Improved addition of phenyllithium to hindered ketones by the use of non-polar media

Article abstract of DOI:10.1016/S0040-4039(02)00597-X

The use of a non-polar medium at room temperature is an efficient, cheap and easy way to improve the low reactivity of six hindered ketones towards phenyllithium.

Full text of DOI:10.1016/S0040-4039(02)00597-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3463–3465
Improved addition of phenyllithium to hindered ketones by the
use of non-polar media
Vincent Lecomte, Elie Ste´phan* and Ge´rard Jaouen
Laboratoire de chimie organome´tallique, Ecole Nationale Supe´rieure de Chimie et CNRS, 11 rue Pierre et Marie Curie,
75005 Paris, France
Received 10 January 2002; accepted 26 March 2002
Abstract—The use of a non-polar medium at room temperature is an efficient, cheap and easy way to improve the low reactivity
of six hindered ketones towards phenyllithium. © 2002 Elsevier Science Ltd. All rights reserved.
We have recently shown that the addition of aryl-
lithium derivatives to a hindered 11-keto-steroid could
be easily achieved by using a non-polar medium (tolu-
ene or a toluene–diethyl ether mixture).1 Such a solvent
seems to favor addition versus enolisation when work-
ing on a hindered and enolisable ketone as this
steroid. However, the results described in the literature
concerning the addition of phenyllithium (PhLi) to this
peculiar kind of ketones show that this addition is
usually performed in ethers (diethyl ether or THF) with
moderated yields. Even if these yields could be
increased with phenylmagnesium bromide2–5 with or
without activation by cerium chloride2,6–8 no mention
was found of the use of a solvent effect to solve this
problem.
5 as an example (Scheme 1) and the results are gathered
in Table 1.
The conditions described for addition of PhLi in
diethylether or THF generally provide modest yields.
However, in all cases the yield of the addition was
improved by using PhMgBr in the presence of cerium
chloride (addition to fenchone,8 menthone2 and
camphor2). It should be noted that cerium chloride may
modify the stereochemistry of the addition8 (addition of
PhMgBr to fenchone).
It thus appeared that a non-polar solvent (such as
toluene or toluene/diethyl ether), at room temperature,
provides high to quantitative addition of PhLi to
ketones 1, 2 and 6. The conditions chosen were those
which allowed the best yields.
The ketones used for this study are (−)-fenchone 1,
(−)-menthone 2, (+)-camphor 3, 3,3,5-trimethylcyclo-
hexanone 4, 3,3,5,5-tetramethylcyclohexanone 5 and
2,4-dimethylpentan-3-one 6. Ketones 2 and 3 are quite
hindered and enolisable, 1 is non-enolisable, 4 and 5
present one or two axial methyls similar to those of
some androstanes and could be used as models for a
subsequent work. The carbonyl compounds 1–5 can
give 2 epimers. The reaction is described for the ketone
Good yields were also obtained with the ketones 4 and
5 (Table 1, entry 4 and 5) but ketone 3 gave only a
lower result (Table 1, entry 3). In this case we observed
the reversibility of the addition. However, the addition
occurs, in all cases, in a stereospecific manner; the
alcohol obtained is the product of addition to the
less-hindered side. It is thus not only possible but even
Scheme 1.
* Corresponding author. E-mail: stephan@ext.jussieu.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00597-X

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V. Lecomte et al. / Tetrahedron Letters 43 (2002) 3463–3465
Table 1. Addition of PhLi to hindered ketones: literature and experimental results
Entry
Ketone
Literature results
Isomer percentage
Yield (%)
Ref.
9,10
Experimental resultsa
Isomer percentage
Yield (%)b
Solvent
Et2O
Solvent
Toluene
(%)
(%)
1
OH-endo (100)
35–64
OH-endo (100)
96
1
2
2
3
Et2O
Et2O
OH-ax (100)
OH-exo (100)
31
58
10
11
Toluene
OH-ax (100)
83
45
Toluene/Et2O 6:4 OH-exo (100)
3
4
5
4
5
6
–
–
–
–
–
–
–
–
–
–
–
–
Toluene
OH-ax (100)
OH-ax (100)
–
71
63
90
Toluene/Et2O
6 :4
Toluene
6
a All examples except entry 3 were carried out as follows: the ketone was dissolved in the selected non-polar solvent under argon. Commercial
PhLi was then added slowly by syringe and the mixture stirred at rt for 2–4 h. For entry 3, PhLi was added at –20°C, and the mixture stirred
at –20°C for 2 h then allowed to warm to rt. The configuration of the adducts was established by 13C NMR according to literature methods.
b As an isolated product after purification by column chromatography.
advantageous to use a non-polar medium for the addi-
tion of PhLi to hindered ketones.
Acknowledgements
The good reactivity of aryl organolithium compounds
with hindered ketones in non-polar media and at room
temperature is probably attributable, amongst other
things, to changes in the mechanism and in the way the
organolithium compounds associate.1
The authors wish to thank B. McGlinchey for her
assistance in translating the manuscript.
References
In conclusion, good levels of selective addition of
phenyllithium onto various hindered ketones can be
obtained in non-polar media at room temperature. This
method is thus inexpensive, safe and easy. An in-depth
study is underway to take advantage of the consider-
able potential of this new and surprisingly simple and
efficient approach.
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