Lewis base-promoted aldol reaction of dimethylsilyl enolates in aqueous dimethylformamide: Use of calcium chloride as a Lewis base catalyst

Article abstract of DOI:10.1021/ja017218l

In the presence of CaCl₂, dimethylsilyl (DMS) enolates smoothly reacted with aldehydes under mild conditions to give aldol adducts in good to high yields. The catalytic activities of various metal and tetrabutylammonium salts have revealed that CaCl₂ works as a Lewis base catalyst to activate DMS enolates. The CaCl₂-promoted reaction proceeded even in the presence of water or in pure water. This catalytic system was applicable to the aldol reaction with aqueous aldehydes such as formalin. Copyright

Full text of DOI:10.1021/ja017218l

Published on Web 01/04/2002
Lewis Base-Promoted Aldol Reaction of Dimethylsilyl Enolates in Aqueous
Dimethylformamide: Use of Calcium Chloride as a Lewis Base Catalyst
Katsukiyo Miura, Takahiro Nakagawa, and Akira Hosomi*
Department of Chemistry, Graduate School of Pure and Applied Sciences, UniVersity of Tsukuba,
Tsukuba, Ibaraki 305-8571, Japan
Received October 2, 2001; Revised Manuscript Received December 7, 2001
Table 1. CaCl2-Promoted Aldol Reaction of DMS Enolatesa
The aldol reactions of silyl enolates have been widely utilized
for highly efficient and stereoselective C-C bond formation.1 A
variety of reagents, particularly Lewis acids, are known to promote
the nucleophilic process.2 Recently, water-stable Lewis acids such
as lanthanide triflates, which enable the aldol reactions in aqueous
solvent or pure water, have received much attention in relation to
the development of economical and environmentally benign
synthetic methods.3 Fluoride ion and other Lewis bases also
b
entry
enolate
aldehyde
product
yield/%
syn:antib
accelerate the aldol reactions by nucleophilic activation of silyl
enolates;4,5 however, the base-catalyzed system has not yet been
utilized in aqueous media to the best of our knowledge. We herein
disclose that CaCl2 works as a Lewis base to promote the aldol
reaction of dimethylsilyl (DMS) enolates even in the presence of
water.6
1
2
3
4
5
6
1a
1a
1a
1b
1b
1b
2a
2b
2c
2a
2b
2c
3aa
3ab
3ac
3ba
3bb
3bc
90 (82)
92 (79)
65 (75)
98 (82)
99 (85)
90 (79)
45:55 (47:53)
50:50 (51:49)
40:60 (39:61)
53:47 (52:48)
42:58 (42:58)
53:47 (54:46)
The uncatalyzed reaction of benzaldehyde (2a) with DMS enolate
1a (2 equiv) at 30 °C for 24 h gave aldol adduct 3aa in 43% yield.7
Addition of an equimolar amount of CaCl2 completed the aldol
reaction in 2 h to achieve a quantitative yield of 3aa. A catalytic
amount of CaCl2 and a small excess of 1a were enough to attain
high reaction efficiency (entry 1 in Table 1). In contrast to the result
with 1a, cyclohexanone TMS enolate was quite insensitive to 2a
under similar conditions. As shown in Table 1, the CaCl2-catalyzed
system was applicable to R,â-unsaturated and aliphatic aldehydes.
DMS enolate 1b showed slightly higher reactivity than 1a.
Encouraged by the initial results with CaCl2, we examined the
aldol reaction using other alkali earth and alkali metal salts. As a
result, some metal salts proved to be effective promoters (eq 1).
a Conditions: 1 (1.00 mmol), 2 (0.50 mmol), CaCl2 (0.125 mmol), DMF
(1 mL), 30 °C, 24 h. b The result with a small excess of 1 (0.60 mmol) and
a half amount of DMF (0.5 mL) is shown in parentheses.
yield of 3aa were as follows: CaCl2, 95; LiCl, 98; Bu4NCl, 67;
CaBr2, 54; MgBr2, 54; LiBr, 52; Bu4NBr, 25; CaI2, 32;10 LiI, 34;10
NaI, 35; KI, 34; Bu4NI, 40; LiOTf, 17; none, 20. Thus, the reaction
efficiency varied with the salts used to a great extent. These results
indicate that the rate-acceleration does not originate from the
increased polarity of the reaction medium,11 and the counteranion
plays a crucial role in promoting the aldol reaction. The rate-
accelerating ability of metal salt increased with increasing intrinsic
nucleophilicity of the counteranion: TfO- < I- e Br- < Cl-.12
13
Judging from the low Lewis acidity of CaCl2 and the rate-
accelerating ability of other metal salts, in the present CaCl2-
catalyzed system, the chloride ion would work as a Lewis base to
activate DMS enolates.4,5 This deduction is supported by the rate-
accelerating effect of Bu4NCl and the insensitivity of cyclohexanone
TMS enolate. In the Bu4NCl-promoted reaction (eq 1), the activation
of 2a is not likely. The latter result is attributable to the steric
bulkiness around the silicon atom, which would interfere with attack
of the chloride ion.
The LiCl- and NaCl-promoted reactions of 2a with 1a for 24 h
gave 3aa in high yields; however, shortening the reaction time
revealed that the rate-accelerating ability of NaCl was much lower
than that of CaCl2 (36% yield of 3aa after 2 h). The low activity
of NaCl would come from the lower solubility to DMF. Interest-
ingly, in the case of Na2CO3, a certain amount of diol 4 was formed
by the tandem aldol-reduction reaction.8 To gain a mechanistic
insight into the present reaction, Bu4NCl was used instead of a
metal salt. The chloride also accelerated the aldol reaction of 1a.
We further investigated the rate-accelerating ability of metal and
tetrabutylammonium salts very soluble to DMF. When the reaction
of 1a with 2a was performed in DMF solution with a certain ion
strength (I ) 1.0-1.1) at 30 °C for 3 h,9 the salt examined and the
In our previous work on the base-catalyzed Mannich-type
reaction of DMS enolates,6 we have found that the reactivity of 1a
to N-tosylimine 5 is much higher than that to 2a under the basic
conditions (entry 1 in Table 2). To confirm the role of CaCl2, we
examined a competitive reaction of 1a with 2a versus 5 in the
CaCl2-catalyzed system (entry 2). As a result, the Mannich-type
reaction with 5 smoothly proceeded in preference to the aldol
reaction with 2a. In contrast, the competitive reaction with TiCl4,
a typical Lewis acid, gave aldol adduct 3aa exclusively (entry 3).
These observations clearly indicate that CaCl2 acts as a Lewis base.
The CaCl2-promoted reaction was strongly affected by the solvent
used (eq 2). The aldol reaction of 1a with 2a smoothly proceeded
in DMSO, while the use of THF, which hardly dissolved CaCl2,
9
536 VOL. 124, NO. 4, 2002 J. AM. CHEM. SOC.
10.1021/ja017218l CCC: $22.00 © 2002 American Chemical Society

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