C O M M U N I C A T I O N S
Table 2. Competitive Reaction of 1aa
proceeded in a regiospecific manner (entries 3-4). The present
system could be successfully utilized for the aldol reactions with
phenylglyoxal monohydrate (2e) and chloral monohydrate (2f)
(entries 5-8).
yield/%
3aa 6
entry
conditionsb
1c
2
3
H2O (0.6), i-Pr2NH (0.024), DMF, -78 °C, 24 h
CaCl2 (1.0), DMF, 30 °C, 24 h
TiCl4 (1.0), CH2Cl2, -78 °C, 2 h
0
10
90
88
quant. trace
In summary, we have revealed that CaCl2 is an effective Lewis
base catalyst for the aldol reaction of DMS enolates. The present
study shows the first example that the Lewis base activation of
silyl enolates, as well as the Lewis acid activation of aldehydes, is
valuable for the aqueous aldol reaction of silyl enolates.
a 1a (0.50 mmol), 1a:2a:5 (molar ratio) ) 1:1:1. b The molar ratio to 1a
is shown in parentheses. c See ref 6.
Table 3. Aldol Reaction of Aqueous Aldehydes in DMFa
Acknowledgment. This work was partly supported by CREST,
Science and Technology Corporation (JST). We thank Dow Corning
Toray Silicone Co. Ltd. and Shin-Etsu Chemical Co. Ltd. for a
gift of organosilicon compounds.
c,d
entry
1:2:CaCl2b
product
yield/%
syn:anti
1
2
3
4
5
6
7
8
1a 2d (R dH)
1b 2d
1:2:1
1:2:0.13
1:2:1
3ad
3bd
3cd
3dd
3ae
3be
3af
78e (58)
99 (30)
77e,f
1c
2d
Supporting Information Available: Experimental details and
spectroscopy data of DMS enolates and unknown aldol adducts (PDF).
This material is available free of charge via the Internet at http://
pubs.acs.org..
1d 2d
1:2:1
83
1a 2e (R ) PhCO) 1.2:1:1g
72 (71)
93 (73)
48 (28)
89 (41)
52:48h
73:27
88:12
91:9
1b 2e
1a 2f (R ) Cl3C)
1b 2f
1:0.5:0.5
1:0.5:0.5
1:0.5:0.5
3bf
References
a Unless otherwise noted, all reactions were performed with 1 (1.00
mmol) in DMF (1.5 mL in entries 1-4 or 1 mL in entries 5-8) at 30 °C
for 24 h. b Molar ratio. c Based on 1 in entries 1-4 or 2 in entries 5-8.
d The result without CaCl2 is shown in parentheses. e At 0 °C. f Cis:trans
) 63:37. g With 0.60 mmol of 1a. h The relative configuration was not
assigned.
(1) (a) Machajewski, T. D.; Wong, C.-H. Angew. Chem., Int. Ed. 2000, 39,
1352. (b) Gennari, C. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 2, p 629.
(2) Mukaiyama, T.; Narasaka, K.; Banno, K. Chem. Lett. 1973, 1011.
(3) Aldol reactions in aqueous media: (a) Kobayashi, S.; Nagayama, S.;
Busujima, T. J. Am. Chem. Soc. 1998, 120, 8287. (b) Kobayashi S.;
Hachiya, I. J. Org. Chem. 1994, 59, 3590. Aldol reactions in pure water:
(c) Loh, T.-P.; Chua, G.-L.; Vittal, J. J.; Wong, M.-W. Chem. Commun.
1998, 861. (d) Manabe K.; Kobayashi, S. Synlett 1999, 547 and references
therein.
(4) Fluoride ion-catalyzed reactions: (a) Noyori, R.; Nishida, I.; Sakata, J. J.
Am. Chem. Soc. 1983, 105, 1598. (b) Nakamura, E.; Shimizu, M.;
Kuwajima, I.; Sakata, J.; Yokoyama, K.; Noyori, R. J. Org. Chem. 1983,
48, 932.
resulted in a low conversion of 2a. The homogeneous reaction in
MeOH gave dehydrated 2:1 adduct 7 as a major product. Surpris-
(5) Other base-catalyzed reactions: (a) Denmark, S. E.; Stavenger, R. A.;
Wong, K.-T. Tetrahedron 1998, 54, 10389. (b) Denmark, S. E.; Wong,
K.-T.; Stavenger, R. A. J. Am. Chem. Soc. 1997, 119, 2333.
(6) For the related work, see: Miura, K.; Tamaki, K.; Nakagawa, T.; Hosomi,
A. Angew. Chem., Int. Ed. 2000, 39, 1958.
(7) We have previously reported that DMS enolates efficiently add to
aldehydes without promoter under slightly severe reaction conditions (50
°C, 48 h). Miura, K.; Sato, H.; Tamaki, K.; Ito, H.; Hosomi, A.
Tetrahedron Lett. 1998, 39, 2585.
ingly, water was an effective solvent although the substrates did
not dissolve well in water.14,15 A control experiment without solvent
proved the utility of water. Aqueous DMF (H2O-DMF 1:1) was
also available for the CaCl2-promoted system.
(8) We have reported the stereoselective synthesis of 1,3-diols by the tandem
aldol-reduction reaction of DMS enolates with aldehydes. Miura, K.;
Nakagawa, T.; Suda, S.; Hosomi, A. Chem. Lett. 2000, 150.
(9) The reactions were run with 1a (0.60 mmol), 2a (0.50 mmol), and a salt
(1.00 mmol for MX or 0.30 mmol for MX2) in DMF (1 mL).
(10) The CaI2- and LiI-induced reactions gave diol 4 and unidentified
byproducts along with 3aa.
The above results induced us to apply the CaCl2-promoted system
to the aldol reaction of aqueous aldehydes. We first investigated
hydroxymethylation reaction with a 37% aqueous solution of HCHO
(2d).3b,16 The uncatalyzed reaction of 1a with 2d (2 equiv) in DMF
at 30 °C for 24 h gave adduct 3ad in 58% yield (entry 1 in Table
3). In the presence of CaCl2, the yield increased to 71%. NaCl and
MgCl2 had similar effects on the reaction efficiency. Lowering the
reaction temperature to 0 °C slightly improved the yield (entry 1).
The use of water as solvent brought a low yield of 3ad. DMS
enolate 1b showed higher reactivity to 2d to give a quantitative
yield of 3bd even in the presence of a catalytic amount of CaCl2
(entry 2). Without CaCl2, the yield of 3bd dropped to 30%. The
hydroxymethylation of DMS enolate 1c and its regioisomer 1d
(11) For salt effects, see: Reichardt, C. SolVent and SolVent Effects in Organic
Chemistry; VCH: Weinheim, 1998.
(12) (a) Weaver, W. M.; Hutchison, J. D. J. Am. Chem. Soc. 1964, 86, 261.
(b) Rodewald, R. F.; Mahendran, K.; Bear, J. L.; Fuchs, R. J. Am. Chem.
Soc. 1968, 90, 6698. (c) Fuchs, R.; Bear, J. L.; Rodewald, R. F. J. Am.
Chem. Soc. 1969, 91, 5797.
(13) CaCl2 has been reported to be ineffective in the aldol reaction of
propiophenone TMS enolate with 2a in THF-H2O (9:1). See ref 3a.
(14) For the aldol reaction in pure water, see refs 3c,d and: (a) Loh, T.-P.;
Feng, L.-C.; Wei, L.-L. Tetrahedron 2000, 56, 7309. (b) Lubineau, A. J.
Org. Chem. 1986, 51, 2141.
(15) The use of Bu4NCl (0.5 equiv) in combination with CaCl2 improved the
yield of 3aa to 88%.
(16) The commercially available HCHO solution including 5-10% of MeOH
as a stabilizer was used.
JA017218L
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J. AM. CHEM. SOC. VOL. 124, NO. 4, 2002 537