Full text of DOI:10.1016/S0040-4039(00)01695-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9277–9280
Stereoselective synthesis of optically active pyridyl alcohols
via asymmetric transfer hydrogenation of pyridyl ketones
Kazuya Okano,a Kunihiko Muratab and Takao Ikariyab,*
aTsukuba Research Center, Mitsubishi Chemical Corporation, 8-3-1, Chuo, Ami, Inashiki, Ibaraki 300-03, Japan
bGraduate School of Science and Engineering, Tokyo Institute of Technology, CREST, 2-12-1 O-okayama,
Meguro-ku, Tokyo 152-8552, Japan
Received 16 August 2000; revised 21 September 2000; accepted 22 September 2000
Abstract
A chiral Ru(II) complex, RuCl[(S,S)-N-(p-toluenesulfonyl)-1,2-diphenyl-ethylenediamine](p-cymene),
serves as an efficient catalyst for asymmetric transfer hydrogenation of 2-acetylpyridine with a substrate
to catalyst molar ratio of 200–1000 with HCOOH as a hydrogen source to give (S)-1-(2-pyridyl)ethanol
in an almost quantitative yield and with 95% ee. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric transfer hydrogenation; formic acid; chiral Ru catalyst; acetylpyridine.
Catalytic asymmetric transfer hydrogenation of ketones or imines using 2-propanol or formic
acid as a hydrogen source has been extensively investigated to access optically active alcohols or
amines because of its operational simplicity and utilization of a cheap and safe hydrogen
source.1 We have recently developed highly efficient chiral diamine-based Ru(II) catalysts,
RuCl(Tsdpen)(h6-arene) (TsDPEN:N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine)2 and its
isoelectronic chiral Rh(III) and Ir(III) catalysts3 for a practical asymmetric transfer hydrogena-
tion with high enantioselectivity and reactivity. Even benzil or benzoin can be rapidly and
stereoselectively reduced with chiral Ru(II) catalysts to optically active hydrobenzoin.4 The
nature of the coordinatively saturated 18 electron chiral Ru(II) catalyst is responsible for the
extremely high stereoselectivity in this asymmetric reduction. Thanks to the characteristic
properties of chiral Ru catalysts, we found that nitrogen containing ketones such as acetylpyridi-
nes or acetylpyrazine are stereoselectively reduced with chiral Ru(II) with formic acid to give the
corresponding optically active pyridylethanols or pyrazylethanol with an excellent ee (Scheme 1).
* Corresponding author. Fax: +81-3-5734-2637; e-mail: tikariya@o.cc.titech.ac.jp
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01695-6

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Scheme 1.
Optically active pyridyl alcohols are useful key compounds, not only as pharmaceutical
intermediates,5 but also as useful chiral ligands and auxiliaries in asymmetric synthesis.6
Although there have been many reports on the synthesis of this important class of compounds
by means of asymmetric alkylation to pyridyl aldehydes,7 stoichiometric or catalytic asymmetric
reduction of acetylpyridines,8,9 enantioselective reduction of N-alkylated pyridinium triflate,10
enzymatic optical resolution of racemic pyridyl alcohols or esters,11 or deracemization of pyridyl
alcohols by enzymes,12 no practical asymmetric synthetic methods have been reported, except for
powerful practical asymmetric hydrogenation catalysts based on Ru–BINAP/chiral diamine
complexes.13
RuCl[(S,S)-Tsdpen](p-cymene) (1) has proved to effect asymmetric transfer hydrogenation of
2-acetylpyridine (2a) with HCOOH as a hydrogen source, giving (S)-1-(2-pyridyl)ethanol (3a)
with an excellent enantioselectivity. The reaction with a substrate to catalyst molar ratio (S/C)
of 200–1000 in a mixture of HCOOH/N(C2H5)3 (acetylpyridine:HCOOH:N(C2H5)3 molar
ratio=1:4.3:2.5) proceeded smoothly to the product at 27°C in an almost quantitative yield and
with up to 95% ee. A chiral Rh complex, Cp*RhCl[(S,S)-Tscydn] (Cp*:pentamethylcyclo-
pentadienyl, (S,S)-TsCYDN:(1S,2S)-N-(p-toluenesulfonyl)-1,2-cyclohexanediamine)3 was not
effective as a catalyst for the reaction under the same conditions. Table 1 summarizes the
experimental results. Increasing the reaction temperature to 50°C caused serious deterioration of
the catalyst performance, possibly because of decomposition of the catalyst under these
conditions. The product pyridylethanol might replace the chiral diamine ligand to give an
inactive catalyst.
The sense of enantioface selection in this asymmetric reduction of the pyridyl ketones was the
same as that attained in the reaction of aromatic ketones.2a The reaction of 3-acetylpyridine (2b)
and 4-acetylpyridine (2c) with chiral catalyst 1 in a HCOOH/N(C2H5)3 mixture under the same
conditions described in Table 1 gave (S)-1-(3-pyridyl)ethanol (3b) and (S)-1-(4-pyridyl)ethanol
(3c) in almost quantitative yields with 89 and 92% ee, respectively. The enantioselectivity
decreased in the order of CH3>C2H5>C6H5 as R groups in the pyridyl ketones. In contrast to the
reaction of a benzophenone derivative reported previously,2d benzoylpyridine 2e gave very poor
enantioselectivity. These results suggests that the neighboring functional group, the nitrogen
atom in this case, must be free from the metal center as observed in asymmetric reduction of
benzils or benzoins.4
In a similar manner, asymmetric reduction of functionalized acetylpyridine bearing the
electron withdrawing group 2f in CH2Cl2 containing a mixture of HCOOH/N(C2H5)3 and
catalyst 1 at 10°C afforded an optically active pyridylethanol 3f in almost quantitative yield and
with 86% ee, which is an intermediate of PNU-142721, a potent synthetic anti-HIV medicine.5
Its derivative 2g was reduced slowly to give the corresponding optically active alcohol with the

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Table 1
Asymmetric transfer hydrogenation of acetylpryridines catalyzed by chiral Ru(II) catalyst (1) with a mixture of
a
HCOOH/N(C2H5)3
Ketone
S/C
200
Temp. (°C)
Time (h)
Yield (%)b
ee (%)b
Config.c
2a
2a
2ad
2a
2a
2b
2c
27
50
27
27
50
27
27
27
27
10
10
27
12
12
24
24
24
24
24
24
24
24
24
24
97
99
24
91
14
99
99
100
84
95
95
91
89
93
78
89
92
89
9
Sh
S
S
200
200
1000
1000
200
200
200
200
200
200
200
S
S
Si
Sj
2d
2e
Sk
Rl
Sm
Sm
S,Sn
2fe
2ge
2hf
86
85
99.6
36
100g
a The reaction of pyridyl ketones (2.5 mmol) was carried out with a ketone/HCOOH/N(C2H5)3 molar ratio=
1:4.3:2.5.
b Unless otherwise noted, yields and ee values were determined by HPLC analysis using a Daicel Chiralcel OD, OJ,
Chiralpak AD column or GC analysis using a Chrompak CP-Cyclodextrin-b-236-M-19 capillary column.
c Unless otherwise noted, determined from the sign of rotation of the isolated product.
d Reaction in 2-propanol, conditions: (S,S)-Ru cat (1) and 1.0 equiv. KOt-Bu, ketone:Ru=200:1, 0.1 M in
2-propanol.
e 1.0 M in CH2Cl2.
f Ketone/HCOOH/N(C2H5)3 molar ratio=1:8.6:5.0.
g dl:meso=91:9.
h [h]D −27.6 (c 0.712, CHCl3) (lit. [h]2D0 −26.4 (c 1.34, CHCl3), \95% ee (S), Ref. 10a).
i [h]D −37.2 (c 1.01, CH3OH) (lit. [h]D +40.3 (c 1.6, CH3OH), (R), Ref. 8c).
j [h]D −39.0 (c 0.82, CH3OH) (lit. [h]2D0 −43.0 (c 1.24, CH3OH), \95% ee (S), Ref. 10a).
k [h]2D8 −61.3 (c 1.40, CH3OH) (lit. [h]2D5 +38.0 (c 1.68, C2H5OH), 52.1% ee (R), Ohno, A.; Nakai, J.; Nakamura,
K.; Goto, T.; Oka, S. Bull. Chem. Soc. Jpn. 1981, 54, 3482).
l [h]2D8 −10.6 (c 1.08, CHCl3) (lit. [h]D25 −113.4 (c 1.0, CHCl3), 92% ee (R), Takemono, M.; Achiwa, K. Chem.
Pharm. Bull. 1998, 46, 577).
m Determined from GLC analysis in comparison to the authentic sample.
n [h]D25 −61.0 (c 1.9, acetone) (lit. [h]2D5 −76.05 (c 1.9, acetone) (S,S), Wallace, J. S.; Baldwin, B. W.; Morrow, C.
J. J. Org. Chem. 1992, 57, 5231).
same enantiomeric excess. The reaction of 2,6-diacetylpyridine (2h) with a mixture of HCOOH/
N(C2H5)3 (8.6:5.0) gave an optically active diol with 99.6% ee in 91% yield together with
meso-diol in 9% yield. This chiral diol can be used as an intermediate of chiral ligands.14
2-Acetylpyrazine (2i) provided 1-(2-pyrazyl)ethanol (3i) in almost quantitative yield with a
moderate ee value, 73%.
This paper describes a practical catalytic synthesis of optically active pyridyl alcohols via
asymmetric transfer hydrogenation of pyridyl ketones with formic acid as the hydrogen source.15

9280
The success of asymmetric reduction of these functionalized ketones is ascribed to the nature of
the coordinately saturated diamine-based Ru(II)–arene complexes with excellent carbonyl group
discrimination ability, in which the metal/NH bifunctionality makes effective hydrogen transfer
possible between ketones and hydrogen donors such as alcohols or formic acid.2f,16
Acknowledgements
We thank Prof. J. Uenishi of Kyoto Pharmaceutical University and Prof. H. Tsukube of
Osaka City University for the generous gift of furapyridyl alcohols. This work was financially
supported by a grant-in-aid from the Ministry of Education, Science, Sports and Culture of
Japan (No. 09238102 and No. 12305057).
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