Efficient asymmetric hydrogenation of pyridines

Article abstract of DOI:10.1002/anie.200453942

Up to four stereocenters can be created efficiently in a single step by the asymmetric hydrogenation of oxazolidinone-substituted pyridines (see scheme). Furthermore, selective chirality transfer and nondestructive cleavage of the chiral auxiliary occur under the same reaction conditions, making an additional cleavage step unnecessary.

Full text of DOI:10.1002/anie.200453942

Communications
Asymmetric Synthesis
to us that whereas conformation 2 should be strongly
preferred for unprotonated pyridines due to dipole-moment
minimization, upon protonation hydrogen bonding between
the pyridinium and the oxazolidinone moiety would favor
conformation 5, in which the auxiliary is oriented coplanar
with the pyridine ring but rotated by 1808. Indeed, on
hydrogenation the iPr substituent shields one of the diaster-
eotopic p-faces and selective hydrogen transfer to the
Efficient Asymmetric Hydrogenation of
Pyridines**
Frank Glorius,* Nick Spielkamp, Sigrid Holle,
Richard Goddard, and Christian W. Lehmann
[
9,10]
opposite side leads to aminal 6 (Scheme 2b).
Dedicated to Professor H. Martin R. Hoffmann
on the occasion ofhis 70th birthday
Substrates 2 can be readily synthesized from oxazolidi-
nones and the corresponding 2-bromo- or chloropyridines 1
[
13]
by copper catalysis (Scheme 2a). Gratifyingly, hydrogena-
Catalytic asymmetric hydrogenation has become a key
tion of pyridine 2d in acetic acid under a hydrogen
[
1]
[2]
technology in academic research and in industry owing
atmosphere of 100 bar with PtO as the catalyst led to the
2
[
3]
to its generally unrivalled efficiency and selectivity. Never-
theless, no satisfactory solution for the asymmetric hydro-
genation of aromatic or heteroaromatic substrates according
formation of (S)-3-methyl piperidine (3d) in 85% ee. Differ-
ent catalysts were screened, and Pd(OH) /C was identified as
2
the optimum catalyst, providing 3d in 98% ee (Table 1,
[
4]
[14]
to Scheme 1 exists, although these compounds are readily
entry 4). Importantly, the reaction does not stop at aminal
6
d, but leads directly to piperidine 3d and oxazolidinone 4.
[
15]
Evidently traceless cleavage of the auxiliary occurs under
the reaction conditions, thereby combining chirality transfer
from and release of the auxiliary into a single operation. We
were pleased to find that after treatment of the crude reaction
mixture with hydrochloric acid, separation and purification of
the less soluble piperidine hydrochloride 3d and the more
soluble auxiliary could be achieved efficiently by simple
extraction with ether/hexanes mixtures. The piperidinium
hydrochloride 3d was obtained in 90% yield (98% ee) and 4
was recovered unchanged (93% yield, > 99% ee), allowing
the recycling of the auxiliary.
Scheme 1. Stereoselective hydrogenation of (hetero)aromatic com-
pounds (YR =CR , N).
1
1
available and the reaction has the potential for the simulta-
neous creation of multiple stereocenters. Here we describe an
efficient and unprecedented auxiliary-based method for the
This method for the stereoselective synthesis of piper-
idines has been applied successfully to a large number of
substrates, whereby the oxazolidinone with a tBu group often
resulted in slightly improved ee values relative to those
1
asymmetric hydrogenation of substituted pyridines (YR =
[
5]
[12]
N), which enables the stereoselective formation of piper-
obtained with the iPr group (Table 1). Substituents in the 4-
[
6]
idines with up to four new chiral centers in a single
operation (Scheme 2a).
, 5- or 6-position of the 2-oxazolidinone-substituted pyridine
can be used to create stereocenters at the corresponding
positions (entries 1–7). Even multiple stereocenters can be
generated, as exemplified by the stereoselective formation of
di- and trisubstituted piperidines in near-quantitative yield
and excellent enantioselectivities (entries 9, 10). As far as we
know this is the first highly asymmetric hydrogenation of an
aromatic compound that selectively generates three stereo-
centers. Under milder conditions we even succeeded in the
stereoselective synthesis (> 95:5) of aminal 6j, which bears
four new chiral centers (entry 11). Furthermore, functional
groups on the pyridine ring are well tolerated (entries 3, 5–6).
The versatility of the process can be increased still further,
since hydrogenation of 2d in the presence of acetaldehyde or
The heterogeneous catalytic hydrogenation of pyridines is
[
7]
usually performed in acidic media. Protonation not only
activates the pyridines for hydrogenation, it also suppresses
catalyst poisoning by the resulting piperidines. We reasoned
[
8]
that single-point attachment of chiral oxazolidinones 4 for
ease of introduction of the auxiliary in the 2-position of the
pyridine would be ideal (Scheme 2a). Moreover, it occurred
+
[
*] Dr. F. Glorius, N. Spielkamp, S. Holle, Dr. R. Goddard,
Dr. C. W. Lehmann
+
Max-Planck-Institut für Kohlenforschung
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr (Germany)
Fax: (+49)208-306-2994
acetic anhydride results in the formation of the corresponding
E-mail: glorius@mpi-muelheim.mpg.de
[16]
(
S)-N-ethylpiperidine 7 (entries 12, 13). The only present
+
[
] X-Ray structure analyses.
limitation concerns 3-substitution of the pyridine ring. A
methyl substituent in the 3-position leads to a less reactive
substrate, presumably because the oxazolidinone is rotated
out of the plane of the pyridine ring thereby shielding both p-
faces. Hydrogenation of 2h results in a nearly racemic product
(entry 8). Finally, we were pleased to find that our method
gives easy access to coniine (3b), the poisonous hemlock
alkaloid, in excellent yield and enantiomeric excess (entry 2).
[
**] We thank Prof. A. Fürstner for generous support and constant
encouragement, the Bundesministerium für Bildung und Forschung
and the Fonds der Chemischen Industrie for financial support
(
Liebig scholarship to F.G.), and S. Ruthe, F. Kohler, and Dr. D.
Belder for numerous ee determinations. Donations of chemicals by
Merck KGaA and Heraeus are also gratefully acknowledged.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
2
850
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200453942
Angew. Chem. Int. Ed. 2004, 43, 2850 –2852

Angewandte
Chemie
Scheme 2. a) Synthesis and asymmetric hydrogenation of oxazolidinone-substituted substrates 2 (X=Br, Cl). b) DFT-generated structures 2g and
[
11]
[12]
5
g
and X-ray structure 6g (chloride anion omitted for clarity).
Table 1: Asymmetric hydrogenation of oxazolidinone-substituted pyri-
[
a]
dines 2 according to Scheme 2.
[
b]
Entry
2
Prod.
HCl salt)
Cat.
T
[8C]
t
[h]
Yield ee
[%]
(
[%]
1
2
3
4
5
6
a
b
3a
3b
3c
3d
3e
3 f
6g
3d
3i
3j
6j
7
Pd(OH) /C 50
22
22
20
93
95
64
91
95
97
98
95
85
>95:5
4
96
2
[
n]
Pd(OH) /C 40
2
[
c, n]
[d]
c
d
e
Pd(OH) /C 25
2
[
e]
[e]
Pd(OH) /C 25, 65 24, 3 90
2
[
n]
Pd(OH) /C 25
26
22
20
72
22
93
92
87
100
2
[
n]
f
Pd(OH)
PtO2
2
/C 45
25
[
f,g]
[h]
7
8
9
1
1
1
1
g
h
[
i]
Rh/C
25
Scheme 3. Probable mechanism for the asymmetric hydrogenation
giving piperidinium salts 3.
[n]
[k]
[k]
i
j
j
Rh/Pd/C
Rh/C
40
94
[f]
0
1
2
3
40, 75 24, 18 92
94
>95:5
93
[
h]
Rh/Pd/C
40
40
22
22
63
87
81
[
[
l]
d
d
Pd(OH) /C 25
involvement of achiral 9h in the hydrogenation of 2h might
explain the observed formation of nearly racemic product
(entry 8).
2
m]
7
Pd(OH) /C 25
95
2
[a] General conditions: 2-mmol scale, AcOH (0.13m), 100 bar H2.
[
b] Enantiomeric excess determined by GC analysis of the N-trifluoro-
In summary, we describe a conceptually novel, practical,
and efficient synthesis of optically active piperidines, an
important substructure of many biologically active com-
pounds. This process is distinguished by the fact that
piperidines with multiple stereocenters can be formed in
very good yields and excellent optical purities. To the best of
our knowledge, this transformation unites for the first time
highly selective chirality transfer and nondestructive and
traceless cleavage of the chiral auxiliary in one reaction. In
addition, the piperidinium hydrochloride and the auxiliary
can be separated easily by extraction and the auxiliary
recycled.
6
acetamide derivatives of the crude reaction products. [c] R =CHO.
[
3
as solvent. [h] Diastereoselectivity determined by NMR. [i] Conversion,
determined by GC-MS. [k] syn/anti>100:1. [l] MeCHO (4 equiv) added.
d] Product purified as N-Boc derivative. [e] 258C for 24 h, then 658C for
h. [f] 150 bar H . [g] Conc. hydrochloric acid (6 equiv) and MeOH used
2
[m] Ac O (4 equiv) added. [n] In these cases, the catalyst 4 with a tBu
2
group instead of the iPr group was used.
A plausible mechanism is depicted in Scheme 3. Satura-
tion of the pyridinium ring in 5 presumably results in the
stereoselective formation of aminal 6. Disintegration of 6 into
[
9]
the oxazolidinone and iminium salt 8, which is in equili-
brium with the respective enaminium salt 9, is followed by
hydrogenation of the resulting CÀN or CÀC double bond
Experimental Section
Typical experimental procedure: No special care was taken to exclude
leading to the observed product 3 in high optical purity. The
air or moisture. A mixture of wet 20% Pd(OH) /C (w/w, 140 mg),
2
Angew. Chem. Int. Ed. 2004, 43, 2850 –2852
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ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2851

Communications
substrate 2b (524 mg, 2 mmol), and acetic acid (15 mL) was stirred in
[7] P. N. Rylander, Hydrogenation Methods, Academic Press, New
York, 1990.
an autoclave under a hydrogen atmosphere (100 bar) at 408C for 22 h.
The mixture was filtered through a short pad of Celite, which was
subsequently washed with MeOH (15 mL). Hydrochloric acid
[8] a) D. A. Evans, J. T. Shaw, Actual. Chim. 2003, 35; b) D. A.
Evans, A. S. Kim in Chiral Reagents for Asymmetric Synthesis
(Ed.: L. A. Paquette), Wiley, New York, 2003, p. 57; c) D. J.
Ager, I. Prakash, D. R. Schaad, Aldrichimica Acta 1997, 30, 3.
[9] It is generally accepted that the hydrogen atoms are transferred
to the face of the pyridinium ring that is adsorbed on the catalyst.
Stepwise hydrogenation may give rise to partially hydrogenated
species with different coordination modes. See: L. A. M. M.
Barbosa, P. Sautet, J. Catal. 2003, 217, 23.
(333 mL, 4.0 mmol) was added, and the solvent was removed by
rotary evaporation until no acetic acid was left. The ee value of 3b was
determined to be 95% by GC analysis of the N-trifluoroacetamide
derivative of the crude reaction product. The remaining white solid
was washed repeatedly with methyl tert-butyl ether/hexanes to yield
hydrochloride 3b (310 mg, 95%, 96% ee) as a white solid. Evapo-
ration of the organic phase left behind (S)-tBu-oxazolidinone
(
251 mg, 88%) as a white solid. All new compounds were fully
[10] In some cases the hydrogenation can be stopped at aminal 6, e.g.
in the case of 6g or 6j. An investigation of their synthetic utility
is ongoing and will be reported in due course.
characterized. The sources and types of catalysts used are given in the
Supporting Information.
[
11] The DFT calculations for 2g and 5g are supported by
comparable X-ray structures of 2c (CCDC-230262) and 5d/
Received: February 5, 2004 [Z53942]
BF (CCDC-230264), respectively.
4
[
12] The absolute stereochemistry of the products was determined
unequivocally by comparison of optical rotation data with
literature values (3a, 3b, 3d; N-Boc derivative of 3c), by X-
ray-analysis of 3i (CCDC-230263), 6g (CCDC-230265), 6j
Keywords: asymmetric synthesis · chiral auxiliaries ·
heterogeneous catalysis · hydrogenation · piperidines
.
(CCDC-230266), and
7
(CCDC-230267). CCDC 230262–
2
30267 contain the supplementary crystallographic data for
[
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ccdc.cam.ac.uk).
[
[
[
13] The reaction conditions are closely related to those developed by
Buchwald et al. for the amidation of aryl halides: A. Klapars, X.
Huang, S. L. Buchwald, J. Am. Chem. Soc. 2002, 124, 7421. Our
general protocol (CuI, ligand, K CO , toluene, 1408C) varies in
1998.
2
3
3] Several criteria for efficiency and selectivity in chemical syn-
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B. M. Trost, Science 1991, 254, 1471; b) “The ideal synthesis”:
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the choice of the optimal ligand: whereas less reactive substrates
benefited from the use of N,N’-dimethylethylendiamine, phe-
nanthroline proved to be superior for more reactive substrates.
[
[
[
14] Catalyst screening in AcOH, 100 bar H , 20 h (catalyst [%
2
conversion of substrate, % ee]): 5% Ru/C [15, n.d.], PtO [100,
8
C [100, 94], 10% Pd/C [100, 97], 20% Pd(OH) /C [100, 98]. In
2
5], 10% Pt/C [100, 85], 5% Rh/C [100, 86], 0.5% Rh/4.5% Pd/
[
4] The few reported highly enantioselective hydrogenations of
heteroaromatic compounds result in partial saturation of the
aromatic system and the creation of a single stereocenter: 2-
Methylquinoxaline to 2-methyl-1,2,3,4-tetrahydroquinoxaline:
a) C. Bianchini, P. Barbaro, G. Scapacci, E. Farnetti, M.
Graziani, Organometallics 1998, 17, 3308; Indoles to indolines:
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Am. Chem. Soc. 2003, 125, 10536; For diastereoselective hydro-
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Delbecq, P. Gallezot, S. Neto, C. Pinel, Chem. Eur. J. 2000, 6, 949.
5] Representative stereoselective hydrogenations of pyridines:
diastereoselective: a) H. Steiner, P. Giannousis, A. Pische-
Jacques, H.-U. Blaser, Top. Catal. 2000, 13, 191; b) A. SolladiØ-
Cavallo, C. Marsol, M. Yaakoub, K. Azyat, A. Klein, M. Roje, C.
Suteu, T. B. Freedman, X. Cao, L. A. Nafie, J. Org. Chem. 2003,
2
all cases the S enantiomer is formed predominantly.
15] Cleavage of a chiral auxiliary often leaves behind an undesired
functional group, whereas in this case, a C H bond is formed on
the parent molecule. The term “traceless cleavage” is usually
used in the context of traceless linkers: S. Brꢀse, S. Dahmen,
Chem. Eur. J. 2000, 6, 1899.
16] Whereas the reaction with acetaldehyde can be explained as a
reductive amination, the reaction with acetic anhydride is less
well understood since amides seem to be tolerated under the
reaction conditions (see Table 1, entry 6).
À
[
68, 7308; c) N. Douja, R. Malacea, M. Banciu, M. Besson, C.
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A 2000, 201, 107 (the maximum de was corrected to 30%; see
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C. Wedemeyer-Exl, J. Mol. Catal. A 1999, 139, 253; g) M. Studer,
C. Wedemeyer-Exl, F. Spindler, H.-U. Blaser, Monatsh. Chem.
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[
2
852
ꢀ 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2004, 43, 2850 –2852