Organocatalytic enantioselective reduction of pyridines

Article abstract of DOI:10.1002/anie.200701158

Metal-free at last! The first enantioselective organocatalytic reduction of pyridine derivatives leads to hexahydrochinolinones and tetrahydropyridines in good yields and with excellent enantioselctivities (up to 92% ee; see scheme). These compounds are s

Full text of DOI:10.1002/anie.200701158

Communications
DOI: 10.1002/anie.200701158
Brønsted Acid Catalysis
Organocatalytic Enantioselective Reduction of Pyridines**
Magnus Rueping* and Andrey P. Antonchick
Asymmetric hydrogenation is one of the most important
enantioselective reactions. Although the hydrogenation,
transfer hydrogenation, and hydrosilylation of various sub-
strates in the presence of metal catalysts have been described,
the asymmetric reduction of aromatic and heteroaromatic
compounds still represents a great challenge.[1] This situation
is particularly true for the enantioselective hydrogenation of
substituted pyridine derivatives,[2] which can be readily
prepared using various methods. The corresponding chiral
piperidines are not only important starting materials for
numerous biologically active compounds, but are also impor-
tant structural building blocks of many alkaloids, including
pumiliotoxins, gephyrotoxins, and over 50 other members of
cantly it would give us direct access to enantiomerically pure
piperidines
Building on our previous results from chiral ion-pair
catalysis,[4] we decided to examine the reduction of pyridines
in the presence of the binol phosphates 3 (binol = 2,2’-
dihydroxy-1,1’-binaphthyl).[4,5] We assumed that the activa-
tion of pyridines by catalytic protonation using a Brønsted
acid would allow a cascade hydrogenation, in which a
Hantzsch dihydropyridine (2) would function as the hydride
source.[6]
Hence, we began our study with the catalytic reduction of
the trisubstituted pyridine 1a in the presence of the binol
phosphate 3a, whereby the reaction parameters (solvent,
temperature, catalyst loading, substrate concentration, and
hydride source) were varied (Table 1). The initial results
demonstrated the success of the new method, and the
partially reduced enantiomerically enriched pyridine deriva-
tive 4a was isolated.
the
class of 2,5-disubstituted decahydroquinolines
(Scheme 1).[3]
Table 1: Evaluation of the reaction parameters for the enantioselective
reduction of pyridines catalyzed by the Brønsted acid 3a.
Entry[a]
Solvent
R
3a [mol%]
ee [%][b]
Scheme 1.
1
2
3
4
5
6
7
8
9
toluene
DCE[c]
Bu2O
benzene
benzene
benzene
benzene
benzene
benzene
Et
Et
Et
Et
Et
Et
tBu
iPr
allyl
5
5
5
71
52
76
78
79
78
75
51
76
We considered it most important to investigate a Brønsted
acid catalyzed enantioselective reduction of pyridines
[Eq. (1)]. This approach would not only be the first example
of such an organocatalytic transformation but more signifi-
5
10
15
5
5
5
[a] Reaction conditions: 1a, 3a (5–15 mol%),
2
(4 equiv), 608C.
[b] Determined by HPLC on a chiral phase (Chiralcel OD-H). [c] DCE=
1,2-dichloroethane.
The best results, with respect to reactivity, yield, and
selectivity, were achieved with the Hantzsch diethyl ester (2,
R = Et) in benzene at 608C (Table 1, entries 4–6). Under
these conditions, 4a was isolated in up to 79% ee. Other
solvents, such as toluene or dibutyl ether, yielded 4a with
comparable enantioselectivities (Table 1, entries 1 and 3).
However, the application of other Hantzsch esters resulted in
lower selectivities (Table 1, entries 7–9).
[*] Prof. Dr. M. Rueping, A. P. Antonchick
Degussa Endowed Professorship
Institute of Organic Chemistry and Chemical Biology
Johann Wolfgang Goethe-Universität Frankfurt
Max-von-Laue-Strasse 7, 60438 Frankfurt am Main (Germany)
Fax: (+49)69-798-29248
E-mail: m.rueping@chemie.uni-frankfurt.de
[**] The authors thank Degussa AG and the DFG (Priority Program
Organocatalysis) for financial support.
In further experiments, differently substituted binol
phosphates 3b–g were examined in the reduction of pyridine
1a (Table 2). The best enantioselectivities were achieved
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 2: Evaluation of the chiral Brønsted acids 3 as catalysts in the
enantioselective reduction of pyridines.
Table 3: Evaluation of the chiral Brønsted acids 3 as catalysts in the
enantioselective reduction of pyridines.
Entry[a]
Ar (3)
ee [%][b]
Entry[a]
Ar (3)
ee [%][b]
1
2
3
4
5
6
7
Ph3Si, [H]8 (3a)
phenyl (3b)
4-biphenyl (3c)
3,5-(CF3)2C6H3 (3d)
3,5-tBu2-4-MeOC6H2 (3e)
anthracenyl (3 f)
9-phenanthryl (3g)
78
1
2
3
4
5
6
7
8
9
Ph3Si, [H]8 (3a)
phenyl (3b)
4-biphenyl (3c)
3,5-(CF3)2C6H3 (3d)
3,5-tBu2-4-MeOC6H2 (3e)
anthracenyl (3 f)
9-phenanthryl (3g)
1-naphthyl (3h)
2-naphthyl (3i)
67
21[c]
19[c]
8[c]
46[c]
44[c]
36[c]
56[c]
89
16[c]
91
82
75
35
[a] Reaction conditions: 1a, 3 (5 mol%), 2 (4 equiv), benzene, 608C.
[b] Determined by HPLC on a chiral phase (Chiralcel OD-H). [c] The
opposite enantiomer was obtained.
32[c]
[a] Reaction conditions: 5a, 3 (5 mol%), 2 (4 equiv), benzene, 608C.
[b] Determined by HPLC on a chiral phase (Chiralcel AS-H). [c] The
opposite enantiomer was obtained.
using the Brønsted acid catalyst 3 f, which gave the product 4a
in 91% ee (Table 2, entry 6). All the other binol phosphates
yielded the product with lower enantioselectivities, in corre-
lation with the steric demand of the substituents on the
catalyst.[4]
Table 4: Substrate scope of the enantioselective reduction of pyridines
catalyzed by the Brønsted acid 3 f.
Product[a]
Yield[b]
Product[a]
Yield[b]
ee[c]
ee[c]
The method developed for the enantioselective organo-
catalytic reduction of pyridines 1 allows access to hexahy-
droquinolinones 4, which are precursors for the synthesis of
various natural products.[7] We decided to apply this new
84%
91% ee
73%
92% ee
method to the reduction of trisubstituted pyridines
5
(Scheme 2). The resulting products 6 are also of great
72%
73%
91% ee
90% ee
69%
55%
89% ee
84% ee
Scheme 2.
66%
92% ee
47%
86% ee
significance, as they can be used as starting compounds for
the synthesis of 2,6-dialkyl 3-hydroxypiperidine natural
products, such as cassine, spectaline, corydendramine, lepto-
phylline, morusimine, and juliprosopine.[8]
Using our optimized conditions, we evaluated the differ-
ent chiral binol phosphates 3a–i as Brønsted acid catalysts in
the enantioselective reduction of pyridine 5a to tetrahydro-
pyridine 6a (Table 3). Once again, the reaction with the
anthracenyl-substituted binol phosphate catalyst 3 f gave the
best enantioselectivities. We were able to isolate the product
6a in 89% ee (entry 6).
83%
87% ee
68%
89% ee
[a] Reaction conditions: 1 or 5, 3 f (5 mol%), 2 (4 equiv), benzene, 508C.
[b] Yields pf product isolated after purification by column chromatog-
raphy. [c] Determined by HPLC on a chiral phase (Chiralcel OD-H, AS-H,
or ADH).
In further experiments, we explored the scope of the
reduction by using differently substituted pyridines 1 and 5 as
substrates (Table 4). The corresponding azadecalinones 4a–f
and tetrahydropyridines 6a–d were isolated in good yields
and with excellent enantioselectivities (up to 92% ee).
The newly developed enantioselective organocatalytic
reduction of pyridines can be used as a key step in the
synthesis of decahydroquinolines from the pumiliotoxin
family (Scheme 3). Hence, the reduction of pyridine 1c,
which can be readily prepared according to the procedure of
Bohlmann and Rahtz,[9] gives the corresponding 2-propylhex-
ahydroquinolinone. This compound can subsequently be
transformed, according to a sequence reported by Hsung
et al.,[7e] into diepi-pumiliotoxin C.
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Communications
Keywords: Brønsted acids · ion-pair catalysis · piperidines ·
.
reduction · transfer hydrogenation
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Scheme 4. Postulated mechanism for the enantioselective organocata-
lytic reduction of pyridines.
first hydride transfer from the Hantzsch ester 2 gives the
adduct B, which is transformed into the iminium ion C
through an acid-catalyzed isomerization. A second hydride
transfer results in the desired product 4 or 6, and the binol
phosphate catalyst 3 is regenerated.
In summary, we have developed the first enantioselective
reduction of pyridines catalyzed by Brønsted acids. The
products, hexahydroquinolinones and tetrahydropyridines,
are isolated in good yields and with excellent enantioselec-
tivities (up to 92% ee). These products serve as starting
compounds for the synthesis of various natural products. As
only metal-catalyzed enantioselective hydrogenations of
pyridines, which did not give the valuable products described
herein and yielded lower enantioselectivities, were described
previously, our newly developed metal-free Brønsted acid
catalyzed procedure represents an important advance.
Received: March 16, 2007
Published online: May 11, 2007
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Chemie
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