Catalytic asymmetric hydrogenation of aldehydes

Article abstract of DOI:10.1039/b703977h

Racemic α-arylaldehydes provide the corresponding primary alcohols via dynamic kinetic resolution in excellent enantioselectivities and yields upon hydrogenation using a Noyori ruthenium catalyst; for example, the biologically active (S)-enantiomer of the non-steroidal anti-inflammatory drug ibuprofen could be synthesized via catalytic enantioselective hydrogenation of aldehyde 1f followed by oxidation with potassium permanganate in 76% isolated yield and 96: 4 er. The Royal Society of Chemistry.

Full text of DOI:10.1039/b703977h

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Catalytic asymmetric hydrogenation of aldehydes
Xiaoguang Li and Benjamin List*
Received (in Cambridge, UK) 15th March 2007, Accepted 27th March 2007
First published as an Advance Article on the web 5th April 2007
DOI: 10.1039/b703977h
Racemic a-arylaldehydes provide the corresponding primary
alcohols via dynamic kinetic resolution in excellent enantio-
selectivities and yields upon hydrogenation using a Noyori
ruthenium catalyst; for example, the biologically active
combination with diamines DPEN (7) or DACH (8). Other
studied diphosphines were selected from the BINAP (3), P-PHOS
7
(4), PHANEPHOS (5), and SDP (6) groups of ligands.
With [RuCl (xylyl-BINAP 3c)(DPEN 7 or DACH 8)] as
2
promising catalyst systems at hand we decided to explore the
scope of our new dynamic kinetic resolution of aldehydes
(
S)-enantiomer of the non-steroidal anti-inflammatory drug
ibuprofen could be synthesized via catalytic enantioselective
hydrogenation of aldehyde 1f followed by oxidation with
potassium permanganate in 76% isolated yield and 96 : 4 er.
(Table 2).{ Interestingly, the use of aldehyde 1a as the model
substrate turned out to be a good choice as many other substituted
derivatives gave even higher enantioselectivities.
The enantioselective transition metal-catalyzed hydrogenation and
transfer hydrogenation of ketones has been developed into a
Similarly to the ketone hydrogenation the reaction is exception-
ally efficient with quantitative conversion at very low catalyst
loading in all cases studied. The enantioselectivity improved with
increasing steric bulk of the alkyl substituent of the a-arylaldehyde
1
powerful method for the synthesis of chiral secondary alcohols.
Remarkably, although both an asymmetric transfer hydrogenation
of 1-d-benzaldehydes and a dynamic kinetic resolution of racemic
2
ketones have been described by Noyori et al., the corresponding
3
reactions of racemic a-branched aldehydes were unknown. We
Table 1 Identification of an efficient catalyst system for the asym-
metric hydrogenation of aldehyde 1a
have recently developed a catalytic asymmetric reductive amina-
tion of a-branched aldehydes via dynamic kinetic resolution
4
Eq. 1]. In this context, we reasoned that an analogous
[
enantioselective hydrogenation of aldehydes to the corresponding
b-branched chiral primary alcohols should also be feasible [Eq. 2].
ð1Þ
ð2Þ
5
Initially considering transition metal-catalyzed, biocatalytic,
and organocatalytic variants, we quickly realized that the most
efficient approach is the enantioselective Ru-catalyzed hydrogena-
tion pioneered by Noyori et al. We found that racemic
a-arylaldehydes provide the corresponding primary alcohols in
excellent enantioselectivity in a dynamic kinetic resolution. During
the preparation of this manuscript, Zhou et al. described a similar
approach elegantly using a spirocyclic diphosphine ligand devel-
6
oped earlier in their laboratories.
As a model reaction we studied the hydrogenation of 2-phenyl-
propanal (1a) in butanol with a selection of [RuCl (diphosphine)
2
t
diamine)] catalysts in the presence of KO Bu (Table 1). We
(
b
er (ee)
Entry
Diphosphine
Diamine
anticipated that under the basic and protic conditions a rapid
racemisation of the aldehyde should precede the asymmetric
hydrogenation to give the desired chiral alcohol in complete
conversion and high enantioselectivity. We were pleased to find
that our reaction design indeed proved fruitful and in all cases
c,d
1
3a
3b
3c
3c
4a
5a
6a
6b
3c
b
7
7
7
7
7
7
7
7
8
78 : 22 (56%)
77 : 23 (54%)
93 : 7 (86%)
93 : 7 (86%)
91 : 9 (82%)
53 : 47 (6%)
74 : 26 (48%)
86 : 14 (72%)
95 : 5 (90%)
c
c,d
2
3
e
4
c
5
f
.
99% conversion was observed. Of the studied diphosphines, (R)-
6
7
8
9
xylyl-BINAP (3c, entry 3) provided the highest enantioselectivity in
d
Max-Planck-Institut f u¨ r Kohlenforschung, Kaiser-Wilhelm-Platz 1,
45470 M u¨ lheim an der Ruhr, Germany.
E-mail: list@mpi-muelheim.mpg.de; Fax: (+208) 306 2999
a
Determined by GC. Determined by HPLC. 1 mol% catalyst.
d
i
In PrOH. In hexanol. With (S,S)-DPEN.
e
n
f
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8
Table 2 Preliminary scope of the catalytic asymmetric aldehyde
hydrogenation
hydroformylation of the corresponding styrene, gave known
alcohol 2f in 96 : 4 er. In this case the catalyst loading could be
reduced to 0.02 mol% without significantly affecting the enantio-
selectivity. Product 2f was obtained in quantitative yield and was
converted into the biologically active (S)-enantiomer of the non-
steroidal anti-inflammatory drug ibuprofen via an established and
9
racemisation-free oxidation with potassium permanganate [Eq. 3].
Entry Aldehyde 1
Alcohol 2
er (ee)
b
1
95 : 5 (90%)
ð3Þ
In summary, we have developed a remarkably efficient and
highly enantioselective hydrogenation of racemic a-branched
aldehydes to the corresponding primary alcohols via dynamic
kinetic resolution. As the best catalyst we have identified a Noyori-
type [Ru(diphosphine)(diamine)]-complex. Under our reaction
conditions the important class of a-methyl substituted aldehydes
including precursors to non-steroidal anti-inflammatory drugs
such as ibuprofen can be effectively processed with enantioselec-
tivities of up to 97 : 3 er. We propose that the sequence
hydroformylation–asymmetric hydrogenation–oxidation could be
of potential use for the industrial synthesis of a-aryl propionic
acids and similar pharmaceutically highly relevant compounds.
We thank Sebastian Hoffmann, Dr Marcello Nicoletti, and Dr
Santanu Mukherjee for kindly donating racemic aldehydes.
Generous support by the Max-Planck-Society, the Fonds der
Chemischen Industrie (Silver Award to BL), and by Novartis
b
2
97 : 3 (94%)
99 : 1 (98%)
97 : 3 (94%)
3
b
4
(Young Investigator Award to BL) is gratefully acknowledged. We
also thank Merck, Saltigo, and Wacker for support and BASF
and Degussa for donating chemicals.
5
97 : 3 (94%)
Notes and references
{
General procedure for the asymmetric hydrogenation of a-arylaldehydes
A 6-mL glass vial was charged with the ruthenium catalyst derived from
(R)-xylyl-BINAP and (R,R)-DPEN (1.1 mg, 1 mmol) in the open air. After
purging with argon three times, n-hexanol (4.8 mL) was introduced and the
c
6
96 : 4 (92%)
t
mixture was stirred for 5 minutes. Then a solution of KO Bu in 2-methyl-2-
propanol (0.12 mL, 1.0 M, 0.12 mmol) was added followed by addition of
the a-arylaldehyde (1 mmol). The vial was transferred to a high pressure
autoclave. After purging with 10 bar H
pressurized with H to 20 bar and the reactions were magnetically stirred at
room temperature for 16–18 h. After carefully releasing H , a sample was
2
three times, the autoclave was
2
2
taken and passed through a small amount of silica gel prior to GC analysis
to determine the conversion and HPLC analysis for enantiomeric ratio
determination.
7
95 : 5 (90%)
1
(a) R. Noyori, Angew. Chem., Int. Ed., 2002, 41, 2008–2022; (b)
T. Ohkuma and R. Noyori, in Transition Metals for Organic Synthesis,
ed. M. Beller and C. Bolm, Wiley-VCH, Weinheim, 2004, pp. 29–113; (c)
H.-U. Blaser, C. Malan, B. Pugin, F. Spindler, H. Steiner and M. Studer,
Adv. Synth. Catal., 2003, 345, 103–151; (d) S. Gladiali and E. Alberico,
Chem. Soc. Rev., 2006, 35, 226–236; (e) J. S. M. Samec, J.-E. B a¨ ckvall,
P. G. Andersson and P. Brandt, Chem. Soc. Rev., 2006, 35, 237–248.
(a) I. Yamada and R. Noyori, Org. Lett., 2000, 2, 3425–3427; (b)
R. Noyori and T. Ohkuma, Angew. Chem., Int. Ed., 2001, 40, 40–73 and
references therein.
Transfer hydrogenations of a-branched aldehydes have been reported but
asymmetric versions are unknown. See: (a) J. R. Miecznikowski and
R. H. Crabtree, Organometallics, 2004, 23, 629–631; (b) X. Wu, J. Liu,
X. Li, A. Zanotti-Gerosa, F. Hancock, D. Vinci, J. Ruan and J. Xiao,
Angew. Chem., Int. Ed., 2006, 45, 6718–6722.
a
b
i
c
Determined by GC. With [RuCl
.5 M and 0.02 mol% catalyst loading, the er of alcohol 2f was 95 : 5
quant. conversion after 18 h).
2
(3c)(8)] in PrOH. With [1f] =
0
(
2
3
substrate. Thus 2-phenylbutyraldehyde (1b) gave the correspond-
ing alcohol in 97 : 3 er (entry 2) and 2-phenylisovaleraldehyde (1c)
provided alcohol 2c in 99 : 1 er (entry 3). Cyclopentyl-substituted
aldehyde 1d furnished alcohol 2d in 97 : 3 er (entry 4). Substituents
at the aryl ring are also tolerated and 2-arylpropionaldehydes 1e–
1
g gave the desired products 2e–2g in ¢ 95 : 5 er (entries 5–7).
4
(a) S. Hoffmann, M. Nicoletti and B. List, J. Am. Chem. Soc., 2006, 128,
13074–13075.
Ibuprofen precursor 1f, which can be easily obtained via
1
740 | Chem. Commun., 2007, 1739–1741
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5
For an asymmetric electroreduction of an a-branched aldehyde in
the presence of an alcohol dehydrogenase, see: (a) R. Yuan,
S. Watanabe, S. Kuwabata and H. Yoneyama, J. Org. Chem., 1997,
D. Herzberg, C. Malan and A. Zanotti-Gerosa, Org. Lett., 2000, 2,
4173–4176; (c) J. Wu, J.-X. Ji, R. Guo, C.-H. Yeung and A. S. C. Chan,
Chem.–Eur. J., 2003, 9, 2963–2968; (d) J.-H. Xie, L.-X. Wang, Y. Fu,
S.-F. Zhu, B.-M. Fan, H.-F. Duan and Q.-L. Zhou, J. Am. Chem. Soc.,
2003, 125, 4404–4405.
8 See for example: J. J. Kim and H. Alper, Chem. Commun., 2005,
3059–3061.
9 M. Cleij, A. Archelas and R. Furstoss, J. Org. Chem., 1999, 64,
5029–5035.
6
2, 2494–2499.
J.-H. Xie, Z.-T. Zhou, W.-L. Kong and Q.-L. Zhou, J. Am. Chem. Soc.,
007, 129, 1868–1869.
6
7
2
(a) T. Ohkuma, M. Koizumi, H. Doucet, T. Pham, M. Kozawa,
K. Murata, E. Katayama, T. Yokozawa, T. Ikariya and R. Noyori,
J. Am. Chem. Soc., 1998, 120, 13529–13530; (b) M. J. Burk, W. Hems,
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Chem. Commun., 2007, 1739–1741 | 1741