Lithium chloride: An active and simple catalyst for cyanosilylation of aldehydes and ketones

Article abstract of DOI:10.1021/jo050791t

LiCl acts as a highly effective catalyst for cyanosilylation of various aldehydes and ketones to the corresponding silylated cyanohydrins. The reaction proceeds smoothly with a substrate/catalyst molar ratio of 100-100 000 at 20-25 °C under solvent-free conditions. α,β-Unsaturated aldehydes are completely converted to the 1,2-adducts. The cyanation products can be isolated by direct distillation of the reaction mixture.

Full text of DOI:10.1021/jo050791t

Lithium Chloride: An Active and Simple
Catalyst for Cyanosilylation of Aldehydes
and Ketones
desired adducts. Recently reported chiral Lewis acid-
Lewis base combined catalysts have been successfully
7
applied to the asymmetric reaction.
3b,5a
,3l BF
3f
Metal halides, such as AlCl
3
,
BiBr
3
3
, InX
3
(X
3o
3m
3e
3f
3f
)
R
Br,
SnCl
F
2
), LnCl
(R ) n-C
3
(Ln ) La, Ce, Sm), MgBr
2
, SnCl
4
,
Nobuhito Kurono, Masayo Yamaguchi, Ken Suzuki, and
Takeshi Ohkuma*
3
j
,3f and ZnI
3a
2
4
9
H , C
H
6 5
), TiCl
4
2
,
are
known to be Lewis acidic catalysts for cyanosilylation of
aldehydes. However, no report has described the catalytic
properties of LiCl, one of the simplest metal halides, for
this reaction.8 We here report an efficient and facile
procedure for cyanosilylation of aldehydes and some
ketones catalyzed by LiCl with a substrate-to-catalyst
molar ratio (S/C) as high as 100 000 under solvent-free
conditions. A series of silylated cyanohydrins can be
isolated by direct distillation.
Division of Chemical Process Engineering, Graduate School
of Engineering, Hokkaido University,
Sapporo 060-8628, Japan
ohkuma@eng.hokudai.ac.jp
Received April 19, 2005
First, the catalytic activity of simple alkaline salts was
tested in the reaction of benzaldehyde (1a) and (CH ) -
3 3
SiCN in a 1:1 ratio at 20-25 °C. As shown in Table 1,
LiCl exhibited excellent catalytic activity under solvent-
free conditions. The reaction with an S/C of 10 000 [1a
(
3 3
72.7 g, 678 mmol), (CH ) SiCN (68.0 g, 685 mmol), LiCl
LiCl acts as a highly effective catalyst for cyanosilylation of
various aldehydes and ketones to the corresponding silylated
cyanohydrins. The reaction proceeds smoothly with a sub-
strate/catalyst molar ratio of 100-100 000 at 20-25 °C
under solvent-free conditions. R,â-Unsaturated aldehydes
are completely converted to the 1,2-adducts. The cyanation
products can be isolated by direct distillation of the reaction
mixture.
(2.5 mg, 59 µmol)] was completed within 1 h, affording
the cyanation product 2a in 100% yield (entry 2). A THF
solution of LiCl could be used for this reaction [1a (1.07
g, 10.1 mmol), (CH ) SiCN (1.02 g, 10.3 mmol), LiCl (29.5
3
3
mM in THF, 34 µL, 1.0 µmol)] without loss of catalytic
activity (entry 3). Turnover frequency (TOF), defined as
moles of product per mole of catalyst per hour, reached
(
4) Chiral catalysts: (a) Reetz, M. T.; Kunisch, F.; Heitmann, P.
Tetrahedron Lett. 1986, 27, 4721-4724. (b) Minamikawa, H.; Hay-
akawa, S.; Yamada, T.; Iwasawa, N.; Narasaka, K. Bull. Chem. Soc.
Jpn. 1988, 61, 4379-4383. (c) Kobayashi, S.; Tsuchiya, Y.; Mukaiyama,
T. Chem. Lett. 1991, 541-544. (d) Ohno, H.; Nitta, H.; Tanaka, K.;
Mori, A.; Inoue, S. J. Org. Chem. 1992, 57, 6778-6783. (e) Corey, E.
J.; Wang, Z. Tetrahedron Lett. 1993, 34, 4001-4004. (f) Hayashi, M.;
Inoue, T.; Miyamoto, Y.; Oguni, N. Tetrahedron 1994, 50, 4385-4398.
(g) Bolm, C.; M u¨ ller, P. Tetrahedron Lett. 1995, 36, 1625-1628. (h)
Abiko, A.; Wang, G. J. Org. Chem. 1996, 61, 2264-2265. (i) Yang, W.-
B.; Fang, J.-M. J. Org. Chem. 1998, 63, 1356-1359. (j) Belocon’, Y.
N.; Caveda-Cepas, S.; Green, B.; Ikonnikov, N. S.; Khrustalev, V. N.;
Larichev, V. S.; Moscalenko, M. A.; North, M.; Orizu, C.; Tararov, V.
I.; Tasinazzo, M.; Timofeeva, G. I.; Yashkina, L. V. J. Am. Chem. Soc.
1999, 121, 3968-3973. (k) Belocon’, Y. N.; North, M.; Parsons, T. Org.
Lett. 2000, 2, 1617-1619. (l) You, J. S.; Gau, H.-M.; Choi, M. C. K.
Chem. Commun. 2000, 1963-1964. (m) Gama, A.; Flores-L o´ pez, L. Z.;
Aguirre, G.; Parra-Hake, M.; Somanathan, R.; Waish, P. J. Tetrahe-
dron: Asymmetry 2002, 13, 149-154. (n) Lundgren, S.; Lutsenko, S.;
J o¨ nsson, C.; Moberg, C. Org. Lett. 2003, 5, 3663-3665. (o) Li, Y.; He,
B.; Qin, B.; Feng, X.; Zhang, G. J. Org. Chem. 2004, 69, 7910-7913.
(5) (a) Evans, D. A.; Truesdale, L. K. Tetrahedron Lett. 1973, 4929-
4932. (b) Ohta, H.; Hayakawa, S.; Moriwaki, H.; Harada, S.; Okamoto,
M. Chem. Pharm. Bull. 1986, 34, 4916-4926. (c) Kobayashi, S.;
Tsuchida, Y.; Mukaiyama, T. Chem. Lett. 1991, 537-540. (d) Matsub-
ara, S.; Takai, T.; Utimoto, K. Chem. Lett. 1991, 1447-1450. (e) Ruble,
J. C.; Fu, G. C. J. Org. Chem. 1996, 61, 7230-7231. (f) Kantam, M.
L.; Sreekanth, P.; Santhi, P. L. Green. Chem. 2000, 47-48. (g)
Wilkinson, H. S.; Grover, P. T.; Vandedbossche, C. P.; Bakale, R. P.;
Bhongle, N. N.; Wald, S. A.; Senanayake, C. H. Org. Lett. 2001, 3, 553-
556. (h) Wang, Z.; Fetterly, B.; Verkade, J. G. J. Organomet. Chem.
2002, 646, 161-166. (i) Kim, S. S.; Rajagopal, G.; Song, D. G. J.
Organomet. Chem. 2004, 689, 1734-1738.
Cyanosilylation of carbonyl compounds is an efficient
procedure for the synthesis of silylated cyanohydrins,
which are readily converted to useful functionalized
compounds, such as R-hydroxy carbonyl compounds and
1,2
â-amino alcohols. Liquid (CH
3 3
) SiCN (bp 118 °C) reacts
with aldehydes in the presence of a catalytic amount of
3
,4
5,6
Lewis acids or nucleophilic compounds to afford the
(
1) (a) North, M. Synlett 1993, 807-820. (b) Effenberger, F. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1555-1564. (c) Gregory, R. J. H. Chem.
Rev. 1999, 99, 3649-3682.
(2) (a) Furin, G. G.; Vyazankina, O. A.; Gostevsky, B. A.; Vyazankin,
N. S. Tetrahedron 1988, 44, 2675-2749. (b) Rasmussen, J. K.;
Heilmann, S. M.; Krepski, L. R. In Advances in Silicon Chemistry;
Larson, G. L., Ed.; JAI Press: London, 1991; Vol. 1, pp 65-187. (c)
North, M. Tetrahedron: Asymmetry 2003, 14, 147-176.
(3) (a) Evans, D. A.; Truesdale, L. K.; Carroll, G. L. J. Chem. Soc.,
Chem. Commun. 1973, 55-56. (b) Lidy, W.; Sundermeyer, W. Chem.
Ber. 1973, 106, 587-593. (c) Noyori, R.; Murata, S.; Suzuki, M.
Tetrahedron 1981, 37, 3899-3910. (d) Greenlee, W. J.; Hangauer, D.
G. Tetrahedron Lett. 1983, 24, 4559-4560. (e) Vougioukas, A. E.;
Kagan, H. B. Tetrahedron Lett. 1987, 28, 5513-5516. (f) Reetz, M. T,;
Drewes, M. W.; Harms, K.; Reif, W. Tetrahedron Lett. 1988, 29, 3295-
3298. (g) Faller, J. W.; Gundersen, L.-L. Tetrahedron Lett. 1993, 34,
2275-2278. (h) Scholl, M.; Fu, G. C. J. Org. Chem. 1994, 59, 7178-
7179. (i) Cozzi, P. G.; Floriani, C. J. Chem. Soc., Perkin Trans. 1 1995,
2557-2563. (j) Whitesell, J. K.; Apodaca, R. Tetrahedron Lett. 1996,
37, 2525-2528. (k) Yang, Y.; Wang, D. Synlett 1997, 1379-1380. (l)
Komatsu, N.; Uda, M.; Suzuki, H.; Takahashi, T.; Domae, T.; Wada,
M. Tetrahedron Lett. 1997, 38, 7215-7128. (m) Loh, T.-P.; Xu, K.-C.;
Ho. D. S.-C.; Sim, K.-Y. Synlett, 1998, 369-370. (n) Saravanan, P.;
Anand, R. V.; Singh, V. K. Tetrahedron Lett. 1998, 39, 3823-3824. (o)
Bandini, M.; Cozzi, P. G.; Garelli, A.; Melchiorre, P.; Unami-Ronchi,
A. Eur. J. Org. Chem. 2002, 3243-3249. (p) King, J. B.; Gabbai, F. P.
Organometallics 2003, 22, 1275-1280. (q) C o´ rdoba, R.; Plumet, J.
Tetrahedron Lett. 2003, 44, 6157-6159. (r) Baleiz a˜ o, C.; Gigante, B.;
Garcia, H.; Corma, A. Tetrahedron Lett. 2003, 44, 6813-6816. (s)
Karimi, B.; Ma’Mani, L. Org. Lett. 2004, 6, 4813-4815.
(6) Chiral catalysts: (a) Holmes, I. P.; Kagan, H. B. Tetrahedron
Lett. 2000, 41, 7453-7456. (b) Holmes, I. P.; Kagan, H. B. Tetrahedron
Lett. 2000, 41, 7457-7460.
(7) (a) Hamashima, Y.; Sawada, D.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 1999, 121, 2641-2642. (b) Shibasaki, M.; Kanai, M.;
Funabashi, K. Chem. Commun. 2002, 1989-1999. (c) Ryu, D. H.;
Corey, E. J. J. Am. Chem. Soc. 2004, 126, 8106-87107.
(8) No catalytic activity of LiCl with triglyme monomethyl ether for
3 3
reaction of camphor and (CH )
SiCN in THF was reported.5g
10.1021/jo050791t CCC: $30.25 © 2005 American Chemical Society
6530
J. Org. Chem. 2005, 70, 6530-6532
Published on Web 06/30/2005

TABLE 1. Cyanosilylation of Benzaldehyde (1a)a
TABLE 2. Cyanosilylation of Aldehydes and Ketonesa
entry
catalyst
methodb
S/Cc
solventd
yield (%)e
1
2
3
4
5
6
7
8
9
LiCl
LiCl
LiCl
LiCl
LiCl
LiCl
NaCl
KCl
CsCl
LiF
A
B
A
A
A
A
B
B
B
A
A
A
A
-
50000f
10000
10000
50000
50000
10000
20
neat
neat
neat
56
100
100
<0.3
7
g
CH2Cl2
g
THF
toluene
g
7
neat
neat
neat
neat
neat
neat
neat
neat
1
20
0.3
22
1
1ad
a
a
b
c
1c
d
1e
1f
1g
1h
1h
i
j
R3Si
S/Cb
time (h) yield of 2 or 3 (%)c
20
10
11
12
13
14
10000
10000
10000
10000
-
<0.3
86
(CH ) Si
10000
100000
10000
5000
10000
10000
10000
5000
1
48
5
100 (94)
99 (f)
3
3
LiBr
LiI
e
1
1
1
1
(CH3)3Si
98
t-C4H9(CH3)2Si
100 (96)
100 (98)
100 (93)
100 (93)
100 (97)
100 (97)
100 (98)
100 (96)
97 (88)h
LiClO4
-
2.5
<0.3
(CH3)3Sig
5
h
(CH3)3Si
0.5
1
0.6
6
0.5
0.4
3
8
22
a
t-C H (CH ) Si
Unless otherwise stated, reactions were conducted using 10
4
9
3 2
1
(CH3)3Si
mmol of 1a and 1 equiv of (CH3)3SiCN in the presence of catalyst
g
at 20-25 °C for 1 h. b A: Catalyst was added as a 29.5 mM solution
3 3
(CH ) Si
c
(CH ) Si
10000
10000
10000
10000
10000
10000
10000
10000
10000
1000
of THF. B: Catalyst was added as a solid. Substrate/catalyst
3 3
d
3 3
(CH ) Si
molar ratio. Neat: Reaction was conducted under solvent-free
conditions. e Determined by GC or H NMR analysis. Reaction
1
f
3 3
(CH ) Si
h
using 72.7 g (678 mmol) of 1a. g [1a] ) 1.0 M. h Reaction without
t-C H (CH ) Si
100 (93)h
4
9
3 2
1
1
1
1
(CH3)3Si
(CH3)3Si
(CH3)3Si
(CH3)3Si
99 (98)
100 (95)
100 (94)
100 (98)
100 (90)
81 (f)
catalyst.
0.5
0.5
0.2
2
k
l
2
8 000 at an S/C of 50 000 (entry 1). Thus, LiCl is one o3f
the most active metal halide catalysts so far reported.
The catalytic efficiency was decreased when the reaction
was conducted in organic solvents ([1a] ) 1.0 M), such
1l
4 9 3 2
t-C H (CH ) Si
i
i
g
1m
(CH3)3Sig
6
1
1
1
m
(CH3)3Si
100
3
100 (96)
80 (f)
100 (94)
i
g
n
(CH3)3Si
1000
6
as CH
NaCl and KCl are totally ineffective for this reaction
entries 7 and 8).9,10 The TOF of the reaction with CsCl
was only 4 (entry 9). The activities of LiBr and LiI were
comparable to that of LiCl (entries 11 and 12), while LiF
gave no adduct under the same conditions (entry 10). The
reaction in the presence of LiClO
which is known as a promoter of cyanosilylation of
aldehydes and ketones, resulted in only 2.5% conversion
2 2
Cl , THF, and toluene (entries 4-6). Insoluble
i
(CH3)3Sig
n
100
2.5
a
Unless otherwise stated, reactions were conducted using 10
(
mmol of 1 and one equiv of R3SiCN in the presence of LiCl added
as a THF solution (24-60 mM), at 20-25 °C under solvent-free
b
c
conditions. Substrate/catalyst molar ratio. Determined by GC
1
or H NMR analysis. The isolated yield is indicated in parentheses.
d
with an S/C of 10 000,
Reaction using 10.8 g (101 mmol) of 1a with LiCl added as a
4
e
f
0
.31 M THF solution. Reaction using 5.3 g (50 mmol) of 1a. Not
g
h
isolated. 1.3 equiv of (CH3)3SiCN was used. No conjugated
1
i
addition product was observed by H NMR analysis. Use of 5
1
1
(
entry 13). These results clearly indicate that the
mmol of 1 with LiCl added as a THF solution (0.20-0.22 M).
-
combination of a lithium cation and a halide anion, Cl ,
-
-
Br , or I , is crucial for obtaining high catalytic activity.
A series of carbonyl compounds 1 reacted with cyano-
trialkylsilanes in the presence of LiCl under solvent-free
conditions at room temperature to give the cyanation
products, 2 and 3, in excellent yield as shown in Table 2.
4
-Methyl and 4-methoxybenzaldehydes, 1b and e, were
less reactive than the simple benzaldehyde 1a. The
reactions in the presence of a 1.3 equiv of (CH SiCN
3 3
)
with an S/C of 5000 were completed in 6 h. The cyanation
of 2-naphthalenecarbaldehyde (1g) with an S/C of 10 000
was completed in 25 min. Cinnamaldehyde (1h) and
1
The obtained products were isolated at >98% purity ( H
NMR analysis) by direct distillation of the reaction
mixture. No extraction or chromatogram separation was
necessary (see Experimental Section). The LiCl catalyzed
2
-octenal (1i) were predominantly converted to the 1,2-
adducts, 2h, i, and 3h, leaving the olefinic function
2
intact. No conjugated addition product was observed.
the reaction of 1a and (CH
affording 2a in 99% yield after 48 h. The sterically
hindered t-C (CH SiCN can be used as a cyanation
reagent. Reaction of ortho- or para-substituted benzal-
dehydes by electron-attracting Cl or CF , 1c, d, and f,
and (CH SiCN in a 1:1 ratio with LiCl (S/C ) 10 000)
was completed within 40 min.
3 3
) SiCN with an S/C of 100 000,
Even higher efficiency was achieved in the cyanation of
aliphatic aldehydes. Reaction of n-octanal (1j) and (CH ) -
3 3
SiCN with LiCl (S/C ) 10 000) was completed in 30 min.
Cyclohexanecarbaldehyde (1k) reacted in the same way.
Notably, sterically congested pivalaldehyde (1l) was
completely converted to the cyanation product 2l in only
0 min (TOF ) 60 000 h ). The reaction with t-C
CH SiCN was completed in 2 h. LiCl was also effective
for cyanosilylation of less reactive ketones. A turnover
number of 810 in 6 h was achieved in the reaction of
acetophenone (1m), an aromatic ketone, with an S/C of
1000 (Table 2). When the reaction was conducted with
4
H
9
3 2
)
3
3 3
)
-
1
1
(
4 9
H -
3 2
)
(
9) Higuchi, K.; Onaka, M.; Izumi, Y. Bull. Chem. Soc. Jpn. 1993,
6
6, 2016-2032.
(
(
10) He, B.; Li, Y.; Feng, X.; Zhang, G. Synlett 2004, 1776-1778.
11) (a) Reetz, M.; T.; Fox, D. N. A. Tetrahedron Lett. 1993, 34,
1
2
119-1122. (b) Azizi, N.; Saidi, M. R. J. Organomet. Chem. 2003, 688,
83-285.
J. Org. Chem, Vol. 70, No. 16, 2005 6531

with decrement of the original signal of (CH
2.07. No peak of (CH SiCl at δ 3.02 was observed. This
result was consistent with the measurement of a mixture
of 18-crown-6, KCN, and (CH SiCN, indicating a methyl
3 3
) SiCN at δ
-
3 3
)
3 3
)
signal at δ 1.91. The 18-crown-6/KCN combination is
known as the representative nucleophilic catalyst for
5
a
14b
cyanosilylation of carbonyl compounds and epoxides,
-
and the pentavalent [(CH
3 3
) Si(NC)
2
] was proposed to be
the reactive species based on the spectroscopic and
theoretical studies.14
In conclusion, LiCl is an active, inexpensive, and
simple catalyst for cyanosilylation of aldehydes and
ketones. The reaction can be conducted with an S/C as
high as 100 000 under solvent-free conditions. A series
of synthetically useful silylated cyanohydrins are obtain-
able by direct distillation of the reaction mixture.
FIGURE 1. Hammett plots for cyanosilylation of p-substi-
tuted benzaldehydes catalyzed by LiCl.
Experimental Section
an S/C of 100, the desired cyanation product 2m was
obtained in 100% yield. Reaction of 5-nonanone (1n), an
aliphatic ketone, afforded the adduct 2n in the same way.
The electronic effect of para substituents of benzalde-
hydes on the rate of the LiCl-catalyzed cyanosilylation
was examined by competition experiments using an
equimolar mixture of 1a and a series of para-substituted
aldehydes. The initial rates of reaction of the substituted
Experimental Procedure for Reaction of Benzaldehyde
(1a) and (CH ) SiCN (S/C ) 10 000). LiCl (130.3 mg, 3.07
3 3
mmol) and THF (10 mL) were placed in a 15-mL two-necked
flask, and the mixture was sonicated for 10 min and used as a
catalyst stock solution. Aldehyde 1a (10.76 g, 101.4 mmol) and
(
3 3
CH ) SiCN (11.40 g, 114.9 mmol) were placed in a 50-mL two-
necked flask, and the mixture was stirred at 20 °C under Ar.
The catalyst solution (33 µL, 10.1 µmol) was added to the
mixture, and the reaction proceeded exothermically. After stir-
ring for 1 h, the reaction mixture was distilled to give 2-phenyl-
2-trimethylsilyloxyacetonitrile (2a) (19.55 g, 94%), bp 92-94 °C/
benzaldehyde (v
calculated from three or four experiment sets. When the
relative rates were plotted against the σ
constant,12
X H
) and the parent aldehyde (v ) were
P
a
2
.0 mmHg. The yield determined by GC was 100%. Caution:
linear relationship with a F value of +1.24 was obtained
as shown in Figure 1. This result clearly indicates the
nucleophilic property of the reactive species.
(
3 3
CH ) SiCN must be used in a well-ventilated hood due to its
high toxicity.
LiCl is a soluble inorganic salt in several organic polar
compounds and acts as a source of nucleophilic Cl .
When LiCl behaves as a nucleophilic catalyst,5,6 Li[(CH
) -
3 3
-
13
Acknowledgment. This work was supported by
Grants-in-Aid from the Japan Society for the Promotion
of Science (JSPS) (No. 15350079) and the Nagase
Science and Technology Foundation.
SiCl(NC)] (4), a pentavalent silicon compound, is a
probable reactive species (eq 1).14
13
A
C NMR experiment
Supporting Information Available: Procedures of cy-
anosilylation of aldehydes and ketones, GC and NMR behavior
3 3
of products and LiCl with (CH ) SiCN, and kinetic experiments
for the Hammett plots. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO050791T
supported this hypothesis (see the Supporting Informa-
tion). A 1:1 mixture of LiCl and (CH SiCN in THF-d
solution at 25 °C indicated a new methyl signal at δ 1.93
3
)
3
8
(13) Nowick, J. M.; Lutterbach, G. In Encyclopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, 1995; Vol.
5
, pp 3063-3064.
(
14) (a) Dixon, D. A.; Hertler, W. R.; Chase, D. B.; Farnham, W. B.;
(12) Hammett, L. P. Physical Organic Chemistry, 2nd ed.; McGraw-
Davidson, F. Inorg. Chem. 1988, 27, 4012-4018. (b) Sassaman, M. B.;
Prakash, G. K. S.; Olah, G. A. J. Org. Chem. 1990, 55, 2016-2018.
Hill: New York, 1970; Chapter 11.
6532 J. Org. Chem., Vol. 70, No. 16, 2005