Borane-Catalyzed Transfer Hydrogenations of Pyridines with Ammonia Borane

Article abstract of DOI:10.1021/acs.orglett.6b02610

With the use of ammonia borane as a hydrogen source, a borane catalyzed metal-free transfer hydrogenation of pyridines was successfully realized for the first time to furnish a variety of piperidines in 44-88% yields with moderate to excellent cis-selecti

Full text of DOI:10.1021/acs.orglett.6b02610

Letter
pubs.acs.org/OrgLett
Borane-Catalyzed Transfer Hydrogenations of Pyridines with
Ammonia Borane
Qiwen Zhou,† Lanqiong Zhang,† Wei Meng,‡,§ Xiangqing Feng,‡,§ Jing Yang,*,† and Haifeng Du*,‡,§
†State Key Laboratory of Chemical Resource, Beijing Key Laboratory of Bioprocess, College of Life Science and Technology, Beijing
University of Chemical Technology, Beijing 100029, China
‡Beijing National Laboratory for Molecular Sciences, CAS Key Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190, China
§University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: With the use of ammonia borane as a hydrogen source, a borane
catalyzed metal-free transfer hydrogenation of pyridines was successfully realized
for the first time to furnish a variety of piperidines in 44−88% yields with
moderate to excellent cis-selectivities. The ease in handling without requiring high
pressure H2 makes this transfer hydrogenation practical and useful.
he chemistry of frustrated Lewis pairs (FLPs) provides an
Timportant and powerful approach for metal-free hydro-
genations. Since the seminal discovery of H2 splitting with FLPs
by Stephan and co-workers in 2006, numerous unsaturated
compounds have become effective substrates for the FLP
catalysis.1,2 In particular, rapid growth for the challenging
asymmetric hydrogenation has been witnessed in recent
years.3,4 Notably, besides the H2 activation, FLP can activate
the Si−H bond as well, which leads to an interesting Piers type
hydrosilylation.5,6 As a hydrogen donor, silane is not atom
economic, but the generally required high pressure in the
hydrogenation is unnecessary in the hydrosilylation. Exploring
novel hydrogen donors with high hydrogen capacity for the
FLP catalysis is therefore an interesting subject with great
importance.
Ammonia borane (1) has been intensively investigated as an
ideal hydrogen storage material owing to its 19.6 wt %
hydrogen capacity, low molecular weight, ease in handling, and
good stability against air and moisture.7 Moreover, ammonia
borane is also often used as a reagent in the transfer
hydrogenations.8 In 2010, Berke and co-workers described a
metal-free transfer hydrogenation of imines with ammonia
borane via a concerted six-membered transition state.9 Later on,
the same group extended the transfer hydrogenation to
polarized olefins and carbonyl compounds.10 In 2014, Kinjo,
Hirao, and co-workers reported a 1,3,2-diazaphospholene
catalyzed transfer hydrogenation of the NN bond.11
Ammonia borane was also used in the transition metal catalysis.
For example, in 2015, Li and co-workers reported an ammonia-
borane activation with cobalt nanoparticles.12 Very recently,
Liu, Luo, and co-workers described a cobalt-catalyzed transfer
hydrogenation of alkynes.13 Despite these advances, to the best
of our knowledge, the activation of ammonia borane by FLPs
has been less reported. In 2010, Stephan and co-workers used
ammonia borane to reduce the zwitterion intermediate
generated from the reaction of CO2 with Al-based FLPs
instead of being activated by FLPs.14 Miller and Bercaw
reported a dehydrogenation of ammonia borane with an FLP.15
In 2016, Aldridge and co-workers described a catalytic
dehydrogenation of ammonia borane by a dimethylxanthene-
derived FLP.16
As an ongoing project in our group, we have been exploring
readily accessible FLPs for metal-free hydrogenation and
hydrosilylation. Using the in situ generated boranes by the
hydroboration of alkenes or alkynes with HB(C6F5)2,17 highly
stereoselective and/or enantioselective hydrogenations and
hydrosilylations have been successfully achieved.18,19 In the
search for novel hydrogen donors other than H2 and silane for
the FLP catalysis, Dixon and Baker’s findings on the formation
of zwitterion species 2 by treating ammonia borane with
B(C6F5)3 in 2007 (Scheme 1)20 provided enlightenment. Based
on our previous work on the FLP-catalyzed hydrogenation of
simple pyridines,19b,21 we envision that the FLPs of pyridines 3
and B(C6F5)3 can split the N−H and B−H bonds of ammonia
Scheme 1. Our Proposal for FLPs-Catalyzed Transfer
Hydrogenations with Ammonia Borane
Received: August 31, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02610
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
borane to generate zwitterion species 4, which leads a
subsequent reduction to produce piperidines 5 (Scheme
1).22,23 Herein, we wish to report our preliminary results on
this subject.
An initial study was carried out with the transfer hydro-
genation of pyridine 3a with ammonia borane (4.0 equiv) as a
model reaction. As shown in Scheme 2, ammonia borane itself
Supporting Information), which is similar to the observation
by Berke and co-workers.9
A variety of 2,6-diarylpyridines 3a−h were then subjected to
the transfer hydrogenation under the optimal reaction
conditions. As shown in Scheme 3, all these reactions
Scheme 3. Transfer Hydrogenation of 2,6-Diarylpyridines
Scheme 2. Initial Studies on the Transfer Hydrogenation
with Ammonia Borane
can react with pyridine 3a in toluene at 120 °C without any
catalysts, but the conversion was very low. With the use of
borane (10 mol %) generated from pentafluorostyrene and
HB(C6F5)2, a 42% conversion was obtained. B(C6F5)3
exhibited higher activities to give piperidine 5 in 64%
conversion with excellent cis-selectivity (99:1).
Optimization of reaction conditions was next conducted to
further improve the reactivities. It was found that increasing the
reaction concentration largely improved the conversions, and
the reaction can be completed in 6 h at a concentration of 0.4
M (Table 1, entries 1−4). Lowering the catalyst loading to 5
proceeded smoothly to furnish the desired piperidines 5a−h
in 63−88% yields with high cis-selectivities. Both substituted
phenyl and aromatic heterocyclyl groups were tolerated well in
this reaction. 2-Aryl-6-methylpyridines 3i−m were also effective
substrates for this transfer hydrogenation, and cis-piperidines
5i−m as predominate isomers were obtained in 56−88% yields
(Scheme 4). When pyridine 5l bearing an electron-donating
substituent was used, a relatively lower yield was given.
Scheme 4. Transfer Hydrogenation of 2-Aryl-6-methyl-
pyridines
Table 1. Optimization on the Transfer Hydrogenation of
Pyridine 3a
a
bc
,
entry 1 (equiv)
solvent
concn (M) time (h) conv (%)
1
2
3
4
5
6
7
8
9
4.0
4.0
4.0
4.0
4.0
3.0
2.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
toluene
toluene
toluene
toluene
toluene
toluene
toluene
C6H5F
0.1
0.2
0.4
0.6
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
12
12
6
64
83
99
96
45
88
59
46
85
75
36
6
d
24
6
6
6
C6H5Br
mesitylene
CH2Cl2
CH3CN
dioxane
hexane
6
10
11
12
13
14
6
6
Moreover, 2,6-dialkylpyridine 3n was a suitable substrate to
give product 5n in 80% yield (Figure 1). Monosubstituted
e
6
nr
nr
e
6
6
33
a
All reactions were carried out with pyridine 3a (0.20 mmol) and
b
borane (10 mol %) in solvent at 120 °C unless other noted. The
conversion was determined by crude H NMR. Cis/trans = 99:1.
mol % of B(C6F5)3 was used. No reaction.
c
d
1
5
e
Figure 1. Transfer hydrogenation of other simple pyridines.
mol % led to a dramatic drop in conversion to 45% (Table 1,
entry 5). Reducing the amount of ammonia borane (1) resulted
in lower reactivities (Table 1, entries 6 and 7). Solvents were
found to influence this reaction largely, and toluene proved to
be a better solvent (Table 1, entries 3 vs 8−14). A 11B NMR
study on the crude reaction mixture disclosed that ammonia
borane (1) was converted into borazine, cyclotriborazane, and
poly(borazylene) after the transfer hydrogenation (see
pyridine 3o was a less reactive substrate and gave piperidine 5o
in a moderate yield. Notably, the transfer hydrogenation of 2,3-
disubstituted pyridines 3p and 3q can also occur to furnish the
desired 5p and 5q in 44−53% yields with moderate cis-
selectivities.
In summary, a borane catalyzed metal-free transfer hydro-
genation of pyridines with ammonia borane as the hydrogen
B
DOI: 10.1021/acs.orglett.6b02610
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
A. P. M.; Manners, I. Chem. Rev. 2010, 110, 4079. (d) Huang, Z.;
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source was successfully realized to furnish the desired
piperidines in 44−88% yields with moderate to excellent cis-
selectivities. In contrast to the FLP-catalyzed hydrogenation
with H2, the current transfer hydrogenation with ammonia
borane successfully avoided use of high pressure H2 (50 bar),19b
which will provide a promising and practical approach for the
transfer hydrogenations. Studies to further understand the
mechanism and explore the application of ammonia borane in
other transfer hydrogenations are underway in our laboratory.
Hurmalainen, J.; Mansikkamaki, A.; Piers, W. E.; Tuononen, H. M.
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Nat. Chem. 2014, 6, 983. (f) Rossin, A.; Peruzzini, M. Chem. Rev. 2016,
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ASSOCIATED CONTENT
* Supporting Information
■
(9) Yang, X.; Zhao, L.; Fox, T.; Wang, Z.-X.; Berke, H. Angew. Chem.,
Int. Ed. 2010, 49, 2058.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02610.
(10) (a) Yang, X.; Fox, T.; Berke, H. Chem. Commun. 2011, 47, 2053.
(b) Yang, X.; Fox, T.; Berke, H. Org. Biomol. Chem. 2012, 10, 852.
(c) Yang, X.; Fox, T.; Berke, H. Tetrahedron 2011, 67, 7121.
(11) Chong, C. C.; Hirao, H.; Kinjo, R. Angew. Chem., Int. Ed. 2014,
53, 3342.
Procedure for the metal-free transfer hydrogenation of
pyridines, characterization of products along with the
NMR spectra (PDF)
(12) Zhao, T.-J.; Zhang, Y.-N.; Wang, K.-X.; Su, J.; Wei, X.; Li, X.-H.
RSC Adv. 2015, 5, 102736.
(13) Fu, S.; Chen, N.-Y.; Liu, X.; Shao, Z.; Luo, S.-P.; Liu, Q. J. Am.
Chem. Soc. 2016, 138, 8588.
AUTHOR INFORMATION
Corresponding Authors
■
́
(14) Menard, G.; Stephan, D. W. J. Am. Chem. Soc. 2010, 132, 1796.
(15) Miller, A. J. M.; Bercaw, J. E. Chem. Commun. 2010, 46, 1709.
(16) Mo, Z.; Rit, A.; Campos, J.; Kolychev, E. L.; Aldridge, S. J. Am.
Chem. Soc. 2016, 138, 3306.
*E-mail: yangj@mail.buct.edu.cn.
*E-mail: haifengdu@iccas.ac.cn.
(17) (a) Parks, D. J.; Spence, R. E. H.; Piers, W. E. Angew. Chem., Int.
Ed. Engl. 1995, 34, 809. (b) Parks, D. J.; Piers, W. E.; Yap, G. P. A.
Organometallics 1998, 17, 5492.
Notes
The authors declare no competing financial interest.
(18) (a) Cao, Z.; Du, H. Org. Lett. 2010, 12, 2602. (b) Feng, X.; Du,
H. Asian J. Org. Chem. 2012, 1, 204.
ACKNOWLEDGMENTS
■
We are grateful for the generous financial support from the
National Natural Science Foundation of China (21222207,
21374005, and 21572231).
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D. A. Angew. Chem., Int. Ed. 2007, 46, 746.
(21) For a mechanistic study by DFT calculation, see: Zhao, J.;
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DOI: 10.1021/acs.orglett.6b02610
Org. Lett. XXXX, XXX, XXX−XXX