Zr(OBut)4 as an effective promoter for the Meerwein-Ponndorf-Verley alkynylation and cyanation of aldehydes: Development of new asymmetric cyanohydrin synthesis

Article abstract of DOI:10.1016/S0040-4020(00)01040-1

Zr(OBu^t)₄ can serve as an effective promoter for the Meerwein-Ponndorf-Verley alkynylation of aldehydes and also facilitate MPV type cyanide transfer to aldehyde carbonyls with commercially available acetone cyanohydrin under mild conditions. Based on this finding, a new procedure for asymmetric cyanohydrin synthesis has been developed employing (4R,5R)-2,2-dimethyl-α,α,α′,α′-tetraph enyl-1,3-dioxolane-4,5-dimethanol (TADDOL, 6) as a chiral ligand. For instance, sequential treatment of CH₂Cl₂ solution of 6 (1 equiv.) with Zr(OBu^t)₄ (1 equiv.) and acetone cyanohydrin (2 equiv.) at room temperature for 1 h, and subsequent reaction with 3-phenylpropanal at -40°C for 7.5 h resulted in formation of the corresponding cyanohydrin 5g [R=Ph(CH₂)₂] in 63% isolated yield with 85% ee. The scope and limitations of this method have been clarified with various aldehydes as substrates.

Full text of DOI:10.1016/S0040-4020(00)01040-1

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 867±873
Zr(OBut)4 As an effective promoter for the Meerwein±Ponndorf±
Verley alkynylation and cyanation of aldehydes: development of
new asymmetric cyanohydrin synthesis
Takashi Ooi,a,b Tomoya Miura,a,b Keisuke Takaya,a,b Hayato Ichikawaa,b and Keiji Maruokaa,b,p
aDepartment of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
bDepartment of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Received 28 April 2000; accepted 8 August 2000
AbstractÐZr(OBut)4 Can serve as an effective promoter for the Meerwein±Ponndorf±Verley alkynylation of aldehydes and also facilitate
MPV type cyanide transfer to aldehyde carbonyls with commercially available acetone cyanohydrin under mild conditions. Based on this
®nding, a new procedure for asymmetric cyanohydrin synthesis has been developed employing (4R,5R)-2,2-dimethyl-a,a,a0,a0-tetraphenyl-
1,3-dioxolane-4,5-dimethanol (TADDOL, 6) as a chiral ligand. For instance, sequential treatment of CH2Cl2 solution of 6 (1 equiv.) with
Zr(OBut)4 (1 equiv.) and acetone cyanohydrin (2 equiv.) at room temperature for 1 h, and subsequent reaction with 3-phenylpropanal at
2408C for 7.5 h resulted in formation of the corresponding cyanohydrin 5g [RˆPh(CH2)2] in 63% isolated yield with 85% ee. The scope and
limitations of this method have been clari®ed with various aldehydes as substrates. q 2001 Elsevier Science Ltd. All rights reserved.
During our recent study on the development of the new
Meerwein±Ponndorf±Verley (MPV) reduction system,1
we discovered that facile alkynyl transfer [A] to aldehyde
carbonyls can be successfully realized by the utilization of
modi®ed aluminum alkoxides (Scheme 1).2 Although this
MPV alkynylation is highly effective for the selective trans-
formation of aldehydes into the corresponding propargyl
alcohols without using organometallic reagents, the reaction
heavily depends on the signi®cant rate-acceleration
provided by o,o0-biphenylenedioxy ligand on aluminum,
because the intrinsic reactivity of the simple aluminum
alkoxide, e.g. Al(OC(CH3)2CuCPh)3 was found to be
exceedingly low as exempli®ed in Scheme 1. This situation
caused us to devote further effort to the search for appro-
priate metal reagents of suf®cient reactivity, which should
expand the generality of the transformation and open it up
for broad synthetic applications.3
desired alkynylation product 2 was obtained in 82% yield
only when Zr(OBut)4 was used as a promoter.4,5 It should be
noted that commonly used, strong Lewis acids such as
BF3´OEt2, TiCl4, and SnCl4 were found to be unsuitable,
and nearly instantaneous decomposition of the propargylic
alcohol was observed. Here, we performed a 13C NMR study
to con®rm the generation of expected zirconium alkoxide.
The original signals of alkoxy a-carbons of Zr(OBut)4 and 1
occurred at d 74.75 and 65.05, respectively. Upon mixing
Zr(OBut)4 and 1 in a 1:4 molar ratio in CD2Cl2 at room
temperature, signi®cant down®eld shift of hydroxy bearing
carbon of 1 was observed at d 71.22 with concurrent appear-
ance of the free t-BuOH signal at d 68.28 and none of the
original signals were detected. This result indicates the
complete alcohol exchange between Zr(OBut)4 and 1 and
therefore Zr(OC(CH3)2CuCPh)4 must be an actual reactive
species in solution, enabling facile MPV-type alkynyl
transfer through a six-membered transition state like A.
First, we examined the reactivity of various metal alkoxides
in the alkynylation of penta¯uorobenzaldehyde. Initially,
metal alkoxide (1 equiv.) was treated with propargylic
alcohol 1 (4 equiv.) in CH2Cl2 at room temperature for
30 min and then penta¯uorobenzaldehyde was added.
Each reaction was monitored by TLC and the results are
listed in Table 1, which unambiguously shows that most
of the metal isopropoxides and/or t-butoxides examined
here turned out to be totally ineffective. Interestingly, the
The ef®ciency of Zr(OBut)4 as a promoter was also empha-
sized in the MPV alkynylation of 2,2-dichlorodecanal.
Thus, treatment of 2,2-dichlorodecanal with Zr(OBut)4 and
1 (4 equiv.) in CH2Cl2 at room temperature for 1 h produced
the acetylenic alcohol 4 in 50% isolated yield, while the use
of Al(OC(CH3)2CuCPh)3 under otherwise identical reac-
tion conditions gave none of the desired product 4 (Scheme
2).
Keywords: cyanohydrin; alkynylation; cyanation.
* Corresponding author. Tel.: 181-75-753-4041; fax: 181-75-753-4000;
e-mail: maruoka@kuchem.kyoto-u.ac.jp
We further applied the present approach to cyanation of
aldehydes using acetone cyanohydrin as a cyanide source.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01040-1

868
T. Ooi et al. / Tetrahedron 57 (2001) 867±873
Scheme 1.
To our surprise, treatment of penta¯uorobenzaldehyde with
a premixed CH2Cl2 solution of Zr(OBut)4 (1 equiv.) and
acetone cyanohydrin (2 equiv.) at room temperature
resulted in a rapid and clean formation of the corresponding
cyanohydrin 5a (RˆC6F5) in 90% yield (entry 1 in Table 2)
and comparable reactivity was also attained in the reaction
with benzaldehyde (entry 2). Other selected examples
summarized in Table 2 clearly demonstrate the ef®ciency
and general applicability of the MPV cyanation: it proceeds
smoothly with various aldehydes under mild reaction con-
ditions by the use of commercially available, safe-to-handle
acetone cyanohydrin as a cyanide source and the only by-
product is relatively non-toxic, volatile acetone.
Based on this ®nding, we set out to investigate the asym-
metric version of the MPV cyanation employing a chiral
zirconium ligand,6 which could provide a new access to
optically active cyanohydrins,7,8 versatile synthetic inter-
mediates of various homochiral compounds such as
a-hydroxy carboxylic acids, a-hydroxy aldehydes,
a-hydroxy ketones, b-hydroxy amines and a-amino acid
derivatives as well as other biologically important organic
molecules.9
Optically active phenols, alcohols and amines were examined
in the cyanation of 3-phenylpropanal as a model substrate
under ®xed reaction conditions (2208C for 2 h). Since it is
well known that ligand exchange between Zr(OBut)4 and
binaphthol derivatives enhances the Lewis acidity,4c we
®rst chose (S)-binaphthol for our purpose with the expec-
tation that the reaction could proceed even at lower
temperature, which would be bene®cial to enantiofacial
control. However, sequential treatment of CH2Cl2 solution
of (S)-binaphthol (1 equiv.) with Zr(OBut)4 (1 equiv.) and
acetone cyanohydrin (2 equiv.) at room temperature for 1 h,
and subsequent reaction with 3-phenylpropanal at 2208C
for 2 h gave rise to the corresponding cyanohydrin,
2-hydroxy-4-phenylbutanenitrile [5g; RˆPh(CH2)2] in
only 7% isolated yield and the enantiomeric excess was
determined to be 23% ee (entry 1 in Table 3). This result
indicates that enhancement of Lewis acidity is not neces-
sarily effective for this MPV-type reaction and preservation
of the appropriate push-pull relay seems to be indispensable.
Although employment of other commercially available,
optically active diols and diamines including (R)-(1)-
1,1,2-triphenyl-1,2-ethanediol5c for the cyanation gave
Table 1. MPV Alkynylation of C6F5CHO with various metal alkoxides (the
reaction was carried out in CH2Cl2 at room temperature with 1 equiv. of
metal alkoxide and 4 equiv. of 1 under indicated conditions)
Entry
Alkoxide
Time (h)
Yield (%)a,b
1
2
3
4
5
6
7
8
9
Al(OPri)3
Al(OBut)3
Ti(OPri)4
TiCl2(OPri)2
Ti(OBut)4
Zr(OPri)4
Zr(OBut)4
Sm(OPri)3
Yb(OPri)3
6
6
6
2
9
6
0.25
6
6
6
10
n.r.
n.r.c
n.r.
n.r.
82
n.r.
n.r.
a Isolated yield of 2.
b n.r.ˆno reaction.
c Decomposition of 1 was mainly observed.
Scheme 2.

T. Ooi et al. / Tetrahedron 57 (2001) 867±873
869
Table 2. Zr(OBut)4-Promoted MPV cyanation of aldehydes (unless other-
wise noted, acetone cyanohydrin (2 equiv.) was treated with Zr(OBut)4
(1 equiv.) in CH2Cl2 at room temperature for 30 min, and then reacted
with aldehyde under the given reaction conditions)
Table 3. Chiral zirconium alkoxides-promoted asymmetric MPV cyanation
of 3-phenylpropionaldehyde (unless otherwise speci®ed, the reaction was
carried out with Zr(OBut)4 (1 equiv.) and chiral ligand (1 equiv.) in CH2Cl2
at 2208C for 2 h)
Entry
Aldehyde (R)
Reaction time (h)
Product
Yield (%)a
1
2
3
4
5
6
7
8
C6F5
Ph
o-Cl-C6H4
p-NO2-C6H4
p-MeO-C6H4
a-Np
0.1
0.5
0.5
0.5
5
2
1
0.5
5a
5b
5c
5d
5e
5f
90
93
76
82
91
91
96
91
Entry
Chiral ligand
Yield (%)a
ee (%)b (con®g)c
Ph(CH2)2
CH3(CH2)6
5g
5h
1
7
23 (R)
9
0.5
5i
82
a Isolated yield.
2
3
4
93
51
11
28 (R)
8 (R)
disappointing results especially in terms of asymmetric
induction as shown in Table 3, on reaction with (4R,5R)-
2,2-dimethyl-a,a,a0,a0-tetraphenyl-1,3-dioxolane-4,5-dimetha-
nol (TADDOL, 6)10 under similar conditions the enantio-
selectivity was greatly improved to 79% ee with satisfactory
chemical yield (67%) (entry 5). With this information, our
attention was focused on the optimization of the reaction
condition and evaluation of the generality of the present
approach. The enantioselectivity was further enhanced by
performing the reaction at 2408C (entry 1 in Table 4). Use
of 4 equiv. of acetone cyanohydrin led to better chemical
yield (80%) with slightly diminished enantiomeric excess
(80% ee) and the enantioselectivity was improved to 91% ee
by lowering the reaction temperature to 2788C, for which
chemical yield was sacri®ced (32%) (entries 2 and 3).
Consequently, we decided to examine a variety of aldehydes
as substrates for this TADDOL-derived zirconium alkoxide-
mediated asymmetric MPV cyanation at 2408C with
2 equiv. of acetone cyanohydrin, and the results are listed
8 (R)d
5
67
79 (R)
a Isolated yield of acetate.
b Enantiomeric excesses were determined by GC analysis of the corre-
sponding acetates with chiral column (GL SCIENCE CP-CHIRASIL-
DEX CB).
c Absolute con®gurations were determined by comparison of optical rota-
tions of cyanohydrins with literature values.
d At 08C for 1 h.
Table 4. Chiral zirconium alkoxides-mediated asymmetric MPV cyanation of aldehydes (unless otherwise noted, 6 (1 equiv.) was sequentially treated with
Zr(OBut)4 (1 equiv.) and acetone cyanohydrin (2 equiv.) in CH2Cl2 at room temperature for 1 h, and then reacted with aldehyde under the given reaction
conditions)
Entry
Aldehyde (R)
Ph(CH2)2
Condition (8C, h)
Product
Yield (%)a
ee (%)b (con®g)c
1
2
3
4
5
6
7
8
240, 7.5
240, 7.5
278, 7.5
240, 5
240, 5
240, 5
5g
63
80
32
63
55
36
47
45
85 (R)
80 (R)d
91 (R)
84 (R)
79 (R)
72 (R)
59 (R)
63 (R)
CH3(CH2)8
c-Hex
t-Bu
PhCH2
Ph
5j
5k
5l
5m
5b
240, 5
240, 18
9
240, 18
5i
30
61 (R)
10
11
240, 18
240, 18
5n
5o
28
25
54 (R)
29 (R)
trans-PhCHvCH
a Isolated yield of acetate.
b Enantiomeric excesses were determined by GC analysis of the corresponding acetates with chiral column (GL SCIENCE CP-CHIRASIL-DEX CB).
c Absolute con®gurations were determined by comparison of optical rotations of cyanohydrins with literature values.
d 4 equiv. of acetone cyanohydrin was used.

870
T. Ooi et al. / Tetrahedron 57 (2001) 867±873
Scheme 3.
in Table 4. In the asymmetric cyanation of aliphatic
aldehydes, as were more substituents on the a-position of
substrates, both reactivity and selectivity were gradually
decreased (entries 4±6). Aromatic aldehydes were also
found to be employable, giving the corresponding cyano-
hydrins in moderate enantioselectivities (entries 8±10).
Unfortunately, the reaction with a,b-unsaturated aldehyde
such as trans-cinnamaldehyde gave less satisfactory results
(entry 11).
chloride was freshly distilled from calcium hydride, and
toluene was freshly distilled from sodium metal. Pyridine
was stored over KOH pellets. Zirconium tetra-tert-butoxide
was purchased from Strem Chemicals Co. Ltd. 2,2-
Dichlorodecanal12 and (4R,5R)-2,2-dimethyl-a,a,a0,a0-
tetraphenyl-1,3-dioxolane-4,5-dimethanol (TADDOL, 6)10a
were prepared according to the literature procedures. Other
simple chemicals were purchased and used as such.
1.2. General procedure for Meerwein±Ponndorf±Verley
(MPV) alkynylation of penta¯uorobenzaldehyde with
various metal alkoxides
In the present MPV cyanation of aldehydes, the amount of
chiral zirconium alkoxide is reducible to catalytic if facile
alcohol exchange with acetone cyanohydrin can regenerate
the catalyst and derivatize the product cyanohydrin in situ.
Since the advantages of the catalytic version are quite
obvious in terms of economy, large-scale preparation and
isolation, we further investigated on this possibility and
2-Methyl-4-phenyl-3-butyn-2-ol (1) (0.32 g, 2 mmol) and
metal alkoxide (0.5 mmol) were placed in a dry, two-neck
¯ask with stirring bar under argon and freshly distilled
CH2Cl2 (5 mL) was introduced, then this mixture was stirred
for 30 min at room temperature. Freshly distilled penta¯uoro-
benzaldehyde (62 mL, 0.5 mmol) was added dropwise and
the reaction mixture was stirred for 0.25±9 h at room
temperature. The reaction was quenched by the addition
of 1N HCl and an extractive workup was performed with
ether. The ethereal extracts were washed with brine and
dried over Na2SO4. Evaporation of solvents and puri®cation
of the residue by column chromatography on silica gel
(ether/hexaneˆ1:4 as eluant) gave the alkynylation product
2.
Ê
found that the presence of 4 A molecular sieves played a
prominent role in establishing the catalytic cycle.8 For
instance, treatment of 3-phenylpropanal with the catalyst
Ê
(20 mol%), prepared with activated, powdered 4 A molecu-
lar sieves in an otherwise similar manner, in CH2Cl2 at
2408C for 15 h gave rise to the cyanation product, 2-hy-
droxy-4-phenylbutanenitrile [5g; RˆPh(CH2)2] in 51% with
72% ee, whereas the cyanation without molecular sieves
under otherwise identical conditions afforded only a trace
amount of 5g as illustrated in Scheme 3.11
1.2.1. 2-Methyl-4-phenyl-3-butyn-2-ol (1).13 This alcohol
was prepared by treatment of acetone with an ether solution
1. Experimental
1.1. General
1
of lithium phenylacetylide at 08C. H NMR (CDCl3) d
7.39±7.46 (2H, m, Ph), 7.27±7.36 (3H, m, Ph), 2.02 (1H,
s, OH), 1.62 (6H, s, 2CH3).
Infrared (IR) spectra were recorded on a Shimadzu FT-IR
8200A spectrometer. H NMR spectra were measured on a
1
1.2.2. 1-(Penta¯uorophenyl)-3-phenyl-2-propyn-1-ol (2).
1H NMR (CDCl3) d 7.41±7.48 (2H, m, Ph), 7.29±7.40 (3H,
m, Ph), 5.98 (1H, d, Jˆ8.1 Hz, CHOH), 2.71 (1H, d,
Jˆ8.1 Hz, OH); IR (KBr) 3172, 2242, 1656, 1506, 1290,
1122, 1053, 984, 915, 756, 693 cm21. Anal. Calcd for
C15H7F5O: C, 60.42; H, 2.37. Found: C, 60.43; H, 2.35.
Varian Gemini-300 spectrometer and a JEOL JNM-FX400
spectrometer. Analytical gas-liquid phase chromatography
(GLC) was performed on Shimadzu GC-14B instruments
equipped with a ¯ame ionization detector and a chiral capil-
lary column of GL Science CP-CHIRASIL-DEX CB
(0.25£25,000 mm) using nitrogen as carrier gas. Optical
rotations were measured on a JASCO DIP-1000 digital
polarimeter. All experiments were carried out under an
atmosphere of dry argon. For thin layer chromatography
(TLC) analysis throughout this work, Merck precoated
TLC plates (silica gel 60 GF254, 0.25 mm) were used.
The products were puri®ed by preparative column chroma-
tography on silica gel (E. Merck 9385). Elemental analyzes
were accomplished at the Center for Instrumental Analysis,
Hokkaido University.
1.3. MPV Alkynylation of 2,2-dichlorodecanal with
Zr(OBut)4
To a solution of 2-methyl-4-phenyl-3-butyn-2-ol (1)
(0.32 g, 2 mmol) in freshly distilled CH2Cl2 (5 mL) was
added a 1 M toluene solution of Zr(OBut)4 (0.5 mL,
0.5 mmol) at room temperature and the mixture was stirred
for 30 min. Freshly distilled 2,2-dichlorodecanal (113 mg,
0.5 mmol) was added dropwise and the reaction mixture
was stirred for 1 h at room temperature. The reaction was
quenched by the addition of 1N HCl and an extractive
workup was performed with ether. The ethereal extracts
In experiments requiring dry solvents, ether was purchased
from Kanto Chemical Co. Ltd as `Dehydrated'. Methylene

T. Ooi et al. / Tetrahedron 57 (2001) 867±873
871
were washed with brine and dried over Na2SO4. Evaporation
of solvents and puri®cation of the residual oil by column
chromatography on silica gel (ether/hexaneˆ1:5 as eluant)
gave the alkynylation product 4 (82 mg, 0.25 mmol; 50%
yield).
(1H, d, Jˆ7.2 Hz, Naph), 7.50±7.67 (3H, m, Naph), 6.20
(1H, s, CHOH), 2.70 (1H, br s, OH); IR (liquid ®lm) 3414,
3055, 2924, 2250, 1601, 1512, 1396, 1358, 1267, 1242,
1167, 1086, 1024, 928, 802, 779 cm21
.
1.4.7. 2-Hydroxy-4-phenylbutanenitrile (5g). Described
below.
1.3.1. 4,4-Dichloro-1-phenyl-1-dodecyn-3-ol (4). 1H NMR
(CDCl3) d 7.44±7.53 (2H, m, Ph), 7.29±7.40 (3H, m, Ph),
4.83 (1H, d, Jˆ8.4 Hz, CHOH), 2.77 (1H, d, Jˆ8.4 Hz,
OH), 2.30±2.40 (2H, m, CCl2CH2), 1.74 (2H, quint, Jˆ
7.8 Hz, CCl2CCH2), 1.18±1.46 (10H, m, 5CH2), 0.88 (3H,
t, Jˆ6.9 Hz, CH3); IR (liquid ®lm) 3423, 3034, 2926, 2855,
2237, 1598, 1491, 1466, 1445, 1379, 1236, 1069, 756,
691 cm21. Anal. Calcd for C18H24Cl2O: C, 66.06; H, 7.39;
Cl, 21.66. Found: C, 65.87; H, 7.58; Cl, 21.45.
1.4.8. 2-Hydroxynonanenitrile (5h).19 1H NMR (CDCl3) d
4.48 (1H, q, Jˆ6.8 Hz, CHOH), 2.27 (1H, br s, OH), 1.85
(2H, m, CH2COH), 1.51 (2H, m, CH2CCOH), 1.20±1.41
(8H, m, 4CH2), 0.89 (3H, t, Jˆ6.8 Hz, CH3); IR (liquid
®lm) 3445, 2955, 2928, 2858, 2250, 1466, 1379, 1333,
1128, 1074, 723 cm21
.
1.4.9. 2-(2-Furyl)-2-hydroxyacetonitrile (5i). Described
below.
1.4. General procedure for MPV cyanation of aldehydes
To a solution of acetone cyanohydrin (92 mL, 1 mmol) in
freshly distilled CH2Cl2 (5 mL) was added a 1 M CH2Cl2
solution of Zr(OBut)4 (0.5 mL, 0.5 mmol) at room tempera-
ture and the mixture was stirred for 30 min. Freshly distilled
aldehyde (0.5 mmol) was added dropwise and the reaction
mixture was stirred for 0.1±5 h at room temperature. The
reaction was quenched with 1N HCl and the aqueous phase
was extracted with ether. The ethereal extracts were washed
with brine and dried over Na2SO4. Evaporation of solvents
and puri®cation of the residual oil by column chroma-
tography on silica gel (ethyl acetate/hexaneˆ1:5 as eluant)
gave the cyanation products 5.
1.5. General procedure for asymmetric MPV cyanation
of aldehydes with TADDOL-derived zirconium alkoxide
(4R,5R)-2,2-Dimethyl-a,a,a0,a0-tetraphenyl-1,3-dioxolane-
4,5-dimethanol (TADDOL, 6) (233 mg, 0.5 mmol) was
placed in a dry, two-neck ¯ask with stirring bar under
argon and freshly distilled CH2Cl2 (5 mL) was introduced.
To this solution was added a 1 M CH2Cl2 solution of
Zr(OBut)4 (0.5 mL, 0.5 mmol) at room temperature and
the mixture was stirred for 30 min. Then distilled acetone
cyanohydrin (92 mL, 1.0 mmol) was added and the stirring
was continued for an additional 30 min. Freshly distilled
aldehyde (0.5 mmol) was slowly added dropwise at
2408C and the reaction mixture was stirred there for
5±18 h. The solution was poured into 1N HCl and an extrac-
tive workup was performed with ether. The ethereal extracts
were washed with brine, dried over Na2SO4 and the volatiles
were evaporated. After the ®ltration through a short silica
gel column, the analytically pure cyanohydrin (5b, 5g, 5i±
5o) was dissolved into CH2Cl2 and treated with pyridine
(101 mL, 1.25 mmol), Ac2O (118 mL, 1.25 mmol) and a
catalytic amount of DMAP at 08C for 30 min. The reaction
was quenched by the addition of water and extracted with
ether. The organic extracts were washed with brine and
dried over Na2SO4. Evaporation of solvents and puri®cation
of the residue by column chromatography on silica gel
(ethyl acetate/hexaneˆ1:9 as eluant) gave the correspond-
ing acetate. Enantiomeric excess was determined by capil-
lary GC analysis with a chiral column (GL SCIENCE
CP-CHIRASIL-DEX CB). The absolute con®gulation of
each cyanohydrin was determined by comparison of the
optical rotation with literature values.
1.4.1. 2-Hydroxy-2-(penta¯uorophenyl)acetonitrile (5a).14
1H NMR (CDCl3) d 5.83 (1H, d, Jˆ8.4 Hz, CHOH), 2.97
(1H, d, Jˆ8.4 Hz, OH); IR (CHCl3) 3414, 3024, 2934, 2860,
1709, 1659, 1512, 1431, 1335, 1306, 1132, 1057, 1001, 893,
669 cm21.
1.4.2. 2-Hydroxy-2-phenylacetonitrile (5b). Described
below.
1.4.3. 2-(o-Chlorophenyl)-2-hydroxyacetonitrile (5c).15
1H NMR (CDCl3) d 7.70±7.85 (1H, m, Ph), 7.37±7.48
(3H, m, Ph), 5.88 (1H, d, Jˆ6.8 Hz, CHOH), 2.90 (1H, d,
Jˆ6.8 Hz, OH); IR (liquid ®lm) 3408, 3107, 2930, 2251,
1595, 1578, 1475, 1445, 1416, 1279, 1192, 1134, 1059,
1036, 941, 920, 818, 758, 729, 710 cm21
.
1.4.4. 2-Hydroxy-2-(p-nitrophenyl)acetonitrile (5d).16 1
H
NMR (CDCl3) d 8.33 (2H, d, Jˆ8.4 Hz, Ph), 7.76 (2H, d,
Jˆ8.4 Hz, Ph), 5.71 (1H, d, Jˆ6.4 Hz, CHOH), 3.04 (1H, d,
Jˆ6.4 Hz, OH); IR (KBr) 3406, 3119, 1609, 1524, 1346,
1229, 1190, 1109, 1067, 858, 808, 746, 704 cm21
.
1.5.1. 2-Hydroxy-2-phenylacetonitrile (5b).17 1H NMR
(CDCl3) d 7.40±7.59 (5H, m, Ph), 5.56 (1H, d, Jˆ7.2 Hz,
CHOH), 2.59 (1H, br s, OH); IR (liquid ®rm) 3423, 3067,
1.4.5. 2-Hydroxy-2-(p-methoxyphenyl)acetonitrile (5e).17
1H NMR (CDCl3) d 7.46 (2H, d, Jˆ8.8 Hz, Ph), 6.96 (2H, d,
Jˆ8.8 Hz, Ph), 5.49 (1H, d, Jˆ7.2 Hz, CHOH), 3.84 (3H, s,
CH3), 2.54 (1H, d, Jˆ7.2 Hz, OH); IR (liquid ®lm) 3414,
3037, 2937, 2841, 2245, 1612, 1514, 1466, 1308, 1256,
3036, 2928, 2858, 2253, 1697, 1495, 1456, 1406, 1244,
1192, 1040, 934, 820, 762, 741, 698 cm21; [a]D
27
ˆ
1
128.948 (c 1.00, CHCl3); 63% ee (R). Acetate of 5b: H
NMR (CDCl3) d 7.42±7.58 (5H, m, Ph), 6.42 (1H, s,
CHOAc), 2.17 (3H, s, Ac); IR (liquid ®lm) 3069, 2953,
1178, 1115, 1032, 926, 835, 770 cm21
.
1755, 1458, 1373, 1217, 1026, 964, 901, 760, 698 cm21
.
1.4.6. 2-Hydroxy-2-(a-naphthyl)acetonitrile (5f).18 1H
NMR (CDCl3) d 8.17 (1H, d, Jˆ8.4 Hz, Naph), 7.96 (1H,
d, Jˆ8.0 Hz, Naph), 7.94 (1H, d, Jˆ7.2 Hz, Naph), 7.85
tRˆ11.4 min for (R)-isomer, 14.3 min for (S)-isomer at the
column temperature of 1408C.

872
T. Ooi et al. / Tetrahedron 57 (2001) 867±873
1.5.2. 2-Hydroxy-4-phenylbutanenitrile (5g).17 1H NMR
(CDCl3) d 7.18±7.37 (5H, m, Ph), 4.44 (1H, q, Jˆ6.4 Hz,
CHOH), 2.86 (2H, dt, Jˆ3.6, 7.6 Hz, PhCH2), 2.24 (1H, d,
Jˆ6.4 Hz, OH), 2.18 (2H, ddt, Jˆ2.6, 6.4, 7.6 Hz,
CH2COH); IR (liquid ®lm) 3441, 3028, 2929, 2862, 2245,
28
[a]D ˆ 116.828 (c 1.17, CHCl3); 72% ee (R). Acetate of
1
5l: H NMR (CDCl3) d 5.07 (1H, s, CHOAc), 2.16 (3H, s,
Ac), 1.09 (9H, s, 3CH3); IR (liquid ®lm) 2972, 2877, 1755,
1481, 1375, 1302, 1232, 1057, 1026, 974, 904 cm21
.
tRˆ10.1 min for (R)-isomer, 14.9 min for (S)-isomer at the
1717, 1605, 1497, 1456, 1304, 1072, 941, 752, 700 cm21
;
column temperature of 1058C.
27
[a]D ˆ26.388 (c 1.03, CHCl3); 85% ee (R). Acetate of 5g:
1H NMR (CDCl3) d 7.16±7.35 (5H, m, Ph), 5.27 (1H, t,
Jˆ6.8 Hz, CHOAc), 2.84 (2H, dt, Jˆ2.0, 8.0 Hz, PhCH2),
2.24 (2H, dt, Jˆ6.8, 8.0 Hz, CH2COAc), 2.13 (3H, s, Ac);
IR (liquid ®lm) 3065, 3030, 2936, 2868, 1755, 1605, 1499,
1456, 1373, 1223, 1043, 752, 702 cm21. tRˆ14.0 min for
(R)-isomer, 15.5 min for (S)-isomer at the column tempera-
ture of 1608C.
1.5.7. 2-Hydroxy-3-phenylpropionenitrile (5m).21 1H
NMR (CDCl3) d 7.19±7.46 (5H, m, Ph), 4.68 (1H, q,
Jˆ6.4 Hz, CHOH), 3.14 (2H, d, Jˆ6.4 Hz, PhCH2), 2.28
(1H, d, Jˆ6.4 Hz, OH); IR (liquid ®lm) 3429, 3065, 3032,
2934, 2250, 1605, 1497, 1456, 1337, 1263, 1080, 1065,
1032, 746, 700 cm21; [a]D ˆ16.368 (c 0.94, CHCl3);
30
1
59% ee (R). Acetate of 5m: H NMR (CDCl3) d 7.20±
7.42 (5H, m, Ph), 5.48 (1H, t, Jˆ6.8 Hz, CHOAc), 3.19
(2H, d, Jˆ6.8 Hz, PhCH2), 2.12 (3H, s, Ac); IR (liquid
®lm) 3067, 3034, 2939, 1755, 1605, 1499, 1456, 1437,
1373, 1225, 1036, 905, 754, 702 cm21. tRˆ19.5 min for
(R)-isomer, 22.5 min for (S)-isomer at the column tempera-
ture of 1408C.
1.5.3. 2-(2-Furyl)-2-Hydroxyacetonitrile (5i).20 1H NMR
(CDCl3) d 7.49 (1H, dd, Jˆ0.8, 2.0 Hz, CvCHOC), 6.62
(1H, dd, Jˆ0.8, 3.6 Hz, CHvCCOH), 6.43 (1H, dd, Jˆ2.0,
3.6 Hz, CHvCOC), 5.55 (1H, d, Jˆ8.0 Hz, CHOH), 2.71
(1H, br s, OH); IR (liquid ®lm) 3420, 3155, 3126, 2928,
2250, 1643, 1500, 1418, 1234, 1150, 1036, 1016, 959,
1.5.8. 2-Hydroxy-2-(2-thienyl)acetonitrile (5n).17 1H
NMR (CDCl3) d 7.43 (1H, dd, Jˆ1.2, 5.2 Hz, CvCHSC),
7.31 (1H, dt, Jˆ1.2, 3.6 Hz, CHvCCOH), 7.05 (1H, dd,
Jˆ3.6, 5.2 Hz, CHvCSC), 5.74 (1H, d, Jˆ7.6 Hz,
CHOH), 2.76 (1H, d, Jˆ7.6 Hz, OH); IR (liquid ®lm)
3414, 3111, 2928, 2250, 1655, 1433, 1269, 1238, 1175,
31
899, 881, 825, 750 cm21; [a]D ˆ123.308 (c 0.92,
1
CHCl3); 61% ee (R). Acetate of 5i: H NMR (CDCl3) d
7.51 (1H, dd, Jˆ0.8, 1.6 Hz, CvCHOC), 6.68 (1H, d, Jˆ
3.2 Hz, CHvCCOAc), 6.48 (1H, s, CHOAc), 6.45 (1H, dd,
Jˆ1.6, 3.2 Hz, CHvCOC), 2.17 (3H, s, Ac); IR (liquid
®lm) 3155, 3130, 2953, 1755, 1499, 1431, 1373, 1217,
1153, 1016, 918, 883, 829, 752 cm21. tRˆ5.8 min for
(R)-isomer, 6.5 min for (S)-isomer at the column tempera-
ture of 1408C.
1134, 1028, 903, 854, 712 cm21; [a]D ˆ134.078 (c 0.72,
28
1
CHCl3); 51% ee (R). Acetate of 5n: H NMR (CDCl3) d
7.46 (1H, dd, Jˆ1.2, 5.2 Hz, CvCHSC), 7.35 (1H, dt,
Jˆ1.2, 3.6 Hz, CHvCCOH), 7.05 (1H, dd, Jˆ3.6, 5.2 Hz,
CHvCSC), 6.64 (1H, s, CHOAc), 2.17 (3H, s, Ac); IR
(liquid ®lm) 3111, 2941, 1753, 1431, 1371, 1285, 1215,
1134, 1020, 945, 903, 856, 843, 716 cm21. tRˆ12.0 min
for (R)-isomer, 14.1 min for (S)-isomer at the column
temperature of 1408C.
1.5.4. 2-Hydroxyundecanenitrile (5j).21 1H NMR (CDCl3)
d 4.48 (1H, q, Jˆ6.8 Hz, CHOH), 2.29 (1H, d, Jˆ6.8 Hz,
OH), 1.85 (2H, m, CH2COH), 1.51 (2H, m, CH2CCOH),
1.20±1.40 (12H, m, 6CH2), 0.88 (3H, t, Jˆ6.8 Hz, CH3);
IR (liquid ®lm) 3441, 2926, 2856, 2250, 1466, 1379, 1128,
1082, 721 cm21; [a]D ˆ17.308 (c 1.09, CHCl3); 84% ee
28
1.5.9. 2-Hydroxy-4-phenyl-3-(E)-butenenitrile (5o).17 1
H
1
(R). Acetate of 5j: H NMR (CDCl3) d 5.31 (1H, t, Jˆ
NMR (CDCl3) d 7.29±7.55 (5H, m, Ph), 6.94 (1H, d,
Jˆ16.0 Hz, PhCHvC), 6.27 (1H, dd, Jˆ5.6, 16.0 Hz,
PhCvCH), 5.17 (1H, dd, Jˆ1.2, 5.6 Hz, CHOH), 2.45
(1H, br s, OH); IR (CHCl3) 3358, 3028, 2926, 2253, 1655,
1493, 1450, 1416, 1300, 1088, 1072, 1024, 976, 926, 818,
6.8 Hz, CHOAc), 2.14 (3H, s, Ac), 1.89 (2H, q, Jˆ6.8 Hz,
CH2COAc), 1.49 (2H, m, CH2CCOAc), 1.18±1.40 (12H, m,
6CH2), 0.88 (3H, t, Jˆ6.8 Hz, CH3); IR (liquid ®lm) 2928,
2856, 1757, 1466, 1373, 1223, 1040 cm21. tRˆ13.1 min for
(R)-isomer, 14.7 min for (S)-isomer at the column tempera-
ture of 1608C.
695 cm21; [a]D ˆ17.908 (c 1.00, CHCl3); 33% ee (R).
30
1
Acetate of 5o: H NMR (CDCl3) d 7.29±7.48 (5H, m,
1.5.5. 2-Cyclohexyl-2-hydroxyacetonitrile (5k).17 1H
NMR (CDCl3) d 4.28 (1H, t, Jˆ6.4 Hz, CHOH), 2.17
(1H, d, Jˆ6.4 Hz, OH), 1.66±1.98 (6H, m, CH and CH2),
Ph), 6.98 (1H, d, Jˆ15.2 Hz, PhCHvC), 6.20 (1H, dd,
Jˆ6.8, 15.2 Hz, PhCvCH), 6.03 (1H, dd, Jˆ1.2, 6.8 Hz,
CHOAc), 2.17 (3H, s, Ac); IR (liquid ®lm) 3061, 3030,
2936, 1753, 1657, 1580, 1499, 1450, 1373, 1217, 1022,
968, 752, 694 cm21. tRˆ10.2 min for (R)-isomer, 10.9 min
for (S)-isomer at the column temperature of 1808C.
1.07±1.38 (5H, m, CH2); IR (liquid ®lm) 3441, 2932, 2856,
2250, 1452, 1086, 1059, 1043, 970, 895 cm21; [a]D
ˆ
27
1
18.128 (c 0.77, CHCl3); 79% ee (R). Acetate of 5k: H
NMR (CDCl3) d 5.18 (1H, d, Jˆ6.4 Hz, CHOAc), 2.14
(3H, s, Ac), 1.66±1.99 (6H, m, CH and CH2), 1.08±1.36
(5H, m, CH2); IR (liquid ®lm) 2934, 2858, 1755, 1452,
1.6. Representative procedure for catalytic asymmetric
MPV cyanation of 3-phenylpropanal
1373, 1225, 1144, 1074, 1038, 989, 916, 887, 770 cm21
.
(4R,5R)-2,2-Dimethyl-a,a,a0,a0-tetraphenyl-1,3-dioxolane-
4,5-dimethanol (TADDOL, 6) (46 mg, 0.1 mmol) was
placed in a dry, two-neck ¯ask with stirring bar and acti-
tRˆ10.5 min for (R)-isomer, 12.6 min for (S)-isomer at the
column temperature of 1408C.
1.5.6. 3,3-Dimethyl-2-hydroxybutanenitrile (5l).17 1H
NMR (CDCl3) d 4.13 (1H, d, Jˆ6.8 Hz, CHOH), 2.23
(1H, br s, OH), 1.09 (9H, s, 3CH3); IR (liquid ®lm) 3449,
2966, 2914, 2878, 2247, 1641, 1479, 1398, 1371, 1321,
Ê
vated, powdered 4 A molecular sieves (100 mg) under
argon and freshly distilled CH2Cl2 (5 mL) was introduced.
To this solution was added a 1 M CH2Cl2 solution of
Zr(OBut)4 (0.1 mL, 0.1 mmol) at room temperature and
the mixture was stirred for 30 min. Then distilled acetone
1290, 1244, 1186, 1076, 1022, 949, 934, 864, 766 cm21
;

T. Ooi et al. / Tetrahedron 57 (2001) 867±873
7. For a review: North, M. Synlett, 1993, 807.
873
cyanohydrin (92 mL, 1.0 mmol) was added and the stirring
was continued for an additional 30 min. Freshly distilled
3-phenylpropanal (66 mL, 0.5 mmol) was slowly added
dropwise at 2408C and the reaction mixture was stirred
there for 15 h. The solution was poured into 1N HCl and
extracted with ether. The ethereal extracts were washed with
brine, dried over Na2SO4 and the volatiles were evaporated.
After the ®ltration through a short silica gel column, the
product 5g was acetylated in a similar manner as described
above to give the corresponding acetate as a colorless oil
(52 mg, 0.26 mmol; 51% yield). Enantiomeric excess was
determined to be 72% ee (R) by capillary GC analysis with a
chiral column (GL SCIENCE CP-CHIRASIL-DEX CB) at
the column temperature of 1608C.
8. Hwang, C.-D.; Hwang, D.-R.; Uang, B.-J. J. Org. Chem. 1998,
63, 6762 and references cited therein.
9. (a) Aketa, K.; Ohno, N.; Itaya, N.; Nakayama, I.; Yoshioka, H.
Agric. Biol. Chem. 1978, 42, 895. (b) Matthews, B. R.;
Gountzos, H.; Jackson, W. R.; Watson, K. G. Tetrahedron
Lett. 1989, 30, 5157. (c) Ziegler, T.; Horsch, B.;
Effenberger, F. Synthesis 1990, 575. (d) Watson, K. G.;
Fung, Y. M.; Gredley, M.; Bird, G. J.; Jackson, W. R.;
Gountzos, H.; Matthews, B. R. J. Chem. Soc., Chem. Commun.
1990, 1018. (e) Jackson, W. R.; Jacobs, H. A.; Jayatilake,
G. S.; Matthews, B. R.; Watson, K. G. Aust. J. Chem. 1990,
43, 2045. (f) Zandbergen, P.; Brussee, J.; van der Gen, A.;
Kruse, C. G. Tetrahedron: Asymmetry 1992, 3, 769.
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Wonnacott, A. Helv. Chim. Acta 1987, 70, 954. (b) Seebach, D.;
Plattner, D. A.; Beck, A. K.; Wang, Y. M.; Hunziker, D.;
Petter, W. Helv. Chim. Acta 1992, 75, 2171.
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