Vanadium-Catalyzed Asymmetric Cyanohydrin Synthesis

Article abstract of DOI:10.1021/ol005893e

(Matrix Presented) Based on a mechanistic understanding of asymmetric cyanohydrin synthesis catalyzed by chiral titanium-salen complexes, a new catalyst based on vanadium(IV) has been developed. The chiral (salen)VO catalyst is more enantioselective than

Full text of DOI:10.1021/ol005893e

ORGANIC
LETTERS
2000
Vol. 2, No. 11
1617-1619
Vanadium-Catalyzed Asymmetric
Cyanohydrin Synthesis
Yuri N. Belokon’, Michael North,* and Teresa Parsons
Department of Chemistry, King’s College, Strand, London, WC2R 2LS, U.K. and A.N.
NesmeyanoV Institute of Organoelement Compounds, Russian Academy of Sciences,
117813 VaViloV 28, Moscow, Russia
michael.north@kcl.ac.uk
Received April 5, 2000
ABSTRACT
Based on a mechanistic understanding of asymmetric cyanohydrin synthesis catalyzed by chiral titanium−salen complexes, a new catalyst
based on vanadium(IV) has been developed. The chiral (salen)VO catalyst is more enantioselective than the titanium-based systems, 0.1 mol
% of the catalyst being sufficient to convert aromatic and aliphatic aldehydes into the corresponding trimethylsilyl ethers of cyanohydrins
with 68−95% enantiomeric excess at room temperature.
In recent papers, we have reported the development of chiral
titanium(salen) complexes (optimally using complex 1 as the
catalyst precursor) as highly active catalysts for the asym-
metric addition of trimethylsilyl cyanide to both aldehydes1
and ketones.2 Detailed mechanistic studies have shown that
the active species in this reaction is a bimetallic titanium-
(salen) complex.3 Other workers have reported similar
catalysts,4 and their use to catalyze the asymmetric addition
of trimethylsilyl cyanide to imines.5 While our titanium-based
system has a number of attractive attributes including:
activity at room temperature, high substrate-to-catalyst ratios,
wide substrate tolerance, and good enantiomeric excesses,
there is still room for improvement in the latter. In this
communication, the design and development of a new
catalyst for asymmetric cyanohydrin synthesis which gives
products with significantly higher enantiomeric excesses than
those observed with the titanium-based system is reported.
The mechanistic studies on our titanium catalyst have
shown that the active species derived from complex 1 is
bimetallic complex 2 which is in equilibrium with catalyti-
cally inactive monometallic complexes 3 (Scheme 1).3
Complex 2 is an extremely active catalyst since reactions
employing it are complete in just a few minutes at room
temperature. If the reactivity of the catalyst could be reduced,
then the enantioselectivity should increase, and one way of
achieving this would be to design a catalyst in which the
(1) (a) Belokon’, Y.; Ikonnikov, N.; Moscalenko, M.; North, M.; Orlova,
S.; Tararov, V.; Yashkina, L. Tetrahedron: Asymmetry 1996, 7, 851. (b)
Belokon’, Y.; Flego, M.; Ikonnikov, N.; Moscalenko, M.; North, M.; Orizu,
C.; Tararov, V.; Tasinazzo, M. J. Chem. Soc., Perkin Trans. 1 1997, 1293.
(c) Belokon’, Y. N.; Yashkina, L. V.; Moscalenko, M. A.; Chesnokov, A.
A.; Kublitsky, V. S.; Ikonnikov, N. S.; Orlova, S. A.; Tararov, V. I.; North,
M. Russian Chem. Bull. 1997, 46, 1936. (d) Belokon’, Y.; Moscalenko,
M.; Ikonnikov, N.; Yashkina, L.; Antonov, D.; Vorontsov, E.; Rozenberg,
V. Tetrahedron: Asymmetry 1997, 8, 3245. (e) Tararov, V. I.; Hibbs, D.
E.; Hursthouse, M. B.; Ikonnikov, N. S.; Malik, K. M. A.; North, M.; Orizu,
C.; Belokon’ Y. N. Chem. Commun. 1998, 387. (f) Tararov, V.; Orizu, C.;
Ikonnikov, N. S.; Larichev, V. S.; Moscalenko, M. A.; Yashkina, L.; North,
M.; Belokon’, Y. N. Russian Chem. Bull. 1999, 48, 1128. (g) Belokon’, 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.
(2) Belokon’, Y. N.; Green, B.; Ikonnikov, N.; North, M.; Tararov, V.
Tetrahedron Lett. 1999, 40, 6105.
(3) Belokon’, Y. N.; Green, B.; Ikonnikov, N.; Larichev, V. S.; Lokshin,
B. V.; Moscalenko, M. A.; North, M.; Orizu, C.; Peregudov, A. S.;
Timofeeva, G. I. Euro. J. Org. Chem., accepted for publication.
(4) (a) Pan, W.; Feng, X.; Gong, L.; Hu, W.; Li, Z.; Mi, A.; Jiang, Y.
Synlett 1996, 337. (b) Jiang, Y.; Gong, L.; Feng, X.; Hu, W.; Pan, W.; Li,
Z.; Mi, A. Tetrahedron 1997, 53, 14327. (c) Hwang, C.-D.; Hwang, D.-R.;
Uang, B.-J. J. Org. Chem. 1998, 63, 6762.
(5) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 5315.
10.1021/ol005893e CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/05/2000

higher) species would be shifted toward the monometallic
species compared to titanium(salen) complexes, and hence
that a chiral vanadium(IV)(salen) complex might generate a
more enantioselective catalyst than that derived from com-
plex 1.
Scheme 1. Equilibria Which Exist in Titanium-Catalyzed
Asymmetric Cyanohydrin Synthesis
Scheme 2. Preparation of Complex 4
To test this hypothesis, vanadium(IV)(salen) complex 4
was prepared by the route shown in Scheme 2. Complex 4
was then found to catalyze the asymmetric addition of
trimethylsilyl cyanide to a range of aromatic and aliphatic
aldehydes (Table 1). Like titanium complex 1, complex 4
was active at room temperature and at substrate-to-catalyst
ratios of 1000:1. However, reactions using complex 4 as the
catalyst precursor were much slower than those using
titanium complex 1 as the catalyst precursor, requiring 24 h
to go to completion rather than being complete in less than
1 h. Gratifyingly, the enantiomeric excess of the silylated
cyanohydrins obtained using the catalyst obtained from
complex 4 were always higher than those obtained from
complex 1 (Table 1), in accord with our expectations based
on the mechanism of the reaction.3
Table 1. Enantioselectivitiesa Obtained Using Catalysts
Derived from Complexes 1 and 4b
aldehyde
complex 4 (ee)
complex 1 (ee)
PhCHO
94
90
90
95
94
73
77
68
88
84
76
90
87
50
52
66
4-MeOC6H4CHO
2-MeC6H4CHO
3-MeC6H4CHO
4-MeC6H4CHO
4-O2NC6H4CHO
CH3CH2CHO
Me3CCHO
equilibrium between catalytically active bimetallic and
catalytically inactive monometallic species favored the
formation of the monometallic species.
A search of crystal structures of metal(salen) complexes
contained in the Cambridge crystal structure database
revealed that unlike oxo-titanium(salen) complexes, oxo-
vanadium(IV)(salen) complexes could be either monometallic
containing a VdO bond,6,7 or polymeric with -V-O-V-
O- units.7 Thus it was apparent that monometallic vana-
dium(IV)(salen) complexes are more stable than the corre-
sponding titanium species. This suggested that in solution,
the equilibrium between monometallic and bimetallic (or
a All enantioselectivities were determined by chiral gas chromatography
as previously reported.1 b All reactions were carried out using 0.1 mol %
of the catalyst in dichloromethane at ambient temperature and the catalyst
derived from complex 4 gave complete conversion of aldehyde to
cyanohydrin trimethylsilyl ether after 24 h. In all cases, the (R,R)-isomer
of the catalyst gave an excess of the (S)-enantiomer of the cyanohydrin
derivative.
An attempt to extend this reaction to ketones2 was less
successful, acetophenone was converted into the correspond-
ing cyanohydrin with 22% ee in just 16% yield after a
reaction time of one week. This is again consistent with the
much lower reactivity of the vanadium-based system com-
pared to the corresponding titanium complexes. Although
chiral complexes of many transition metals have been studied
(6) (a) Schmidt, H.; Bashirpoor, M.; Rehder, D. J. Chem. Soc., Dalton
Trans. 1996, 3865. (b) Zamian, J. R.; Dockal, E. R.; Castellano, G.; Oliva,
G. Polyhedron 1995, 14, 2411. (c) Bonadies, J. A.; Butler, W. M.; Pecoraro,
V. L.; Carrano, C. J. Inorg. Chem. 1987, 26, 1218.
(7) Nakajima, K.; Kojima, M.; Azuma, S.; Kasahara, R.; Tsuchimoto,
M.; Kubozono, Y.; Maeda, H.; Kashino, S.; Ohba, S.; Yoshikawa, Y.; Fujita,
J. Bull. Chem. Soc. Jpn. 1996, 69, 3207.
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Org. Lett., Vol. 2, No. 11, 2000

as catalysts for the asymmetric addition of trimethylsilyl
cyanide to aldehydes,8 this is the first time that a vanadium
complex has been found to form an effective catalyst. Chiral
vanadium(salen) complexes have previously been used as
catalysts for the asymmetric oxidation of sulfides to sulfox-
ides.7,9
To investigate the mechanism of this vanadium-catalyzed
asymmetric cyanohydrin synthesis, a kinetics study was
undertaken using the methodology previously reported3 for
the study of titanium complex 1. The reaction (using
benzaldehyde as substrate) was found to obey the rate
equation: rate ) 76[4]1.45[Me3SiCN], while for the same
reaction using titanium complex 1, the rate equation has
previously been found to be: rate ) 634[1]1.3[Me3SiCN].
Comparison of these two rate equations shows that they have
the same general form which is consistent with the reactions
following the same mechanism. In particular, the concentra-
tion of benzaldehyde does not appear in either rate equation,
and in both cases, the reactions are first order in trimethylsilyl
cyanide concentration.
The rate constant for the vanadium-catalyzed reaction is
almost a factor of 10 lower than the rate constant for the
titanium-catalyzed reaction, which is consistent with the
longer reaction times needed for the vanadium-catalyzed
system. The order of reaction with respect to the catalyst is
higher for the vanadium-catalyzed system than for the
titanium-derived system. This value (which must be between
one and two for a bimetallic species to be the active catalyst)
is determined by the equilibrium constant between the
monometallic and bimetallic species present in the reaction
mixture.3 A higher value for the vanadium-containing system
than for the titanium-derived system is indicative that the
equilibrium between the mono- and bimetallic species favors
the monometallic complexes more in the case of vanadium
than titanium. Thus, the kinetics study indicates that the
vanadium-catalyzed reaction probably follows the same
mechanism as the titanium-catalyzed reaction, but that the
concentration of the catalytically active bimetallic species
is lower for the vanadium-containing species as intended.
Also consistent with a common mechanism for the
titanium- and vanadium-catalyzed reactions is the fact that
both complexes derived from the (R,R)-salen ligand prefer-
entially catalyze the formation of the (S)-enantiomer of
cyanohydrin trimethylsilyl ethers, which indicates that in both
cases the aldehyde is coordinated to the metal complex to
allow addition of cyanide to occur preferentially on the re-
face of the carbonyl bond. In addition, both catalyst systems
display the same enantioselectivity versus substrate trend,
with electron rich aromatic aldehydes giving better enantio-
selectivities than electron deficient aromatic, or aliphatic
substrates. The formation of a vanadium complex analogous
to complex 2 requires that the salen ligands adopt nonplanar
coordination geometries to allow the µ-O and cyanide ligands
(and µ-O and coordinated aldehyde ligands) to adopt
locations cis to one another. There is literature precedent10
for the formation of an octahedral vanadium(IV)(salen)
complex in which the salen ligand is coordinated in this way,
showing that this is feasible.
In summary, the first vanadium-derived catalyst for the
asymmetric addition of trimethylsilyl cyanide to aldehydes
has been developed based on the previously determined
mechanism of asymmetric cyanohydrin synthesis catalyzed
by titanium(salen) complexes. The vanadium-catalyzed
system gives higher enantioselectivites than those previously
reported for the titanium-catalyzed system and the kinetics
suggest that the reactions follow the same mechanism as the
titanium-catalyzed reaction. Our work on the asymmetric
catalysis of carbon-carbon bond forming reactions is
continuing and will be reported in due course.
Acknowledgment. The authors thank the EPSRC for a
studentship (to T.P.) and the EU for an INCO-COPERNICUS
grant.
(8) For reviews see: (a) North, M. Synlett 1993, 807. (b) Effenberger F.
Angew. Chem., Int. Ed. Engl. 1994, 33, 1555. (c) North, M. ComprehensiVe
Organic Functional Group Transformations; Katritzky, A. R., Meth-Cohn,
O., Rees, C. W., Pattenden, G., Eds.; Pergamon Press: Oxford, 1995; Vol.
3, Chapter 18.
OL005893E
(9) (a) Nakajima, K.; Kojima, K.; Kojima, M.; Fujita, J. Bull. Chem.
Soc. Jpn. 1990, 63, 2620. (b) Nakajima, K.; Kojima, M.; Toriumi, K.; Saito,
K.; Fujita, J. Bull. Chem. Soc. Jpn. 1989, 62, 760.
(10) Vergopoulos, V.; Jantzen, S.; Rodewald, D.; Rehder, D. J. Chem.
Soc., Chem. Commun. 1995, 377.
Org. Lett., Vol. 2, No. 11, 2000
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