Copper (I) mediated conjugate addition of Grignard reagents to 2-oxoethylcyclohexenols. A versatile, efficient and diastereoselective route to anti, Z 6-alkyl-2-trialkylsilyloxy-1-(2-trimethylsilyloxypropylid-1-ene)-cyclohexanes

Article abstract of DOI:10.1055/s-1999-2748

The copper (I) mediated conjugate addition reactions of Grignard reagents to 2-silyloxycyclohexenyl methylketones lead exclusively to the corresponding anti, Z 1-(2-trimethylsilyloxypropylid-1-ene)-cyclohexan-2-ols in almost quantitative yields and with h

Full text of DOI:10.1055/s-1999-2748

LETTER
1057
Copper (I) Mediated Conjugate Addition of Grignard Reagents to 2-
Oxoethylcyclohexenols. A Versatile, Efficient and Diastereoselective Route to
anti, Z 6-Alkyl-2-trialkylsilyloxy-1-(2-trimethylsilyloxypropylid-1-ene)-
cyclohexanes
Valéry Dambrin, Monique Villiéras, Hassen Amria, Jacques Lebreton, Jean Villiéras*
Laboratoire de Synthèse Organique, UMR CNRS 6513, Faculté des Sciences et Techniques, 2, rue de la Houssinière, BP 92208 - F44322
Nantes Cedex 03, France
Fax +33 (2) 51 12 54 12; E-mail: villiera@chimie.univ-nantes.fr
a Laboratoire de Chimie Organique et Organométallique, Faculté des Sciences, Campus Universitaire -1060-Tunis-Tunisie
Received 12 April 1999
Abstract: The copper (I) mediated conjugate addition reactions of
Grignard reagents to 2-silyloxycyclohexenyl methylketones lead
exclusively to the corresponding anti, Z 1-(2-trimethylsilyloxypro-
pylid-1-ene)-cyclohexan-2-ols in almost quantitative yields and
with high diastereoselectivities (d.e. ≥ 95%).
Key words: conjugate addition, polyfunctional Michael acceptor,
enolate trapping, silyl enols ethers, diastereoselectivity
In our continuing interest towards the synthesis of 5- and
6-membered ring cycloalkanol carboxylates substituted at
three contiguous atoms, we would like to report our recent
results concerning the behaviour of acetyl-substituted an-
Scheme 2
alogues. While, in the case of 2-silyloxycycloalkenes
(inseparable mixture of diastereoisomers) was observed
as resulting from conjugate addition to 3.
carboxylates1, copper (I) mediated conjugate addition re-
actions of Grignard reagents afforded related alkylated
cycloalkanols in high yields and diastereoselectivities
(Scheme 1), ketocycloalkenols have led to quite unexpect-
ed results.
Conjugate addition to the 6-membered ring analogues 5b-
c was less disappointing. In this case, the reaction pro-
ceeded smoothly at -10 °C affording the corresponding
enoxysilanes 6a-i, without formation of 7, in almost quan-
titative yields (no cyclohexene was recovered) and high
diastereoselectivities (one single isomer detected, accord-
ing to 1H- and13C NMR) (Scheme 3 and Table 1).
Scheme 1
Under the same conditions the keto analogs 2a-b led al-
ways to quantitative formation of 3, probably through an
addition-elimination process, while no desired cycloalk-
anols could be observed (Scheme 2).
Scheme 3
The use of stronger electrophiles in order to trap the inter-
As previously reported for the ester analogues, the forma-
tion of 6 and 7 must be considered as the result of concur-
rent O-silylation and b-elimination on the intermediate
keto-enolate resulting of the addition reaction. It seems to
be a reflection of the nucleophilic behaviour of these eno-
lates for O-silylation. This phenomenon seems to be
mediate enolate (TMSBr, TMSI, TMSOTf or TBDMSCl)
yielding to a potentially more stable enoxysilane, however
did not provide any change in the course of the reactions.
Besides, in the presence of HMPA (0.5 eq.) or at reaction
temperatures up to - 30 °C, concomitant formation of 4
Synlett 1999, No. 07, 1057–1058 ISSN 0936-5214 © Thieme Stuttgart · New York

1058
V. Dambrin et al.
LETTER
Table 1 Preparation of the enoxysilanes 6a-i
Acknowledgement
We thank G. Nourisson for recording of the mass spectra and Dr. A.
Guingant for fruitful discussions.
References and Notes
(1) (a) V. Dambrin, M. Villiéras, C. Moreau, H. Amri, L. Toupet,
J. Villiéras, Tetrahedron Lett. 1996, 37, 6323-6326. (b) V.
Dambrin, M. Villiéras, J. Lebreton, L. Toupet, H. Amri, J.
Villiéras, Tetrahedron Lett. 1999, 40, 871-874. (c) V.
Dambrin, M.Villiéras, P. Janvier, J. Lebreton, L. Toupet, H.
Amri, J. Villiéras Tetrahedron, submitted.
(2) E. J. Corey, B. B. Snider, J. Am. Chem. Soc. 1972, 94, 2549-
2550.
(3) Typical procedure : anti, (Z)-6-n-Butyl-2-dimethyl-tert-
butylsilyloxy-(2-trimethylsiloxypropylid-1-ene)-cyclohexane
6b.
aEstimated according to 1H NMR. bQuantitative crude yields without
purification over silica gel in order to prevent from b-elimination. cSi-
lica gel chromatography could be achieved successfully on this com-
To a solution of 2.5 mmol (1 eq.) of 5b in 40 mL THF at -
10 °C was added 0.25 mL (0.1 eq.) of a 1N solution of
LiCuBr2 in THF and trimethylsilyl chloride (0.8 mL, 6.25
mmol, 2.5 eq.). After 5 min, a solution of the Grignard reagent
(7 mmol, 2.8 eq.) was slowly added during ca. 1 h and the
mixture was stirred for another hour until completion. Then
the mixture was quenched with saturated aqueous NH4Cl.
After extraction with diethyl ether, the combined organic
layers were washed with brine and dried (MgSO4). Removal
of the solvents under vacuum yielded the crude silyl enol 6b
as a colourless viscous oil, which was not purified over silica
gel in order to prevent b-elimination (1.05 g, quant.), d.e.
> 95%. 1H NMR (200 MHz, CDCl3 / TMS) : d 4.40 (1H, m,
HC-OSi), 2.84 (1H, m, HC-nBu), 1.97 (3H, s, CH3), 1.79-1.27
(12H, m), 0.90 (9H, s, t-Bu), 0.9 (3H, broad t, CH3 (n-Bu)),
0.18 (6H, s, Me-Si), 0.08 (9H, m, SiMe3).
d
pound (96%). Estimated since no other diastereoisomers could be
observed in 1H and 13C NMR.
strongly ring-size dependent since cyclopentylidene eno-
lates seems to be much less stable than cyclohexylidenes
enolates. As a consequence, subsequent rate-limiting O-
silylation with TMSX is much more favoured in the 6-
membered ring series.
Structure determination of 6 could be accomplished by
comparison with our previous results1 on 6-membered
ring silyl ketene acetals. Indeed spectral data analogy with
a
related 3-n-butyl-2-(ethoxytrimethylsilyloxymethyl-
13C NMR (50 MHz, CDCl3) : d 139.7 (C=COSiMe3), 123.0
(C=COSIMe3), 69.5 (CH-OSi), 36.1 (HC-n-Bu)), 35.9
(C=C-CH3), 30.7 (CH2), 30.6 (2CH2), 26.3 (CH2), 25.9
(C(CH3)3), 25.7 (CH2), 22.8 (CH2), 19.8 (C(CH3);), 14.2
(CH3), 0.66 (SiMe2 and SiMe3).
ene)-cyclohexan-1-ol dimethyl-tert-butylsilyl ether led us
to assign the exclusive relative anti, Z configuration for
6b. All attempts to purify over silica gel (with or without
Et3N) or basic alumina, however consisted in the sole for-
mation of the b-elimination by-products 7. The same re-
sults were obtained by trying to regenerate the carbonyl
moiety with various acids (including aqueous HF,
CF3CO2H, Amberlyst (15)), with TBAF2 or with MeLi,
whereas acetic acid did leave the enoxysilanes 6 un-
changed. Despite this, the method seems particularly at-
tractive by enabling a short and diastereoselective
synthesis of numerous disubstituted exocyclic 6-mem-
bered ring enoxysilanes under very simple operating con-
ditions.3 Furthermore, it can be considered as an
alternative and efficient route to the previously described
methods(zinc enolate silylation,4 ketene alkylation-silyla-
tion,5 C. Ainsworth6).
MS m/z (CI) 385 (M-H+)
IR n max (thin film) 1673 (C=C), 1096 (broad, O-Si).
(4) C. Ainsworth, F. Chen, K. Yu-Neng, J. Organomet. Chem.
1972, 46, 59-71.
(5) G. M. Rubottom, Synth. Commun. 1977, 7, 327-332.
(6) L. M. Baigrie, D. Lenoir, H. R. Seikaly, T. T. Tidwell, J. Org.
Chem. 1985, 50, 2105-2109.
(7) Selected papers of related interest: (a) L. A. Telan, C.-D.
Poon, S. A. Evans Jr, J. Org. Chem. 1996, 61, 7455-7462.
(b) J. Otera, Y. Fujita, S. Fukuzumi, Tetrahedron 1996, 52,
9409-9418. (c) A. Bernardi, G. Colombo, C. Scolastico,
Tetrahedron Lett. 1996, 37, 8921-8924. (d) C. Palazzi, L.
Colombo, C. Gennari, Ibid. 1986, 27, 1735-1738. (e) C. H.
Heathcock, S. K. Davidesn, K. T. Hug, L. A. Flippin, J. Org.
Chem. 1986, 51, 3027-3037.
There is no doubt that those preliminary results will offer
new opportunities in the field of multi-step synthesis in-
volving asymetric aldolisation and related Mukaiyama re-
actions.7
Article Identifier:
1437-2096,E;1999,0,07,1057,1058,ftx,en;G07799ST.pdf
Synlett 1999, No. 07, 1057–1058 ISSN 0936-5214 © Thieme Stuttgart · New York