Highly regioselective alkylation at the more hindered α-site of unsymmetrical ketones by use of their potassium enolates. A comparative study with lithium enolates

Article abstract of DOI:10.1055/s-1998-1668

Alkylation of regioisomeric potassium enolates 4 and 6 obtained from corresponding silyl enol ethers 2 and 3 occurs at the most substituted site affording ketones 8. Alkylation of corresponding lithium enolates 5 and 7 occurs at the expected site affording ketones 8 or 9. As an application the one pot synthesis of spiroketones 13 from silyl enol ethers 12 is described.

Full text of DOI:10.1055/s-1998-1668

April 1998
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Highly Regioselective Alkylation at the More Hindered α-Site of Unsymmetrical Ketones by
Use of Their Potassium Enolates. A Comparative Study with Lithium Enolates
✝
Yannick Quesnel, Laure Bidois-Sery, Jean-Marie Poirier and Lucette Duhamel*
Université de Rouen, UPRES-A 6014, IRCOF, F-76821 Mont Saint Aignan, Cedex (France)
Fax 02 35 52 24 11; Lucette.Duhamel@univ-rouen.fr
✝
Deceased on May 7, 1997
Received 19 November 1997
Abstract: Alkylation of regioisomeric potassium enolates 4 and 6
obtained from corresponding silyl enol ethers 2 and 3 occurs at the most
substituted site affording ketones 8. Alkylation of corresponding lithium
enolates 5 and 7 occurs at the expected site affording ketones 8 or 9. As
Scheme 1
an application the one pot synthesis of spiroketones 13 from silyl enol
ethers 12 is described.
In this paper we report a comparative study of the reactions of
Alkylation of enolates is a very useful reaction to form carbon-carbon
potassium and lithium enolates obtained in these conditions toward
alkylhalides.
1
bonds. It is well-known that starting from an unsymmetrical ketone
such as 2-methylcyclopentanone 1a or 2-methylcyclohexanone 1b, the
Starting from 2-methylcyclopentanone 1a and 2-methylcyclohexanone
1b, we prepared the tetra- and tri-substituted trimethylsilyl enol ethers 2
regioselectivity of the alkylation, in non equilibrating conditions, is
2-10
directly controlled by the structure of the starting enolate.
Thus,
16
and 3, their corresponding potassium enolates 4 and 6, and lithium
intensive efforts have been made to generate either the less substituted
14,15
2-15
enolates 5 and 7 according to previous procedures (Schemes 1, 2).
enolate or the more substituted one.
Lithium enolates have been
In all cases, control experiments using their condensation with acetyl
chloride have shown that the structure of the initial silyl enol ethers was
retained.
intensively studied whereas only comparatively few papers concern
potassium enolates. This is due to a lack of convenient methods for
6,14
regioselective and stereoselective preparation of potassium enolates
2-4,10-13
in contrast to their lithium counterparts.
We have reported that
We studied the alkylation of these eight enolates with allylbromide and
benzylbromide in THF (-78°C, 1h for K enolates, -15°C, 15h for Li
regiocontrolled and stereocontrolled potassium enolates could be
prepared by treating corresponding silyl enol ethers with potassium tert-
butoxide; a metal exchange using five equivalents of lithium bromide
17
enolates) (Table 1, runs 1-16). The composition of the crude product
1
was determined by H NMR and the major alkylated ketones were
14
led to the corresponding lithium enolates (Scheme 1).
isolated. As shown in Table 1, lithium enolates 5 and 7 led

414
LETTERS
SYNLETT
15
predominantly to the expected monoalkylated ketones 8 and 9,
respectively. Surprisingly, starting from potassium enolates 4 and 6, the
2,2-disubstituted ketones 8 were obtained independently from structure
4 or 6 as the starting enolates (Scheme 2); the regioisomeric
disubstituted ketone 9 was detected as a very minor by-product, in
Lastly, the complementary results obtained from the aldolisation and
the alkylation of potassium enolates must be noted. The aldolisation
occurs on the less substituted site, the alkylation on the most substituted
one, whatever the starting potassium enolate (Scheme 4). Concerning
aldolisation all reactions are equilibrated and the result reflects the
relative stability of the potassium aldolates. The formation of alkylated
ketones 8 or 9 is obviously non reversible and the alkylation takes place
with the most nucleophilic tetrasubstituted enolate.
18
addition to the minor dialkylation product 10. The predominant
ketones 8 or 9 were purified by chromatography on silica gel and
isolated from the crude material without contamination with other
ketones (Scheme 2).
Scheme 4
In conclusion alkylation of unsymmetrical ketones via their potassium
enolates obtained from silyl enol ethers occurs at the more substituted
α-site whatever the regioisomeric structure of the starting silyl enol
ethers, due to the equilibration as the alkylation starts. The proposed
method is very convenient for preparative purposes. Only the alkylated
ketone 8 has been obtained starting from a mixture of silyl enol ethers 2
and 3.
Acknowledgment
We thank the Ministère de la Recherche et de la Technologie for a grant
(Y.Q.) and Rhône Poulenc Industrialisation for a financial support
(L.B.S).
Scheme 2
Methylation of potassium enolates 4a and 6a using methyliodide (THF,
-75°C, 2h) confirms the preceding results (Table 1, runs 17-19): the
composition of the crude product was the same, whatever the structure
of the starting silyl enol ethers 2a, 3a and 2,2-dimethylcyclopentanone
References and notes
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Transformation; V.C.H. Publishers: New-York, 1989, p 737-784.
19
was the main methylation product.
These results can be explained by the known propensity of potassium
7,15
enolates to equilibrate.
The equilibration 6 ↔ 4 occurs via the ketone
1 and can be initiated by a catalytic amount of a ketonic compound
(ketone 8 or 9). The alkylation reaction takes place on the most
20
(2) Stork, G.; Hudrlik, P.F. J. Am. Chem. Soc.; 1968, 90, 4462-4465.
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nucleophilic tetrasubstituted potassium enolate 4 (Scheme 2). With
lithium enolates, the tightness of the oxygen-metal bond is generally
2,21
sufficient to prevent proton transfer.
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Chem. Soc. 1982, 104, 6831-6833.
We used the above property to prepare in one pot, spiroketones 13 from
silyl enol ethers 12 by dialkylation of their potassium enolates with 1,4-
dibromobutane (Scheme 3). This one pot procedure afforded ketones 13
with a 78% yield which compares favorably with those reported in the
22
literature.
(6) Negishi, E.; Matsushita, H.; Chatterjee, S.; John, R.A. J. Org.
Chem. 1982, 47, 3188-3190. Negishi, E.; Luo, F.T. J. Org. Chem.
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(8) Noyori, R.; Nishida, I.; Sakata, J. J. Am. Chem. Soc. 1983, 105,
1598-1608.
Scheme 3
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Bates, R.B.; Taylor, S.R. J. Org. Chem. 1993, 58, 4469-4470.
Cahiez G.; Figadère, B.;. Cléry P Tetrahedron Lett. 1994, 35,
3065-3068. Cahiez, G.; Chau, K.; Cléry, P. Tetrahedron Lett.
1994, 35, 3069-3072.
In connection with these results, the regioselective alkylation at the
more hindered α−site of the unsymmetrical ketones has been recently
reported using another methodology : alkylation of the tetrasubstituted
lithium enolates generated by the combined use of aluminium tris(2,6-
(10) Saito, S.; Ito, M.; Yamamoto H. J. Am. Chem. Soc. 1997, 119,
10
diphenylphenoxide) and LDA.
611-612.

April 1998
SYNLETT
415
13
(11) Stork, G.; Rosen, P.; Goldman, N.L. J. Am. Chem. Soc. 1961, 83,
2965-2966. Weiss, M.J.; Schaub, R.E; Poletto, J.F.; Jr Allen,
G.R.; Coscia, C.J. Chemistry and Industry 1963, 118-119.
C NMR : 23.1, 25.7, 36.1, 39.7, 40.2, 56.9, 213.2.
1
Spiro[4,5]decane 13b : H NMR : 1.2-1.65 (8H, m); 1.73 (4H,
dd, J=6.1 and 13.0); 2.31 (4H, t, J=6.1).
13
C NMR : 22.7; 25.1; 27.2; 35.3 ; 39.3; 39.8; 56.7; 214.4.
(12) House, H.O.; Trost, B.M. J. Org. Chem. 1965, 30, 1341-1348 and
MS (m/z) : 152, 111, 95, 81, 67, 55.
2502-2509.
(18)
(13) Stork, G.; Uyeo, S.; Wakamatsu T.; Grieco, P.; Labovitz, J. J. Am.
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S.H.; Hulce, M. Synlett 1992, 485-488.
(14) Duhamel, P.; Cahard, D.; Poirier, J.M. J. Chem. Soc. Perkin
Trans. I 1993, 21, 2509-2511.
(19) 2,2-Dimethylcyclopentanone was difficult to isolate from the
crude product by silica gel chromatography or distillation. For
other entries to 2,2-dimethylcyclopentanone from alkali enolates
(15) Duhamel, P.; Cahard, D.; Quesnel, Y.; Poirier, J.M. J. Org. Chem.
1996, 61, 2232-2235.
12
of 1a see and Bouveault, L.; Locquin, R. Bull. Soc. Chim. Fr.
(16) Cazeau, P.; Moulines, F.; Laporte, O.; Duboudin, F. J.
Organomet. Chem. 1980, 201, C9-C13. Cazeau, P; Duboudin, F.;
Moulines, F.; Babot O.; Dunoguès J.Tetrahedron 1987, 43, 2075-
2088.House, H.O. Rec. Chem. Prog. 1967, 28, 98-120. House,
H.O.; Czuba, L.J.; Gall, M.; Olmstead, H.D. J. Org. Chem. 1969,
34, 2324-2336.
1908, 3, 437-441. Haller, A.; Cornubert, R. Bull. Soc. Chim. Fr.
1926, 39, 1724-1732. In all these references, the polyalkylation
was also reported.
(20) The reaction of 2-methylcyclohexanone potassium enolates
prepared from ketone 1b (tBuOK (1 eq.), THF, -20°C, 1h) with
benzyl bromide (THF, -78°C, 1h) yielded ketone 8b (R = benzyl)
with a 38% chromatographed yield. The regioisomeric ketone 9b
(R = benzyl) was not detected. A large amount of unreacted
ketone 1a was detected by GC in the crude material.
(17) Prior to use, tetrahydrofuran (THF) was distilled from sodium
benzophenone ketyl and stored under argon. Potassium tert-
butoxide was purchased from Aldrich and sublimed prior to use.
Lithium bromide was dried by heating under reduced pressure.
General procedure for alkylation of potassium enolates 4 and
6. To a solution of silyl enol ether 2 or 3 (5 mmol) in THF (10 mL)
under argon was added at -15°C a solution of potassium tert-
butoxide (5 mmol) in THF (5mL) and then stirred for 45 min.
After cooling to -78°C, alkyl halide (5mmol) in THF (5mL) was
added and stirred for 1 hour at this temperature. The mixture was
quenched with water (10mL) at -78°C and extracted with diethyl
5
(21) With onium (TBA, TAS) enolates obtained from silyl enol
ethers, the alkylation is reported to maintain the structure of the
starting silyl enol ether due to the enhanced nucleophilicity of
8
these naked enolates, compared with lithium enolates. The
alkylation conditions are also to be noted : the onium enolates are
not preformed but obtained in the presence of the alkylating
reagent, thus trapped as soon as they are formed, preventing
proton transfer and their equilibration before alkylation.
ether. The extract was dried over anhydrous MgSO and
4
(22) Cram, D.J.; Steinberg, H. J. Am. Chem. Soc. 1954, 76, 2753-2757.
Krieger, H.; Ruotsalainen, H.; Montin, J. Chem. Ber. 1966, 99,
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Comm. 1981, 30-32. Piers, E.; Lau, C.K.; Nagakura, I. Can. J.
Chem. 1983, 61, 288-297. Fitjer, L.; Schlotmann, W.;
Noltemeyer, M. Tetrahedron Lett. 1995, 36, 4985-4988.
concentrated in vacuo. The ratio of regioisomers was determined
by H NMR analysis of the crude mixture (Bruker A. C.
Spectrometer 200 MHz in chloroform-d). The alkylated ketones 8
were isolated by flash chromatography on silica gel (petroleum
ether:ether = 98:2) (see table 1).
General procedure for alkylation of lithium enolates 5 and 7.
To a solution of silyl enol ether (5 mmol) in THF (10 mL) under
argon was added at -15°C a solution of potassium tert-butoxide (5
mmol) in THF (5mL) and then stirred for 45 min. 5 equiv. of LiBr
(0.217 g) was added at this temperature and stirring was continued
for 20 min. Then alkyl halide (5mmol) in THF (5mL) was added
and stirred for 15h at this temperature. The mixture was quenched
with water (10mL) at -78°C and extracted with diethyl ether. The
1
(23) Coates, R. M.; Sowerby, R.L. J. Am. Chem. Soc. 1971, 93, 1027-
1029.
(24) Medarde, M.; Lòpez, J.L.; Morillo, M.A.; Tomé, F.; Adeva, M.;
Feliciano, A.S. Tetrahedron Lett. 1995, 44, 8097-8098.
(25) Jacks, T.E.; Nibbe, H.; Wiemer, D.F. J. Org. Chem. 1993, 58,
4584-4588.
extract was dried over anhydrous MgSO and concentrated in
(26) Cornubert, R.; Borrel, C.H.R. Bull. Soc. Chim. Fr. 1930, 47, 958-
4
vacuo. Ketones were isolated by flash chromatography on silica
gel (petroleum ether:ether = 98:2). Ketones 9 (R=allyl, benzyl)
were eluted after corresponding ketones 8. Cis and trans isomers
of 9 were separated, the cis isomers were first eluted. Ketones 8
966.
(27) House, H.O.; Manning, D.T.; Melillo, D.G.; Lee, L.F.; Haynes,
O.R.; Wilkes, B.E. J. Org. Chem. 1976, 41, 855-863.
1
13
(28) Tsuda, T.: Okada, M.; Nishi, S.; Saegusa, T. J. Org. Chem. 1986,
51, 421-426.
and 9 were characterized by their H and C NMR spectra. They
23
27
24
28
25
were known: R = allyl: 8a, 8b, 9a, 9b. R = benzyl: 8a,
29
26
29
8b, 9a, 9b.
(29) Noyori, R.; Nishida, I.; Sakata, J. Tetrahedron Lett. 1980, 21,
2085-2088. House, H.O.; Gall, M.; Olmstead, H.D. J. Org. Chem.
1971, 36, 2361-2371.
1
Spiro[4,5]nonane 13a : H NMR : 1.2-1.65 (6H, m); 1.82 (4H,
dd, J=5.9 and 12.5); 2.42 (4H, t, J=5.9).