Oxovanadium(V)-catalyzed enantioselective Meerwein-Ponndorf-Verley cyanation of aldehydes using acetone cyanohydrin

Article abstract of DOI:10.1016/j.tetlet.2004.06.099

Oxovanadium(V)(salen) complex was found to be a promising catalyst for asymmetric MPV cyanation of aliphatic aldehydes. Oxovanadium(V)(salen) complex 4 was found to catalyze Meerweina€"Ponndorfa€" Verley cyanation of aliphatic aldehydes with good to high

Full text of DOI:10.1016/j.tetlet.2004.06.099

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6229–6233
Oxovanadium(V)-catalyzed enantioselective
Meerwein–Ponndorf–Verley cyanation of aldehydes using
acetone cyanohydrin
Akira Watanabe, Kazuhiro Matsumoto, Yuya Shimada and Tsutomu Katsuki*
Department of Chemistry, Faculty of Science, Graduate School, Kyushu University 33, 6-10-1 Hakozaki, Higashi-ku,
Fukuoka 812-8581, Japan
CREST, Japan Science and Technology Agency (JST), Japan
Received 24 May 2004; revised 25 June 2004; accepted 25 June 2004
Abstract—Oxovanadium(V)(salen) complex 4 was found to catalyze Meerwein–Ponndorf–Verley cyanation of aliphatic aldehydes
with good to high enantioselectivity. This cyanation showed a positive nonlinear effect.
Ó 2004 Elsevier Ltd. All rights reserved.
Asymmetric cyanation of carbonyl compounds is a cur-
rent topic in organic synthesis, because cyanohydrins are
versatile building blocks. Thus, many catalysts including
peptide derivatives and metal complexes have been
developed and good to excellent levels of enantioselec-
tivity have been achieved.1,2 Of these catalysts, some
serve as a Lewis acid3 but most of the catalysts giving
satisfactory results possess a function for dual activation
of carbonyl and cyanide compounds.1b For example,
ShibasakiÕs catalysts carry Lewis acid/Lewis base parts.2
On the other hand, chiral salen ligands have been pro-
ven to be excellent chiral auxiliaries for various asym-
metric reactions.4 In 1996, two groups independently
reported asymmetric cyanation using a Ti(salen) com-
plex as catalyst.5 Later, Bu et al. also reported asymmet-
ric cyanation using a slightly modified Ti(salen) complex
as the catalyst.6,7 Although high enantioselectivity has
been achieved in these reactions, temperature as low as
ꢀ78°C is required. However, introduction of a di-l-
oxo-Ti(salen) complex 1 brought about a breakthrough
in metallosalen-catalyzed asymmetric cyanation: high
enantioselectivity was achieved in the reaction at room
temperature.8 This reaction has been proposed to pro-
ceed through a cis-b-l-oxo Ti complex 2, in which both
the aldehyde and the cyanide are, respectively, coordi-
nated to the titanium ion and react in an intramolecular
fashion with enantioselectivity higher than 80% ee (Fig.
1). Furthermore, an oxovanadium(IV)(salen) complex
was found to be a better catalyst especially for asymmet-
ric cyanation of aromatic aldehyde.9 This reaction has
also been proposed to proceed through the same reac-
tion pathway as the reaction using 1 as the catalyst.
These reactions, however, need toxic hydrogen cyanide
or relatively expensive trimethylsilyl cyanide as a cya-
nide source. On the other hand, Maruoka et al. recently
reported Zr-catalyzed asymmetric Meerwein–Ponndorf–
Verley (MPV) cyanation using more manageable ace-
tone cyanohydrin as a cyanide source, in which the cy-
anohydrin and aldehyde were coordinated to the metal
ion and reacted intramolecularly, showing high enantio-
selectivity.10 This reaction needs low temperature to
obtain high enantioselectivity. Since 1993, we have
demonstrated that salen ligands including a binaphthyl
unit are excellent chiral auxiliaries and their metal com-
plexes catalyze various types of reactions with excellent
enantioselectivities.4 In the course of our study, we have
also found that Ti(salen) complex 3 bearing this type of
salen ligand can be converted to the corresponding cis-
b-di-l-oxo-Ti(salen) complex under the reported condi-
tions8 and the complex is an excellent catalyst for asym-
metric sulfoxidation using hydrogen peroxide, in which
the complex is converted into a monomeric peroxoTi
species bearing a cis-b salen ligand and oxidizes sul-
fides.11 This result suggests that a metallosalen complex
Keywords: Asymmetric catalysis; Meerwein–Ponndorf–Verley cyana-
tion; Cyanohydrin; Oxovanadium(V)(salen) complex.
*
Corresponding author. Tel.: +81-92-642-2586; fax: +81-92-642-
2607; e-mail: katsuscc@mbox.nc.kyushu-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.099

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A. Watanabe et al. / Tetrahedron Letters 45 (2004) 6229–6233
Figure 1.
bearing our ligand can take a cis-b structure under
appropriate conditions and allow coordination of two
substrates cis to each other.12 Thus, we expected that a
monomeric cis-b Ti(salen) species would catalyze MPV
cyanation with high enantioselectivity. Indeed, complex
3 catalyzed the cyanation but, contrary to our expecta-
tion, enantioselectivity of the reaction was poor (<5%
ee).
MPV cyanation of 3-phenylpropanal with acetone cyano-
hydrin (4equiv) was carried out at room temperature in
CH2Cl2 in the presence of complex 4 (5mol%) (Table 1,
entry 1). As expected, good enantioselectivity of 84% ee
was observed but the reaction was slow. Addition of tri-
ethylamine accelerated the reaction but reduced enantio-
selectivity to a considerable extent (entry 2). Addition of
the amine might also promote reversed hydrocyanation
of acetone cyanohydrin generating a cyanide anion that
undergoes direct cyanation and diminish the enantiose-
lectivity. Thus, we next examined the additive effect of
less basic pyridine derivatives. Addition of pyridine did
not affect enantioselectivity, but the rate of enhancement
was small (ca. 2.6 times), probably because the presence
of pyridine hindered the coordination of the aldehyde
(entry 3). Therefore, we examined the additive effect of
2,4,6-collidine and 2,6-dichloropyridine. Addition of
2,4,6-collidine accelerated the reaction remarkably, al-
beit with slightly diminished enantioselectivity (entry
4). In contrast, addition of 2,6-dichloropyridine deceler-
ated the reaction (entry 5). Lowering the reaction tem-
perature to 10°C in the presence of 2,4,6-collidine
Different from oxovanadium(IV) complexes with salen
ligands that usually adopt five-coordinate square-
pyramidal geometry even in the donor solvent, oxovana-
dium(V) complexes exhibit a tendency to retain octahe-
dral six-coordination, in which the donor solvent or
counter ion coordinates in an apical position.13 There-
fore, we expected that oxovanadium(V) complexes
would adopt a monomeric cis-b structure more easily
than oxovanadium(IV) complexes14 and be a suitable
catalyst for asymmetric cyanation using acetone cyano-
hydrin. Here, we report asymmetric MPV cyanation
using oxovanadium(V)(salen) complexes 4 and 5 as the
catalyst.
Table 1. MPV cyanation of 3-phenylpropanal using oxovanadium(V) complex 4 or 5 as catalyst
Entry
Catalyst
Base
Temp (°C)
Yield (%)a
ee (%)b (config)c
1
4
4
4
4
4
4
4
4
5
None
Et3N
Pyridine
rt
rt
rt
rt
rt
10
10
0
13
>99
34
99
4
84 (R)
65 (R)
85 (R)
70 (R)
72 (R)
86 (R)
82 (R)
90 (R)
48 (S)
2
3
4
2,4,6-Collidine
2,6-Dichloropyridine
2,4,6-Collidine
2,4,6-Collidine
2,4,6-Collidine
2,4,6-Collidine
5
6
57
87
25
99
7d
8d
9
rt
a Yield was determined by 1H NMR (400MHz) analysis.
b ee was determined by HPLC analysis (Daicel Chiralpak AS-H, hexane–2-propanol=98:2).
c Absolute configuration was determined by comparison of the optical rotation of the cyanohydrin with the literature value (Ref. 10).
d Reaction time was 48 h.

A. Watanabe et al. / Tetrahedron Letters 45 (2004) 6229–6233
6231
improved enantioselectivity to 86% ee, though the chem-
ical yield was reduced (entry 6). The reaction at 0°C fur-
ther improved enantioselectivity to 90% ee, but the
reaction was very slow (entry 8). Prolonged reaction
time increased the yield of the product but its enantio-
purity somewhat decreased, suggesting the product
was racemized slowly through equilibrium between the
reactant and the product under the conditions (entry
7). The reaction using 5, the diastereomer of 4, showed
only moderate selectivity (entry 9).
version, 12h) was opposite to that of the product of the
above cyanation. This explains why the ee of benzalde-
hyde cyanohydrin that underwent the reversed reaction
at a considerable rate was only modest and also
the observation that the ee of the cyanation product
decreased as the reaction time was prolonged (vide
supra).
Although the mechanism of asymmetric induction in
this reaction is unclear at present, we have assumed that
the present reaction proceeds in an intramolecular man-
ner with the participation of the cis-b vanadium(V)(sa-
len) species (vide supra), as Maruoka proposed.10,17 It
has been reported that a simple vanadium(V)(salen)
complex can take a non-oxo cis-b structure.18 Asymmet-
ric sulfoxidation with di-l-oxo-Ti(salen) complex shows
strong positive nonlinear effect, indicating that a pair of
enantiomeric Ti(salen) complexes make the correspond-
ing di-l-oxo-Ti complex much easier than a pair of the
same complexes.10b Thus, we expected that a pair of
enantiomeric vanadium(V) species could also produce
a dimmer 7 if they can adopt a cis-b structure, and the
reaction with 4 as catalyst would show a nonlinear effect
(Scheme 1). Indeed, a positive nonlinear effect was ob-
served as shown in Figure 2. We also observed that,
when a solution of enantiomeric (aS,R)-4 in dichloro-
methane was added to a solution of (aR,S)-4, a fern-
green solid was precipitated.
Under the optimized conditions, reactions of several
other aldehydes were examined (Table 2). Nonbranched
aliphatic aldehydes gave the corresponding cyanohydrin
in moderate to good yields with high enantioselectivity
(entries 1 and 2).15,16 Cyanation of cyclohaxanecaboxal-
dehyde also showed good enantioselectivity (entry 3).
However, the reaction of 2,2-dimethylpropanal was
slow, albeit with good enantioselectivity. On the other
hand, the yield of benzaldehyde cyanohydrin was very
low and enantioselectivity was modest (entry 5). How-
ever, as described above, the present cyanation seemed
reversible and the retro-cyanation of the cyanohydrin
of this reaction was considered to be rapid. Thus, we ex-
posed racemic benzaldehyde cyanohydrin that was pre-
pared by MaruokaÕs method10 to the present reaction
conditions in the presence of acetone and found that
the reversed reaction occurred and the enantiomer cor-
responding to the major enantiomer of the above cyana-
tion product was decomposed in preference to the
enantiomer corresponding to the minor one: the chiral-
ity of the recovered cyanohydrin (50% ee, ca. 50% con-
CD measurement of a solution of the solid in di-
chloromethane demonstrated that it was a 1:1 mixture
of (aS,R)-4 and (aR,S)-4. These results support that
Table 2. MPV cyanation of various aldehydes with oxovanadium(V) complex 4 as catalyst
Entry
R=
Yield (%)a
ee (%) (config)b
1
2
3
4
5
n-C7H15
PhO(CH2)5
c-Hex
75 (65)
61 (59)
79 (55)
—f (29g)
13h
84c
79d
76c (R)
67e (R)
45e (R)
(CH3)3C
Ph
a Yield of cyanohydrin was determined by 1H NMR analysis. The number in parentheses is the isolated yield as the corresponding acetate.
b Absolute configuration was determined by comparison of the optical rotation of the cyanohydrin with the literature value (Ref. 10).
c ee was determined by GLC analysis using Shimadzu GC-1700 [HP Chiral (20% permethylated b-cyclodextrin)].
d ee was determined by HPLC analysis (Daicel Chiralpak AS-H, hexane–2-propanol=90:10).
e ee was determined by HPLC analysis (Daicel Chiralcel OJ-H, hexane–2-propanol=90:10).
f Not determined.
g Isolated yield of the corresponding benzoate.
h The reaction time was 12h.
Scheme 1.

6232
A. Watanabe et al. / Tetrahedron Letters 45 (2004) 6229–6233
6. Liang, S.; Bu, X. R. J. Org. Chem. 2002, 67, 2702–
2704.
7. Li(salen) has been used as a catalyst: Holmes, I. P.;
Kagan, H. B. Tetrahedron Lett. 2000, 41, 7457–
7460.
8. (a) BelokonÕ, Y.; Caveda-Cepas, S.; Green, B.; Ikonnikov,
N.; Khrustalev, V.; Larichev, V.; Moskalenko, M.; North,
M.; Orizu, C.; Tararov, V.; Tasinazzo, M.; Timofeeva, G.;
Yashkina, L. J. Am. Chem. Soc. 1999, 121, 3968–3973; (b)
BelokonÕ, Y.; Green, B.; Ikonnikov, N.; Larichev, V.;
Lokshin, B.; Moskalenko, M.; North, M.; Orizu, C.;
Peregudov, A.; Timofeeva, G. Eur. J. Org. Chem., 2000,
2655–2661; (c) BelokonÕ, Y.; Green, B.; Ikonnikov, N.;
North, M.; Parsons, T.; Tararov, V. Tetrahedron 2001, 57,
771–779.
Figure 2. Positive nonlinear effect observed in MPV cyanation of 3-
phenylpropanal with oxovanadium(V) complex 4 at room tempera-
ture.
9. BelokonÕ, Y.; North, M.; Parsons, T. Org. Lett. 2000, 2,
1617–1619.
10. Ooi, T.; Miura, T.; Takaya, K.; Ichikawa, H.; Maruoka,
K. Tetrahedron 2001, 57, 867–873.
11. (a) Saito, B.; Katsuki, T. Tetrahedron Lett. 2001, 42,
3873–3876; (b) Saito, B.; Katsuki, T. Tetrahedron Lett.
2001, 42, 8333–8336.
12. (a) Zr(salen) complex catalyzes Baeyer–Villiger reaction,
in which a ketone and hydrogen peroxide are coordinated
to the zirconium ion and reacted to give a chiral lactone:
Watanabe, A.; Uchida, T.; Ito, K.; Katsuki, T. Tetrahe-
dron Lett. 2002, 43, 4481–4485; (b) Watanabe, A.; Uchida,
T.; Irie, R.; Katsuki, T. Proc. Natl. Acad. Sci. USA 2004,
101, 5737–5742.
13. (a) Nakajima, K.; Kojima, K.; Kojima, M.; Fujita, J. Bull.
Chem. Soc. Jpn. 1990, 63, 2620–2630; (b) BelokonÕ, Y.;
Carta, P.; Gutnov, A.; Maleev, V.; Moskalenko, M.;
Yashkina, L.; Ikonnikov, N.; Voskoboev, N.; Khrustalev,
V.; North, M. Helv. Chim. Acta 2002, 85, 3301–
3312.
complex 4 can be converted into the desired cis-b vana-
dium(V)(salen) complex.19 On the other hand, cyanation
of 3-phenylpropanal with acetone cyanohydrin in the
presence of the BelokonÕs vanadium(IV) complex was
sluggish (65% ee, 7%, 7h at rt), while the corresponding
vanadium(V) complex catalyzed the cyanantion
smoothly with modest enantioselectivity (45% ee, 99%,
12h at rt). These results agree with the above assump-
tion that a vanadium(V) complex is a suitable catalyst
and demonstrate that use of oxovanadium(V) complex
bearing the salen ligand including a binaphthyl unit is
essential for achieving high enantioselectivity in the pre-
sent MPV cyanation, though we could not completely
rule out the possibility that the reaction proceeds
through a l-oxo vanadium species as proposed for
asymmetric cyanation using trimethylsilyl cyanide.
14. Participation of a cis-b vanadium(salen) species has been
proposed by North and co-workers.9
15. Typical experimental procedure was as follows: catalyst 4
(5.0mg, 5lmol) was dissolved in a 0.01M CH2Cl2 solution
of 2,4,6-collidine (0.5mL) at room temperature. Acetone
cyanohydrin (36.5lL, 0.40mmol) was added to the
solution. The solution was cooled to 10°C. Octylaldehyde
(15.6lL, 0.10mmol) was added and the solution was
stirred at the temperature. After 48h, the reaction was
quenched by 1M HCl and extracted by CH2Cl2. The
extract was evaporated in vacuo. The resultant cyanohyd-
rin was acetylated by Ac2O (24lL, 0.25mmol), pyridine
(20lL, 0.25mmol) and a catalytic amount of 4-(N,N-
dimethylamino)pyridine in CH2Cl2 (1.0mL) at 0°C. After
2h, the reaction was quenched by water and extracted by
CH2Cl2. The extract was concentrated in vacuo and the
residue was chromatographed on silica gel (n-hex-
ane:AcOEt=19:1) to give the acetate (11.5mg, 65%).
Enantiomeric excess of the acetylated cyanohydrin was
determined by GLC analysis as described in the footnote
of Table 2.
In conclusion, we were able to demonstrate that oxova-
nadium(V)(salen) complex 4 serves as a catalyst for
asymmetric MPV cyanation. Further study on the
mechanism of the present reaction is under way.
References and notes
1. (a) Mori, A.; Inoue, S. In Comprehensive Asymmetric
Catalysis, Jacobsen, E. N., Pfaltz, A., Yamamoto, H.,
Eds.; Springer: Berlin, 1999; Vol. 2, pp. 983–994; (b)
North, M. Tetrahedron: Asymmetry 2003, 14, 147–176; (c)
Brunel, J.; Holmes, I. Angew. Chem. Int. Ed. 2004, 43,
2752–2778.
2. Shibasaki, M.; Kanai, M. Chem. Pharm. Bull. 2001, 49,
511–524.
3. (3) Hayashi, M.; Miyamoto, Y.; Inoue, T.; Oguni, N. J.
Org. Chem. 1993, 58, 1515–1522; (a) Zhou, X.-G.; Huang,
J.-S.; Ko, P.-H.; Cheng, K.-K.; Che, C.-M. J. Chem. Soc.,
Dalton. Trans. 1999, 3303–3309.
16. All the cyanohydrins and the corresponding acetates gave
satisfactory 1H NMR spectra that were in agreement with
the reported ones (Ref. 10), except for the cyanohydrin
and the acetate derived from 6-phenoxyhexanal. The
cyanohydrin and acetate are unknown compounds. The
benzoate derived from 2,2-dimethylpropanal also gave a
4. Katsuki, T. Synlett 2003, 281–297.
5. (a) Pan, W.; Feng, X.; Gong, L.; Hu, W.; Li, Z.; Mi, A.;
Jiang, Y. Synlett 1996, 337–338; (b) Belokon, Y.; Ikon-
nikov, N.; Moscalenko, M.; North, M.; Orlova, S.;
Tararov, V.; Yashkina, L. Tetrahedron: Asymmetry
1996, 7, 851–855.
1
satisfactory H NMR spectrum.
17. This assumption requires participation of a cis-b vana-
dium(V)(salen) species (see also Ref. 19), because coordi-
nation of two neutral ligands (acetone cyanohydrin

A. Watanabe et al. / Tetrahedron Letters 45 (2004) 6229–6233
and aldehyde) at the apical site of trans-oxovanadium(sa-
6233
len) complex 4 is considered to be unlikely due to the
presence of the bulky 2-phenylnaphthyl group at C3
and 30.
18. Non-oxo cis-b structure of vanadium(V)(salen)benzilate
complex has been identified by 51V NMR study:
Vergopoulos, V.; Jantzen, S.; Rodewald, D.; Rehder, D.
J. Chem. Soc., Chem. Commun. 1995, 377–378.
19. There are two possible mechanisms described in the
following scheme, for MPV cyanation catalyzed by a cis-
b vanadium(V)(salen) species. At present, we cannot
determine which mechanism is more likely
.