1,4 Additions with lithium bis(methylenecyclopropyl)cuprate

Article abstract of DOI:10.1016/S0040-4039(00)01957-2

Addition of lithium bis(methylenecyclopropyl) cuprate to α,β-unsaturated ketones provides an efficient route to methylenecyclopropyl ketones which on treatment with TiCl₄ give a range of cyclised products.

Full text of DOI:10.1016/S0040-4039(00)01957-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 347–349
1,4 Additions with lithium bis(methylenecyclopropyl)cuprate
Guillaume Peron,a David Norton,a John Kitteringhamb and Jeremy D. Kilburna,*
aDepartment of Chemistry, University of Southampton, Southampton SO17 1BJ, UK
bSynthetic Chemistry Department, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow,
Essex CM19 5AW, UK
Received 22 September 2000; revised 30 October 2000; accepted 2 November 2000
Abstract—Addition of lithium bis(methylenecyclopropyl) cuprate to a,b-unsaturated ketones provides an efficient route to
methylenecyclopropyl ketones which on treatment with TiCl4 give a range of cyclised products. © 2000 Elsevier Science Ltd. All
rights reserved.
Methylenecyclopropane derivatives have been used ex-
tensively in synthesis and in a range of novel transfor-
mations including cycloaddition reactions,1 radical
based annulation reactions2 and radical cyclisation re-
actions.3 Most recently it has been shown that, medi-
ated by Lewis acids, methylenecyclopropanes can be
coupled to ketones, both inter-4 and intramolecularly.5
Thus, we have shown that treatment of methylenecyclo-
propyl ketone 1 with TiCl4 gives the cyclohexenol 2 as
the major product (Scheme 1).5a Alternatively, treat-
ment of ketones such as 1 with samarium iodide leads
to methylene cyclohexanol 3 via a radical ring expan-
sion pathway.3a
most useful methods for the preparation of substituted
methylenecyclopropanes.6 However, and perhaps rather
surprisingly, there have been very few reports of the
preparation of organocuprates derived from lithiated
methylenecyclopropane,7 nor of the use of such a
reagent in 1,4-addition reactions.8 We now report that
lithium bis(methylenecyclopropyl)cuprate undergoes
clean 1,4-addition to a range of a,b-unsaturated ke-
tones to give methylenecyclopropyl ketones, which, in
turn, can be cyclised with TiCl4 to give a range of
cyclised products.
The desired cuprate was prepared by addition of
methylenecyclopropane to a solution of BuLi in THF
at −30°C, warming to room temperature and recooling
to −25°C, followed by cannular addition of the result-
ing lithiated methylenecyclopropane to a suspension of
CuI in THF, also at −25°C. Michael addition was
In this earlier work,5b ketone 1 was prepared by alkyla-
tion of lithiated methylenecyclopropane with an iodo
ketal (Scheme 1), and indeed the alkylation of lithiated
methylenecyclopropane has proven to be one of the
Scheme 1.
Keywords: methylenecyclopropane; cuprate; Lewis acid.
* Corresponding author. E-mail: jdk1@soton.ac.uk
0040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01957-2

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G. Peron et al. / Tetrahedron Letters 42 (2001) 347–349
Table 1.
carried out using slow addition of a mixture of a,b-un-
saturated ketone and trimethylsilyl chloride9 to the
cuprate at −78°C. After acid hydrolysis and column
chromatography, the ketone products were isolated in
good yields (Table 1).
Lewis acid mediated cyclisation of the ketones was
carried out using TiCl4 in CH2Cl2. As previously de-
scribed,5b cyclisation of ketone 1 under optimal condi-
tions, at −40°C, gave cyclohexenol 2 in 50% yield,
accompanied by the bicyclic ether 13 in 9% yield
(Scheme 2). Cyclisation of ketone 6, however, pro-
ceeded rapidly at −78°C to give cyclohexenol 14 in 65%
yield, reflecting the influence of the gem-dimethyl on
the cyclisation (Thorpe–Ingold effect).
Addition to methyl vinyl ketone 4 gave the previously
described ketone 1 in 79% yield. Likewise, addition to
the hindered enone 5 proceeded in good yield. Addition
to enones 7 and 9 gave mixtures of four diastereoiso-
meric ketones in each case with little stereoselectivity,
and addition to cyclohexenone 11 gave a 1:1 mixture of
the two possible diastereoisomers. Attempted addition
to chalcone or to the a,b-unsaturated esters methyl
crotonate and methyl acrylate did not give any of the
desired products under the conditions described above.
Cyclisation of the diastereoisomeric mixtures of ketones
8 and 10 both gave good overall yields of cyclised
products (73 and 67%, respectively), but as complex
mixtures of diastereoisomeric cyclohexenes, methylene-
cyclohexanes and highly substituted aromatics, a third
of these clearly resulting from elimination of H2O and
Scheme 2.
Scheme 3.

G. Peron et al. / Tetrahedron Letters 42 (2001) 347–349
349
Scheme 4.
HCl from the first two (Scheme 3). Indeed treatment of
the mixtures of 15 and 16, or 18 and 19, with DBU,
cleanly transformed them into the corresponding aro-
matic products 17 and 20, respectively.
3. (a) Boffey, R. J.; Santagostino, M.; Whittingham, W.;
Kilburn, J. D. Chem. Commun. 1998, 1875; (b) Pike, K.
G.; Destabel, C.; Anson, M.; Kilburn, J. D. Tetrahedron
Lett. 1998, 39, 5877; (c) Santagostino, M.; Kilburn, J. D.
Tetrahedron Lett. 1995, 36, 1365; (d) Destabel, C.; Kil-
burn, J. D.; Knight, J. Tetrahedron 1994, 38, 11267 and
11289.
Cyclisation of ketone 12, on the other hand, yielded the
anticipated bicyclic alcohol 21 in 35% yield, the allyl
chloride 22 and starting ketone, but as a single
diastereoisomer (Scheme 4). Clearly only one of the
diastereoisomeric ketones is able to cyclise under the
reaction conditions used, but does so very efficiently.10
4. Miura, K.; Takasumi, M.; Hondo, T.; Saito, H.; Hosomi,
A. Tetrahedron Lett. 1997, 38, 4587.
5. (a) Peron, G. L. N.; Kitteringham, J.; Kilburn, J. D.
Tetrahedron Lett. 2000, 41, 1615; (b) Peron, G. L. N.;
Kitteringham, J.; Kilburn, J. D. Tetrahedron Lett. 1999,
40, 3045.
6. For a review of the synthesis of methylenecyclopropanes
and derivatives, see: (a) Brandi, A.; Goti, A. Chem. Rev.
1998, 98, 589; for original work on the alkylation of
lithiated methylenecyclopropane, see: (b) Sternberg, E.;
Binger, P. Tetrahedron Lett. 1985, 26, 301; (c) Thomas, E.
W. Tetrahedron Lett. 1983, 24, 1467.
7. The preparation of a higher-order cuprate of methylene-
cyclopropane, and its addition to a glycine cation equiva-
lent, has been described: Kozhushkov, S. I.; Brandl, M.;
Yufit, D. S.; Machinek, R.; de Meijere, A. Liebigs Ann.
Receuil 1997, 2197.
8. In the review on the preparation of methylenecyclo-
propane derivatives (Ref. 6a) the addition of the lower
order cuprate of bicyclopropylidene to methyl vinyl ke-
tone is mentioned, Goti, A.; Vargas, A.; Brandi, A.;
Tamm, M.; Kozhushkov, S. I.; de Meijere, A. Unpub-
lished results.
In conclusion, lithium bis(methylenecyclopropyl)
cuprate adds cleanly to enones and provides a simple
route to highly substituted methylenecyclopropyl ke-
tones, which have not previously been readily accessi-
ble. The cyclisation of such ketones using Lewis acids
has been examined and this extends the scope of this
methodology for the preparation of functionalised cy-
clohexanols, and potentially of highly substituted
aromatics.
Acknowledgements
We thank SmithKline Beecham for supporting this
work.
9. Nakamura, E. Organocopper Reagents; Taylor, R. J. K.,
Ed.; OUP, 1994; pp. 129–142.
References
10. We prepared several derivatives of the single diastereoiso-
meric ketone 23 (e.g. arylhydrazones) but were unable to
produce X-ray quality crystals of any of these derivatives
to allow us to determine the stereochemistry of 23, and
thus of the other diastereoisomer which is able to cyclise.
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