The chemistry of acylals. 3. Cyanohydrin esters from acylals with cyanide reagents

Article abstract of DOI:10.1021/ol005535b

(equation presented) When treated with KCN in DMSO at room temperature, acylals from aliphatic aldehydes gave the corresponding cyanohydrin esters in good to excellent yields. Acylals from aromatic aldehydes were less reactive and gave several byproducts in addition to fair yields of cyanohydrin under the same conditions. Trimethylsilyl cyanide mixed with titanium(IV) chloride afforded cyanohydrin esters in good to excellent yields from both aliphatic and aromatic aldehydes.

Full text of DOI:10.1021/ol005535b

ORGANIC
LETTERS
2000
Vol. 2, No. 5
687-689
The Chemistry of Acylals. 3.
Cyanohydrin Esters from Acylals with
Cyanide Reagents
Marcel Sandberg and Leiv K. Sydnes*
Department of Chemistry, UniVersity of Bergen, Alle´gt. 41, NO-5007 Bergen, Norway
leiV.sydnes@kj.uib.no
Received January 11, 2000
ABSTRACT
When treated with KCN in DMSO at room temperature, acylals from aliphatic aldehydes gave the corresponding cyanohydrin esters in good
to excellent yields. Acylals from aromatic aldehydes were less reactive and gave several byproducts in addition to fair yields of cyanohydrin
under the same conditions. Trimethylsilyl cyanide mixed with titanium(IV) chloride afforded cyanohydrin esters in good to excellent yields
from both aliphatic and aromatic aldehydes.
Although acylals, or gem-bis(acyloxy)alkanes, are easily
accessible by several methods1 in large quantities, their
chemical properties have not been extensively investigated.2
Most studies have focused on acylal stability under basic
and acidic conditions;2 otherwise, only a few reactions,
mainly involving nitrogen,3 oxygen4 and carbon2,5 nucleo-
philes, have been reported. In general, useful products were
obtained only when acylals from aldehydes were treated with
various organometallic reagents containing carbanions; with
such reagents one of the acyloxy groups is substituted by
the carbanion, giving esters of secondary alcohols in moder-
ate to good yields.2,5 On the basis of these results and the
fact that cyanide is a very reactive carbon nucleophile, we
anticipated that treatment of acylals with cyanide under the
right conditions would give cyanohydrin esters, which are
useful intermediates in organic synthesis and compounds of
potential commercial interest in their own right.6 Such a
(1) Selected references: (a) Knoevenagel, E. J. Liebigs Ann. Chem. 1914,
402, 111-125. (b) Hurd, C. D.; Cantor, S. M. J. Am. Chem. Soc. 1938, 60,
2677-2687. (c) Man, E. H.; Sanderson, J. J.; Hauser, C. H. J. Am. Chem.
Soc. 1950, 72, 847-848. (d) Hopff, H.; Hegar, G. HelV. Chim. Acta 1961,
44, 2016-2021. (e) Scheeren, J. W.; Tax, W. J. M.; Schijf, R. Synthesis
1973, 151-153. (f) Shaw, J. E.; Kunerth, D. C. J. Org. Chem. 1974, 39,
1968-1970. (g) Marshall, J. A.; Wuts, P. G. M. J. Org. Chem. 1977, 42,
1794-1798.
(2) For an overview, see Sydnes, L. K.; Sandberg, M. Tetrahedron 1997,
53, 12679-12690 (Part 1).
(3) (a) Michael, A.; Weiner, N. J. Am. Chem. Soc. 1936, 58, 680-684.
(b) Hurd, C. D.; Green, F. O. J. Am. Chem. Soc. 1941, 63, 2201-2204. (c)
Narayana, C.; Padmanabhan, S.; Kabalka, G. W. Tetrahedron Lett. 1990,
31, 6977-6978. (d) Sandberg, M.; Sydnes, L. K. Tetrahedron Lett. 1998,
39, 6361-6364 (Part 2).
(6) (a) Effenberger, F. Angew. Chem., Int. Ed. Engl. 1994, 33, 1555. (b)
Elliot, M. In The Future for Insecticides; Needs and Prospects; Metcalf,
M. L., McKelvey, J. J., Eds.; Wiley and Sons: New York, 1976; Vol. 6,
pp 163-190.
(7) (a) Torii, S.; Inokuchi, T.; Kobayashi, T. Chem. Lett. 1984, 897-
898. (b) Soga, T.; Takenoshita, H.; Yamada, M.; Mukaiyama, T. Bull. Chem.
Soc. Jpn. 1990, 63, 3122-3131. (c) Ito, Y.; Imai, H.; Segoe, K.; Saegusa,
T. Chem. Lett. 1984, 937-940.
(8) The acylals were obtained in the following yields: 2a, 78%; 2b, 83%;
2c, 90%; 2d, 79%; 2e, 70%; 2f, 65%; 2g, 80%; 2h, 51%; 2i, 82%; 2j,
60%; 2k, 88%; 2l, 75%; 2m, 75%; 2n, 84%; 2o, 75%.
(9) All compounds were characterized by their IR, 1H NMR, and 13C
NMR spectra, and most new compounds also by HRMS.
(4) (a) Gallucci, R. R.; Going, R. C. J. Org. Chem. 1982, 47, 3517-
3521. (b) Kochhar, K. S.; Bal, B. S.; Deshpande, R. P.; Rajadhyaksha, S.
N.; Pinnick, H. W. J. Org. Chem. 1983, 48, 1765-1767. (c) Ku, Y.-Y.;
Patel, R.; Sawick, D. Tetrahedron Lett. 1993, 34, 8037-8040.
(5) (a) Kryshtal, G. V.; Bogdanov, V. S.; Yanovskaya, L. A.; Volkov,
Y. P.; Trusova, E. I. IzV. Akad. Nauk SSSR, Ser. Khim. 1981, 2820-2823.
(b) Kryshtal, G. V.; Bogdanov, V. S.; Yanovskaya, L. A.; Volkov, Y. P.;
Trusova, E. I. Tetrahedron Lett. 1982, 23, 3607-3610. (c) Trost, B. M.;
Vercauteren, J. Tetrahedron Lett. 1985, 26, 131-134. (d) Ghribi, A.;
Alexakis, A.; Normant, J. F. Tetrahedron Lett. 1984, 25, 3079-3082.
(10) Reactions of acylals with potassium cyanide in DMSO. In a
typical experiment a dry, nitrogen-filled, 50 mL, round-bottomed flask was
charged with an aliphatic acylal (4.94 mmol), and a mixture of KCN (0.33
g, 5.04 mmol, 1.2 equiv) and dry DMSO (10 mL) was added. The reaction
was completed by stirring overnight, at room temperature to 80 °C for the
aromatic acylals and at room temperature for the aliphatic acylals. Workup
was carried out by addition of H2O (50 mL) and extraction with Et2O (3 ×
30 mL). The combined etheral extracts were washed with H2O (5 × 50
mL). Drying (MgSO4), filteration, and concentration under vacuum afforded
spectroscopically pure products as pale yellow liquids.
10.1021/ol005535b CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/11/2000

transformation would be analogous to the conversion of
acetals to the corresponding cyanohydrin ethers, which has
been achieved by using several reagents.7
The acylals (2), obtained by reacting the corresponding
aldehydes (1) with carboxylic anhydrides under boron
trifluoride catalysis (Scheme 1),1c,2 were obtained in good
considerably faster, but the yields were in general slightly
lower due to formation of the corresponding cyanohydrins.
Cyanide displacement at room temperature is therefore
preferred.
Acylals from aromatic aldehydes, however, reacted dif-
ferently and gave more complex reaction mixtures. The
corresponding cyanohydrin esters 3 were still formed, but
in fair yields at best (<45%). The low yields are obviously
in part due to low acylal reactivity because significant
amounts of unreacted starting material were present even
after stirring for 10 h at ambient temperature. Furthermore,
two other products were formed in most cases: the corre-
sponding aldehyde 1, obtained in minor amounts, and the
ester of the symmetric benzoin adduct (4) from the same
aldehyde (Scheme 2). Both products were obtained in
Scheme 1
Scheme 2
to excellent yields8,9 and were reacted with cyanide under a
variety of reaction conditions. Exploratory experiments,
carried out with selected acylals, showed that the cleanest
product mixtures9 and the best results were obtained with
potassium cyanide in dimethyl sulfoxide (KCN/DMSO) and
trimethylsilyl cyanide in the presence of a Lewi acid catalyst
(titanium(IV) chloride) (TMSCN/TiCl4). Thus, reactions with
these reagents were thoroughly investigated.
KCN/DMSO. When this reagent was used it appeared that
acylals deriVed from aliphatic aldehydes were consumed
much faster and gave less complex reaction mixtures than
acylals from aromatic aldehydes. The former acylal group
reacted smoothly at room temperature10 and afforded the
corresponding cyanohydrin esters 3 as the only product in
good to excellent yields when reacted overnight (Table 1).
At elevated temperatures (50-80 °C) the reaction was
variable yields. The situation did not improve when the
reaction temperature was increased; although the relative
amount of unreacted acylal decreased, a concomitant increase
in the yields of the byproducts was observed as well.
Aldehyde formation in reactions with acylals from aro-
matic aldehydes might be anticipated since acylals give
significant amounts of the corresponding aldehydes in
reactions with Grignard reagents at room temperature.2
Furthermore, when aldehydes are formed, subsequent forma-
tion of 4 is not unexpected under these conditions, because
a benzoin-type condensation may conceivably occur. Such
a reaction sequence is supported by the observation that the
expected benzoin acetate was obtained when a mixture of
benzaldehyde and the corresponding acylal 2f was stirred at
room temperature with potassium cyanide in DMSO.
TMSCN/TiCl4. Trimethylsilyl cyanide combined with a
Lewis acid has been used to convert acetals to the corre-
sponding cyanohydrin ethers in good yields.7,11 The success-
ful Lewis acid originally used was titanium(IV) chloride,12
which was therefore employed.
Table 1. Cyanohydrin Esters (3) from Reactions of Aliphatic
Acylals with Potassium Cyanide in DMSO at Room
Temperature
substrate
isolated yield of 3 (%)
When 2 was reacted at room temperature with a mixture
2f
87
82
91
80
92
43
91
97
of TMSCN and TiCl4,13 both used in 10% molar excess, the
2g
2h
2i
2j
2k
2l
(11) (a) Utimoto, K.; Wakabayashi, Y.; Shishiyama, Y.; Inoue, M.;
Nozaki, H. Tetrahedron Lett. 1981, 22, 4279-4282. (b) Utimoto, K.;
Wakabayashi, Y.; Horrie, T.; Inoue, M.; Shishiyama, Y.; Obayashi, M.;
Nozaki, H. Tetrahedron 1983, 39, 967-973. (c) Mukaiyama, T.; Soga, T.;
Takenoshita, H. Chem. Lett. 1989, 997-1000. (d) Mukaiyama, T.; Soga,
T.; Takenoshita, H. Chem. Lett. 1989, 1273-1276.
2m
(12) Au, A. T. Synth. Commun. 1984, 14, 743-748.
688
Org. Lett., Vol. 2, No. 5, 2000

corresponding cyanohydrin esters 3 were obtained, usually
tively), which gave a significant amount of the corresponding
in very good yield (Table 2). Under these conditions, acylals
R-chloronitrile in addition to 3 (Scheme 3). The reason for
Scheme 3
Table 2. Cyanohydrin Esters (3) from Reactions of Acylals
with Trimethylsilyl Cyanide in the Presence of a Stoichiometric
Amount of Titanium(IV) Chloride
entry
substrate
isolated yield of 3 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
93
75a
87
53b
96
82
80
74
93
94
87
89
92
96
91
this deviating behavior is not clear.
Experiments were also performed to reduce the amount
of TiCl4 to a catalytic level without affecting the yield of 3.
The goal was reached with the acylals from the aromatic
aldehydes; with these substrates the yield of the correspond-
ing cyanohydrin esters did not drop significantly even when
the amount of Lewis acid was reduced to 0.10 equiv. The
consumption of the aliphatic acylals, on the other hand,
dropped considerably when the amount of TiCl4 was reduced
below a 1:1 ratio.
a In addition, the corresponding R-chloronitrile was obtained in 21%
yield. b In addition, the corresponding R-chloronitrile was obtained in 42%
yield.
Finally, it should be mentioned that treatment of acylals
with KCN under phase-transfer conditions14 also furnished
cyanohydrin esters, but in most cases additional products
were obtained. Acylals from aromatic aldehydes gave a 70-
80% yield of the esters, sometimes with small amounts of
the parent aldehyde being formed as well. Acylals derived
from alkanals and alkenals generally afforded cyanohydrin
esters in around 70% yield, but in these cases 10-20% of
the corresponding cyanohydrins were also obtained. It is also
noteworthy that both 2e and 2n, which afford the respective
cyanohydrin esters (3e and 3n) in 96% yield with TMSCN/
TiCl4 (Table 2, entries 5 and 14), are completely unreactive
toward KCN under phase-transfer conditions.
from aliphatic aldehydes (entries 6-13) exhibited reactivities
similar to those of the aromatic analogues (entries 1-5, 14,
and 15). However, two aromatic acylals show a somewhat
deviating behavior: 4-methylbenzylidene diacetate (2b) and
4-chlorobenzylidene diacetate (2d) (entries 2 and 4, respec-
(13) Treatment of 2 with trimethylsilyl cyanide in the presence of
titanium(IV) chloride. The acylals were reacted on a 3.5-5.0 mmol scale.
In a typical experiment a 50 mL, nitrogen-filled round-bottom flask was
charged with acylal in CH2Cl2 (5 mL) and trimethylsilyl cyanide (TMSCN)
(1.10 equiv). The reaction mixture was cooled to -78 °C with a dry ice-
acetone bath, and titanium(IV) chloride (1.10 equiv) was added with stirring.
The mixture was allowed to reach room temperature and was stirred at this
temperature for 2 h. H2O (50 mL) was added, and the products were
extracted with Et2O (3 × 30 mL). The combined extracts were washed
with H2O (2 × 50 mL), dried (MgSO4), filtered and concentrated under
vacuum. The crude products were subjected to further purification by flash
chromatography if necessary.
Acknowledgment. Significant financial support from
Nycomed Amersham/Nycomed Imaging and the Research
Council of Norway is very highly appreciated.
Supporting Information Available: Spectroscopic and
spectrometric data. This material is available free of charge
via the Internet at http://pubs.acs.org.
(14) (a) Starks, C. M.; Liotta, C. Phase Transfer Catalysis; Academic
Press: New York, 1978; Chapter 4.II, pp 94-112 (b) Dehmlow, E. V.;
Dehmlow, S. S. Phase Transfer Catalysis, 3rd ed.; VCH: Weinheim,
Germany, 1993.
OL005535B
Org. Lett., Vol. 2, No. 5, 2000
689