High-pressure-promoted uncatalyzed cyanation of acetals using trimethylsilyl cyanide as a cyanide source in nitromethane

Article abstract of DOI:10.1055/s-2006-947347

A new uncatalyzed method for the preparation of cyanohydrin O-alkyl ethers was developed using the high-pressure-promoted reaction of acetals with trimethylsilyl cyanide in nitromethane. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-947347

1968
LETTER
High-Pressure-Promoted Uncatalyzed Cyanation of Acetals Using
Trimethylsilyl Cyanide as a Cyanide Source in Nitromethane1
High
P
ressure-Pr
o
o
moted
U
ncat
j
alyze
d
i
Cyanation of
K
A
cetals umamoto, Keiji Nakano, Yoshiyasu Ichikawa, Hiyoshizo Kotsuki*
Laboratory of Natural Product Chemistry, Faculty of Science, Kochi University, Akebono-cho, Kochi 780-8520, Japan
Fax +81(888)448359; E-mail: kotsuki@cc.kochi-u.ac.jp
Received 2 May 2006
Table 1 Cyanation of Benzaldehyde Dimethyl Acetal 1 under
Abstract: A new uncatalyzed method for the preparation of cyano-
hydrin O-alkyl ethers was developed using the high-pressure-
promoted reaction of acetals with trimethylsilyl cyanide in nitro-
methane.
Various Conditionsa
OMe
CN
8 h
TMSCN
(1.2 equiv)
+
Ph
Ph
solvent
OMe
OMe
Key words: cyanation, acetals, trimethylsilyl cyanide, nitro-
1a
2a
methane, high pressure reaction
Entry
Solvent
Pressure Temp
Yield
(%)b
Recovery
(GPa)
0.8
0.8
0.8
0.8
0.8
0.6
0.4
0.2
0.8
0.8
0.8
0.8
(°C)
60
60
60
60
60
60
60
60
50
40
60
60
of 1a (%)b
Cyanohydrins and their trimethylsilyl ether derivatives
are known to be versatile intermediates in organic synthe-
sis because they are convenient precursors for the prepa-
ration of a-hydroxy acids, b-amino alcohols, and related
molecules.2 In general, these compounds are prepared by
the reaction of trimethylsilyl cyanide (TMSCN) or its
analogues with carbonyl compounds in the presence of
various Lewis acid or Lewis base catalysts. On the other
hand, cyanohydrin O-alkyl ethers are obtained from ace-
tals and TMSCN with the assistance of Lewis acids such
as TiCl4, SnCl4, BF3·OEt2, and TMSOTf,3 since acetals
are normally inert toward nucleophilic substitution under
basic or neutral conditions. However, in view of the im-
portance of an environment-friendly non-metal-catalyzed
synthesis, there is a growing need for the development of
new catalyst-free approaches to the transformation of
acetals into the corresponding cyanohydrin O-alkyl ether
derivatives.4
1
2
THF
0
0
93
90
90
39
0
Et2O
3
CH2Cl2
MeCN
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
DMF
0
4
54
94
48
23
0
5
6
50
74
95
42
60
34
77
7
8
9
56
38
22
0
10
11c
12c
DMSO
a All reactions were conducted in the listed solvent (ca. 1.2 mL) using
1a (1.0 mmol) and TMSCN (1.2 mmol).
In connection with our ongoing projects to incorporate
high pressure reactions into new synthesis protocols,5 we
anticipated that acetals could react with a cyanide nucleo-
phile without the use of any catalysts or additives. This
stems from the fact that bond formation and ionization
both have a large negative activation volume.6 Herein we
describe the realization of this expectation in the addition
reaction of TMSCN to acetals.
b Determined by GC analysis of the crude reaction mixture using
n-pentadecane as an internal standard.
c Considerable amount of unidentified by-products was formed.
went to completion with a nearly quantitative yield (entry
6). On the other hand, when the reaction was conducted in
DMF or DMSO, considerable decomposition of 1a was
observed (entries 11 and 12).
To test the feasibility of the above strategy, we first exam-
ined the reaction of benzaldehyde dimethyl acetal (1a)
with TMSCN (1.2 equiv) at 0.8 GPa and 60 °C in various
organic solvents. As shown in Table 1, there is a strong
solvent effect. While the use of common less-polar sol-
vents including THF, Et2O, and CH2Cl2 gave no product
(entries 1–3), in acetonitrile the desired phenylacetonitrile
2a was formed in 54% yield (entry 4).7 To our delight,
when nitromethane was used as the solvent, the reaction
As expected, the reaction was highly dependent on both
pressure and temperature: pressures above 0.8 GPa and
temperatures above 60 °C are both necessary to achieve
synthetically useful results (entries 5–10).
The basis of the dramatic effect of nitromethane in this
cyanation is unclear at present. However, it is conceivable
that an increase in pressure may strongly intensify the
charge density at the oxygen atoms of nitromethane,
which acts as a dual anchor to assemble each component
via coordination with the silicon atom, thereby increasing
SYNLETT 2006, No. 12, pp 1968–1970
0
1
.0
8
.2
0
0
6
Advanced online publication: 24.07.2006
DOI: 10.1055/s-2006-947347; Art ID: U05306ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
High Pressure-Promoted Uncatalyzed Cyanation of Acetals
1969
Table 2 Cyanation of Acetals with TMSCN under High Pressurea
Entry
Substrate
Temp (°C)
Time (h)
24
Product
Yield (%)b
85
TMSO
NC
O
O
1
60
O
1b
2b
2c
TMSO
NC
O
2
60
24
89
O
O
1c
CN
OMe
OMe
OMe
3
4
5
60
60
80
9
100
99
MeO
MeO
2d
1d
OMe
OMe
CN
OMe
20
24
Cl
Cl
1e
2e
CN
OMe
OMe
OMe
80
NC
NC
2f
1f
CN
OMe
OMe
S
S
6
7
60
60
20
20
97
96
OMe
1g
2g
CN
OMe
OMe
Ph
OMe
Ph
2h
1h
OMe
OMe
CN
OMe
8c
9c
80
80
24
24
39
46
1i
1j
2i
2j
CN
OMe
OMe
OMe
a All reactions were performed at 0.8 GPa in MeNO2 (ca. 1.2 mL) using acetal 1 (1.0 mmol) and TMSCN (1.2 mmol).
b Isolated yield.
c Considerable decomposition of the starting material was observed.
the nucleophilicity of TMSCN8,9 and stabilizing an oxo-
carbenium ion intermediate through electrostatic inter-
action (Scheme 1).
OMe
OMe
high pressure
+
TMSCN
Ar
MeNO2
‡
Me
Me
With the optimal conditions in hand, we then examined a
variety of acetals to establish the general utility of this
transformation (Table 2).10 All reactions were performed
at 0.8 GPa in nitromethane. Cyclic acetals 1b and 1c re-
acted smoothly with TMSCN to afford 2b and 2c in high
yields (entries 1 and 2). The difference in the reactivity of
several para-substituted benzaldehyde acetals 1d–f
clearly reflects the relative stability of the intermediate
oxocarbenium ions (entries 3–5).11 Acetals 1g and 1h also
showed adequate reactivity, and provided 2g and 2h,
Me
Me
–
–
–
–
+
+
δ
δ
δ
δ
N
N
HO
O
O
O
Ar
MeO
Ar
O
O
SiMe3
SiMe3
MeO
N≡C
N≡C
+
CN
+
TMSOMe
Ar
OMe
Scheme 1
Synlett 2006, No. 12, 1968–1970 © Thieme Stuttgart · New York

1970
K. Kumamoto et al.
LETTER
(4) (a) Manju, K.; Trehan, S. J. Chem. Soc., Perkin Trans. 1
respectively, in excellent yields (entries 6 and 7). Com-
pared with these substrates, aliphatic acetals such as 1i
and 1j were resistant to cyanation under these conditions,
and 2i and 2j were produced in somewhat lower yields
(entries 8 and 9).
1995, 2383. (b) Watahiki, T.; Ohba, S.; Oriyama, T. Org.
Lett. 2003, 5, 2679. (c) Iwanami, K.; Hinakubo, Y.;
Oriyama, T. Tetrahedron Lett. 2005, 46, 5881.
(5) Kotsuki, H.; Kumamoto, K. Yuki Gosei Kagaku Kyokai-shi
2005, 63, 770.
(6) Organic Synthesis at High Pressure; Matsumoto, K.;
Acheson, R. M., Eds.; John Wiley and Sons: New York,
1991.
The present method was also effective for the cyanation of
ortho esters (Scheme 2).12 When 3 and 5 were each treated
with TMSCN in nitromethane at high pressure, the corre-
sponding monocyanides 4 and 6 were obtained in essen-
tially quantitative yields. These products were quite stable
under these conditions, and no bis-cyanation occurred
even with the use of excess TMSCN.
(7) We also examined the same reaction in the presence of
inorganic lithium salts (1.5 equiv) in MeCN, but no
significant improvement was observed: LiBF4, 65%; LiOTf,
32%. There are some precedents regarding the effect of
lithium salts in cyanohydrin formation: (a) Jenner, G.
Tetrahedron Lett. 1999, 40, 491. (b) Kurono, N.;
Yamaguchi, M.; Suzuki, K.; Ohkuma, T. J. Org. Chem.
2005, 70, 6530.
OMe
OMe
OMe
OMe
CN
TMSCN (1.2 equiv)
(8) For previous examples on the activation of TMSCN by
coordination with the oxygen atom of heteroatom oxides,
see: (a) Chen, F.; Feng, X.; Qin, B.; Zhang, G.; Jiang, Y.
Org. Lett. 2003, 5, 949. (b) Kim, S. S.; Kim, D. W.;
Rajagopal, G. Synlett 2004, 213. (c) Zhou, H.; Chen, F.-X.;
Qin, B.; Feng, X.; Zhang, G. Synlett 2004, 1077. (d) Li, Y.;
He, B.; Feng, X.; Zhang, G. Synlett 2004, 1598. (e) Kim, S.
S.; Rajagopal, G.; Kim, D. W.; Song, D. H. Synth. Commun.
2004, 34, 2973. (f) Chen, F.-X.; Zhou, H.; Liu, X.; Qin, B.;
Feng, X.; Zhang, G.; Jiang, Y. Chem. Eur. J. 2004, 10,
4790. (g) Chen, F.-X.; Qin, B.; Feng, X.; Zhang, G.; Jiang,
Y. Tetrahedron 2004, 60, 10449. (h) Chen, F.-X.; Feng, X.
Synlett 2005, 892. (i) Wen, Y.; Huang, X.; Huang, J.; Xiong,
Y.; Qin, B.; Feng, X. Synlett 2005, 2445. (j) Takahashi, E.;
Fujisawa, H.; Yanai, T.; Mukaiyama, T. Chem. Lett. 2005,
34, 604. (k) Yamagiwa, N.; Tian, J.; Matsunaga, S.;
Shibasaki, M. J. Am. Chem. Soc. 2005, 127, 3413. (l) Ryu,
D. H.; Corey, E. J. J. Am. Chem. Soc. 2005, 127, 5384.
(m) Hatano, M.; Ikeno, T.; Miyamoto, T.; Ishihara, K. J. Am.
Chem. Soc. 2005, 127, 10776. (n) Liu, X.; Qin, B.; Zhou,
X.; He, B.; Feng, X. J. Am. Chem. Soc. 2005, 127, 12224.
(o) Kim, S. S.; Kwak, J. M. Tetrahedron 2006, 62, 49.
(9) A similar type of silicon atom coordination has been
proposed by others: (a) Dixon, D. A.; Hertler, W. R.; Chase,
D. B.; Farnham, W. B.; Davidson, F. Inorg. Chem. 1988, 27,
4012. (b) Sassaman, M. B.; Prakash, G. K. S.; Olah, G. A. J.
Org. Chem. 1990, 55, 2016. (c) Kobayashi, S.; Tsuchiya,
Y.; Mukaiyama, T. Chem. Lett. 1991, 537. (d) Wang, Z.;
Fetterly, B.; Verkade, J. G. J. Organomet. Chem. 2002, 646,
161. (e) Wang, L.; Huang, X.; Jiang, J.; Liu, X.; Feng, X.
Tetrahedron Lett. 2006, 47, 1581. (f) See also ref. 8f–h, 8o.
(10) General Procedure.
0.8 GPa, 60 °C, 24 h
MeNO2
OMe
4 (96%)
3
TMSCN (1.2 equiv)
OMe
OMe
OMe
CN
0.8 GPa, 60 °C, 24 h
MeNO2
OMe
OMe
5
6 (94%)
Scheme 2
In conclusion, we have developed a new direct method for
the cyanation of acetals to cyanohydrin O-alkyl ethers us-
ing a TMSCN/nitromethane system under high pressure.
Notably, this reaction can be performed under completely
uncatalyzed and essentially neutral conditions, and should
be useful for preparing cyanohydrin derivatives in a quite
simple manner. Further studies to extend the scope of this
reaction are now in progress.
Acknowledgment
This work was supported in part by a Scientific Research on Priority
Areas (18037053 & 18032055) from MEXT, as well as by a Special
Research Grant for Green Science from Kochi University. We also
thank the Asahi Glass Foundation for financial support of this work.
K.K. thanks JSPS for a research fellowship for Young Scientists.
References and Notes
(1) High Pressure Organic Chemistry. Part 32. For Part 30, see:
(a) Saleha, A.; Kumamoto, K.; Uegaki, K.; Ichikawa, Y.;
Kotsuki, H. Tetrahedron Lett. 2006, 47, 587. (b) Part 31:
Kumamoto, K.; Iida, H.; Hamana, H.; Kotsuki, H.;
Matsumoto, K. Heterocycles 2005, 66, 675.
A mixture of acetal (1.0 mmol) and TMSCN (1.2 mmol) in
MeNO2 (ca. 1.2 mL) was placed in a Teflon reaction vessel,
and the mixture was allowed to react at 0.8 GPa at the
appropriate temperature for the specified time (Table 2).
After the mixture was cooled and the pressure was released,
the mixture was concentrated in vacuo. The crude product
was purified by silica gel column chromatography (elution
with hexane–EtOAc) to afford the pure product in good to
excellent yields.
(2) Reviews: (a) Furin, G. G.; Vyazankina, O. A.; Gostevsky, B.
A.; Vyazankin, N. S. Tetrahedron 1988, 44, 2675.
(b) North, M. Synlett 1993, 807. (c) Effenberger, F. Angew.
Chem., Int. Ed. Engl. 1994, 33, 1555. (d) Gregory, R. J. H.
Chem. Rev. 1999, 99, 3649. (e) North, M. Tetrahedron:
Asymmetry 2003, 14, 147. (f) Brunel, J.-M.; Holmes, I. P.
Angew. Chem. Int. Ed. 2004, 43, 2752.
(11) Consistent with this expectation, benzaldehyde diacetyl
acetal was also unreactive under similar conditions (in
MeNO2, 0.8 GPa, 80 °C, 24 h).
(12) For recent examples of the use of this type of transformation,
see: (a) Takaoka, L. R.; Buckmelter, A. J.; La Cruz, T. E.;
Rychnovsky, S. D. J. Am. Chem. Soc. 2005, 127, 528.
(b) LaCruz, T. E.; Rychnovsky, S. D. Org. Lett. 2005, 7,
1873.
(3) For recent examples of Lewis acid catalyzed transformation
of acetals into the corresponding cyanohydrin O-alkyl
ethers, see: (a) Sandberg, M.; Sydnes, L. K. Org. Lett. 2000,
2, 687. (b) Tanaka, N.; Miura, T.; Masaki, Y. Chem. Pharm.
Bull. 2000, 48, 1010. (c) Kimura, M.; Kuboki, A.; Sugai, T.
Tetrahedron: Asymmetry 2002, 13, 1059. (d) Iwanami, K.;
Oriyama, T. Chem. Lett. 2004, 33, 1324.
Synlett 2006, No. 12, 1968–1970 © Thieme Stuttgart · New York