Metal-free borane-catalyzed highly stereoselective hydrogenation of pyridines

Article abstract of DOI:10.1021/ja406761j

A metal-free direct hydrogenation of pyridines was successfully realized by using homogeneous borane catalysts generated from alkenes and HB(C ₆F₅)₂ via in situ hydroboration. The reaction affords a broad range of piperidines in high yields with excellent cis stereoselectivities.

Full text of DOI:10.1021/ja406761j

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Communication
Metal-Free Borane-Catalyzed Highly
Stereoselective Hydrogenation of Pyridines
Yongbing Liu, and Haifeng Du
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 14 Aug 2013
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Metal-Free Borane-Catalyzed Highly Stereoselective Hydro-
genation of Pyridines
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Yongbing Liu and Haifeng Du*
Beijing National Laboratory of Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190, China
Supporting Information Placeholder
hydrogenation of anilines with B(C6F5)3 (1.0 equiv) to
afford cyclohexyl-amine derivatives.13d Very recently,
Stephan and coworkers also described an interesting
example for the reduction of pyridines 1 under H2 using
a stoichiometric amount of B(C6F5)3 to furnish piperidi-
um salts 2 (Scheme 1).14 The replacement of one pen-
tafluorophenyl group of B(C6F5)3 by other groups, for
example, mesityl and alkenyl substitutents by Soós10h,11b
and Erker,13c respectively, provides a number of efficient
FLP catalysts for hydrogenation.9 Previously, we accom-
plished a highly enantioseletive hydrogenation of imines
on the basis of an in situ catalyst generation strategy by
hydroboration of alkenes with HB(C6F5)2.15,16 We envi-
sion that this strategy also provides a good opportunity
to develop the challenging metal-free catalytic hydro-
genation for simple pyridines, especially for 2,6-
disubstituted pyridines which are often inert substrates
in the reported work (Scheme 1). Herein, we report our
preliminary results on this subject.
ABSTRACT: A metal-free direct hydrogenation of pyri-
dines was successfully realized by using homogeneous
borane catalysts generated from alkenes and HB(C6F5)2
via an in situ hydroboration to afford a broad range of
piperidines in high yields with excellent cis-
stereoselectivities.
Piperidines are very important moieties contained in
a wide range of biologically active compounds, and nu-
merous methodologies have been established for their
synthesis.1 The catalytic hydrogenation of pyridines with
H2 undoubtedly provides a simple and straightforward
approach for accessing piperidines, although it is essen-
tial to overcome some inherent challenges on the catalyst
deactivation and the pyridine dearomatization.2 Various
heterogeneous transition-metal catalysts and several ho-
mogeneous Rh, Ir, and Ru complexes have been studied
for the direct hydrogenation of pyridines, but harsh reac-
tion conditions and/or specific pyridines bearing activat-
ing groups are often required due to the low activity and
selectivity of catalysts.3,4 Recently, an organocatalytic
transfer hydrogenation for partial reduction of electron-
deficient pyridines with Hantzsch esters has also been
reported.5 Moreover, the hydrogenation of relatively
more reactive pyridine derivatives, such as pyridinium
salts, pyridine N-oxides, and N-iminopyridium ylides,
by either heterogeneous or homogeneous catalysts, pro-
vides an alternative and efficient strategy for the synthe-
sis of piperidines.6,7 Despite these advances, the direct
hydrogenation of pyridines is still a challenge. In particu-
lar, the metal-free catalytic hydrogenation of simple pyr-
idines is of great interest and has rarely been reported.
B(C6F5)3 (1.0 equiv)
[HB(C6F5)3]
R
N
H2
R'
Stephan D. W.
H2
2
R
N
R'
this work
1
R
N
H
R'
B(C6F5)2
R
3
HB(C6F5)2 in situ
R
(10 mol %)
Scheme 1. Metal-free hydrogenation of pyridines by bo-
ranes.
We initially selected a variety of commercially availa-
ble alkenes to examine the hydrogenation of 2,6-
diphenylpyridine (1a) with H2 (50 bar) in toluene at
100 °C for 20 h (Table 1). Piers’ borane HB(C6F5)2 itself
can catalyze this reaction to give 2,6-diphenylpiperidine
(3a) in 21% conversion (Table 1, entry 1). While, the
majority of boranes generated in situ by the hydrobora-
tion of alkenes with HB(C6F5)2 exhibited obviously high-
The lately emerging frustrated Lewis pairs (FLPs)
have become one promising class of catalysts for the
metal-free homogeneous hydrogenation.8,9
A broad
range of substrates, such as imines,10 N-heterocycles,11
nitriles,10a alkenes,10b,c,h,i,12 and so on,13 can be efficiently
hydrogenated under the catalysis of FLPs. In particular,
Stephan and coworkers achieved an amazing aromatic
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er activities to furnish piperidine 3a with an excellent cis-
Page 2 of 5
stituents were well tolerated to produce piperdines 3l-u
in 80-99% yield with excellent cis-selectivity (Table 3,
1
2
3
4
5
6
7
8
selectivity (Table 1, entries 2-14). The electron-deficient
alkenes were found to be more effective for this trans-
formation (Table 1, entries 7-8 and 12), and terminal
alkene 4g gave a satisfactory conversion and 98/2 dr
(Table 1, entry 8). Further decreasing the reaction tem-
perature to 60 °C or the catalyst loading to 5 mol % led a
slight loss of reactivity (Table 1, entries 15 and 16).
entries 1-10).
Table 2. Hydrogenation of 2,6-diarylpyridinesa
4g (10 mol %)
HB(C6F5)2 (10 mol %)
Ar
N
H
Ar'
H2 (50 bar)
toluene, 100 °C, 20 h
Ar
N
Ar'
1a-k
3a-k
Table 1. Evaluation of alkenes for hydrogenation of pyridinesa
9
entry product (3)
yield (%)b cis:transc
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60
alkene 4 (10 mol %)
HB(C6F5)2 (10 mol %)
1
2
3
4
5
6
7
8
9
3a: Ar = Ar’ = Ph
98
97
99
99
99
97
98
99
99
93
92
98:2
98:2
98:2
98:2
98:2
Ph
N
H
3a
Ph
H2 (50 bar)
toluene, 100 °C, 20 h
Ph
N
Ph
3b: Ar = Ar’ = 4-MeC6H4
3c: Ar = Ar’ = 4-MeOC6H4
3d: Ar = Ar’ = 4-tBuC6H4
3e: Ar = Ar’ = 3-MeC6H4
3f: Ar = Ar’ = 3-MeOC6H4
3g: Ar = Ar’ = 2-MeC6H4
3h: Ar = Ar’ = 2-MeOC6H4
3i: Ar = Ar’ = 2-naphthyl
1a
Ar
4a: Ar = Ph
4b: Ar = 4-MeOC6H4
4c: Ar = 4-ClC6H4
4d: Ar = 2-ClC6H4
Ph
C6F5
tBuO
Ph
Ph
4g
4j
4h
4i
98:2
4e: Ar = 2,4,6-Me3C6H2
4f: Ar = 3,5-(CF3)2C6H3
Br
C4F9
>99:1
>99:1
98:2
90:10
99:1
4k
4l
4m
entry 4
1c --
cis:transb entry
4
cis:transb
conv
(%)b
conv
(%)b
10 3j: Ar = Ar’ = 2-furyl
21
59
72
62
67
65
95
ndd
95:5
95:5
96:4
96:4
96:4
97:3
98:2
9
10
11
4h
4i
4j
31
21
15
89
34
ndd
ndd
ndd
96:4
ndd
ndd
98:2
98:2
11
3k: Ar = 4-FC6H4
2
3
4
5
6
7
8
a
4a
Ar’ = 4-MeOC6H4
4b
4c
4d
4e
4f
a
All reactions were carried out with pyridine 1 (0.25
mmol) in toluene (2.0 mL). b Isolated yield. c Determined by
crude 1H NMR.
12 4k
13 4l
14e 4m 44
Table 3. Hydrogenation of 2-aryl-6-methylpyridinesa
15f 4g
16g 4g
79
93
4g (10 mol %)
HB(C6F5)2 (10 mol %)
4g >99
N
H
3l-u
Ar
H2 (50 bar)
toluene, 100 °C, 20 h
N
Ar
1l-u
All reactions were carried out with pyridine 1a (0.25
b
1
mmol) and toluene (2.0 mL). Determined by crude H
NMR. Without alkene. Not determined. 5 mol % of
entry product (3)
yield (%)b cis:transc
c
d
e
alkene 4m. At 60 °C. g 5 mol % of catalyst.
f
1
2
3
4
5
6
7
8
9
3l: Ar = Ph
96
98
96
86
88
96
93
99
99
80
95:5
96:4
96:4
97:3
96:4
96:4
96:4
97:3
96:4
96:4
3m: Ar = 4-MeOC6H4
3n: Ar = 4-PhC6H4
3o: Ar = 4-CF3C6H4
3p: Ar = 4-ClC6H4
3q: Ar = 3-MeOC6H4
3r: Ar = 3,5-Me2C6H3
3s: Ar = 2-MeOC6H4
3t: Ar = 2-naphthyl
With this interesting result in hand, we next exam-
ined the substrate scope under the optimal condition
(Table 1, entry 8). As shown in Table 2, the metal-free
hydrogenation of 2,6-diarylpyridines 1a-i went smoothly
to give piperidines 3a-i in 97-99% yield with 98/2->99/1
dr (entries 1-9). 2,6-Difurylpyridine (1j) was also an ef-
fective substrate to give a high yield but with a relatively
lower cis-selectivity (Table 2, entry 10). When piperidine
1k containing both electron-withdrawing and electron-
donating substituents was used, the desired product 3k
was obtained in 92% yield with 99/1 dr (Table 2, entry
11). However, the electron-deficient 2,6-bis(4-fluoro-
phenyl)pyridine was not a suitable substrate to lead only
23% conversion. The cis-configuration of piperidines 3 is
supported by an X-ray structure of piperidine 3c (see
Supporting Information).
10 3u: Ar = 4-allyloxyC6H4
a
All reactions were carried out with pyridine 1 (0.25
mmol) in toluene (2.0 mL). b Isolated yield. c Determined by
crude 1H NMR.
Moreover, the hydrogenation scope can be further
expanded to some interesting pyridine substrates. A re-
duction of the vinyl group occurred under the current
reaction conditions when using pyridine 1v as a sub-
strate to give piperidine 3v in 96% yield with 94/6 dr
A series of 2-aryl-6-methylpyridines 1l-u were also
subjected to the metal-free catalytic hydrogenation. Both
electron-donating and electron-withdrawing aryl sub-
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Journal of the American Chemical Society
piperidines (Table 4, entries 2 and 7). In comparison, the
(Table 4, entry 1). For 2-bromopyridines, an unexpected
1
2
3
4
dehalogenation was observed, which provides an alterna-
tive approach for the synthesis of mono-substituted
direct hydrogenation of mono-substituted pyridine 1x
required a higher catalyst loading and gave a lower yield
(Table 4, entry 3). 2,4,6-Triaryl and 2,6-dialkyl substitut-
ed pyridines were hydrogenated to give moderate yields
(Table 4, entries 4-6). Significantly, 2,2’-bipyridines
proved to be effective substrates for the current catalytic
system (Table 4, entries 8 and 9). For 6,6’-dimethyl-2,2’-
bipyridine (1C), one of the pyridine cycles was selective-
ly hydrogenated to give compound 3C as the predomi-
nant product in 59% yield. While, both pyridine cycles
were preferred to be reduced for 6,6’-ditolyl-2,2’-
bipyridine (1D). Moreover, under the current conditions,
pyridine 1E can be hydrogenated to furnish racemic
isosolenopsin A in 60% yield with 93/7 dr (Scheme 2).
Table 4. Hydrogenation of simple pyridinesa
5
6
yield
entry
pyridine (1)
product (3)
(%)b,c
7
8
9
96
(94:6)
1
N
N
H
3v
1v
OMe
OMe
10
11
12
13
14
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2
80
64
Br
N
N
H
1w
3w
OMe
OMe
3d
N
N
H
Our strategy for generation of borane catalysts in situ
from alkenes and Piers’ borane also provides a possible
opportunity to achieve the asymmetric hydrogenation of
pyridines by using chiral alkenes. Several chiral dienes15
were therefore tentatively tested for the asymmetric hy-
drogenation of pyridine 1C. Unfortunately, only moder-
ate conversion and very low enantioselectivity (<10% ee)
were obtained. The asymmetric version of this transfor-
mation is still a formidable challenge and awaits further
studies. Alternatively, both enantioisomers of com-
pounds 3C can be easily accessed via a simple resolution
process using L- or D-tartaric acid as a resolution rea-
gent (Scheme 3). The absolute configuration was deter-
mined by the X-ray structure of crystal 1. The interesting
structures of enantiomericallyl pure compounds 3C
make them have a potential utilization as chiral organo-
catalysts or ligands for asymmetric catalysis.
1x
3w
OMe
OMe
Ph
Ph
44
4 d
5
(98:2)
p-Tol
N
H
3y
p-Tol
p-Tol
N
p-Tol
1y
58
(92:8)
RO
OR
RO
OR
N
R = 4-MeC6H4
1z
N
H
3z
Me
N
Me
Ph
6e
51
68
Me
N
Me
O
1A
3A
N
Me
7e
8 f
Br
N
Me
Ph
O
1B
3B
L-(+)-tartaric acid
(1.0 equiv)
59
(96:4)
N
N
NH
N
NH
N
+
liquid
crystal 1
EtOH/acetone
Me
Me
Me
Me
Me
Me
1C
3C
3C
1. NaOH
2. D-tartaric acid
(1.0 equiv)
75
(>99:1)
NaOH
9g
N
N
NH HN
p-Tol
p-Tol
p-Tol
p-Tol
EtOH/acetone
1D
3D
a
NaOH
All reactions were carried out with pyridine 1 (0.25
mmol)，alkene 4g (10 mol %) and HB(C6F5)2 (10 mol %)
under H2 (50 bar) in toluene (2.0 mL) at 100 °C for 20 h
unless other noted. b Isolated yield. c The ratio (cis/trans) in
crystal 2
NH
(S,S)-3C
73% (>99% ee)
N
NH
(R,R)-3C
74% (>99% ee)
N
Me
Me
Me
Me
Scheme 3. Resolution of racemic piperidine.
1
d
parenthesis was determined by crude H NMR. The reac-
tion was run with 20 mol % of catalyst under H2 (75 bar) at
In summary, a broad range of pyridines have been
directly hydrogenated under H2 using catalytic amount
of simple borane catalysts generated in situ from com-
mercially available alkenes and HB(C6F5)2 to furnish im-
portant piperidines in high yields with excellent cis-
stereoselectivities. To the best of our knowledge, the cur-
rent study represents the first successful example of met-
al-free catalytic hydrogenation of pyridines with H2. Fur-
ther studies on searching for more efficient borane cata-
lysts, expanding substrate types, and exploring asymmet-
ric transformations, are underway in our laboratory.
e
120 °C for 30 h. The resulting piperidines were directly
treated with phenylacetyl chloride and Et3N, the yield for
two steps. f Pyridine 1D (1.0 mmol) was used.
alkene 4g (10 mol %)
HB(C6F5)2 (10 mol %)
H2 (50 bar)
N
C11H23
N
C11H23
toluene, 100 °C, 20 h
H
1E
60% yield
(cis:trans = 93:7)
isosolenopsin A
anti-HIV, antibacterial
activity
Scheme 2. Synthesis of isosolenopsin A
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Page 4 of 5
(7) For homogeneous hydrogenation, see: (a) Legault, C. Y.; Cha-
ASSOCIATED CONTENT
rette, A. B. J. Am. Chem. Soc. 2005, 127, 8966-8967. (b) Ye, Z.-S.; Chen,
M.-W.; Chen, Q.-A.; Shi, L.; Duan, Y.; Zhou, Y.-G. Angew. Chem. Int.
Ed. 2012, 51, 10181-10184. (c)Wu, J.; Tang, W.; Pettman, A.; Xiao, J.
Adv. Synth. Catal. 2013, 355, 35-40.
1
2
3
4
5
6
7
8
Supporting Information. Procedures for the synthesis of
pyridines, hydrogenation of pyridines, and resolution of
racemic piperidine, characterization of products, X-ray
structures of 3c, 3D, and crystal 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
(8) For a seminal work, see: Welch, G. C.; Juan, R. R. S.; Masuda, J.
D.; Stephan, D. W. Science 2006, 314, 1124-1126.
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3136. (c) Stephan, D. W.; Erker, G. Angew. Chem. Int. Ed. 2010, 49,
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Chem. 2012, 10, 5740-5746. (g) Erker, G. Pure Appl. Chem. 2012, 84,
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AUTHOR INFORMATION
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Corresponding Author
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haifengdu@iccas.ac.cn
Funding Sources
No competing financial interests have been declared.
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718-723.
(14) Mahdi, T.; del Castillo, J. N.; Stephan, D. W. Organometallics
2013, 32, 1971-1978. For relevant references, see: (a) Geier, S. J.;
Stephan, D. W. J. Am. Chem. Soc. 2009, 131, 3476-3477. (b) Geier, S. J.;
Gille, A. L.; Gilbert, T. M.; Stephan, D. W. Inorg. Chem. 2009, 48,
10466-10474.
ACKNOWLEDGMENT
We are grateful for the generous financial support from the
National Natural Science Foundation of China (20802079,
21222207), and the National Basic Research Program of
China (973 program, 2011CB808600).
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