Table 1 Enantioselective synthesis of O-acetyl cyanohydrinsa
Enantiomeric
excessc(%)
(configuration)
Aldehyde
PhCHO
Catalyst
Yield (%)b
1a
93
90 (S)
89 (R)
93 (R)
93 (R)
90 (S)
89 (R)
92 (S)
93 (R)
85 (S)
82 (R)
89 (R)
86 (S)
88 (R)
84 (S)
82 (R)
69 (S)
72 (R)
62 (S)
60 (R)
1b
1b
1b
1a
1b
1a
1b
1a
1b
1b
1a
1b
1a
1b
1a
1b
1a (1b)
1b
1b
92d
74
p-MeOC6H4CHO
m-MeOC6H4CHO
m-PhOC6H4CHO
99
99
99
98
99
87
86
99
p-FC6H4CHO
o-FC6H4CHO
m-FC6H4CHO
o-ClC6H4CHO
87
89d
80
PhCH2CH2CHO
Me2CHCHO
Me3CHO
79d
64
Fig. 1 First order kinetic plots at 20 °C.
62d
40
40d
No reaction
bases, thiols, thiourea, carbon disufide, sodium tetraphenylbor-
ate, mineral carbonates, surfactants, phosphines and phosphine
oxides for this purpose, but the most successful proved to be the
use of imidazole (10 mol% relative to benzaldehyde), tert-butyl
alcohol or water (100 mol% relative to benzaldehyde), as the
data of Fig. 1 illustrate (Fig. 1, compare curves 1–5). The
addition of acids generally and acetic acid in particular
decreased the rate of the reaction (Fig. 1, curve 1) whereas
replacement of potassium cyanide with hydrogen cyanide as
well as addition of hydrogen cyanide (100 mol% with respect to
potassium cyanide) to the reaction mixture led to a dramatic loss
of optical purity (0% ee and 29% ee respectively). An attempt to
use acetyl cyanide in place of the potassium cyanide–acetic
anhydride failed, as no O-acetyl derivative of mandelonitrile
was found in the reaction mixture under the standard reaction
conditions.
The accelerating effects of water and tert-butyl alcohol were
almost equal at rt (Fig. 1, curves 3 and 4) with both the reactions
furnishing O-acetyl mandelonitrile in 90–91% chemical yield
and 76–78% ee within 3 h. At a lower reaction temperature
(242 °C), tert-butyl alcohol became a more efficient (and
reliable) additive, as compared with water although the ee of the
reaction (90%) remained generally the same in both cases. The
advantage of using tert-butyl alcohol became even more evident
when conducting preparative experiments where chemical
yields as high as 99% were obtained using this additive at 242
°C. Reactions have been carried out on up to a 200 g of aldehyde
scale in a 2 L round bottomed flask without difficulty. With
water as the additive the chemicals yields at 242 °C were
disappointingly low.
Table 1 summarizes the results of asymmetric synthesis of
different O-acetyl cyanohydrins, promoted by 1a or 1b under
the optimal conditions found for the reaction using benzalde-
hyde as substrate. As can be seen from the data, aromatic
aldehydes proved to be much better substrates than aliphatic
aldehydes, and acetophenone was not a substrate for the
reaction.
As HCN seems to be ruled out as a reagent in the reaction, the
mechanism seems to be very similar to the one elaborated
earlier for the asymmetric trimethylsilyl cyanation reaction of
aldehydes promoted by 1a or 1b.4 Notably, the ee’s and sense of
chirality of the cyanohydrin esters closely resemble the
corresponding data for trimethylsilyl derivatives obtained with
1a and 1b.4 The key feature of the mechanism is the formation
of an intermediate chiral titanium–cyanide–metalloacetal com-
plex where the cyanide ion attacks the aldehyde carbonyl
carbon atom intramolecularly with the formation of a titanium-
coordinated cyanohydrin. The breaking of the titanium–oxygen
PhCOMe
a Reaction conditions: aldehyde (0.37–0.4 M), KCN, Ac2O (mol ratio =
1+4+4), promoted by 1 mol% of 1b (or 1a) at 242°C, CH2Cl2, t-BuOH,
stirring, 7 h.b Determined by NMR, adding an internal standard to the
evaporated reaction mixture unless indicated otherwise.c Determined by
chiral GLC.d Yield of isolated product.
bond by interaction with acetic anhydride or ROH may be the
rate limiting step of the reaction. The latter feature of the
mechanism can explain why imidazole, water and tert-butyl
alcohol catalyse the reaction. The free cyanohydrins formed in
this way undergo easy acylation without racemization, as
control experiments indicated.
Mechanistic investigations of the process as well as further
attempts to increase both optical and chemical yields (especially
for aliphatic aldehydes) are still in progress and will be reported
in due course. In summary, we have developed a very efficient
procedure to prepare enantiomerically enriched O-protected
cyanohydrins with very good chemical yields and ee’s, starting
with inexpensive and non-volatile starting materials.
This work was supported by Award No RC1-2205 of the US
Civilian Research and Development Foundation for the Inde-
pendent States of the Former Soviet Union (CRDF) and also by
the Russian Fund for Fundamental Sciences (Grant No
99-03-32970).
Notes and references
1 M. North, Synlett, 1993, 807; F. Effenberger, Angew. Chem., Int. Ed.
Engl., 1994, 33, 1555; M. North, in Comprehensive Organic Functional
Group Transformations, Vol. 3, Chapter 18, ed. A. R. Katritzky, O.
Meth-Cohn, C. W. Rees and G. Pattenden, Pergamon Press, Oxford,
1995R. J. H. Gregory, Chem. Rev., 1999, 99, 3649.
2 A. Schmid, J. S. Dordick, B. Hauer, A. Kiener, M. Wubbolts and B.
Witholt, Nature, 2001, 409, 258; H. Hirohara and M. Nishizawa, Biosci.,
Biotechnol., Biochem., 1998, 62, 1.
3 J.-I. Oku, N. Ito and S. Inoue, Macromol. Chem., 1979, 180, 1089; A.
Mori, Y. Ikeda, K. Kinoshita and S. Inoue, Chem. Lett., 1989, 2119.
4 Yu. N. Belokon’, S. Caveda-Cepas, B. Green, N. S. Ikonnikov, V. N.
Khrustalev, V. S. Larichev, M. A. Moscalenko, M. North, C. Orizu, V. I.
Tararov, M. Tasinazzo, G. I. Timofeeva and L. V. Yashkina, J. Am.
Chem. Soc., 1999, 121, 3968; Yu. N. Belokon’, B. Green, N. S.
Ikonnikov, V. S. Larichev, B. V. Lokshin, M. A. Moscalenko, M. North,
C. Orizu, A. S. Peregudov and G. I. Timofeeva, Eur. J. Org. Chem., 2000,
2655; Yu. N. Belokon’, B. Green, N. S. Ikonnikov, M. North, T. Parsons
and V. I. Tararov, Tetrahedron, 2001, 57, 771.
5 Y. Hamashima, M. Kanai and M. Shibasaki, Tetrahedron Lett., 2001, 42,
691; Y. Hamashima, D. Sawada, H. Nogami, M. Kanai and M. Shibasaki,
Tetrahedron, 2001, 57, 805.
6 This work has been patented: patent application number 0018973.8.
CHEM. COMMUN., 2002, 244–245
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