J . Org. Chem. 2000, 65, 5823-5830
5823
Th eor etica l Stu d y of In tr a m olecu la r Ald ol Con d en sa tion of
1,6-Dik eton es: Tr im eth ylsilyl Su bstitu en t Effect
J ean-Philippe Bouillon, Charles Portella, J ames Bouquant, and Ste´phane Humbel*
UMR 6519, Universite´ de Reims Champagne-Ardenne/ CNRS, UFR Sciences BP 1039,
F-51687 REIMS Cedex 2, France
stephane.humbel@univ-reims.fr
Received J une 15, 2000
Diastereoselective intramolecular aldol condensations are investigated in an experimental and
computational study of 1,6-diketones. Ab initio results show the importance of the acid medium
and disapprove the possibility of a spontaneous cyclization, even for silylated compounds. The
combination of both experimental and computational approaches brings valuable information on
the mechanism and on the selectivity of the aldol reaction. It is found that the enolization of the
diketone is a key step in acid-catalyzed mechanism. The cyclization step bears a very small activation
energy. The dehydration of the aldols are discussed.
In tr od u ction
new functionalized organosilicon compounds. In view of
sensitivity of bis(acylsilane) to basic conditions,6 the aldol
reaction was mainly investigated under neutral or acidic
activation. Thus, the enol form 2 (Scheme 1) is the
reactive nucleophile. It can cyclize directly with the
second carbonyl function via a proton transfer from the
hydroxyl to the carbonyl group (Scheme 1, uncatalyzed
mechanism). A protonated carbonyl tautomer p 2 would
also produce first the intermediate p 4 then the aldols
4a or 4b after a deprotonation step (Scheme 1, acid-
catalyzed mechanism). As shown in Scheme 1, two
diastereomers 4a and 4b can in principle be formed. For
each mechanism two different paths, named path a
(leading to 4a ) and path b (leading to 4b) can occur.
As previously reported,7 the aliphatic bis(acylsilane)
1 (R ) TMS) underwent spontaneous yet very slow
cyclization to the aldol 4a (R ) TMS) (45% after storage
for six months in a refrigerator). Moreover, addition of a
catalytic amount (10%) of p-toluenesulfonic acid (PTSA)
to bis(acylsilane) 1 (R ) TMS) and distillation in a
kugelrohr apparatus gave a mixture of the aldol 4a (R )
TMS) (46%), the condensation product 5 (R ) TMS)
(16%), and the starting material (7%) (Scheme 2, Table
1). We obtained only the diastereomer 4a (R ) TMS). To
study the effect of a trimethylsilyl group on the aldol
reaction, we synthesized two other 1,6-diketones 1 with
An aldol reaction is the reaction of one carbonyl
compound, acting as a nucleophile in the form of its enol
or enolate derivative, with another one, acting as an
electrophile. The primary product is a â-hydroxycarbonyl
compound. Under some conditions, this initial product
undergoes dehydration, resulting in an R,â-unsaturated
carbonyl compound.1,2 The general reaction is subject to
either base or acid catalysis. The addition reaction of
enolate (basic conditions) with carbonyl compounds is of
very broad scope and great synthetic importance.3 It is
also possible to carry out the aldol condensation under
acidic conditions,4 but there is little study of its stereo-
chemistry in these conditions. The two carbonyl com-
pounds may or not be the same. Moreover, the carbonyl
moieties may be included in the same compound as it is
the case for dialdehydes, keto aldehydes, or diketones.
Intramolecular aldol reactions of 1,6-dialdehydes and
-diketones have been described in many reports,2 most
of these being base-promoted and leading directly to
cyclopentenones.5 In this paper, we are interested mostly
in 1,6-dicarbonyl compounds that are nonenolizable at
the external R- and R′-carbon atoms (except for the octa-
2,7-dione).
Ald ol Cycliza tion . The first intramolecular aldol
condensations were performed with bis(acylsilanes) to
examine various potential synthetic applications of these
t
methyl (R ) Me) and tert-butyl groups (R ) Bu). The
octa-2,7-dione was prepared by reaction of the corre-
sponding carboxylic acid dichloride with lithium dimeth-
ylcuprate(I) according to literature.8 The tert-butyl ana-
logue was obtained by condensation of tert-butyllithium
with diethyl adipate.9
* To whom correspondence should be addressed. Tel: 33 (0)3 26 91
33 59. Fax: 33 (0)3 26 91 31 66.
(1) Nielsen, A. T.; Houlihan, W. J . Org. React. (N.Y.) 1968, 16, 1.
(2) Heathcock, C. H. Comprehensive Organic Synthesis; Trost, B.
M., Ed.; Pergamon Press: New York, 1991; p 133.
(3) Carey, F. A.; Sundberg, R. J . Advanced Organic Chemistry, 3rd
ed.; Plenum Press: New York and London, 1990, Part B, Chapter 2, p
55.
(4) (a) Baigrie, L. M.; Cox, R. A.; Slebocka-Tilk, H.; Tencer, M.;
Tidwell, T. T. J . Am. Chem. Soc. 1985, 107, 3640. (b) Noyce, D. S.;
Snyder, L. R. J . Am. Chem. Soc. 1959, 81, 620.
Methyl and tert-butyl derivatives were thermolyzed by
the same procedure using 10% of PTSA. However, the
conversion was very low (39% for the methyl substituted
case and 6% for the tert-butyl analogue, Table 1: entries
2, 4). No aldol product was detected in the crude mixture;
(5) (a) Brown, J . B.; Henbest, H. B.; J ones, E. R. H. J . Chem. Soc.
1950, 3634. (b) Harayama, T.; Takatani, M.; Yamanaka, A.; Ikeda, H.;
Ohno, M.; Inubushi, Y. Chem. Pharm. Bull. 1981, 29, 766. (c) Nakane,
M.; Hutchinson, C. R. J . Org. Chem. 1980, 45, 4233. (d) Murai, A.;
Tanimoto, N.; Sakamoto, N.; Masamune, T. J . Am. Chem. Soc. 1988,
110, 1985. (e) Meyer, W. L.; Wolfe, J . F. J . Org. Chem. 1962, 27, 3263.
(f) Aunmiller, J . C.; Whittle, J . A. J . Org. Chem. 1976, 41, 2955.
(6) Brook, A. G. Acc. Chem. Res. 1974, 7, 77.
(7) Bouillon, J . P.; Portella, C. Eur. J . Org. Chem. 1999, 1571.
(8) Posner, G. H.; Whitten, C. E.; McFarland, P. E. J . Am. Chem.
Soc. 1972, 94, 5106.
(9) Petrov, A.; Sokolowa, E.; Lan, G.-C. Bull. Soc. Chim. Fr. 1958,
178.
10.1021/jo005544y CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/11/2000