as
well developed, although several valuable methods have
been reported, including the classic Meerwein-Ponndorf-
Verley reduction3,4 and more recent catalytic variants,5
lithium n-butylborohydride,6 borane-THF complex,7 ac-
tivated sodium hydride,8 the lithium aluminum hydride-
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(3) Wilds, A. L. Org. React. 1944, 2, 178-223.
(4) de Graauw, C. F.; Peters, J. A.; van Bekkum, H.; Huskens, J.
Synthesis 1994, 1007-1017.
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1990, 55, 5911-5915.
(5) Campbell, E. J.; Zhou, H.; Nguyen, S. T. Org. Lett. 2001, 3, 2391-
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(9) Eliel, E. L.; Rerick, M. N. J. Am. Chem. Soc. 1960, 82, 1367-
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(6) Kim, S.; Moon, Y. C.; Ahn, K. H. J. Org. Chem. 1982, 47, 3311-
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(10) Maruoka, K.; Sakurai, M.; Yamamoto, H. Tetrahedron Lett.
1985, 26, 3853-3856.
(7) Cha, J. S.; Moon, S. J.; Park, J. H. J. Org. Chem. 2001, 66, 7514-
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(11) Cha, J. S.; Kwon, O. O. J. Org. Chem. 1997, 62, 3019-3020.
10.1021/jo049300f CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/19/2004
J. Org. Chem. 2004, 69, 9289-9291
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