Lewis base-catalyzed cyanomethylation of carbonyl compounds with (trimethylsilyl)acetonitrile

Article abstract of DOI:10.1246/cl.2005.1508

Catalytic cyanomethylation of various carbonyl compounds with (trimethylsilyl)acetonitrile (TMSCH₂CN) in the presence of Lewis bases such as cesium or lithium acetate proceeded smoothly to afford the corresponding cyanomethylated adducts in good yields. Copyright

Full text of DOI:10.1246/cl.2005.1508

1508
Chemistry Letters Vol.34, No.11 (2005)
Lewis Base-catalyzed Cyanomethylation of Carbonyl Compounds
with (Trimethylsilyl)acetonitrile
Yoshikazu Kawano,y;yy Nobuya Kaneko,y;yy and Teruaki Mukaiyamaꢀy;yy
yCenter for Basic Research, The Kitasato Institute, 6-15-5 (TCI) Toshima, Kita-ku, Tokyo 114-0003
yyKitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641
(Received July 26, 2005; CL-050970)
Catalytic cyanomethylation of various carbonyl compounds
with (trimethylsilyl)acetonitrile (TMSCH2CN) in the presence
of Lewis bases such as cesium or lithium acetate proceeded
smoothly to afford the corresponding cyanomethylated adducts
in good yields.
Table 1. Screening of catalyst on cyanomethylation
OH
O
H+
Me3SiCH2CN
(1.4 equiv.)
AcOLi (10 mol%)
CN
+
Ph
Ph
H
DMF, 0 °C−rt, 3 h
Entry
Cat. (10 mol %)
AcOLi
AcOLi (1 mol %) 91
Yielda/% Entry Cat. (10 mol %) Yielda/%
1
2
3
4
98 (96)b
5
6
7
8
AcOCs
94
96
AcO-nNBu4
AcOLi (THF)c
none
ꢀ-Hydroxy nitriles are known as useful building blocks
since they may readily be converted to ꢀ-hydroxycarboxylic
acids or ꢁ-amino alcohols.1 In general, ꢀ-hydroxy nitriles are
prepared by the condensation of carbonyl compounds with alkali
acetonitriles that are formed by ꢂ-deprotonation of nitriles.2
However, the yields of this condensation are not always satisfac-
tory because this reaction is a reversible one, and the produced
ꢀ-hydroxy nitrile is dehydrated easily to afford the ꢂ,ꢀ-unsatu-
rated nitrile. Therefore, several methods have been devised and
tried to improve yields in preparing ꢀ-hydroxy nitriles.3,4
Among them, the method that uses TMSCH2CN is considered
quite synthetically efficient because the reverse reaction is pre-
vented in the starting carbonyl compounds and nitrile by trap-
ping the formed alkoxide with TMSCH2CN.4 Palomo et al. re-
ported a TASF5-catalyzed cyanomethylation in the presence of
TMSCH2CN to give the adduct in moderate yields.4c More re-
cently, Shibasaki et al. reported on a copper fluoride-catalyzed
cyanomethylation of carbonyl compounds in the presence of
(EtO)3SiF.4d
AcONa
AcOK
97
94
N.D.
N.D.
aYield was determined by 1H NMR analysis (270 MHz) using Cl2HCCHCl2 as
an internal standard. bIsolated yield. cTHF was used as a solvent.
in DMF at room temperature and the desired product was ob-
tained in 98% yield (Table 1).8 The above reaction proceeded
smoothly even when the amount of AcOLi decreased to
1 mol % (Entry 2). The acetates having such counter cations as
sodium, potassium, cesium, or ammonium ion also worked
effectively in the above reaction to afford the desired products
in high yields (Entries 3–6). In the absence of the catalyst, on
the other hand, the cyanomethylated adduct was not detected.
The reactions with various carbonyl compounds under the
optimized conditions are summarized in Table 2. Aromatic alde-
hydes having electron-donating or -withdrawing groups reacted
smoothly to afford the cyanomethylated adducts in excellent
yields. Acid- or base-sensitive aldehydes also afforded the de-
sired products in high yields (Entries 4, 5, and 13). Further, an
Trimethylsilylacetonitrile is a popular reagent for Peterson
olefination as an excellent precursor of ꢂ-cyano carbanions.6 Be-
haviors of TMSCH2CN in synthetic reactions are also interesting
mechanistic problems (Scheme 1).
It was reported in the previous communications that the oxy-
gen containing-anions generated from carboxylic acids were
shown to be effective Lewis base catalysts for the activation of
carbon-silicon bond of Me3SiCN or Me3SiCF3.7 In order to
extend the synthetic utility of a Lewis base catalyst, a cyano-
methylation reaction between TMSCH2CN and carbonyl com-
pounds was considered.
Table 2. Cyanomethylation of various carbonyl compounds
O
OH
H+
Me3SiCH2CN
(1.4 equiv.)
AcOLi (10 mol%)
CN
+
R
R'
R
DMF, 0 °C−rt, 3 h
R'
Entry
RC(O)R0
Yield/% Entry
RC(O)R0
Yield/%
1
2
3
4
5
6
7
8
9
4-MeOC6H4CHO
C6H5CHO
94
98
95
97
91
94
95
99
97
10 (E)-PhCH=CHCHO
11 C6H11CHO
12 PhCH2CH2CHO
99
80
61
81
85
42
77
92
85
4-ClC6H4CHO
4-MeCO2C6H4CHO
4-NCC6H4CHO
4-NO2C6H4CHO
2-NaphthylCHO
2-FurylCHO
13
14
15
16
17
18
1
2
3
4
5
6
In the first place, cyanomethylation of benzaldehyde with
TMSCH2CN was tried in the presence of 10 mol % of AcOLi
2-QuinolylCHO
Peterson Type
aYield was determined by 1H NMR analysis (270 MHz) using 1,1,2,2-tetra-
chloroethane as an internal standard.
O
Bu−Li+
H
H
H
R
H
CN
CN
O
O
O
Me3Si
H
O
CN
R
R
H
Me3Si
CN
Me
Me
Addition Type
O
O N
2
N
OH
Boc
2
O
4
3
1
F−
H
R
H
O
Me3Si
CN
CN
CF
3
5
Scheme 1.
6
Copyright ꢀ 2005 The Chemical Society of Japan

Chemistry Letters Vol.34, No.11 (2005)
1509
Table 3. Cyanomethylation with various (trimethylsilyl)-aceto-
nitrile derivatives
catalysts such as lithium acetate proceeded smoothly via the
activation of carbon–silicon bond of TMSCH2CN. This method
is applied to the synthesis of various ꢀ-hydroxy nitriles under
mild conditions. Further investigation on this reaction is now
in progress.
R2
R1
Catalyst (mol%) H+
OH
R1
O
+
CN
R2
Me3Si
CN
(1.4 equiv.)
Ph
Ph
H
DMF, 0 °C−rt, 3 h
Entry
Reagent
Catalyst (mol %) Yielda/% syn:anti
This study was supported in part by the Grant of the 21st
Century COE Program from Ministry of Education, Culture,
Sports, Science and Technology (MEXT), Japan.
1
2
3
4
R1 = Me, R2 = Me
R1 = Me, R2 = Me
R1 = Me, R2 = H
R1 = Et, R2 = H
7
7
8
9
AcOLi (10)
AcOCs (10)
AcOCs (10)
AcOCs (10)
14
98b
98
97
—
—
57:43
58:42
References and Notes
aYield was determined by 1H NMR analysis (270 MHz) using 1,1,2,2-tetra-
chloroethane as an internal standard. bThe reaction time was 6 h.
1
2
Y. Fukuda and Y. Okamoto, Tetrahedron, 58, 2513 (2002).
a) E. W. Kaiser and C. R. Hauser, J. Am. Chem. Soc., 89, 4566
(1967). b) E. W. Kaiser and C. R. Hauser, J. Org. Chem., 33,
3402 (1968).
ꢂ,ꢀ-unsaturated carbonyl compound gave the corresponding
1,2-adduct as a sole product (Entries 10 and 18). However,
enolizable ketones that were less reactive afforded the desired
products in moderate yields because the competitive abstraction
of ꢂ-proton took place to give the corresponding silyl enol ether
(Entry 15).
Next, the Lewis base-catalyzed cyanomethylation reaction
was tried by using several trimethylsilylacetonitriles (Table 3).
When trimethylsilylacetonitrile derivative 7 was used as a sub-
strate, the corresponding ꢀ-hydroxy nitrile was obtained in
low yields only because of the steric hindrance. Then, various
Lewis bases were screened and reaction conditions were opti-
mized so as to improve the yields. Consequently, it was noted
that the corresponding cyanomethylated adduct was obtained
in high yield when the reaction was carried out in the presence
of a catalytic amount of AcOCs (Entry 2). Similarly, trimeth-
ylsilylacetonitrile derivatives 8 or 9 smoothly reacted with
carbonyl compounds to afford the desired product in good yields,
although the diastereoselectivity must to be optimized (Entries 3
and 4).
3
4
a) J. J. P. Zhou, B. Zhong, and R. B. Silverman, J. Org. Chem., 60,
2261 (1995). b) P. Kisanga, D. McLeod, B. D’Sa, and J. Verkade,
J. Org. Chem., 64, 3090 (1999). c) N. Kumagai, S. Matsunaga, and
M. Shibasaki, J. Am. Chem. Soc., 126, 13632 (2004).
a) B. A. Gostevskii, O. A. Kruglaya, A. I. Albanov, and N. S.
Vyazankin, J. Organomet. Chem., 187, 157 (1980). b) R.
Latouche, F. Texier-Boullet, and J. Hamelin, Tetrahedron Lett.,
´
32, 1179 (1991). c) C. Palomo, J. M. Aizpurua, M. C. Lopez,
and B. Lecea, J. Chem. Soc., Perkin Trans. 1, 1989, 1692. d) Y.
Suto, N. Kumagai, S. Matsunaga, M. Kanai, and M. Shibasaki,
Org. Lett., 5, 3147 (2003). e) Y. Kawanami, H. Yuasa, F.
Toriyama, S. Yoshida, and T. Baba, Catal. Commun., 4, 455
(2003).
5
6
TASF: Tris(dimethylamino)sulfur(trimethylsilyl)difluoride.
a) L. Birkofer, A. Ritter, and H. Wiedden, Chem. Ber., 95, 971
(1962). b) I. Matsuda, S. Murata, and Y. Ishii, J. Chem. Soc.,
Perkin Trans. 1, 1979, 26. c) Y. Yamakado, M. Ishiguro, N. Ikeda,
and H. Yamamoto, J. Am. Chem. Soc., 103, 5568 (1981).
a) T. Mukaiyama, Y. Kawano, and H. Fujisawa, Chem. Lett., 34,
88 (2005). b) Y. Kawano, H. Fujisawa, and T. Mukaiyama, Chem.
Lett., 34, 422 (2005). c) E. Takahashi, H. Fujisawa, T. Yanai, and
T. Mukaiyama, Chem. Lett., 34, 318 (2005).
Typical experimental procedure is as follows (Table 1, Entry 1): to
a stirred solution of AcOLi (2.6 mg, 0.04 mmol) in DMF (0.7 mL)
were added successively a solution of benzaldehyde (42.4 mg,
0.4 mmol) in DMF (0.3 mL) and TMSCH2CN (76.5 mL, 0.56
mmol) at 0 ꢁC. And the reaction mixture slowly warmed to room
temperature. The mixture was stirred for 3 h at the same tempera-
ture and quenched with 1 M HCl (1.0 mL) and MeOH (1.0 mL).
The mixture was extracted with AcOEt and organic layer
was washed with brine and dried over anhydrous Na2SO4, and
evaporated. The crude product was purified by passing through
short SiO2 column to afford the desired product (56.6 mg, 96%)
as colorless oil.
7
8
AcOM
SiMe3
Me3SiCH2CN
DMF
O
R
CH2CN
O−
+
M+
−
M+
OAc
Me
Me
AcOSiMe3
Si Me
R
CH2CN
CH2CN
A
B
O
M = Li, Na, K, Cs, n-NBu4
R
H
9
It is reported that the reaction with TMSCH2CN in acetonitrile
forms a pentacoordinate silicon species: D. J. Adams, J. H. Clark,
L. B. Hansen, V. C. Sanders, and S. J. Tavener, J. Fluorine Chem.,
92, 123 (1998).
Scheme 2.
Although the mechanism of this reaction is not clear yet, an
assumed catalytic cycle is illustrated in Scheme 2.9,10 In the first
place, a Lewis base catalyst coordinates to a silicon atom of
TMSCH2CN to form a hypervalent silicate A or a corresponding
hexacoordinate silicate with an additional coordination of the
solvent. The nucleophilicity of the silicate A is then grow suffi-
cient to react with carbonyl compounds to form alkoxide B and
TMSOAc. Subsequent silylation of B by thus formed TMSOAc
afforded O-silyl ether along with the regeneration of the catalyst
to establish a catalytic cycle.
10 Cyanomethylation reaction was studied by using trimethylsilyl
acetonitrile derivatives 8 in CH3CN. When Bu4NPh3SiF2 was
used as a catalyst, the ꢀ-hydroxy nitrile 10 was obtained in 30%
yield along with the desired ꢀ-hydroxy nitrile 11. However, the
ꢀ-hydroxy nitrile 10 was not detected when Bu4NOAc was used.
It is considered that these reactions proceeded via two different
mechanisms.
H+
Me
H
OH
O
Cat. (20 mol%)
+
CN
Me3Si
CN
Ph
CH3CN
0 °C−rt, 3 h
Ph
H
(1.4 equiv.)
H
R
Thus, it is noted that a catalytic cyanomethylation of various
carbonyl compounds with TMSCH2CN by using Lewis base
Bu4NPh3SiF2 10 : R = H; 30% 11 : R = Me; 49%
Bu4NOAc 10 : R = H; N.D. 11 : R = Me; 96%
Published on the web (Advance View) October 8, 2005; DOI 10.1246/cl.2005.1508