Dibutyltin dimethoxide-catalyzed aldol reaction of enol trichloroacetates

Article abstract of DOI:10.1016/S0040-4039(03)01840-9

A catalytic aldol condensation of aldehydes with enol trichloroacetates was achieved using dibutyltin dimethoxide as a novel catalyst in a mixed solvent consisting of THF and MeOH. Various β-hydroxy ketones were diastereoselectively obtained in high yields up to 99%.

Full text of DOI:10.1016/S0040-4039(03)01840-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7163–7166
Dibutyltin dimethoxide-catalyzed aldol reaction of enol
trichloroacetates
Akira Yanagisawa* and Takayuki Sekiguchi
Department of Chemistry, Faculty of Science, Chiba University, Inage, Chiba 263-8522, Japan
Received 15 May 2003; revised 10 July 2003; accepted 25 July 2003
Abstract—A catalytic aldol condensation of aldehydes with enol trichloroacetates was achieved using dibutyltin dimethoxide as
a novel catalyst in a mixed solvent consisting of THF and MeOH. Various b-hydroxy ketones were diastereoselectively obtained
in high yields up to 99%.
© 2003 Elsevier Ltd. All rights reserved.
Aldol reaction is a beneficial method to prepare b-
hydroxy carbonyl compounds, which can be further
transformed into useful organic molecules.1 In addition,
the functionality is often seen in natural products and
that is a reason why the reaction has so far been
frequently applied to organic synthesis. We report here
a novel example of catalytic aldol reaction of enol
trichloroacetates catalyzed by dibutyltin dimethoxide,
Bu2Sn(OMe)2 (Scheme 1).
reactive metal methoxide. First, we examined catalytic
ability of several methoxysilanes and methoxystannanes
(VI) in the reaction of 1-trichloroacetoxy cyclohexene5
with benzaldehyde in the presence of 1 equiv. of
MeOH, and found that Bu2Sn(OMe)2 gave the desired
aldol adduct in the highest yield, whereas employment
of less toxic methoxysilanes led to totally unsatisfactory
results. Yields of the product obtained by the reaction
employing 10 mol% of the catalyst in THF at room
temperature: for Me2Si(OMe)2 (25 h), <1%; for
MeSi(OMe)3 (109 h), <1%; for Si(OMe)4 (117 h), 7%;
for Bu3SnOMe (2 h), 28%; for Bu2Sn(OMe)2 (2 h), 56%.
Trialkyltin(IV) enolates are known to have good nucle-
ophilicity towards aldehydes;2 however, their use in
aldol reaction is rather limited due to their toxicity.3 To
solve this problem, we have developed a new aldol
reaction of an enol ester catalyzed by tributyltin
methoxide, which is recycled by the addition of
methanol.4 Although the reaction is environmentally
benigner because the amount of organotin compound is
reduced to a catalytic amount, this process has the
disadvantage that aliphatic aldehydes show almost no
reactivity. Thus, we planned to develop an alternative
catalytic aldol reaction of enol esters employing more
Then, the catalyst was fixed for the tin dimethoxide and
some enol esters of cyclohexanone were screened under
similar reaction conditions. As a result, the enol
trichloroacetate was found to be the enol ester of
choice.6 The reaction of 1-acetoxy cyclohexene was
sluggish at room temperature and the corresponding
enol triflate and enol diphenylphosphate showed almost
no reactivity even at 80°C. In contrast, the targeted
product was obtained in moderate yield from enol
trifluoroacetate of cyclohexanone but this latent enolate
was sensitive to hydrolysis.
We then optimized the reaction conditions and found
that an increase in MeOH improved the chemical yield
(entries 1–4, Table 1). Since it was desired to decrease
the amount of environmentally less benign organotin
compounds from a practical viewpoint, we attempted
the reaction using less than 0.1 equiv. of Bu2Sn(OMe)2
and found that 75% yield of the product was obtained
under the influence of 0.05 equiv. of the catalyst (entry
5). However, use of 2 mol% of the catalyst resulted in
unsatisfactory results (53–36% yield, entries 6–8). Fur-
Scheme 1.
Keywords: catalytic aldol reaction; dibutyltin dimethoxide; enol
trichloroacetates; aldehydes; b-hydroxy ketones.
* Corresponding author. Fax: +81-(0)43-290-2789; e-mail: ayanagi@
scichem.s.chiba-u.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01840-9

7164
A. Yanagisawa, T. Sekiguchi / Tetrahedron Letters 44 (2003) 7163–7166
Table 1. Optimization of aldol reaction of 1-trichloroacetoxy cyclohexene with benzaldehyde catalyzed by dibutyltin
dimethoxidea
Entry
a (equiv.)
b (equiv.)
c (equiv.)
d (h)
Yield (%)b,c
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
2
2
2
2
0.1
0.1
0.1
0.1
0.05
0.02
0.02
0.02
0.02
0.02e
0.01
0.01
1
2
3
5
3
3
5
5
5
2
2
2
2
2
2
2
4
4
4
4
4
49
63
75
72
75
36
42
53d
91
<1
63f
71g
9
10
11
12
5
5
10
a Unless otherwise noted, the reaction was carried out using dibutyltin dimethoxide (0.01–0.1 equiv.), 1-trichloroacetoxy cyclohexene (1 or 2
equiv.), and benzaldehyde (1 equiv.) in dry THF containing MeOH (1–10 equiv.) at room temperature for 2 or 4 h.
b Isolated yield.
c The syn/anti ratios of the product were 75/25–67/33.
d A dehydrated product was obtained in 4% yield.
e Bu3SnOMe was used as catalyst instead of Bu2Sn(OMe)2.
f A dehydrated product was obtained in 12% yield.
g A dehydrated product was obtained in 7% yield.
ther improvement in the yield was achieved when 2
equiv. of the enol trichloroacetate was introduced and
the highest yield (91%) was attained by the reaction for
4 h without formation of any dehydrated products
(entry 9). It is noteworthy that the reaction still pro-
ceeds smoothly even in the presence of 1 mol% of
Bu2Sn(OMe)2 (entries 11 and 12). Reactivity of the tin
dimethoxide is remarkable compared to that shown by
Bu3SnOMe (entries 9 vs 10).
Optimal reaction conditions were thus established using
2 mol% of the tin catalyst, 2 equiv. of the enol ester,
and 5 equiv. of MeOH, and we next carried out the
catalytic aldol reaction with various aldehydes under
these conditions. The results are summarized in Table
2.7 From aromatic aldehydes, the corresponding aldol
adducts were obtained in almost quantitative yield with
syn-diastereoselectivity (entries 1–3). In the reaction
with (E)-cinnamaldehyde, an a,b-unsaturated aldehyde,
Table 2. Bu2Sn(OMe)2-catalyzed aldol reaction of 1-trichloroacetoxy cyclohexene with various aldehydesa
Entry
RCHO
Yield (%)b
syn/antic
1
2
3
PhCHO
91
98
98
93
78
85
<1
73/27
64/36
75/25
66/34
35/65
11/85
–
4-MeOC6H4CHO
4-BrC6H4CHO
(E)-PhCHꢀCHCHO
Ph(CH2)2CHO
c-C6H11CHO
4
5d
6
7e
a Unless otherwise noted, the reaction was carried out using dibutyltin dimethoxide (0.02 equiv.), 1-trichloroacetoxy cyclohexene (2 equiv.), and
aldehyde (1 equiv.) in dry THF containing MeOH (5 equiv.) at room temperature for 4 h.
b Isolated yield.
c Determined by 1H NMR analysis.
d 10 equiv. of MeOH was used.
e Bu3SnOMe was used as catalyst instead of Bu2Sn(OMe)2.

A. Yanagisawa, T. Sekiguchi / Tetrahedron Letters 44 (2003) 7163–7166
7165
Table 3. Bu2Sn(OMe)2-catalyzed aldol reaction of various enol trichloroacetates with benzaldehydea
Entry
R1
R2
a (equiv.)
b (equiv.)
c (h)
Yield (%)b
syn/antic
1
2
3
4
5
-(CH2)3-
-(CH2)5-
0.02
0.02
0.05
0.1
5
10
20
5
1
4
12
8
>99
>99
85
80
77
58/42
78/22
86/14
Et
Ph
Ph
Med
H
Mee
0.05
20
24
91/9
a Unless otherwise noted, the reaction was carried out using dibutyltin dimethoxide (0.02–0.1 equiv.), enol trichloroacetate (2 equiv.), and
benzaldehyde (1 equiv.) in dry THF containing MeOH (5–20 equiv.) at room temperature for 1–24 h.
b Isolated yield.
c Determined by 1H NMR analysis.
d The E/Z ratio was 13/87.
e The E/Z ratio was 91/9.
a 1,2-adduct was formed exclusively (entry 4). Aliphatic
aldehydes also showed high reactivity with the opposite
anti-selectivity (entries 5 and 6), though employment of
Bu3SnOMe resulted in almost no yield (entry 7).
the aldehyde to provide the tin alkoxide of aldol adduct
3. Finally, protonation of 3 with MeOH completes the
catalytic cycle yielding 4 and regenerating the tin
dimethoxide. From the aforementioned results, MeOH
is considered to react with the alkoxide 3 more rapidly
than with the in situ generated tin enolate 2.
The utility of the present Bu2Sn(OMe)2-catalyzed aldol
reaction was further demonstrated by employing enol
trichloroacetates derived from different types of ketones
(Table 3). Not only cyclic substrates, but acyclic ketone
derivatives also reacted syn-selectively with benzalde-
hyde in high yields. Acyclic enol trichloroacetates indi-
cated higher syn-selectivity than that given by cyclic
ones irrespective of the double-bond geometry (entries 3
and 5). In the case of acyclic substrates, increased
amounts of the catalyst and/or MeOH and longer
reaction time were necessary in order to acquire satis-
factory yields (entries 3–5).
In summary, we have demonstrated a novel example of
aldol reaction of enol trichloroacetates catalyzed by
dibutyltin dimethoxide. The catalytic activity of
Bu2Sn(OMe)2 is much higher than that of previously
reported Bu3SnOMe.4 The procedure can be performed
without any difficulty employing readily available
chemicals and can provide a variety of b-hydroxy
ketones not only from aromatic and a,b-unsaturated
aldehydes but also from aliphatic aldehydes mainly
with syn-selectivity in high yields up to 99%. The
present method is environmentally friendlier since the
amount of the toxic organotin catalyst is decreased to
up to 2 mol%. Further work is now in progress on the
catalytic reaction.
Figure 1 provides a plausible catalytic mechanism of
the reaction of an enol trichloroacetate 1 with an
aldehyde. Initially, the enol ester
1 reacts with
Bu2Sn(OMe)2, forming the tin enolate 2 and methyl
trichloroacetate. The enolate 2 is then able to add to
Acknowledgements
We gratefully acknowledge financial support from the
Mitsubishi Foundation and the Sumitomo Foundation.
References
1. For reviews, see: (a) Heathcock, C. H. In Comprehensive
Organic Synthesis; Trost, B. M.; Fleming, I.; Heathcock,
C. H., Eds.; Pergamon: Oxford, 1991; Vol. 2, p. 133 and
related chapters; (b) Braun, M. In Houben-Weyl: Methods
of Organic Chemistry; Helmchen, G.; Hoffmann, R. W.;
Mulzer, J.; Schaumann, E., Eds.; Georg Thieme Verlag:
Stuttgart, 1995; Vol. E 21, p. 1603.
Figure 1. A plausible catalytic mechanism for the aldol reac-
tion catalyzed by Bu2Sn(OMe)2.

7166
A. Yanagisawa, T. Sekiguchi / Tetrahedron Letters 44 (2003) 7163–7166
2. (a) Noltes, J. G.; Creemers, H. M. J. C.; van der Kerk, G.
J. M. J. Organomet. Chem. 1968, 11, P21; (b) Shenvi, S.;
Stille, J. K. Tetrahedron Lett. 1982, 23, 627; (c) Labadie, S.
S.; Stille, J. K. Tetrahedron 1984, 40, 2329; (d) Kobayashi,
K.; Kawanisi, M.; Hitomi, T.; Kozima, S. Chem. Lett.
1983, 851.
3. For reviews, see: (a) Pereyre, M.; Quintard, J.-P.; Rahm,
A. Tin in Organic Synthesis; Butterworths: London, 1987;
p. 286; (b) Davies, A. G. Organotin Chemistry; VCH:
Weinheim, 1997; p. 185.
4. (a) Yanagisawa, A.; Matsumoto, Y.; Asakawa, K.;
Yamamoto, H. J. Am. Chem. Soc. 1999, 121, 892; (b)
Yanagisawa, A.; Matsumoto, Y.; Asakawa, K.;
Yamamoto, H. Tetrahedron 2002, 58, 8331.
5. Libman, J.; Sprecher, M.; Mazur, Y. Tetrahedron 1969, 25,
1679.
cyclohexene (487 mg, 2.00 mmol) and benzaldehyde (0.102
mL, 1.00 mmol) were dissolved in dry THF (5 mL) under
argon atmosphere and then a solution of dibutyltin
dimethoxide (5.9 mg, 0.020 mmol) in dry THF (1 mL) was
added to the resulting solution at room temperature. To
the mixture was added dropwise MeOH (0.203 mL, 5.00
mmol). After being stirred for 4 h at this temperature, the
mixture was treated with MeOH (2 mL), brine (2 mL), and
solid KF (ca. 1 g) at ambient temperature for 30 min. The
resulting precipitate was filtered off and the filtrate was
dried over Na2SO4 and concentrated in vacuo after filtra-
tion. The residual crude product was purified by column
chromatography on silica gel to give a mixture of the aldol
adducts (185 mg, 91% yield) as white solids. The syn/anti
ratio was determined to be 73/27 by 1H NMR analysis.
1
Spectral data (TLC, IR, H NMR, and 13C NMR) of the
syn and anti isomers indicated good agreement with
6. Yields of the product obtained by the reaction using
various enol esters of cyclohexanone: for enol acetate (rt, 8
h), 3%; for enol trichloroacetate (rt, 2 h), 49%; for enol
trifluoroacetate (rt, 1 h), 42%; for enol triflate (80°C, 6 h),
<1%; for enol diphenylphosphate (80°C, 6 h), 5%.
7. Typical procedure for aldol reaction of aldehydes with enol
trichloroacetates catalyzed by dibutyltin dimethoxide: Syn-
thesis of 2-(hydroxyphenylmethyl)cyclohexanone (entry 9
in Table 1 and entry 1 in Table 2). 1-Trichloroacetoxy
reported data.8
8. (a) Juaristi, E.; Beck, A. K.; Hansen, J.; Matt, T.; Mukho-
padhyay, T.; Simson, M.; Seebach, D. Synthesis 1993,
1271; (b) Denmark, S. E.; Winter, S. B. D.; Su, X.; Wong,
K.-T. J. Am. Chem. Soc. 1996, 118, 7404; (c) Denmark, S.
E.; Wong, K.-T.; Stavenger, R. A. J. Am. Chem. Soc.
1997, 119, 2333; (d) Denmark, S. E.; Stavenger, R. A.;
Wong, K.-T.; Su, X. J. Am. Chem. Soc. 1999, 121, 4982.