An environmentally friendly procedure for Mukaiyama aldol and Mukaiyama-Michael reactions using a catalytic amount of DBU under solvent- and metal-free conditions

Article abstract of DOI:10.1016/j.tetlet.2004.11.099

Mukaiyama aldol and Mukaiyama-Michael reactions can proceed smoothly in the presence of a catalytic amount of DBU (20% mmol), to afford the corresponding products in moderate to good yields. This solvent- and metal-free approach provides an environmentall

Full text of DOI:10.1016/j.tetlet.2004.11.099

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 507–508
An environmentally friendly procedure for Mukaiyama aldol and
Mukaiyama–Michael reactions using a catalytic amount of
DBU under solvent- and metal-free conditions
Zhi-Liang Shen,a,b Shun-Jun Jib,* and Teck-Peng Loha,b,
*
aDepartment of Chemistry, 3 Science Drive 3, National University of Singapore, Singapore 117543, Singapore
bKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering of Suzhou
University, Suzhou 215006, China
Received 23 July 2004; revised 4 November 2004; accepted 5 November 2004
Available online 7 December 2004
Abstract—Mukaiyama aldol and Mukaiyama–Michael reactions can proceed smoothly in the presence of a catalytic amount of
DBU (20% mmol), to afford the corresponding products in moderate to good yields. This solvent- and metal-free approach provides
an environmentally friendly procedure for Mukaiyama reactions.
ꢀ 2004 Elsevier Ltd. All rights reserved.
In recent years, much efforts have been directed towards
the development of new organic transformations under
environmentally friendly conditions. In relation to this,
much studies have been focused on the development of
new C–C bond formation reactions in green media with-
out the use of metal catalyst.1 For example, our group
has established an efficient method to promote the
Mukaiyama aldol reaction without metal catalyst in
water2 as well as in ionic liquids.3 In connection with
our efforts to develop new organic transformations with-
out the use of metal complexes, we would like to report
that 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) catalyzes
Mukaiyama aldol4 and Mukaiyama–Michael4 reactions
under solvent-free condition.
presence of DBU to afford the desired products in mod-
erate to good yields.
Table 1. DBU-catalyzed Mukaiyama aldol reaction of ketene silyl
acetals with different aldehydes under solvent-free conditionsa,5
R2
R2
OTMS
OMe
OH
O
O
1. DBU/neat, r.t., 24 h
2. 1M HCl/THF
+
R1
OMe
R1
H
R2 R2
Entry
R1
R2
Product
Yield (%)b
1
2-NO2C6H4
2-NO2C6H4
4-ClC6H4
4-ClC6H4
C6H5
CH3
H
1a
1b
1c
1d
1e
1f
67
60c
73
60
77
51
79
55
68
33
83
65
63d
79d
58
64
2
3
CH3
H
4
5
CH3
H
6
C6H5
Initial studies were focused on the Mukaiyama aldol
reaction of aldehydes with ketene silyl acetals. The reac-
tions were conducted at room temperature using a cata-
lytic amount of DBU (20% mmol) under solvent-free
condition. All the results are summarized in Table 1.
7
4-MeC6H4
4-MeC6H4
2-OMeC6H4
2-OMeC6H4
C6H5CH@CH
C6H5CH@CH
3-C5H4N
CH3
H
1g
1h
1i
8
9
CH3
H
10
11
12
13
14
15
16
1j
CH3
H
1k
1l
As shown in Table 1, we could observe that the solvent-
free reactions proceeded efficiently in all cases in the
CH3
H
1m
1n
1o
1p
3-C5H4N
n-C8H17
n-C8H17
CH3
H
a The reactions were carried out at room temperature for 24 h using
aldehydes (1 mmol), ketene silyl acetals (2 mmol), DBU (0.2 mmol).
b Isolated yield.
c An aldol condensation product was obtained in 22% yield.
d Including TMS protected aldol product.
Keywords: Mukaiyama reaction; DBU; Organic catalyst; Solvent-free
condition; Metal-free.
*
Corresponding authors. Tel.: +65 874 1781; fax: +65 779 1691;
e-mail: chmlohtp@nus.edu.sg
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.099

508
Z.-L. Shen et al. / Tetrahedron Letters 46 (2005) 507–508
Table 2. DBU-catalyzed Mukaiyama–Michael reaction of enones with
ketene silyl acetals under solvent-free conditiona,5
yields of the products can make this procedure an
attractive alternative to conventional methodologies,
which using organic solvents and metal-containing
Lewis acids or bases with inherent limitations.
O
O
R2
R2
OTMS
OMe
1. DBU/neat, r.t., 24 h
R3
R3
+
O
2. 1M HCl/THF
n
OMe
R2 R2
n
(n=1 and 2)
Acknowledgements
Entry
R2
R3
n
Product
Yield (%)b
We thank the National University of Singapore and the
National Natural Science Foundation of China (No.
20172039 and 20472062) for providing the research
funding. We are also grateful to Medicinal Chemistry
Programme (R-143-600-600-712) for financial support.
1
2
3
4
5
6
Me
H
H
2
2
1
1
1
1
2a
2b
2c
2d
2e
2f
76
70
H
Me
H
H
71
H
81
Me
H
Me
Me
68c
61c
a The reactions were carried out at room temperature for 24 h using
enone (1 mmol), ketene silyl acetals (2 mmol), DBU (0.2 mmol).
b Isolated yield.
References and notes
c Diastereoselectivity was not determined.
1. (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001,
40, 3726–3748; (b) McDaid, P.; Chen, Y. G.; Deng, L.
Angew. Chem., Int. Ed. 2002, 2, 41; (c) Narayan, S.;
Seelhammer, T.; Gawley, R. E. Tetrahedron Lett. 2004, 45,
757–759; (d) Palomo, C.; Oiarbide, M.; Garcia, J. M.;
Gonzalez, A.; Lecumberri, A.; Linden, A. J. Am. Chem.
Soc. 2002, 124, 10288–10289; (e) Ahrendt, K. A.; Borths, C.
J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2000, 122,
4243–4244.
It was worthy to note that the reaction system also
worked well with aliphatic aldehydes such as nonyl alde-
hyde (Table 1, entries 15 and 16). For conjugated alde-
hyde (Table 1, entries 11 and 12), a good yield of aldol
product was selectively obtained without detection of
the 1,4-adduct. Similar results were obtained with 1-
methoxy-1-[(trimethylsilyl)oxy]ethane.
2. Loh, T.-P.; Feng, L.-C.; Wei, L.-L. Tetrahedron 2000, 56,
7309–7312.
3. Chen, S.-L.; Ji, S.-J.; Loh, T.-P. Tetrehedron Lett. 2004, 45,
375–377.
In addition, we also carried out the DBU-catalyzed
Mukaiyama aldol reaction in different organic solvents
using benzaldehyde as substrate, however, low yields
were obtained in organic solvents (MeOH: 5% yield;
THF: 53% yield; CH2Cl2: 32% yield; DMF: 67%
yield) in comparison with neat condition (77% yield).
4. (a) Mukaiyama, T.; Banno, K.; Narasaka, K. J. Am. Chem.
Soc. 1974, 96, 7503–7509; (b) Smith, M. B.; March, J.
Advanced Organic Chemistry Reactions Mechanisms and
Structure; Wiley-Interscience: New York, 2001; pp 1223–
1224, and references cited therein; (c) Sato, T.; Wakahara,
Y.; Otera, J.; Nozaki, H. Tetrahedron 1991, 47, 9773–9782;
(d) Huffman, J. W.; Potnis, S. M.; Satish, A. V. J. Org.
Chem. 1985, 50, 4266–4270; (e) Rajan Babu, T. V. J. Org.
Chem. 1984, 49, 2083–2089, and references cited therein;
(f) Mukaiyama, T.; Nakagawa, T.; Fujisawa, H. Helv.
Chim. Acta 2002, 85, 4518–4531; (g) Miura, K.; Nakagawa,
T.; Hosomi, A. J. Am. Chem. Soc. 2002, 124, 536–537;
(h) Loh, T.-P.; Wei, L.-L. Tetrahedron 1998, 54, 7615–
7624.
Next, we extended this method to Mukaiyama–Michael
reactions involving a,b-unsaturated carbonyl com-
pounds. The results are summarized in Table 2.
As shown in Table 2, the reactions proceeded smoothly
under solvent-free conditions with the addition of a cat-
alytic amount (20% mmol) of DBU.
5. Representative experimental procedure: A mixture of benz-
aldehyde (1 mmol), 1-methoxy-2-methyl-1-trimethylsilyl-
oxypropene (2 mmol) and DBU (0.2 mmol) was stirred at
room temperature for 24 h. After that, 2 mL of 1 M
aqueous HCl and 2 mL THF were added to the reaction
system. After stirring vigorously for a while, the product
was extracted with diethyl ether (3 · 10 mL). The combined
organic phases were washed with brine and dried over
anhydrous Na2SO4. The solution was concentrated in
vaccuo followed by the purification using flash silica gel
chromatography to give desired products. All the new
It is assumed that the Mukaiyama reactions might pro-
ceed via the activation of trimethylsilyl enol ether by
forming a hypervalent silicate between nitrogen atom
of DBU and silicon atom of the enolate.
In summary, we have developed an efficient and envi-
ronmentally friendly protocol for Mukaiyama reactions,
employing a catalytic amount of DBU under solvent-
free conditions at room temperature. Mild reaction con-
ditions, environmental benign catalytic system, cheap
organic catalyst, good selectivity and a moderate to high
1
products are characterized by H NMR, 13C NMR, FTIR
and mass spectrometry.