B(C6F5)3-Promoted hydrogenations of N-heterocycles with ammonia borane

Article abstract of DOI:10.1039/c7cc04709f

A transition-metal-free method for the B(C₆F₅)₃-promoted hydrogenations of N-heterocycles using ammonia borane under mild reaction conditions has been developed. The reaction affords a broad range of hydrogenated products in moderate to good yields. The enantioselective versions for the corresponding products were also investigated via our approach, showing good feasibility.

Full text of DOI:10.1039/c7cc04709f

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B(C6F5)3-promoted hydrogenations of N-heterocycles with
ammonia borane
Fangwei Ding,ab Yiliang Zhang,ab Rong Zhao,ab Yanqiu Jiang,a Robert Li-Yuan Bao,ab
Kaifeng Lina and Lei Shi*ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
transition-metal-free method for the B(C6F5)3-promoted considerable attention owing to its ideally high storage
hydrogenations of N-heterocycles using ammonia borane under capacity and good stability against air and moisture compare
mild reaction conditions has been developed. The reaction affords to hydrosilanes. Although hydrosilanes are employed as low
a broad range of hydrogenated products in moderate to good toxic, highly active and handling easily hydrogen donors, silane
yields. The enantioselective versions for corresponding products is not atom economic.19 Ammonia borane is usually employed
were also investigated by our approach, showing good feasibility.
as hydrogen source in the reductive reactions.20-28 It is notable
that the transfer hydrogenations of N-heterocycles with
ammonia borane by FLPs has been less reported. In 2016, Du
and co-workers described a frustrated Lewis pair catalyzed
asymmetric transfer hydrogenation of imines29 and borane-
catalyzed transfer hydrogenations of pyridines19 and
quinoxalines30 with ammonia borane. However, the
hydrogenations of quinoline and indole derivatives have not
been reported. Our group has been devoting our efforts
towards hydrogenations of complex N-heterocycles.31 Herein,
The past decade has witnessed spectacular advances in metal-
free catalytic reductions,1 which in particular hydrogenations
of unsaturated nitrogen-containing compounds are one of the
simplest and most practical chemical processes in organic
synthesis. Although a variety of insightful methods provide
alternative ways to direct hydrogenations, the frustrated Lewis
pairs (FLPs) have received considerable attention as powerful
tools for metal-free hydrogenations.2 The feasibility of FLPs
systems to activate H2 and hydrogenate unsaturated
substrates, particularly heteroaromatic rings, has been
examined.3-8 In 2010, Stephan firstly reported metal-free
reductions of N-heterocycles via FLPs.9 Repo described the
asymmetric hydrogenations of unsaturated nitrogen-
containing compounds (up to 37% ee).10 Soós developed the
size-exclusion design of Lewis acids, and completed the
synthesis of cuspareine under the FLPs conditions.6 In addition,
Du had a breakthrough on hydrogenations of pyridines,11 2,3-
disubstituted quinoxalines8 and substituted quinolines12,13 by
using homogeneous borane catalysts generated in situ from
alkenes and HB(C6F5)2. Besides the H2 activation, FLPs can also
activate the Si−H bond.6,14-17 The reductions of substituted
indoles,15 quinolines16 and pyridines18 were investigated using
silane and B(C6F5)3.
a
new method B(C6F5)3-promoted hydrogenations of N-
heterocycles with ammonia borane under transition-metal-
free conditions is presented.
Initially, the hydrogenation of quinaldine with ammonia
borane was chosen as the model reaction to optimize the
reaction conditions, and the results were summarized in Table
1. When quinaldine was treated with ammonia borane (3
equiv.), B(C6F5)3 (5 mol%) in toluene at room temperature for
24 h, the expected product was obtained in 15% yield (Table 1,
entry 1). Surprisingly, when the reaction temperature was
raised to 80 °C, the yield of 2a was dramatically increased to
81% (Table 1, entry 2). However, when the reaction was
carried out at 60 °C or 100 °C, the yields of 2a were achieved in
43% and 79% yields, respectively (Table 1, entries 3-4).
Subsequently, various solvents were investigated in the
presence of 5 mol% of B(C6F5)3 and three equivalents of
ammonia borane at 80 °C (Table 1, entries 5-8). Results
showed that toluene as solvent was better than MeCN, THF,
dioxane and 1,2-dichloroethane. Moreover, when the reaction
was carried out in the absence of B(C6F5)3 at 80 °C, only 9%
yield of 2a was obtained (Table 1, entry 9). The amount of
ammonia borane was also investigated, three equivalents of
ammonia borane was suitable for the reaction (Table 1, entries
10-11). Thus, the optimum reaction condition is as follows:
In recent years, ammonia borane (AB) has also received
a.MIIT Key Laboratory of Critical Materials Technology for New Energy Conversion
and Storage, School of Chemistry and Chemical Engineering, Harbin Institute of
Technology, Harbin 150001, China. E-mail: lshi@hit.edu.cn
http://homepage.hit.edu.cn/shilei
b.Shenzhen Graduate School, Harbin Institute of Technology, Shenzhen 518055,
China
†Electronic Supplementary Informaꢀon (ESI) available: [details of any
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substrates (1 equiv.) ammonia borane (3 equiv.), B(C6F5)3 (5
mol %) in toluene at 80 °C for 8 h.
Table 2 Hydrogenations of various N-heterocycles catalyzed by
a,b
Table 1 Optimization studies for the hydrogenation of B(C6F5)3
a
quinaldine catalyzed by B(C6F5)3
X
Y
R
R
N
N
H
2
X = CH, N
Y = CH2, NH
B(C6F5)3 5 mol%
NH3•BH3
1
H
B
B
A
toluene, 80°C, 8 h
A = S, NH
B = N, CH
R
R
A
3
4
N
N
H
N
N
H
H
H
NH2
Br
2a
81%
2b 72%
82%
2d 61%
2c
Br
Br
O
N
H
Br
Cl
N
H
N
H
N
H
OH
Br
2e 50%
2f 78%
2g 70%
65%
2h
2l
H
N
H
N
H
N
H
N
N
H
N
H
N
H
N
H
a Reactions were performed on a 0.5 mmol scale using B(C6F5)3
(5 mol%) and ammonia borane (3 equiv.) with solvent (1.5 mL)
2j
2k
4a
76%
81%
60%
2i 80%
b
at the investigated temperature for 8 h. Yield of isolated
F
product. c No catalyst.
N
H
N
H
N
N
HN
H
With optimum procedure in hand, substrates of this
protocol were investigated and the results are represented in
the Table 2. At first, various N-heterocycles with six-membered
ring, such as quinoline derivatives and quinoxaline derivatives,
were allowed to react with ammonia borane under the
optimized reaction conditions. Quinolines with substituents in
the 2- or 8- position, which provide sufficient bulk to hinder
adduct formation, were explored for FLPs reactivity. As shown
in the Table 2, all the reactions were completed within 8 h, and
led to the desired products in moderate to good yields. For
example both 1a with electron-donating group (R = 2-Me) and
1f with electron-withdrawing group (R = 6-OCH3) gave the
corresponding products 2a and 2f in 81% and 78% yields,
respectively. In addition, The substituting effects were also
investigated. To our satisfaction, even polysubstituted 1g
formed the product 2g in 70% yield. The remarkable functional
group tolerance of our experimental conditions was observed
in the hydrogenations of N-heterocycles. Bromo and chloro
substituted N-heterocycles afforded the corresponding
2n 50%
4b 82%
76%
81%
2m
Br
N
H
N
O
N
H
N
H
H
4c 87%
4d 71%
4e 79%
4f 77%
H
S
N
Ph
Ph
Ph
N
H
N
H
N
H
N
H
5
67%
4i
4g
85%
72%
4h 80%
a
Reaction conditions: substrates (0.5 mmol, 1 equiv.) and
ammonia borane (1.5 mmol, 3 equiv.) with B(C6F5)3 (5 mol%) in
toluene (1.5 mL) at 80 °C for 8 h. b Yield of isolated product.
Due to achievement of the reduction of N-heterocycles with
six-membered ring, it seems to be suitable for hydrogenations
of other N-heterocycles. So we made a further investigation of
the hydrogenations of N-heterocycles with five-membered ring.
Taking various indole derivatives into consideration in the
Table 2. Specially, indoles with substituents in the 2- or 7-
position, which provide sufficient bulk to hinder adduct
formation, were explored for transfer hydrogenations via FLPs.
All the substituded indoles proceeded smoothly, affording
products (2d, 2e, 2g, and 2k) in moderate to high yields, which
might be employed for further structural manipulations such
as the coupling reaction. Furthermore, it could be further
modified at the hydroxy or amino group (2b and 2g), which is
useful in synthetic chemistry and pharmaceutical chemistry.
corresponding Indolines (4a
is notable that other N-heterocycles (1m
bond containing open chain compound were successfully
-
4h) in good to excellent yields. It
,
1n and 3i) and N=N
Comparing to quinoline derivatives, quinoxaline derivatives hydrogenated to corresponding product by FLPs.
afforded corresponding products in good yields. It was found
After accomplishment of the hydrogenations of N-
that the property and the position of substitutes did not heterocycles with ammonia borane, we further devoted our
obviously effect on the yields. 1i
,
1j
,
1k and 1l gave the target efforts to the catalytic asymmetric transformation of
quinolines and 1,4-benzoxazine derivatives. The reaction
products ranging from 60% to 81%.30
conditions for the asymmetric transfer hydrogenation of 1o
2 | J. Name., 2012, 00, 1-3
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Table 3 Asymmetric transfer hydrogenations of quinolines and “Fundamental
Research
Funds
for
the
Central
1,4-benzoxazine derivativesa,b
University”(HIT.BRETIV.201502), the NSFC (21202027), the
NCET (NCET-12-0145), Open Project Program of Hubei Key
Laboratory of Drug Synthesis and Optimization, Jingchu
University of Technology (No.OPP2015ZD01), and the
“Technology Foundation for Selected Overseas Chinese Scholar”
of Ministry of Human Resources and Social Security of China
(MOHRSS).
Notes and references
1
2
D. W. Stephan, Acc. Chem. Res., 2015, 48, 306.
D. W. Stephan and G. Erker, Angew. Chem. Int. Ed., 2015, 54
6400.
,
3
4
5
S. J. Geier and D. W. Stephen, J. Am. Chem. Soc., 2009, 131,
3476.
G. Erős, H. Mehdi, I. Pápai, T. A. Rokob, P. Király, G. Tárkányi
and T. Soós, Angew. Chem. Int. Ed., 2010, 49, 6559.
D. W. Stephan, S. Greenberg, T. W. Graham, P. Chase, J. J.
Hastie, S. J. Geier, J. M. Farrell, C. C. Brown, Z. M. Heiden, G.
C. Welch and M. Ullrich, Inorg. Chem., 2011, 50, 12338.
6
7
G. Erős, K. Nagy, H. Mehdi, I. Pápai, P. Nagy, P. Király, G.
Tárkányi and T. Soós, Chem. Eur. J., 2012, 18, 574.
L. D. Curless, E. R. Clark, J. J. Dunsford and M. J. Ingleson,
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a More details please see Supporting Information. b Yield of isolated
product. c The ee values were determined by HPLC. d Reactions
were treat with additive (1 equiv of 4-morpholinopyridine).
8
9
Z. Zhang and H. Du, Angew. Chem. Int. Ed., 2015, 54, 623.
S. J. Geier, P. A. Chase and D. W. Stephan, Chem. Commun.,
2010, 46, 4884.
were optimized to improve the enantioselectivity (Table S1, S2
in the Supporting Information). Under the optimal reaction
conditions, a variety of 2-substituted quinolines and 1,4-
benzoxazine derivatives were examined for the asymmetric
transfer hydrogenations. As shown in the Table 3, all of these
10 V. Sumerin, K. Chernichenko, M. Nieger, M. Leskelä, B.
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reactions proceeded smoothly to give the desired products 2a
,
2o−2u in 65−81% yields with 8−29% ee. It is worth menꢀoning
that biologically active tetrahydroquinoline alkaloids 2t and 2u
were obtained with 29% ee and 24% ee, respectively.
Subsequently, we also investigated other catalysts, such as
quinine and chinchonine. Although, high enantioselectivities
were not observed, this result presented here confirmed the
feasibility and potential of developing FLPs/chiral ligands
mediated asymmetric hydrogenations of N-heterocycles.
15 G. T. Beng, R. Meesala, M. N. Mordi and S. M. Mansor, Synth.
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a wide range of N-heterocycles were
17 L. Greb, S. Tamke and J. Paradies, Chem. Commun., 2014, 50
2318.
,
successfully reduced to corresponding products with ammonia
borane by FLPs, which provided a promising and practical
method for the transition-metal-free transfer hydrogenations.
In contrast to the FLPs-catalyzed hydrogenations with H2, the
B(C6F5)3/NH3•BH3 system successfully avoids use of high
pressure H2, and this finding provides a new approach for
hydrogenation of unsaturated nitrogen-containing compounds.
Moreover, enantioselectivities for some N-heterocycles were
primarily investigated, affording up to 29% ee.
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The work was financially supported by the “Hundred Talents
Program” of Harbin Institute of Technology (HIT), the
21 H. Berke, ChemPhysChem, 2010, 11, 1837.
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A transition-metal-free method for the B(C6F5)3-promoted hydrogenations of N-heterocycles
using ammonia borane under mild reaction conditions has been developed.