Synthesis of chiral pyridyl alcohols using a two-step catalytic approach

Article abstract of DOI:10.1055/s-2007-990903

Chira l pyridyl alcohols have been prepared by developing a two-step approach that uses the asymmetric cyanation of aldehydes to give cyanohydrins and subsequent [2+2+2]-cyclotrimerization reaction with acetylene. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990903

PAPER
69
Synthesis of Chiral Pyridyl Alcohols Using a Two-Step Catalytic Approach
T
wo-Step Catalyt
a
ic
A
pproac
r
h to Chi
b
ral Pyridyl
A
a
lcohols ra Heller,*a Dmitry Redkin,a Andrey Gutnov,b Christine Fischer,a Werner Bonrath,c Reinhard Karge,c
Marko Hapke*a
a
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Fax +49(381)12815000; E-mail: barbara.heller@catalysis.de; marko.hapke@catalysis.de
ChiroBlock GmbH, Andresenstr. 1a, 06766 Wolfen, Germany
DSM Nutritional Products Ltd., Process Research NRD-CR, P.O. Box 3255, Bldg. 214/1.57, 4002 Basel, Switzerland
b
c
Received 14 September 2007
alysts and ligands for enantioselective synthesis and
catalysis. Examples amenable to catalysis with pyridyl al-
cohols include the epoxidation of allylic alcohols,6f the
conjugate addition of dialkylzinc reagents to a,b-unsatur-
ated ketones,6g–i and the nucleophilic addition of dialkyl-
zinc reagents to aldehydes.6j–n Recently, phosphorus
ligands derived from pyridyl alcohols were successfully
applied to iridium-catalyzed asymmetric hydrogenation.6o
Many enantiomerically pure pyridyl alcohols are also bi-
ologically relevant compounds and key intermediates for
commercial drugs [e.g. (R,S)-mefloquine or (S)-carbinox-
amine].
Abstract: Chiral pyridyl alcohols have been prepared by develop-
ing a two-step approach that uses the asymmetric cyanation of
aldehydes to give cyanohydrins and subsequent [2+2+2]-cyclotri-
merization reaction with acetylene.
Key words: asymmetric synthesis, cyclotrimerization, cyanohy-
drin, pyridine, aldehyde
Over the few last decades, the principle of constructing
benzene and, more recently, pyridine ring systems by cy-
clotrimerization reactions of acetylenes and nitriles cata-
lyzed by transition-metal complexes has found a great
deal of attention.1 While the synthesis of achiral pyridines
has already been thoroughly explored,1a,b,d the selective
synthesis of chiral derivatives by this methodology was,
until recently, still in its infancy. However, several exam-
ples have been reported in the literature of the cyclotrim-
erization of alkynes with chiral nitriles,2 which also
describe problems with the sometimes drastic conditions
that could negatively influence the stereochemical out-
come. Aiming for more convenient conditions, we have
recently developed in our laboratory an efficient method
not only for the synthesis of biaryls possessing axial
chirality,3 but also for the synthesis of pyridine derivatives
by light-promoted cobalt(I)-catalyzed cyclotrimerization
of two molecules of an acetylene with one molecule of a
nitrile.4 The mild conditions under which the reaction can,
in general, be successfully performed has already proved
to be very promising for the synthesis of chiral pyridines
when the stereogenic center was attached to the nitrile.4a
The products in these reactions contained the preserved
stereochemical information without loss.
We have developed a novel two-step catalytic approach to
pyridyl alcohols starting from aldehydes and involving a
[2+2+2]-cyclotrimerization step for the assembly of the
pyridine moiety (Scheme 1).
cyclotrimerization
with acetylene
asymmetric
cyanation
OH
ORP
CN
RP = Ac, TMS
O
R
R
R
H
H
H
N
Scheme 1 Proposed two-step synthetic route to pyridyl alcohols
starting from aldehydes
We started our investigations by synthesizing two differ-
ent cyanohydrin derivatives as precursor compounds for
the cyclotrimerization reaction. They only differ in the
protection of the free hydroxy group: the acetyl and tri-
methylsilyl groups were chosen as convenient protection
groups. Recent progress in the transition-metal-catalyzed
asymmetric synthesis of cyanohydrins has made these im-
We are looking to apply our methodology in the synthesis portant chiral building blocks increasingly readily avail-
of interesting classes of chiral compounds and came able in industry and in academia.7 We decided to utilize
across the cyanohydrins, a well-known class of chiral chiral transition-metal–salen complexes as reliable source
building blocks.5 These nitriles are easy accessible in of asymmetric induction for the preparation of the chiral
enantiomerically pure form by a number of methods, but
cyanohydrins. Here, binuclear titanium(IV)–salen and
have not previously been used as nitrile components in cy- mononuclear vanadium(IV)–salen catalysts (such as 2
clotrimerization reactions. Applying the chiral nitriles to- and 5) based on the Jacobsen ligand system are worthy of
gether with acetylenes in cyclotrimerizations would, particular attention. They have been introduced into prac-
therefore, yield pyridyl alcohols.6a–e Chiral pyridyl alco- tical use by Belokon and North and exhibit excellent ac-
hols have seen a number of applications as privileged cat- tivity and selectivity in the cyanation of aldehydes with
different reagents such as trimethylsilyl cyanide,8 potassi-
um cyanide/acetic anhydride,9 ethyl cyanoformate,10 or
SYNTHESIS 2008, No. 1, pp 0069–0074
Advanced online publication: 15.11.2007
DOI: 10.1055/s-2007-990903; Art ID: Z21907SS
x
x
.
x
x
.2
0
0
7
acetyl cyanide.11
© Georg Thieme Verlag Stuttgart · New York

70
B. Heller et al.
PAPER
Initial experiments with benzaldehyde using a chiral tita-
nium(IV)–salen complex and hydrogen cyanide for the
synthesis of the unprotected cyanohydrins gave good
yields (90–93%), but fairly low enantioselectivities (49–
68% ee) even at low temperatures (up to –40 °C). We en-
visioned that the most effective method to fix this problem
and prevent side reactions and racemization that lower the
enantiomeric excess of the desired cyanohydrins could be
an in situ derivatization procedure. Therefore, we
screened reaction conditions that, in addition to the hydro-
gen cyanide, also contained acetic anhydride and potassi-
um carbonate as in situ acylation reagents (Table 1,
entries 1–3). While the yields of 3a were very good
(>93%) with benzaldehyde under all conditions tested, the
highest enantioselectivity was obtained at a reaction tem-
perature of –40 °C. Comparable reaction conditions were
then applied to 4-methoxybenzaldehyde (3b, Table 1, en-
tries 4 and 5). While the yields of 3b were, in both cases,
very good to excellent, the reaction at room temperature
again proceeded only with mediocre enantioselectivity.
The same reaction at –40 °C needed a significantly longer
reaction time but the enantioselectivity found was compa-
rable to the same experiment with benzaldehyde (Table 1,
entry 3). However, this procedure afforded feasible O-
acylated cyanohydrin substrates 3a and 3b for the subse-
quent investigation of the cyclotrimerization with acety-
lene in the presence of (h5-cyclopentadienyl)(h4-cyclo-
octa-1,4-diene)cobalt [CoCp(cod)].
Table 1 Synthesis of Acylated Cyanohydrins by Catalytic Asym-
metric Cyanationa
O
OAc
HCN, Ac2O, K2CO3
(R,R)-Ti(IV) cat. 2
R
H
R
CN
H
1a,b
3a,b
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
N
N
O
O
N
N
O
O
Ti
Ti
O
O
t-Bu
t-Bu
2
Entry Product
Temp. Time
Yield eeb
(°C)
(h)
(%)
(%)
R
1
2
3
4
5
3a
3a
3a
3b
3b
Ph
Ph
Ph
25
–20
–40
25
24
93
99
98
98
87
53 (S)
81 (S)
88 (S)
56 (S)
86 (S)
4
18
4-MeOC6H4
4-MeOC6H4
144
72
Trimethylsilyl cyanide is the reagent of choice for the syn-
thesis of the trimethylsilyl-protected cyanohydrins 6. Its
use as a reliable source for cyanide in transition-metal-
catalyzed asymmetric addition reactions has already been
reported in the literature.7,8 The resulting cyanohydrins
are quite stable compounds and the subsequent deprotec-
tion step after the cyclotrimerization can be performed in
situ under very mild and racemization-free conditions, so
that no extra workup of the intermediate silyl ether would
be required. The preparation of the starting material uses
the addition reaction of trimethylsilyl cyanide to the alde-
hyde catalyzed by a well-defined vanadium(IV)–salen
complex 5 under remarkably convenient reaction condi-
tions (CH2Cl2, r.t., in air). The reaction proceeds smoothly
in the presence of only 0.1–0.2 mol% of the catalysts
(R,R)-5 and (S,S)-5 (Table 2).
–40
a Conditions: concentration of 1 0.75 M with molar ratio of 1/HCN/
Ac2O/K2CO3, 1:2:2:2 in the presence of 1 mol% of catalyst 2.
b Determined by chiral HPLC.
temperatures above 100 °C, longer reaction times, and
high catalyst concentrations.2 These rather drastic reac-
tion conditions sometimes result in racemization of the
starting nitrile and the enantiomeric excess strongly de-
creases in many cases.2a–c In particular, this affects sub-
strates with acidic a-hydrogens that can easily racemize at
elevated temperatures and in the presence of a base, such
as the resulting pyridines. Here we use our photochemical
approach, which delivers the necessary energy via irradi-
ation at ambient temperature and atmospheric pressure,
thus minimizing the problems associated with drastic re-
action conditions. This is especially useful in the case of
sensitive substrates such as cyanohydrins. For the model
reaction we used O-acetyl mandelonitriles 3a,b as sub-
strates and 1–5 mol% of [CoCp(cod)] as a catalyst under
visible light irradiation (350–500 nm) and atmospheric
pressure of acetylene (Table 3).
Here, the catalyst (R,R)-5 gave the S-enantiomers, where-
as (S,S)-5 yielded the opposite (R)-cyanohydrins. Distilla-
tion of the crude reaction mixtures gave the silylated
cyanohydrins 6 in high yields (78–94%) and very good
enantiomeric excesses in the range of 81–93% ee
(Table 2). Another advantage is the easy accessibility of
both the S- and R-enantiomers of the cyanohydrins.
After efficiently furnishing the required cyanohydrin sub-
strates 3 and 6 by catalytic asymmetric cyanation with ti-
tanium and vanadium complexes, we were focussed on
the cyclotrimerization reaction in the next step. The ther-
mally initiated variant of this reaction has been carried out
by employing acetylene pressures above 10 bar, reaction
The results of these experiments were disappointing, but
did show that the O-acetyl cyanohydrins 3a,b have rather
low activities in the cyclotrimerization reaction with acet-
ylene; yields did not exceed 25% under various conditions
(Table 3). These low yields did not allowed the determi-
nation of the enantioselectivity of the cyclotrimerization
Synthesis 2008, No. 1, 69–74 © Thieme Stuttgart · New York

PAPER
Two-Step Catalytic Approach to Chiral Pyridyl Alcohols
71
reactions. This failure may be for several reason, one of
which could be the insufficient purity of the O-acetyl cy-
anohydrins 3 even after chromatographic purification and
distillation. The cobalt-catalyzed cycloaddition reactions
are occasionally affected by even small amounts of impu-
rities or byproducts. Other reasons that can be suggested
for this failure are catalyst inhibition from the acetylated
pyridyl alcohol product or insufficient stability of the
acetyl groups.
Table 2 Synthesis of Silylated Cyanohydrins by Catalytic Asym-
metric Cyanationa
OTMS
CN
OTMS
CN
O
TMSCN
or
cat. (R,R)-5 or (S,S)-5
R
R
R
H
H
H
(S)
(R)
4a–e
6a–e
Even though cyanohydrin acetates are potentially desir-
able substrates for the cyclotrimerization process, we
turned our attention to the trimethylsilyl-protected deriva-
tives. We investigated the reactivity of O-trimethylsilyl
cyanohydrins 6 in cyclotrimerization experiments under
comparable conditions in the presence of only 0.5 mol%
of [CoCp(cod)] catalyst with visible light irradiation. The
obtained excellent results with 6 were incomparably bet-
ter than those observed with the acetyl derivatives 3
(Table 4). In the case of 2-phenyl-2-(trimethylsiloxy)ace-
tonitriles 6a the pyridines 9a were obtained with very
good 85% yield via the silylated intermediates 8a. The
enantiomeric excesses of products 9a corresponds to that
of the starting cyanohydrins 6a for both enantiomers. The
deprotection step with tetrabutylammonium fluoride in
methanol could reasonably be assumed to proceed quanti-
N
O
N
O
V
t-Bu
t-Bu
O
t-Bu
t-Bu
(R,R)-5 or (S,S)-5
Entry Product
R
Catalyst 5
Yieldb eec
(mol%)
(%)
(%)
1
2
3
4
5
Ph
(S)-6a
(R)-6a
(R,R)-5 (0.1)
(S,S)-5 (0.1)
78
71
92
91
94
91
92
4-MeOC6H4
3-MeOC6H4
4-ClC6H4
t-Bu
(S)-6b
(R)-6b
(R,R)-5 (0.2)
(S,S)-5 (0.2)
90
91
(S)-6c
(R)-6c
(R,R)-5 (0.1)
(S,S)-5 (0.1)
93
93
Table 4 Synthesis of the Chiral Pyridyl Alcohols 9a
(S)-6d
(R)-6d
(R,R)-5 (0.2)
(S,S)-5 (0.2)
88
88
OH
OTMS
OTMS
MeOH
R
R
R
CN
Bu4NF (cat.)
(S)-6e
(R)-6e
(R,R)-5 (0.1)
(S,S)-5 (0.1)
81
82
H
H
N
H
N
(S)-6
cat. Co(I)
C2H2
(S)-8
(S)-9
a Conditions: 4, TMSCN (mol ratio of aldehyde/TMSCN 1:1.1),
(R,R)-5 or (S,S)-5, +25 °C, CH2Cl2, stirring, 24 h.
b Isolated yields.
or
OTMS
OH
OTMS
c Determined by chiral GC or HPLC.
R
CN
MeOH
R
R
H
Bu4NF (cat.)
H
H
N
N
(R)-6
(R)-8
(R)-9
Table 3 Cyclotrimerization Experiments with the Acylated Cyano-
hydrins 3a,b
Entry Substrate Product
R
Yieldb
(%)b
eec
(%)
[CoCp(cod)], C2H2,
THF or n-hexane
OAc
OAc
R
R
CN
H
H
N
1
2
3
4
5
(S)-6a
(R)-6a
Ph
(S)-9a
(R)-9a
85
72
84
81
91
91
92
3a,b
7a,b
(S)-6b
(R)-6b
4-MeOC6H4
3-MeOC6H4
4-ClC6H4
t-Bu
(S)-9b
(R)-9b
91
91
Entry Product
R
[CoCp(cod)] Solvent
mol%
Yield
(%)
(S)-6c
(R)-6c
(S)-9c
(R)-9c
92
93
1
2
3
4
Ph
Ph
Ph
7a
7a
7a
1
5
5
1
THF
7
25
12
4
(S)-6d
(R)-6d
(S)-9d
(R)-9d
88
88
THF
n-hexane
THF
(S)-6e
(R)-6e
(S)-9e
(R)-9e
82
82
4-MeOC6H4
7b
a Conditions: 6, acetylene, [CoCp(cod)] (0.5 mol%), +25 °C, THF,
stirring, irradiation (l ~420 nm), 12 h.
b Isolated yields.
a Conditions: 3, acetylene, [CoCp(cod)], +25 °C, stirring, irradiation
(l ~420 nm), 24 h.
c Determined by chiral GC or HPLC.
d Performed in n-hexane.
Synthesis 2008, No. 1, 69–74 © Thieme Stuttgart · New York

72
B. Heller et al.
PAPER
Determination of Enantiomeric Excesses for Compounds 6 and
9
The enantiomeric excesses were analyzed by HPLC with a Liquid
Chromatograph 1090 equipped with DAD (Hewlett Packard) and
Chiralyser (IBZ Messtechnik GmbH), except for two cases (6a and
6e), where a Agilent 6890N GLC was used. The conditions for each
individual compound are as follows.
tatively. The investigation of the other chiral O-trimethyl-
silyl cyanohydrins 6b–e as substrates for the
cyclotrimerization led to identical results: the silylated py-
ridyl alcohols 8b–e were obtained with high yields while
retaining the starting enantiomeric excess. These com-
pounds were deprotected without isolation to give the
desired pyridyl alcohols 9b–e in 72–91% isolated yield
for the overall process (Table 4).
Cyanohydrins: 6a: Lipodex E, 25 m × 0.25 mm; 80–180 °C with 2
°C/min; 6b: Chiralcel OJ-H, n-hexane–EtOH (98:2); 6c: Chiralcel
OJ-H, n-hexane–EtOH (98:2); 6d: Chiralpak AD-H, n-hexane–
i-PrOH (95:5); 6e: Lipodex E, 25 m × 0.25 mm; 75 °C isotherm.
The enantiomeric excess could generally be increased by
recrystallization, but more effective enantiomeric enrich-
ment was achieved by precipitation of the alcohols with
picric acid and recrystallization of the corresponding pi-
crate salts from alcoholic solvents (MeOH, EtOH, i-
PrOH) to give the highest enantiomeric purity (>99% ee).
In addition a modified procedure was developed, which
included the treatment of crude silylated derivatives 8
with alcoholic solutions of picric acid, and the enantio-
merically pure picric salts of the free alcohols 9 usually
precipitated after a period of time.
Pyridyl alcohols: 9a: Chiralcel OJ-H, n-hexane–EtOH (90:10); 9b:
Chiralcel OJ-H, n-hexane–EtOH (90:10); 9c: Chiralpak AD-H, n-
hexane–EtOH (95:5); 9d: Chiralcel OJ-H, n-hexane–EtOH (95:5);
9e: Chiralpak AD-H, n-hexane–EtOH (99:1).
2-Acetoxy-2-arylacetonitriles 3a,b; General Procedure
Anhyd CH2Cl2 (4 mL) was added to solid K2CO3 (0.42 g, 3.0 mmol)
and catalyst 2 (18.5 mg, 0.015 mmol, 1 mol%) under argon, fol-
lowed by aldehyde 1 (1.5 mmol) and Ac2O (0.3 mL, 3.0 mmol). The
mixture was cooled to –40 °C, and 3.7 M HCN in CH2Cl2 soln (0.8
mL, 3 mmol) was then added to the mixture with a precooled sy-
ringe. The mixture was stirred at –40 °C (see Table 1 for reaction
times) and filtered through a column of silica gel (1.5 × 4 cm,
CH2Cl2). For further purification the residue was chromatographed
(silica gel, petroleum ether–EtOAc, 5:1).
In summary, we presented a two-step catalytic approach
for the synthesis of chiral pyridyl alcohols starting from
aldehydes. In the first step the synthesis of cyanohydrins
by cyanation of aldehydes in the presence of chiral transi-
tion-metal–salen complexes 2 or 5 was investigated using
either hydrogen cyanide or trimethylsilyl cyanide as cya-
nide sources. In both cases the acetyl- 3a,b or trimethyl-
silyl-protected cyanohydrins 6a–e could be obtained in
high yields and good enantiomeric excesses. The behavior
of O-acetyl cyanohydrins 3 in the light-promoted co-
balt(I)-catalyzed cyclotrimerization with acetylene has
been studied, however, the results were disappointing and
yields did not exceed 25%. In contrast, O-trimethylsilyl-
protected cyanohydrins 6 have shown excellent yields in
the racemization-free photochemical cyclotrimerization
with acetylene to pyridines. The in situ deprotection of si-
lylated pyridyl alcohols 8 afforded the desired pyridyl al-
cohols 9 in high yields, which were isolated in
enantiomerically pure form by recrystallization. The de-
veloped procedures allow an easy two-step access to ver-
satile chiral pyridyl alcohols.
2-[Acetoxy(aryl)methyl]pyridines 7a,b; General Procedure
A 100-mL thermostated (25 °C) reaction vessel was loaded with O-
acetyl cyanohydrin 3 (6.4 mmol) and [CoCp(cod)] (1–5 mol%).
Solvent (30 mL) was added, and the vessel was connected to an
acetylene measuring and delivering device providing a constant
pressure of acetylene. Alternatively, acetylene may simply be bub-
bled through the soln. The mixture was stirred and irradiated by 2
460-W lamps (l ~420 nm) for 24 h. The reaction was quenched by
switching off the lamps and simultaneously letting in air. The extent
of the reaction, i.e. conversion of 3, was determined by GC.
(S)-2-Phenyl-2-(trimethylsiloxy)acetonitrile [(S)-6a]; Typical
Procedure14
Benzaldehyde (4a, 5.3 g, 5.08 mL, 50 mmol), vanadium(IV)–salen
catalyst (R,R)-5 [giving S-cyanohydrins] or (S,S)-5 [giving R-cy-
anohydrins] (30.6 mg, 0.05 mmol) were dissolved in anhyd CH2Cl2
(80 mL), and TMSCN (5.49 g, 6.9 mL, 55.3 mmol) was added in
one portion at 20 °C with stirring. The mixture was stirred for 24 h,
the solvent was evaporated, and the residue was fractionally dis-
tilled in vacuo to give (S)-6a (8 g, 78%) as a colorless liquid; bp 72–
74 °C/2.2·10–1 mbar; 91% ee (HPLC). The catalyst could be recov-
ered from the residue.
[a]D22 –26.1 (c 1, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.43–7.35 (m, 5 H), 5.46 (s, 1 H),
0.20 (s, 9 H).
NMR spectra were recorded on a Bruker ARX 400 spectrometer at
298 K. MS spectra were obtained with a Varian AMD-402 instru-
ment at an ionization voltage of 70 eV. In general the enantiomeric
excesses were analyzed by HPLC with a Liquid Chromatograph
1090 equipped with DAD (Hewlett Packard) and Chiralyser (IBZ
Messtechnik GmbH) using appropriate chiral columns (for some
compounds detailed conditions are listed below). Melting points
were measured with a Büchi 540 melting point determination appa-
ratus. Optical rotations were determined on a Gyromat-HP polarim-
eter. HCN was prepared as described previously,6g–i dissolved in
CH2Cl2 to make a 3.7 M soln [HCN (1 g) in CH2Cl2 (10 mL)] and
stored at –40 °C until needed, at which point it was warmed to 0 °C
and transferred via a precooled syringe. The analytical data for com-
pounds 3a12 and 3b13 have been reported elsewhere. In each case the
analytical data for one pure enantiomer of compounds 6 and 9 are
reported for better comparison.
13C NMR (100 MHz, CDCl3): d = 136.5, 129.6, 129.2, 126.6, 119.5,
63.9, 0.0.
MS (70 eV): m/z (%) = 205 [19, M+], 190 (100), 135 (3), 116 (20),
105 (17), 89 (11), 84 (24), 77 (6), 45 (4).
The product should be carefully degassed (3 freeze–thaw cycles)
and redistilled under argon to ensure high yields in the next step.
(S)-2-(4-Methoxyphenyl)-2-(trimethylsiloxy)acetonitrile [(S)-
6b]14
Colorless liquid.
[a]D22 –20.8 (c 1, CHCl3).
Synthesis 2008, No. 1, 69–74 © Thieme Stuttgart · New York

PAPER
Two-Step Catalytic Approach to Chiral Pyridyl Alcohols
73
1H NMR (400 MHz, CDCl3): d = 7.46–7.43 (m, 2 H), 6.99–6.96 (m,
2 H), 5.49 (s, 1 H), 3.86 (s, 3 H), 0.26 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 161.4, 148.3, 143.7, 137.3, 129.0,
128.2, 127.5, 122.9, 121.8, 75.5.
13C NMR (100 MHz, CDCl3): d = 160.6, 128.7, 128.2, 119.6, 114.5,
63.6, 55.6, 0.0.
MS (70 eV): m/z (%) = 185 (79, M+), 167 (12), 108 (83), 79 (100),
52 (52).
MS (70 eV): m/z (%) = 235 [36, M+], 220 (55), 146 (100), 135 (22),
105 (7), 84 (9), 73 (9), 45 (4).
(S)-4-Methoxyphenyl(pyridin-2-yl)methanol [(S)-9b]15
Colorless crystals; mp 63–65 °C, >99% ee.
(S)-2-(3-Methoxyphenyl)-2-(trimethylsiloxy)acetonitrile [(S)-
[a]D22 +137.4 (c 1, CHCl3).
1H NMR (400 MHz, CDCl3): d = 8.51–8.43 (d, 1 H), 7.58–7.51 (m,
1 H), 7.26–7.18 (m, 2 H), 7.14–7.04 (m, 2 H), 6.67–6.72 (m, 2 H),
5.62 (s, 1 H), 5.18 (br s, 1 H), 3.71 (s, 3 H).
6c]14
Colorless liquid.
[a]D22 –26.4 (c 1, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.19–7.14 (m, 1 H), 6.90–6.87 (m,
2 H), 6.78–6.74 (m, 1 H), 5.32 (s, 1 H), 3.67 (s, 3 H), 0.09 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 161.2, 159.3, 147.8, 136.8, 135.5,
128.38, 122.3, 122.7, 121.3, 77.3, 55.3.
13C NMR (100 MHz, CDCl3): d = 160.3, 138.0, 130.3, 119.4, 118.8,
115.1, 112.1, 63.8, 55.6, 0.0.
MS (70 eV): m/z (%) = 215 [100, M+], 198 (4), 186 (9), 167 (3), 154
(4), 137 (45), 121 (30), 108 (25), 94 (10), 79 (60), 52 (7), 28 (31).
MS (70 eV): m/z (%) = 235 [27, M+], 220 (100), 146 (20), 135 (13),
116(5), 103 (4), 84 (14), 73 (5), 45 (3).
(S)-3-Methoxyphenyl(pyridin-2-yl)methanol [(S)-9c]16
Oil; >99% ee.
(S)-2-(4-Chlorophenyl)-2-(trimethylsiloxy)acetonitrile [(S)-
[a]D22 +141.4 (c 0.71, CHCl3).
1H NMR (400 MHz, CDCl3): d = 8.83–8.82 (m, 1 H), 7.91–7.87 (m,
1 H), 7.55–7.45 (m, 3 H), 7.26–7.22 (m, 2 H), 7.11–7.08 (m, 1 H),
6.01 (m, 1 H), 5.54 (br s, 1 H), 4.05 (s, 3 H).
6d]14
Colorless liquid.
[a]D22 –16.3 (c 1, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.36–7.29 (m, 4 H), 5.40 (s, 1 H),
0.17 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 161.2, 160.2, 148.2, 145.3, 137.3,
130.0, 122.9, 121.7, 119.8, 113.8, 112.8, 75.3, 55.6.
13C NMR (100 MHz, CDCl3): d = 135.6, 135.1, 129.4, 127.9, 119.1,
63.3, 0.0.
MS (70 eV): m/z (%) = 215 (100, M+), 198 (10), 154 (12), 135 (10),
108 (66), 194 (11), 79 (66).
MS (70 eV): m/z (%) = 239 [11, M+], 226 (38), 224 (100), 204 (14),
150 (29), 139 (12), 123 (8), 105 (8), 93 (7), 84 (30), 73 (8), 45 (6).
(S)-4-Chlorophenyl(pyridin-2-yl)methanol [(S)-9d]15
Colorless crystals, mp 84–86 °C; >99% ee.
(S)-3,3-Dimethyl-2-(trimethylsiloxy)butanenitrile [(S)-6e]14
Colorless liquid.
[a]D22 –43.0 (c 1, CHCl3).
1H NMR (400 MHz, CDCl3): d = 3.78 (s, 1 H), 0.80 (s, 9 H), 0.00
(s, 9 H).
13C NMR (100 MHz, CDCl3): d = 119.8, 71.3, 36.3, 25.4, 0.0.
MS (70 eV): m/z (%) = 185 [0.1, M+], 170 (2), 143 (47), 129 (100),
[a]D22 +109 (c 1, CHCl3).
1H NMR (400 MHz, CDCl3): d = 8.50–8.41 (d, 1 H), 7.61–7.48 (m,
1 H), 7.33–7.20 (m, 4 H), 7.17–7.10 (m, 1 H), 7.09–7.00 (m, 1 H),
5.65 (br s, 1 H), 5.25 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 160.3, 147.9, 141.8, 137.0, 133.6,
128.8, 128.4, 122.7, 121.3, 74.2.
MS (70 eV): m/z (%) = 219 [62, M+], 201 (4), 190 (3), 166 (5), 154
(3), 141 (12), 125 (9), 108 (66), 79 (100), 53 (32), 28 (13).
114 (5), 100 (15), 84 (11), 75 (40), 73 (31), 57 (38), 41 (12).
(S)-2,2-Dimethyl-1-(pyridin-2-yl)propan-1-ol [(S)-9e]17
Oil; >99% ee.
[a]D22 –21.4 (c 1.1, CHCl3).
1H NMR (400 MHz, CDCl3): d = 8.51–8.49 (m, 1 H), 7.62–7.57 (m,
1 H), 7.20–7.13 (m, 2 H), 4.42 (br s, 1 H), 4.33 (br s, 1 H), 0.89 (s,
9 H).
13C NMR (100 MHz, CDCl3): d = 148.3, 135.9, 123.3, 122.7, 80.8,
36.7, 26.3.
MS (70 eV): m/z (%) = 165 (0.1, M+), 150 (2), 132 (6), 117 (6), 108
(100), 78 (15).
Phenyl(pyridin-2-yl)methanol [(S)-9a]; Typical Procedure15
A 100-mL thermostated (25 °C) reaction vessel was loaded with
(S)-2-phenyl-2-(trimethylsiloxy)acetonitrile [(S)-6a, 1.7 g, 8.28
mmol) and [CoCp(cod)] (9.6 mg, 0.0414 mmol, 0.5 mol%). THF
(10 mL) was added, and the vessel was connected to an acetylene
measuring and delivering device providing a constant pressure of
acetylene. Alternatively, acetylene may simply be bubbled through
the soln. The mixture was stirred and irradiated by two 460-W
lamps (l ~420 nm) for 12 h. The reaction was quenched by switch-
ing off the lamps and simultaneously letting in air. The extent of the
reaction, i.e. conversion of (S)-8a, was determined by GC. The mix-
ture was evaporated, and the residue was dissolved in MeOH (50
mL), together with Bu4NF·3 H2O (200 mg, 6.3 mmol). The mixture
was stirred at r.t. for 24 h, the solvent was removed, and the oily res-
idue was purified by chromatography [silica gel, hexane–EtOAc,
1:1; Rf = 0.84 (siloxy-pyridine), Rf = 0.45 (deprotected pyridine)] to
give (S)-9a (1.31 g, 85%); mp 64–65 °C; 91% ee (HPLC). A single
crystallization (EtOAc–hexane) gave (S)-9a (861 mg, 56%); >99%
ee (HPLC).
Purification as the Picrate Salt; General Procedure
The picrate salt was obtained by addition of a soln of picric acid (1.5
equiv) in EtOH to an ethereal soln of the pyridyl alcohol, and the
bright yellow precipitate was filtered, washed with Et2O and crys-
tallized from alcoholic solvents (MeOH, EtOH, i-PrOH). The enan-
tiomerically pure picric salt was hydrolyzed in H2O and the free
alcohol was extracted with Et2O (3 ×). The organic phase was dried
(Na2SO4), filtered, and concentrated to obtain the desired pyridyl al-
cohols with >99% ee.
[a]D22 +158 (c 0.51, CHCl3).
1H NMR (400 MHz, CDCl3): d = 8.8 (m, 1 H), 7.87–7.83 (m, 1 H),
7.65–7.51 (m, 5 H), 7.44–7.4 (m, 2 H), 6.01 (m, 1 H), 5.63 (m, 1 H).
Synthesis 2008, No. 1, 69–74 © Thieme Stuttgart · New York

74
B. Heller et al.
PAPER
M.; Sharpless, K. B. Tetrahedron Lett. 1987, 28, 2825.
Acknowledgment
Conjugate addition of dialkylzinc reagents to a,b-
unsaturated ketones: (g) Bolm, C.; Ewald, M. Tetrahedron
Lett. 1990, 31, 5011. (h) Bolm, C. Tetrahedron: Asymmetry
1991, 2, 701. (i) Bolm, C.; Ewald, M.; Felder, M. Chem.
Ber. 1992, 125, 1205. Nucleophilic addition of dialkylzinc
reagents to aldehydes: (j) Ishizaki, M.; Fujita, K.;
Shimamoto, M.; Hoshino, O. Tetrahedron: Asymmetry
1994, 5, 411. (k) Ishizaki, M.; Hoshino, O. Tetrahedron:
Asymmetry 1994, 5, 1901. (l) Ishizaki, M.; Hoshino, O.
Chem. Lett. 1994, 1337. (m) Bolm, C.; Schlingo, H.; Harms,
K. Chem. Ber. 1992, 125, 1191. (n) Chelucci, G.; Soccolini,
F. Tetrahedron: Asymmetry 1992, 3, 1235. Asymmetric
hydrogenation: (o) Drury, W. J. III; Zimmermann, N.;
Keenan, M.; Hayashi, M.; Kaiser, S.; Goddard, R.; Pfaltz, A.
Angew. Chem. Int. Ed. 2004, 43, 70; Angew. Chem. 2004,
116, 72.
We are grateful to Mrs. B. Friedrich for technical assistance, Mrs.
S. Buchholz for GLC and Mrs. K. Reincke and Mrs. S. Schareina
for HPLC investigations. We would like to thank Prof. Uwe Rosen-
thal for helpful discussions.
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Synthesis 2008, No. 1, 69–74 © Thieme Stuttgart · New York