2180
J . Org. Chem. 1999, 64, 2180-2181
Sch em e 1. Ad d ition of Keton e En ola te to
Th e F ir st Mich a el Ad d ition of Meta l Keton e
En ola tes to r,â-Un sa tu r a ted Ester s u n d er
Ca ta lytic Con d ition s: Tin En ola te w ith a
Ca ta lytic Am ou n t of Tetr a bu tyla m m on iu m
Br om id e
r,â-Un sa tu r a ted Ester a
Makoto Yasuda, Noriyuki Ohigashi, Ikuya Shibata, and
Akio Baba*
Department of Applied Chemistry, Faculty of Engineering,
Osaka University, 2-1 Yamadaoka,
Suita, Osaka 565-0871, J apan
a
Metal enolate 1 (3.0 equiv), methyl acrylate 2a (1.0 equiv). b-78
Received J anuary 13, 1999
°C, 48 h. -78 °C, 15 min. dLess than 10% yield under any conditions
c
e
of (-78 °C, 15 min), (-78 °C, 2 h), (25 °C, 6 h), or (40 °C, 12 h). Less
The Michael addition is an important reaction in organic
syntheses,1 in which, classically, enolate anions derived from
active methylene or methine compounds are used as nu-
cleophiles under basic conditions. In modern synthetic
methodology, the metal enolates have been elegantly utilized
under nearly neutral conditions.2,3 However, the Michael
addition of metal ketone enolates to R,â-unsaturated esters
without equimolar additives has not been reported, although
ester enolates are readily used for Michael donors toward
R,â-unsaturated esters under catalytic or thermal condi-
tions.4,5 We, therefore, tested the reaction of methyl acrylate
2a with metal enolates 1 (M ) Li, Si, or Sn), and the results
are shown in eq 1 (Scheme 1).
The lithium enolate is considered to be a typical metal
enolate, and no formation of the desired Michael adduct 3a
was detected at all. This result can be explained by the
thermodynamics of this reaction course. The initial product
before protonolysis is 4, which includes the metal ester
enolate moiety. A metal ester enolate is generally more labile
than a metal ketone enolate if the two metals are the same.
Thus, a reaction of the type as shown in eq 1 would be
thermodynamically disfavored in using any metals.6,7 When
silyl enolate was used, TiCl4 was effectively utilized as an
equimolar accelerator (Mukaiyama-type Michael addition).8
The new Ti-O bond formation contributes to the stabiliza-
tion of the product system.9 However, the catalytic use of
TiCl4 resulted in low yield. The catalytic fluoride anion (Bu4-
NF or CsF), which coordinates to the silicon center, also gave
poor yields, although the equimolar addition accelerates the
than 20% yield under any conditions of (-78 °C, 15 min), (0 °C, 0.5 h),
(25 °C, 6 h), or (63 °C, 6 h). 63 °C, 6 h. g63 °C, 12 h.
f
reaction.10 To design a catalytic or thermal system in the
reaction of ketone enolates with R,â-unsaturated esters, a
number of groups have developed various indirect ap-
proaches using ortho esters,11 thioesters,12 a cationic spe-
cies13 or trifluoromethyl-substituted enoates14 as unsatur-
ated ester equivalents and â-lithiated enamines15 as ketone
enolate equivalents in place of the direct use of ketone
enolates and R,â-unsaturated esters. Of course, a tin enolate
also gave no products when no additive was used. Unexpect-
edly, we found that the tin enolate provided the Michael
adduct 3a quantitatively under the conditions in the pres-
ence of a catalytic amount of Bu4NBr. In this paper, we
report the first example of this type of reaction, which is
performed using tin enolate with a catalyst under neutral
conditions, and provide the rationale of this unexpected
reaction course.
In view of the interest in the generality of this method,
we explored several sets of representative enolates and
unsaturated carbonyls as summarized in Table 1. In almost
all cases, the effective formation of δ-dicarbonyl compounds
3 was observed. 2-Thienyl-substituted enolate 1b gave the
keto ester 3b in 91% yield. The enolates substituted at the
reaction site showed similar reactivities (entries 3 and 4).
The reaction of cyclic enolate 1c proceeded even at 25 °C
because of its high reactivity while the tin enolate 1e
afforded a low yield.16,17 This reaction system was also
applied to R,â-unsaturated amide 2c. The reaction with
unsaturated ketones 2d and 2e afforded 1,4-adducts 3g and
3h exclusively in high yields without 1,2-adducts.3,18
It is indicated that the reaction of tin enolates would be
thermodynamically favored, since this system is carried out
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(5) We should note the difference in the reactivities between ketone
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tion.
(6) Hashimoto, Y.; Machida, S.; Saigo, K.; Inoue, J .; Hasegawa, M. Chem.
Lett. 1989, 943-946.
(7) The subsequent step such as cyclization after Michael addition
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Tetrahedron Lett. 1973, 3333-3336.
(8) (a) Narasaka, K.; Soai, K.; Mukaiyama, T. Chem. Lett. 1974, 1223-
1224. (b) Narasaka, K.; Soai, K.; Aikawa, Y.; Mukaiyama, T. Bull. Chem.
Soc., J pn. 1976, 49, 779-783.
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(11) Kobayashi, S.; Mukaiyama, T. Chem. Lett. 1987, 1183-1186.
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94.
(13) Hashimoto, Y.; Mukaiyama, T. Chem. Lett. 1986, 755-758.
(14) The interaction between Li and F contributes to the stabilization of
the product system. (a) Yamazaki, T.; Haga, J .; Kitazume, T.; Nakamura,
S. Chem. Lett. 1991, 2175-2178. (b) Yamazaki, T.; Hiraoka, S.; Kitazume,
T. J . Org. Chem. 1994, 59, 5100-5103.
(15) (a) Duhamel, L.; Duhamel, P.; Enders, D.; Karl, W.; Leger, F.; Poirier,
J . M.; Raabe, G. Synthesis 1991, 649-654. (b) Enders, D.; Karl, W.
SYNLETT 1992, 895-897 and references therein.
(16) Organotin enolates exist as equilibrium mixtures of keto- and/or enol
forms; 1e and 1c exclusively exist in keto and enol forms, respectively:
Pereyre, M.; Bellegarde, B.; Mendelsohn, J .; Valade, J . J . Organomet. Chem.
1968, 11, 97-110.
(17) Enol forms generally show higher reactivity than keto forms:
Kobayashi, K.; Kawanisi, M.; Hitomi, T.; Kozima, S. Chem. Lett. 1983, 851-
854. The low yield in the reaction of keto form enolate was probably caused
by thermodynamic factors.
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1982, 23, 3267-3270.
10.1021/jo990062b CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/13/1999