Mukaiyama aldol reaction using ketene silyl acetals with carbonyl compounds in ionic liquids

Article abstract of DOI:10.1016/j.tetlet.2003.10.155

Mukaiyama aldol reactions using ketene silyl acetals with various aldehydes proceed smoothly in ionic liquids to afford the corresponding aldol products in moderate yields.

Full text of DOI:10.1016/j.tetlet.2003.10.155

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 375–377
Mukaiyama aldol reaction using ketene silyl acetals with carbonyl
compounds in ionic liquids
Shui-Ling Chen,a Shun-Jun Jib,* and Teck-Peng Loha,b,
*
aDepartment of Chemistry, 3 Science Drive 3, National University of Singapore, Singapore 117543, Singapore
bCollege of Chemistry and Chemical Engineering, Suzhou University, Jiangsu 215006, China
Received 10 September 2003;revised 16 October 2003;accepted 24 October 2003
Abstract—Mukaiyama aldol reactions using ketene silyl acetals with various aldehydes proceed smoothly in ionic liquids to afford
the corresponding aldol products in moderate yields.
Ó 2003 Elsevier Ltd. All rights reserved.
The Mukaiyama aldol reaction is one of the most
important reactions in organic synthesis.1;2 Although
the Mukaiyama aldol reaction has been extensively
studied, the Mukaiyama aldol reaction at ambient
temperature in the absence of Lewis acid catalysis or
any special activation continues to pose a great chal-
lenge for organic chemists.3 Recently our group has
developed a water-accelerated Mukaiyama aldol reac-
tion using ketene silyl acetals.3d Using this method,
Mukaiyama aldol reactions can proceed in water at
ambient temperature without any Lewis acid catalysis
or special activation to afford the corresponding aldol
products in moderate to good yields. However, this
reaction only works with reactive aldehydes. No re-
action was observed with aliphatic aldehydes. There-
fore, a more general method that could work with a
wide variety of aldehydes is highly desirable. In this
paper, we report Mukaiyama aldol reactions in ionic
liquids, which proceeded smoothly with various alde-
hydes including aliphatic aldehydes at ambient tem-
perature without Lewis acid catalysis or special
activation.
this study, the Mukaiyama aldol product, as compared
to the Mannich product, increases with the increase in
the carbon chain length of the ionic liquids. These
findings, coupled with the highly polar nature of these
solvents, encouraged us to investigate further the effect
of ionic liquids in Mukaiyama aldol reactions.
The Mukaiyama aldol reaction of nonyl aldehyde and
1-methoxy-2-methyl-1-trimethylsilyloxypropene was car-
ried out at room temperature using different ionic
liquids.7 As shown in Table 1, the Mukaiyama aldol
reaction proceeded to afford the product. As predicted,
ionic liquids with long cation carbon chain length
afforded better yields of the aldol products (entries 3, 5,
and 7). In addition, the [Clꢀ]-type ionic liquids were the
preferred solvent systems (entries 6 and 7).
X
N
N
OH O
OTMS
OMe
O
n = 3 to 7
n
+
OMe
H
X = Cl, BF4, PF6
Ionic liquids have attracted great attention because of
their potential use as Ôgreen solventsÕ.4;5 Recently, our
group has reported the asymmetric Mannich-type reac-
tion in 1-R-3-methylimidazolium based ionic liquids.6 In
Next, we investigated the reaction of 1-methoxy-2-
methyl-1-trimethylsilyloxypropene with various alde-
hydes using [omim][Clꢀ] (n ¼ 7). The results are shown
in Table 2. In all cases, the products were obtained in
moderate to good yields. It is important to note that
even unreactive aldehydes such as aliphatic (entries 2, 3,
and 9) and aromatic aldehydes (entries 8, 10, and 11)
reacted with the ketene silyl acetal to afford the products
in good yields.8
Keywords: Mukaiyama aldol reaction;ionic liquids.
* Corresponding authors. Tel.: +65-874-1781;fax: +65-779-1691;
e-mail: chmlohtp@nus.edu.sg
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.155

376
S.-L. Chen et al. / Tetrahedron Letters 45 (2004) 375–377
Table 1. Investigation of Mukaiyama aldol reaction using various
ionic liquids
temperature without any Lewis acid or/and other special
activation. This method works with a wide variety of
aldehydes. The mild reaction conditions and the sim-
plicity of the reaction procedure will certainly attract
interest among organic chemists. The combinatorial
synthesis of other ionic liquids for this aldol reaction,
the development of an asymmetric version and the
application of this method for the synthesis of complex
molecules are in progress.
Entry
Ionic liquid
Yielda (%)
1
2
3
4
5
6
7
[bmim][PFꢀ6 ], n ¼ 3
[hmim][PFꢀ6 ], n ¼ 5
[omim][PFꢀ6 ], n ¼ 7
[bmim][BFꢀ4 ], n ¼ 3
[hmim][BFꢀ4 ], n ¼ 5
[hmim][Clꢀ], n ¼ 5
[omim][Clꢀ], n ¼ 7
4
6
12
8
29
50
51
a Isolated yield of aldol product.
Acknowledgements
Cl
N
N
OH O
OTMS
O
n
n = 7
We thank the National University of Singapore for
providing the research funding, the Singapore Millen-
nium Foundation for providing the research scholarship
and the National Natural Science Foundation of China
(no. 20172039).
+
R
OMe
R
H
OMe
Table 2. Mukaiyama aldol reaction using [omim][Clꢀ] with various
aldehydes
Entry
1
Aldehyde
Yielda (%)
50
References and Notes
O
H
1. Mukaiyama, T.;Banno, K.;Narasaka, K. J. Am. Chem.
Soc. 1974, 96, 7503–7509.
2. Smith, M. B.;March, J. Advanced Organic Chemistry:
Reactions, Mechanisms and Structure. 5th ed. Wiley-Inter-
science: New York, 2001. pp. 1223–1224, and references
cited therein.
O
2
51
H
O
H
N
3
53b
58
59b
60
62
63
68
72
74
3. For example, see: (a) Chan, H. T.;Li, C. J.;Wei, Z. Y. J.
Chem. Soc., Chem. Commun. 1990, 505–507;(b) Lubineau,
A. J. Org. Chem. 1986, 51, 2142–2145;(c) Kobayashi, S.;
Hachiya, I. Tetrahedron Lett. 1992, 33, 1625–1628;(d) Loh,
T. P.;Feng, L. C.;Wei, L. L. Tetrahedron 2000, 56, 7309–
7312;(e) Li, C. J.;Chan, T. H. Organic Reaction in Aqueous
Media;Wiley: New York, 1997, and references cited
O
O
H
4
O
H
5
ꢀ
therein;(f) Lubineau, A.;Aug e, J.;Queneau, Y. Synthesis
N
O
1994, 741–760, and references cited therein;(g) Grieco, P.
A. Organic Synthesis in Water;Blackie Academic &
Professional: Glasgow, 1998, and references cited therein.
4. Review articles: (a) Sheldon, R. A. Chem. Commun. 2001,
2399–2407;(b) Gordon, C. M. Appl. Catal. A: Genaral
2001, 222, 101–117;(c) Wasserscheid, P.;Keim, W. Angew.
Chem., Int. Ed 2000, 39, 3772–3789;(d) Holbrey, J. D.;
Seddon, K. R. Clean Prod. Processes 1999, 1, 223–236;(e)
Welton, T. Chem. Rev. 1999, 99, 2071–2084.
H
6
NO2
O
H
7
MeO
O
8
BnO
O
H
^
5. For example, see: (a) Blanchard, L. A.;H ancu, D.;
Beckman, E. J.;Brennecke, J. F. Nature 1999, 399, 28–29;
(b) Brown, R. A.;Pollet, P.;Mckoon, E.;Eckert, C. A.;
Liotta, C. L.;Jessop, P. G. J. Am. Chem. Soc. 2001, 123,
1254–1255;(c) Leitner, W. Nature 2003, 423, 930–931;(d)
Yang, X. F.;Wang, M. W.;Li, C. J. Org. Lett. 2003, 5,
657–660;(e) Loh, T. P.;Feng, L. C.;Yang, H. Y.;Yang, J.
Y. Tetrahedron Lett. 2002, 43, 8741–8743.
H
9
OH
O
H
10
11
O
6. Chen, S. L.;Ji, S. J.;Loh, T. P. Tetrahedron Lett. 2003, 44,
2405–2408.
H
7. Representative experimental procedure:
A mixture of
Cl
benzaldehyde (1 mmol) and 1-methoxy-2-methyl-1-trimeth-
ylsilyloxypropene (1.1 mmol) in the ionic liquid (0.5 mL)
was stirred at room temperature for 6 h. Another 1.1 mmol
of 1-methoxy-2-methyl-1-trimethylsilyloxypropene was
added subsequently and the reaction mixture was allowed
to stir at room temperature for 12 h. After that, 2 mL of
1 M HCl was added and the product was then extracted
with diethyl ether. The combined organic phases were
a Isolated yield of aldol product.
b Including TMS protected aldol product.
In summary, we have developed a general Mukaiyama
aldol reaction using ionic liquids as solvent at room

S.-L. Chen et al. / Tetrahedron Letters 45 (2004) 375–377
377
washed with brine and dried over anhydrous Na2SO4. The
solution was then concentrated in vacuo followed by the
purification using flash silica gel chromatography. 1H
NMR (300 MHz): d 7.32–7.28 (m 5H, Ph), 4.90 (d,
J ¼ 3:81, 1H, CHOH), 3.73 (s, 3H, OCH3), 3.05 (d,
J ¼ 3:81, 1H, CHOH), 1.15 (s, 3H, C(CH3)(CH3)), 1.12
(s, 3H, C(CH3)(CH3)) ppm; 13C NMR (75.4 MHz): 178.0,
148.0, 127.6, 126.6, 127.5, 78.5, 51.9, 47.7, 22.8, 19.0 ppm;
FTIR (KBr, neat): 1721.8, 1257.0, 704.9 cmꢀ1;HRMS (EI):
calculated (C12H16O3, [Mþ]): 208.1099, found: 208.1103.
8. At this stage we do not have a explanation for either why
the reaction proceeds with unreactive aldehydes or why the
reaction proceeds without any Lewis acid or/and other
1
special activation. H NMR, 13C NMR, FTIR, and mass
spectrometry were used to confirm the structures of the
other products.