Lewis base-catalyzed transformation of α,β-unsaturated aldehydes to saturated carboxylic acids, esters and amides

Article abstract of DOI:10.1016/S0040-4039(02)01133-4

The reactions of α,β-unsaturated aldehydes such as (E)-cinnamaldehyde and 2- or 4-methoxycinnamaldehyde with trimethylsilyl cyanide in the presence of a catalytic amount of a Lewis base such as TTMPP and DBU afforded the corresponding saturated carboxylic acids after hydrolysis.

Full text of DOI:10.1016/S0040-4039(02)01133-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5645–5647
Lewis base-catalyzed transformation of a,b-unsaturated
aldehydes to saturated carboxylic acids, esters and amides
Hirotoshi Kawabata and Masahiko Hayashi*
Department of Chemistry, Faculty of Science, Kobe University, Kobe 657-8501, Japan
Received 9 May 2002; revised 5 June 2002; accepted 7 June 2002
Abstract—The reactions of a,b-unsaturated aldehydes such as (E)-cinnamaldehyde and 2- or 4-methoxycinnamaldehyde with
trimethylsilyl cyanide in the presence of a catalytic amount of a Lewis base such as TTMPP and DBU afforded the corresponding
saturated carboxylic acids after hydrolysis. © 2002 Elsevier Science Ltd. All rights reserved.
In 1991, Mukaiyama and his co-workers reported
Lewis base-catalyzed formation of cyanohydrin
trimethylsilyl ethers by the reaction of trimethylsilyl
cyanide with some aldehydes.1 The Lewis bases they
employed were amines (Et3N, i-Pr2NEt, i-Pr2NH, 1-
ethylpiperidine, N,N,N%,N%-tetramethylethylenediamine,
2,2,6,6-tetramethylpiperidine), phosphines (n-Bu3P,
Ph3P), arsine (Ph3As) and antimony (Ph3Sb). In all
cases they examined, the reaction products were
trimethylsilyl ethers of cyanohydrin.
Here we would like to report that some strong Lewis
bases such as tris(2,4,6-trimethoxyphenyl)phosphine
(TTMPP)2–4 and 1,8-diazabicyclo[5,4,0]undec-7-ene
Table 1. Reaction of (E)-cinnamaldehyde with Me3SiCN catalyzed by a variety of Lewis basesa
Entry
Catalyst (mol%)
Conditions
Time (h)
Products (% yield)b
Temp (°C)
2
3
1
2
3
4
5
6
7
8
9
PhP3 (20)
28
31
31
32
32
29
31
25
28
25
3.5
3.5
3.5
2
46
87
23
10
7
0
4
0
0
0
0
TMPP (20)
TDMPP (20)
TTMPP (5)
TTMPP (10)
TTMPP (20)
n-Bu3P (20)
DBU (5)
70
86
87
90
74
79
91
94
2
3.5
2.5
2
2
2
DBU (10)
DBU (20)
10
0
a All reactions were carried out in CH3CN.
b The yields of the products were the isolated yields after hydrolysis.
Keywords: Lewis base; a,b-unsaturated aldehyde; carboxylic acid.
* Corresponding author. Tel.: +81-78-803-5687; fax: +87-78-803-5688; e-mail: mhayashi@kobe-u.ac.jp
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01133-4

5646
H. Kawabata, M. Hayashi / Tetrahedron Letters 43 (2002) 5645–5647
Table 2. Solvent effect in the reaction of (E)-cinnamaldehyde with Me3SiCNa
Entry
Solvent
Conditions
Time (h)
Products (% yield)b
Temp (°C)
2
3
1
2
3
4
5
6
7
CH3CN
THF
Toluene
CH2Cl2
DMF
29
32
32
32
20
30
32
3.5
3
3.5
3.5
3
0
90
76
74
51
14
4
15
14
42
74
94
96
EtOH
Et2O
2
2
1
a All reactions were carried out in the presence of 20 mol% of TTMPP.
b The yields of the products were the isolated yields after hydrolysis.
(DBU) catalyze mild and direct conversion of a,b-
unsaturated aldehydes to the corresponding saturated
carboxylic acids, esters and amides.
afforded trimethylsilyl ethers of cyanohydrin,
exclusively.
The reaction would be initiated by trimethylsilylcyana-
tion of aldehydes affording trimethylsilyl ether of
cyanohydrin, which was followed by base-catalyzed
isomerization to produce saturated acids after hydroly-
sis. Actually, trimethylsilyl ether of cyanohydrin can be
used as a substrate. Furthermore, before hydrolysis, the
generation of the intermediate a-trimethylsiloxy vinyl
cyanide, which was the isomerization product of
We first examined the effect of the nature of the Lewis
base catalysts on the distribution of the products, that
is, cyanohydrin trimethylsilyl ether and saturated car-
boxylic acid, in the reaction of (E)-cinnamaldehyde (1)
with trimethylsilyl cyanide followed by hydrolysis
(Table 1). Among the Lewis bases we examined,
TTMPP and DBU worked most effectively for the
conversion of (E)-cinnamaldehyde (1) to 3-phenylpropi-
onic acid (3). That is, the reaction of 1 with trimethylsi-
lyl cyanide in the presence of 20 mol% of TTMPP or 5
mol% of DBU in acetonitrile at room temperature for
2–3.5 h, then hydrolysis with 1 M HCl afforded 3 in
90% and 95% yield, respectively. In both cases, the
trimethylsilyl ether of cyanohydrin was not obtained.
DBU was found to be more effective than TTMPP for
the above conversion. In the case of other Lewis bases
such as triphenylphosphine, tris(4-methoxyphenyl)-
phosphine (TMPP), and tris(2,6-dimethoxyphenyl)-
phosphine (TDMPP), the products were only unsatu-
rated cyanohydrin 2 or a mixture of cyanohydrin 2 and
saturated carboxylic acid 3 (entries 1–3, 7). It should be
mentioned that even in the reaction of TTMPP, use of
a lesser amount of TTMPP led to the formation of a
small amount of cyanohydrin (entries 4, 5). The ten-
dency of the preferred formation of saturated acid 3
approximately correlates with the acidity of the conju-
gated acid of the bases used. The nature of the solvent
also affected the distribution of cyanohydrin and acid
(Table 2). The result of the reaction in acetonitrile was
completely in contrast with that in ethanol and diethyl
ether. That is, the reaction in ethanol and diethyl ether
afforded cyanohydrin 2, exclusively. The reactions in
other solvents afforded mixtures of unsaturated
cyanohydrin 2 and saturated acid 3.
1
cyanohydrin trimethylsilyl ether, was confirmed by H
NMR and mass spectral analyses of the reaction mix-
ture. At this stage, the formation of acyl cyanide was
not observed.
As for the direct conversion of (E)-cinnamaldehyde (1)
to 3-phenylpropionic acid (3), Vries et al. reported a
reaction catalyzed by RuCl3·H2O/PCy3 system; how-
ever, this reaction needed high temperature (180°C),
and the yield was only moderate (46% yield).5 Our
present method is superior to the ruthenium-catalyzed
method from the viewpoint of yield of the product and
mildness of the reaction conditions.
Methanolysis instead of hydrolysis afforded saturated
methyl esters in high yield. That is, the reaction of
(E)-cinnamaldehyde (1) with trimethylsilyl cyanide by
the aid of 20 mol% of TTMPP or 5 mol% of DBU
1) catalyst,
CH3CN
CHO
CO2H
+
Me3SiCN
2) 1N HCl
OMe
OMe
20 mol% TTMPP; 92% (25 °C, 5 h)
5 mol% DBU; 90% (25 °C, 3 h)
1) catalyst,
CH3CN
CHO
The reactions of a,b-unsaturated aldehydes other than
(E)-cinnamaldehyde were also examined. 2- and 4-
Methoxy-(E)-cinnamaldehyde were converted to the
corresponding saturated acid in high yield by the aid of
TTMPP and DBU (77–96% yield) (Scheme 1). On the
other hand, the reactions of a-methyl-(E)-cinnamalde-
hyde, (E)-2-hexenal and (E)-2-nonenal with trimethylsi-
lyl cyanide by in the presence of 20 mol% of TTMPP
+
Me3SiCN
2) 1N HCl
CO2H
MeO
MeO
20 mol% TTMPP; 77% (25 °C, 95 h)
5 mol% DBU; 96% (25 °C, 4 h)
Scheme 1.

H. Kawabata, M. Hayashi / Tetrahedron Letters 43 (2002) 5645–5647
5647
3.5 h. After confirmation of the consumption of alde-
hyde and then cyanohydrin trimethylsilyl ether by TLC
analysis, the mixture was poured into a mixture of 1 M
HCl solution (10 mL) and diethyl ether (10 mL), and
stirred vigorously for 3 h at room temperature. Usual
extractive work-up, then silica gel column chromato-
graphy using hexane–ethyl acetate (3/1) as an eluent
gave 3-phenylpropionic acid (3) (1.08 g, 90%), mp
47–49°C.
followed by addition of methanol gave methyl 3-
phenylpropionate (4) in 63% and 67%, respectively
(28°C, 3.5–6 h) (Eq. (1)). Ethyl 3-phenylpropionate (5)
and i-propyl 3-phenylpropionate (6) were also obtained
by treatment with ethanol or isopropyl alcohol (Eq.
(1)). Furthermore, quenching by 1.2 equiv. of diethyl-
amine or piperidine afforded the corresponding amides
(7 and 8) in 77–81% and 95–97%, respectively (Eqs. (2)
and (3)).
In conclusion, some Lewis bases such as TTMPP and
DBU promote novel and efficient transformation of
a,b-unsaturated aldehydes into saturated carboxylic
acids and the corresponding esters and amides. Study
of the detailed reaction mechanism and synthetic appli-
cations of the method are now in progress in our
laboratory.
1) cat.
Lewis base
CHO
CO2R
+
Me3SiCN
2) ROH
1
R = Me (4), 20 mol% TTMPP; 63% (28 °C, 6 h)
5 mol% DBU; 67% (28 °C, 3.5 h)
R = Et (5), 20 mol% TTMPP; 69% (25 °C, 4.5 h)
5 mol% DBU; 77% (25 °C, 4.5 h)
R = i-Pr (6), 20 mol% TTMPP; 46% (25 °C, 22 h)
5 mol% DBU; 49% (25 °C, 2.5 h)
(1)
Acknowledgements
O
1) cat.
CHO
This research was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan. H.K.
is grateful to the Japan Society for the Promotion of
Science (JSPS) Research Fellowships for Young Scien-
tists.
Lewis base
NEt2
+
Me3SiCN
2) Et2NH
1
7
20 mol% TTMPP; 77% (25 °C, 4.5 h)
5 mol% DBU; 81% (25 °C, 4.5 h)
(2)
References
CHO
O
1) cat.
Lewis base
N
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2. Wada, M.; Higashizaki, S. J. Chem. Soc., Chem. Commun.
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1
+
8
Me3SiCN
20 mol% TTMPP; 95% (25 °C, 7 h)
5 mol% DBU; 97% (25 °C, 7 h)
1984, 482–483.
3. Matsukawa, S.; Okano, N.; Imamoto, T. Tetrahedron Lett.
2000, 41, 103–106.
(3)
4. Yoshimoto, K.; Kawabata, H.; Nakamichi, N.; Hayashi,
Typical experimental procedure is as follows: In a flask
were placed (E)-cinnamaldehyde (1) (1.06 g, 8.0 mmol)
and CH3CN (7 mL). To this mixture were added
trimethylsilyl cyanide (1.3 mL, 9.75 mmol) and TTMPP
(855 mg, 1.6 mmol). The whole was stirred at 29°C for
M. Chem. Lett. 2001, 934–935.
5. de Vries, J. G.; Roelfes, G.; Green, R. Tetrahedron Lett.
1998, 39, 8329–8332. See also, Murahashi, S.-I.; Naota, T.;
Ito, K.; Maeda, Y.; Taki, H. J. Org. Chem. 1987, 52,
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