Water-accelerated aldol reaction of ketene silyl acetals with carbonyl compounds

Article abstract of DOI:10.1016/S0040-4020(00)00630-X

The aldol reactions of ketene silyl acetals with reactive aldehydes proceed smoothly in water to afford the corresponding aldol products in good yields. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00630-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 7309–7312
Water-Accelerated Aldol Reaction of Ketene Silyl Acetals with
Carbonyl Compounds
*
Teck-Peng Loh, Li-Chun Feng and Lin-Li Wei
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
Received 26 May 2000; revised 20 June 2000; accepted 6 July 2000
Abstract—The aldol reactions of ketene silyl acetals with reactive aldehydes proceed smoothly in water to afford the corresponding aldol
products in good yields. ᭧ 2000 Elsevier Science Ltd. All rights reserved.
Introduction
product quantitatively after 6 h (Fig. 1). The absence of
resonances corresponding to ketene silyl acetal 1 is due to
its insolubility in water. This unexpected result prompted us
to further investigate the aldol reaction of ketene silyl acetal
1 with various aldehydes in pure water at ambient tempera-
ture in the absence of Lewis acid catalysis or any special
activation (Eq. (2)). The results are shown in Table 1.
Aldol reactions in water at ambient temperature in the
absence of Lewis acid catalysis or any special activation
pose a great challenge for organic chemists.1–6 The first
aldol reaction in water using carbonyl compounds and
silyl enol ethers without Lewis acid catalysis has been
elegantly demonstrated to be feasible by Lubineau.5 Unfor-
tunately, the aldol reaction in pure water without special
activation afforded the product in low yield.6 In this paper,
we demonstrate that various reactive aldehydes can react
with ketene silyl acetals in water at ambient temperature
without Lewis acid catalysis or special activation to afford
the corresponding aldol product in moderate to good yields.
ꢀ1†
ꢀ2†
Results and Discussion
Recent studies from our group have shown that Mannich-
type reactions of imines and silyl enol ethers or ketene silyl
acetals in water proceed smoothly to afford the correspond-
ing b-amino carbonyl compounds in the presence of indium
trichloride, a well-established water-stable Lewis acid
(Eq. (1)).7 These successful results encouraged us to investi-
gate the role of indium trichloride by monitoring the
reaction using NMR. Furthermore, to investigate the rela-
tive reactivity of imine versus aldehyde in water, we carried
out the Mannich reaction of 2-pyridine carboxaldehyde and
aniline with ketene silyl acetal 1 in D2O. It was found that
ketene silyl acetal 1 selectively reacts with imine in the
presence of indium trichloride to afford the b-amino car-
bonyl compounds in good yields. To our surprise, in the
absence of any Lewis acid, the aldol reaction of 2-pyridine
carboxaldehyde with ketene silyl acetal 1 proceeded
smoothly in D2O at room temperature to afford the aldol
For comparison purposes, we also carried out the aldol reac-
tion of 2-pyridine carboxaldehyde with ketene silyl acetal 1
in various solvents (Table 1, entries 1–3). Of special interest
is that the aldol reaction of 2-pyridine carboxaldehyde
proceeded smoothly to afford the product in very good
yield when carried out in water (Table 1, entry 3). The
reaction carried out in organic solvents afforded the aldol
product in much lower yield (Table 1, entries 1 and 2).
Therefore, various aldehydes were reacted with ketene
silyl acetal 1 in water. As shown in Table 1, except for
benzaldehyde, the reactions proceeded smoothly to afford
the corresponding aldol products in moderate to high yields.
Of special interest is the high yields observed for all the
reactive aldehydes. Even in the case of methyl glyoxylate8
which prefers to exist in the hydrate form in water, the aldol
product was obtained in good yield (entry 7).
Keywords: water-accelerated aldol reaction; ketene silyl acetal; carbonyl
compounds.
* Corresponding author.
Of mechanistic interest is that the addition of pyridine,
0040–4020/00/$ - see front matter ᭧ 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00630-X

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T.-P. Loh et al. / Tetrahedron 56 (2000) 7309–7312
Figure 1.
DMAP, 2,6-di-tert-butylpyridine, 1,4-diazabicyclo-[2,2,2]
octane or quinidine in the reaction of benzaldehyde does
not increase the yield of the aldol product. This result
rules out the possibility of the involvement of the nitrogen
atom. At this moment, we do not know whether this aldol
reaction proceeds via direct addition of silyl ketene acetal to
aldehyde or desilylation of the silyl ketene acetal in water
followed by the aldol reaction. Although the true mechan-
ism of this reaction is still unknown, the yield of this aldol
reaction is dependent on the reactivity of the aldehyde.
moment, it is difficult to come up with a transition state to
explain these observed stereochemistries.
Conclusions
In summary, we have found that the Mukaiyama-aldol reac-
tion using ketene silyl acetals with aldehydes in water can
afford the aldol products even without the use of Lewis acid
or special activation. This untapped territory of reaction
carried out in water without the use of metal complex and
organic solvent remains to be explored. The use of chiral
silicon containing silyl ketene acetals to investigate the
mechanism as well as to develop an asymmetric version
of this reaction is in progress.
Next, we investigated the simple diastereoselectivity of this
aldol reaction using ketene silyl acetal 3 and 4 with various
aldehydes in water (Eq. (3)). The results are detailed in
Tables 2 and 3.
Table 2. The reaction of ketene silyl acetal 3 with various aldehydes in
water
Entry
RCHO
Yield (%)
syn/antia
ꢀ3†
5a–5d
a
b
c
d
2-Pyridinecarboxaldehyde
3-Pyridinecarboxaldehyde
2-Furaldehyde
95
76
42
63
35/65
42/58
54/46
43/57
Similarly, in all cases, the reactions proceeded smoothly to
afford the corresponding aldol products in moderate to high
yields. Unfortunately, only low to moderate diastereo-
selectivities were observed in all cases. Therefore, at this
Methyl glyoxylate
a Relative stereochemistry determined based on similarity.9
Table 3. The reaction of ketene silyl acetal 4 with various aldehydes in
water
Table 1. The reaction of ketene silyl acetal 1 with various aldehydes in
water
Entry
RCHO
Yield (%)
syn/antia
Entry
RCHO
Solvent
Product
Yield (%)
5a–5d
1
2
3
4
5
6
7
2-Pyridinecarboxaldehyde
2-Pyridinecarboxaldehyde
2-Pyridinecarboxaldehyde
Benzaldehyde
2-Furaldehyde
3-Pyridinecarboxaldehyde
Methyl glyoxylate
THF
CH2Cl2
H2O
H2O
H2O
2a
2a
2a
2b
2c
2d
2e
26
23
95
20
50
95
70
a
b
c
d
2-Pyridinecarboxaldehyde
3-Pyridinecarboxaldehyde
2-Furaldehyde
84
83
48
58
33/67
36/64
46/54
47/53
Methyl glyoxylate
H2O
H2O
a Relative stereochemistry determined based on similarity.9

T.-P. Loh et al. / Tetrahedron 56 (2000) 7309–7312
7311
Experimental
(2), 178 (4), 150 (16), 108 (100), 87 (74), 41 (41), 27 (28);
HRMS: calcd. for C11H15O3N 209.1052, found 209.1072.
General methods and materials
Dimethyl 3-hydroxy-2,2-dimethylbutane-1,4-dioate (2e).
Colorless oil; yield 70%; H NMR d (ppm) 4.36 (1H, d,
1
NMR spectra were recorded on a Bruker ACF 300 NMR.
MS spectra were obtained with a Hewlett–Packard 5890A
gas chromatograph. HR-mass spectra (EI) were obtained
with V.G. Micromass 7035. IR spectra were measured
with a Perkin–Elmer 1600 FTIR spectrometer. Column
chromatography was performed on silica gel, Merck grade
60 (40–63 mm particle size). All the solvents were distilled
before use. Silyl ketene acetals were prepared according to
the references or purchased from Fluka. All the aldehydes
were distilled before use. Indium trichloride were purchased
(Aldrich) and used directly.
Jˆ6.6 Hz, CHOH), 3.78 (3H, s, OMe), 3.72 (3H, s, OMe),
3.19 (1H, d, Jˆ6.6 Hz, CHOH), 1.26 (3H, s, Me), 1.18 (3H,
s, Me); 13C NMR d (ppm) 175.93, 173.52, 75.59, 52.62,
52.14, 46.71, 21.82, 20.40; IR (thin film): 1729.7,
1263.3 cmϪ1; MS (m/z, relative intensity) 131 (64), 99
(66), 43 (100), 29 (32).
Methyl 3-hydroxy-2-methyl-3-(2-pyridyl)propanoate (5a).
Mixture of two isomers; colorless oil; yield 95%, 84% (syn)
1H NMR d (ppm) 8.53–8.52 (1H, m, pyr), 7.72–7.66 (1H,
m, pyr), 7.37–7.32 (1H, m, pyr), 7.23–7.18 (1H, m, pyr),
5.18 (1H, d, Jˆ4.2 Hz, CHOH), 4.40 (1H, br, CHOH), 3.69
(3H, s, OMe), 3.07–2.94 (1H, m, CHMe), 1.03 (3H, d,
Jˆ7.3 Hz, CHMe); 13C NMR d (ppm) 175.18, 159.84,
148.17, 136.42, 122.28, 120.61, 73.13, 51.61, 45.58,
Representative procedure
2-Pyridinecarboxaldehyde (1 mmol, 103 mg) was added to
the suspension of ketene silyl acetal 1 (2 mmol, 366 mg) in
water (5 mL). The ultimate suspension was stirred for 24 h
at ambient temperature. The reaction mixture was extracted
with ethyl acetate (3×50 ml). The combined organic solvent
was washed with brine (1×), dried over anhydrous
magnesium sulfate, and the solvent evaporated in vacuo.
Purification of crude product by flash chromatography
(hexane/ethyl acetateˆ6:1) gave the expected product as a
colorless oil in excellent yield (95%, 198.94 mg); Rf (20%
ethyl acetate/hexane) 0.2.
1
10.02; (anti) H NMR d (ppm) 8.53–8.52 (1H, m, pyr),
7.72–7.66 (1H, m, pyr), 7.37–7.32 (1H, m, pyr), 7.23–
7.18 (1H, m, pyr) 4.86 (1H, d, Jˆ6.6 Hz, CHOH), 4.40
(1H, br, CHOH), 3.66 (3H, s, OMe), 3.07–2.94 (1H, m,
CHMe), 1.1 (3H, d, Jˆ7.0 Hz, CHMe); 13C NMR d (ppm)
175.18, 159.96, 148.46, 136.51, 122.54, 121.29, 75.22,
51.48, 46.20, 13.42, IR (thin film): 1731.0, 1196.3 cmϪ1
;
MS (m/z, relative intensity) 195 (0.5), 162 (40), 117 (92),
108 (100), 52 (100), 27 (75); HRMS: calcd. for C10H13O3N
195.0895, found 195.0905.
Methyl 3-hydroxy-2-methyl-3-(3-pyridyl)propanoate (5b).
Mixture of two isomers; colorless oil; yield 76, 83%; (syn)
1H NMR d (ppm) 8.42–8.37 (2H, m, pyr), 7.73–7.70 (1H,
m, pyr), 7.31–7.23 (1H, m, pyr), 5.08 (1H, d, Jˆ4.9 Hz,
CHOH), 3.63 (3H, s, OMe), 2.87–2.73 (1H, m, CHMe),
1.16 (3H, d, Jˆ7.3 Hz, CHMe); 13C NMR d (ppm)
175.31, 148.63, 147.40, 137.93, 134.15, 123.16, 71.57,
Methyl 3-hydroxy-2,2-dimethyl-3-(2-pyridyl) propano-
ate (2a). Colorless oil, yield 95%, H NMR (CDCl3): d
1
(ppm) 8.39–8.37 (1H, m, pyr), 7.57–7.51 (1H, m, pyr),
7.17–7.05 (2H, m, pyr), 4.88 (1H, s, CHOH), 3.58 (3H, s,
OMe), 1.06 (3H, s, Me), 0.97 (3H, s, Me); 13C NMR (CDCl3)
d (ppm) 177.00, 158.42, 147.82, 135.98, 122.55, 121.92,
76.90, 51.63, 48.20, 20.67, 20.60; IR (thin film): 1726.6,
1258.2 cmϪ1; MS (m/z, relative intensity) 209 (4), 178
(42), 132 (46), 108 (100), 78 (65), 52 (47), 27 (20);
HRMS: calcd. for C11H15NO3 209.1052, found 209.1075.
1
51.63, 46.63, 11.15; (anti) H NMR d (ppm) 8.42–8.37
(2H, m, pyr), 7.73–7.70 (1H, m, pyr), 7.31–7.23 (1H, m,
pyr), 4.79 (1H, d, Jˆ8.7 Hz, CHOH), 3.72 (3H, s, OMe),
2.87–2.73 (1H, m, CHMe), 0.98 (3H, d, Jˆ7.0 Hz, CHMe);
13C NMR d (ppm) 175.46, 148.63, 148.08, 137.70, 134.51,
123.45, 73.54, 51.73, 47.03, 13.85; IR (thin film):
1731.6 cmϪ1; MS (m/z, relative intensity) 195 (3), 164 (4),
135 (3), 108 (100), 88 (53), 57 (44), 27 (21) HRMS: calcd.
for C10H13O3N 195.0895, found 195.0913.
Methyl 3-hydroxy-2,2-dimethyl-3-phenylpropanoate (2b).
Colorless oil, yield 20%; 1H NMR d (ppm) 7.27 (5H, s, Ph),
4.86 (1H, s, CHOH), 3.68 (3H, s, OMe), 3.31 (1H, br,
CHOH), 1.12 (3H, s, Me), 1.07 (3H, s, Me); 13C NMR d
(ppm) 177.96, 140.02, 127.58, 127.55, 127.51, 78.44, 51.88,
47.68, 22.70, 19.00; IR (thin film): 1721.8, 1257.0,
704.9 cmϪ1; MS (m/z, relative intensity) 208 (4), 119 (34),
102 (85), 43 (100), 27 (45); HRMS: calcd. for C12H16O3
208.1099, found 208.1118.
Methyl 3-(2-furyl)-3-hydroxy-2-methylpropanate (5c).
Mixture of two isomers; colorless oil; yield 42, 48%; (syn)
1H NMR d (ppm) 7.38–7.35 (1H, m, furyl), 6.34–6.27 (2H,
m, furyl), 5.01 (1H, br, CHOH), 3.73 (3H, s, OMe), 3.16
(1H, br, CHOH), 3.07–2.93 (1H, m, CHMe), 1.21 (3H, d,
Jˆ7.2 Hz, CHMe); 13C NMR d (ppm) 175.85, 154.25,
141.92, 110.20, 106.71, 68.86, 51.96, 44.10, 11.67; (anti)
1H NMR d (ppm) 7.38–7.35 (1H, m, furyl), 6.34–6.27 (2H,
m, furyl), 4.80–4.76 (1H, m, CHOH); 3.69 (3H, s,OMe),
3.07–2.93 (1H, m, CHMe), 1.80 (1H, br, CHOH), 1.09
(3H, d, Jˆ7.2 Hz, CHMe); 13C NMR d (ppm) 175.21,
154.09, 142.34, 110.20, 107.54, 69.77, 51.96, 44.61,
14.17; IR (thin film): 1734.5 cmϪ1; MS (m/z, relative inten-
sity) 184 (44), 135 (12), 97 (100), 57 (61), 27 (36); HRMS:
calcd. for C9H12O4 184.0736, found 184.0723.
Methyl 3-(2-furyl)-3-hydroxy-2,2-dimethylpropanoate
(2c). Known.10
Methyl 3-hydroxy-2,2-dimethyl-3-(3-pyridyl) propano-
ate (2d). Colorless oil; yield 95%; 1H NMR d (ppm)
8.33–8.28 (2H, m, pyr), 7.71 (1H, d, Jˆ8.0 Hz, pyr),
7.25–7.20 (1H, m, pyr), 5.84 (1H, s, CHOH), 4.97 (1H, s,
CHOH), 3.66 (3H, s, OMe), 1.15 (3H, s, Me), 1.04 (3H, s,
Me); 13C NMR d (ppm) 176.90, 148.11, 147.77, 136.65,
135.38, 122.61, 75.31, 51.61, 47.72, 21.48, 19.02; IR (thin
film): 1726.9, 1264.2 cmϪ1; MS (m/z, relative intensity) 209

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T.-P. Loh et al. / Tetrahedron 56 (2000) 7309–7312
Dimethyl 2-hydroxy-3-methylbutane-1,4-dioate (5d).
Mixture of two isomers; colorless oil; yield 63, 58%; (syn)
1H NMR d (ppm) 4.62 (1H, d, Jˆ3.5 Hz, CHOH), 3.82 (3H,
s, OMe), 3.80 (3H, s, OMe), 3.08–3.00 (1H, m, CHMe),
1.78 (1H, br, CHOH), 1.30 (3H, d, Jˆ7.3 Hz, CHMe); 13C
NMR d (ppm) 173.64, 173.58, 72.48, 52.67, 51.97, 43.16,
References
1. Mukaiyama, T.; Banno, K.; Narasaka, T. J. Am. Chem. Soc.
1974, 96, 7503.
2. Li, C. J.; Chan, T. H. Organic Reactions in Aqueous Media,
Wiley: New York, 1997 (and references cited therein).
3. Lubineau, A.; Auge, J.; Queneau, Y. Synthesis 1994, 741–760
(and references cited therein).
4. Grieco, P. A. Organic Synthesis in Water, Blackie Academic &
Professional: Glasgow, 1998 (and references cited therein).
5. Lubineau, A. J. Org. Chem. 1986, 51, 2142–2144.
6. Lubineau, A.; Meyer, E. Tetrahedron 1988, 44, 6065–6070.
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8. Kelly, T. R.; Schmidt, J. D.; Haggerty, J. K. Synthesis 1972,
554.
1
13.06; (anti) H NMR d (ppm) 4.28 (1H, d, Jˆ3.2 Hz,
´
CHOH), 3.74 (3H, s, OMe), 3.69 (3H, s, OMe), 2.99–2.90
(1H, m, CHMe), 1.78 (1H, br, CHOH), 1.17 (3H, d,
Jˆ7.3 Hz, CHMe); 13C NMR d (ppm) 173.64, 173.58,
71.47, 52.78, 52.12, 42.98, 10.63; IR (thin film): 1731.7,
1213.0 cmϪ1; MS (m/z, relative intensity) 176 (0.5), 159
(1), 117 (97), 85 (100), 57 (98), 29 (87); HRMS: calcd.
for C7H12O5 176.0684, found 176.0674.
9. Mikami, K.; Terada, M.; Nakai, T. J. Org. Chem. 1991, 56,
5456–5459.
Acknowledgements
10. Le Roux, C.; Gaspard-Iloughmane, H.; Dubac, J. Bull. Soc.
Chim. Fr. 1993, 130, 832–842.
We are grateful to the National University of Singapore for
their generous financial support.