An efficient palladium-catalyzed synthesis of 1-heteroaryl-4-aminopiperidine derivatives from heteroaryl chlorides

Article abstract of DOI:10.1016/j.tetlet.2017.04.014

An efficient protocol for the synthesis of 1-heteroaryl-4-(N-methyl)aminopiperidines starting from heteroaryl chloride derivatives is described. A broad range of 1-heteroaryl-4-(N-Boc-N-methyl)aminopiperidine derivatives were obtained in good to excellent

Full text of DOI:10.1016/j.tetlet.2017.04.014

Accepted Manuscript
An Efficient Palladium-Catalyzed Synthesis of 1-Heteroaryl-4-aminopiperidine
Derivatives from Heteroaryl Chlorides
Kena Zhang, Hui Li, Jingya Li, Dapeng Zou, Yangjie Wu, Yusheng Wu
PII:
S0040-4039(17)30441-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.04.014
TETL 48806
Reference:
Tetrahedron Letters
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Revised Date:
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2 April 2017
4 April 2017
Please cite this article as: Zhang, K., Li, H., Li, J., Zou, D., Wu, Y., Wu, Y., An Efficient Palladium-Catalyzed
Synthesis of 1-Heteroaryl-4-aminopiperidine Derivatives from Heteroaryl Chlorides, Tetrahedron Letters (2017),
doi: http://dx.doi.org/10.1016/j.tetlet.2017.04.014
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An Efficient Palladium-Catalyzed Synthesis
of 1-Heteroaryl-4-aminopiperidines
Derivatives from Heteroaryl Chlorides
Kena Zhang, Hui Li, Jingya Li, Dapeng Zou∗, Yangjie Wu∗, Yusheng Wu∗

1
Tetrahedron Letters
journal homepage: www.els evier.com
An Efficient Palladium-Catalyzed Synthesis of 1-Heteroaryl-4-aminopiperidine
Derivatives from Heteroaryl Chlorides
Kena Zhang a, Hui Li a, Jingya Li b, c, Dapeng Zou a, b ∗, Yangjie Wu a ∗, Yusheng Wu b, d
∗
a The College of Chemistry and Molecular Engineering, Zhengzhou University, Zhengzhou, 450052, PR China.
b Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, PR China.
c Tetranov Biopharm, LLC., No.75 Daxue Road, Zhengzhou, 450052, PR China.
d Tetranov International, Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA.
ARTICLE INFO
ABSTRACT
Article history:
Received
An efficient protocol for the synthesis of 1-heteroaryl-4-(N-methyl)aminopiperidines starting
from heteroaryl chloride derivatives is described. A broad range of 1-heteroaryl-4(N-Boc-N-
methyl)aminopiperidine derivatives were obtained in good to excellent yields using DavePhos as
optimal ligand for Pd-catalyzed Buchwald-Hartwig amination reaction. After a mild and
efficient acidolysis the amination products could be obtained successfully.
Received in revised form
Accepted
Available online
Keywords:
2016 Elsevier Ltd. All rights reserved.
1-pyridyl-4-aminopiperidine
Buchwald-Hartwig amination
heteroaryl chlorides
Introduction
H
N
N
N
N
F
F
Small nitrogen-containing heterocycles are highly desirable
structural motifs, which can provide beneficial attributes when
installed within molecules and they are widely used in
pharmaceutical industries. 1 Among all these nitrogen-containing
moieties, piperidine is ranked as the most frequent nitrogen
F
O
N
N
antiobesity
N
NH
N
2
heterocycle in the FDA approved drugs. Due to its special
biological activities, a lot of 1-heteroaryl-4-aminopiperidines-
containing compounds have been used in many kinds of
N
H
N
NC
NH
N
antiproliferative
N
N
Cl
N
N
3a
pharmaceuticals, 3 such as antiobesity, antiretroviral therapy of
human immunodeficiency virus (HIV) and antiproliferative
3b
3c
N
antiretroviral therapy of HIV
(Fig. 1).
Traditional synthesis of 1-hereroaryl-4-aminopiperidines requires
Figure 1. Some pharmaceutical compounds containing N-heteroaryl-
4-aminopiperidine scaffolds.
the appropriate N-heteroaryl-4-piperidinone precursor and
corresponding amine. However, this synthetic strategy suffers
4
from several limitations: (i) the use of the appropriate N-
heteroaryl-4-piperidinone precursor, which requires multiple
synthesis steps; (ii) a narrow range of substrates. Since
Buchwald–Hartwig amination reaction was reported in the late
2000s, it has been playing an important role in the formation of
amination have been dramatically improved. After thorough
search, there are only two patents reporting the synthesis of 1-
heteroaryl-4-aminopiperidine via Buchwald–Hartwig amination
reaction, which both started from heteroaryl bromides. In 2002,
10
Stamford
aminopiperidines using 4-(N-Cbz-N-methyl)aminopiperidine as
firstly reported the synthesis of 1-hereroaryl-4-
5
C-N bonds. During the last decades, with the development of
6
kinds of bulky electron-rich phosphine ligands, N-heterocyclic
3a
the amine source. Instead, Greenlee
synthetic routine regarding 4-(N-Boc-N-methyl)aminopiperidine
reported the similar
7
8
carbenes (NHC) as well as some active precatalysts and
palladacycles 9, the efficiency and scope of Buchwald–Hartwig
as the amine source.
∗ Corresponding author. Tel.: +1 732 253 7326; fax: +1 732 253 7327; e-mail: yusheng.wu@tetranovglobal.com, zdp@zzu.edu.cn,
wyj@zzu.edu.cn

2
Tetrahedron
As we know, organic chlorides are one of the most attractive
carbon electrophiles, because they are readily available with
mL) at 120˚C in the presence of t-BuONa (1.2 mmol), Pd(OAc)2
(0.05 mmol) and CyJohnPhos (0.05 mmol) for 12 hours under
argon atmosphere, the desired product 3 was obtained in 86%
yield detected by HPLC analysis (Table 1, entry 1). Firstly,
different ligands including the mono- and bi- dentate ligands
(Table 1, entries 1-8) were tested, and DavePhos gave a better
yield (90 %, Table 1, entry 2). Secondly, when replacing
Pd(OAc)2 with other palladium precursors, such as PdCl2 or
Pd(acac)2, the yields dropped to 86% and 78% respectively
(Table 1, entries 9 and 10). Interestingly, the yield increased to
95% when reducing the catalyst loading to 3 mol% (Table 1,
entry 11). Increasing or lowering the amount of the ligand did not
improve the yield (Table 1, entries 12 and 13). Next, when a
series of bases such as t-BuOK, K3PO4, Cs2CO3, NaOH and Et3N
were screened, t-BuONa proved to be the optimal base. The use
of polar aprotic solvents, such as NMP or DMA reduced the yield
dramatically (Table 1, entries 21-23). Toluene was found to be
better compared with dioxane (Table 1, entry 20). Finally, the
reaction temperature and time were tested at last. The best yield
was obtained under 120 °C for 12 hours (Table 1, entries 24-27).
Thus, after a series of experimentations, the optimum reaction
conditions was obtained as 1.0 mmol 3-chloropyridine and 1.3
mmol 4-(N-Boc-N-methyl)aminopiperidine stirring in 3 mL
toluene under argon atmosphere at 120 °C in the presence of
0.03 mmol Pd(OAc)2, 0.03 mmol DavePhos, 1.2 mmol t-BuONa
for 12 hours.
11
various substrates and cheap on industrial scale.
research work has been done for the activation of the C–Cl bond
Plenty of
12
to enable efficient coupling with various organic compounds.
Some remarkable success in the cross-coupling of aryl chlorides
with various amines have been made as well. 13 Herein we aimed
to seek after a more convenient and efficient method to obtain the
1-hereroaryl-4-aminopiperidines starting from heteroaryl
chlorides.
Results and discussion
To optimize the reaction conditions, the nonsubstrated 3-
chloropyridine (1) was chosen as the electrophile. 4-(N-Boc-N-
methyl)aminopiperidine (2) was used as the amine source,
because it could avoid the regioselectivity of the activation of the
N-H bond and the deprotection group of Boc was easy-handled.
The results were shown in Table 1.
Table 1. Screening of reaction conditions for the cross-coupling
of 3-chloropyridine with 4-(N-Boc-N-methyl)aminopiperidine a
With the optimized reaction condition in hand, the coupling
reactions between 3-chloropyridine derivatives and 4-(N-Boc-N-
methyl)aminopiperidine were carried out to explore the scope of
this catalytic system, and the results were summarized in Table 2.
It could be noted that most reactions proceeded smoothly to
provide the corresponding products in moderate to good yields.
Pd Source
(mol %)
Ligand (mol
%)
Yield b
(%)
Entry
1
Base
Solvent
toluene
CyJohnPhos
(5)
Pd(OAc)2 (5)
t-BuONa
86(79c)
2
3
Pd(OAc)2 (5) DavePhos (5)
Pd(OAc)2 (5) S-Phos (5)
Pd(OAc)2 (5) X-Phos (5)
Pd(OAc)2 (5) RuPhos (5)
Pd(OAc)2 (5) XantPhos (5)
Pd(OAc)2 (5) BINAP (5)
Pd(OAc)2 (5) dppf (5)
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuOK
Cs2CO3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dixoane
NMP
90
87
4
83
Table 2. The coupling reaction of 4-(N-Boc-N-
methyl)aminopiperidine and 3-chloropyridine derivativesa
5
86
6
40
7
32
8
10
9
PdCl2 (5)
DavePhos (5)
86
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24d
25e
26f
27g
Pd(acac)2 (5) DavePhos (5)
Pd(OAc)2 (3) DavePhos (3)
Pd(OAc)2 (3) DavePhos (6)
Pd(OAc)2 (3) DavePhos (1)
Pd(OAc)2 (3) DavePhos (3)
Pd(OAc)2 (3) DavePhos (3)
Pd(OAc)2 (3) DavePhos (3)
Pd(OAc)2 (3) DavePhos (3)
Pd(OAc)2 (3) DavePhos (3)
Pd(OAc)2 (3) DavePhos (3)
Pd(OAc)2 (3) DavePhos (3)
Pd(OAc)2 (3) DavePhos (3)
Pd(OAc)2 (3) DavePhos (3)
Pd(OAc)2 (3) DavePhos (3)
Pd(OAc)2 (3) DavePhos (3)
78
95(90c)
Entry
1
Substrate
Product
Yield (%)
90
93
Boc
N
65
82
N
65
N
NEt3
n.d.
7
Boc
K3PO4
N
K2CO3
n.d.
trace
71
N
2
91
NaOH
N
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
t-BuONa
13
DMA
34
3
4
5
76
87
88
DMF
12
toluene
toluene
toluene
toluene
91
Pd(OAc)2 (3)
DavePhos (3)
88
Pd(OAc)2 (3) DavePhos (3)
Pd(OAc)2 (3) DavePhos (3)
95
88
a
1.0 mmol 3-chloropyridine, 1.3 mmol 4-(N-Boc-N-methyl)aminopiperidine,
1.2 mmol base, 3 mL solvent, 120 °C, 12 h, argon atmosphere.
b Yields determined by HPLC. c Isolated yield.
d 110 °C. e 130 °C. f 14 h. g 10 h.
When 3-chloropyridine (1.0 mmol) and 4-(N-Boc-N-
methyl)aminopiperidine (1.3 mmol) was treated in toluene (3

3
the two N-H bonds of PhHN- and the starting material of 2; (ii)
the formation of palladium chelate compound with the starting
material which inhibited the catalytic activity. However the 5-
position substrate gave 15 % yield of the desired product which
was quite lower than the other substrates, but better than that on
the 2- or 6-position (Table 2, entries 7-9). Further study on the
effect of the position of functional group indicated that the
position of the group on the 3-chloropyridine also influenced the
efficiency of coupling reaction. Compared with the group on the
para-position, the yield of the ortho-position product (Table 2,
entries 10-14) decreased to some degree due to the steric
hindrance. Functional group compatibility was further explored
to determine the tolerance of these substituents in the outlined
reaction conditions. Substrates possessing whether an electron-
donating or electron-withdrawing group at the meta- position
were coupled successfully with the amine to afford the products
in moderate to very good yields (Table 2, entries 15-17).
6
70
7
8
trace
trace
15
9
Interestingly, 2,3-dichloro-5-(trifluoromethyl)pyridine was
transferred to its corresponding amination product in 63% yield
and there was only one product which reacted on the 2-position
(Table 3, entry 1). Inspired by this phenomenon, we next turned
our attention towards the synthesis of 2-substituted amination
product to test our synthetic methodology. The results were
summarized in Table 3. As could be seen, the unsubstituted 2-
chloropyridine gave the corresponding product in good yield
85% (Table 3, entry 2). The high yields were also acquired as to
either electron-donating group methyl or electron-withdrawing
group trifluoromethyl substituted 2-chloropyridine derivatives
(Table 3, entries 3-5). Unfortunately, the substrate of 2-chloro-3-
methyl-5-nitropyridine gave the expected product in a quite low
yield (Table 3, entry 6). To further extend the reaction scope, the
coupling reactions of 4-(N-Boc-N-methyl)aminopiperidine with
4-chloropyridine hydrochloride and other N-heteroaryl chlorides
were also researched under the optimized conditions. In case of
4-chloropyridine hydrochloride, 50% yield was obtained (Table
3, entry 7). Moreover, 3-chloroquinoline, 4-chloroquinoline and
2-chloropyrazine afforded the corresponding products in 80%,
60% and 80% yield respectively (Table 3, entries 8-10). We also
checked the applicability of 3-bromoquinoline, and found they
also proceeded successfully (Table 3, entry 11).
10
11
12
66
77
84
13
14
trace
89
Table 3.
The coupling reaction of
4-(N-Boc-N-
methyl)aminopiperidine with other N-heteroaryl chloridesa
15
16
17
80
93
91
Entry
1
Substrate
Product
Yield (%)
63
a Reaction conditions: 1.0 mmol 3-chloropyridine derivatives, 1.3 mmol 4-(N-
Boc-N-methyl)aminopiperidine, 3 mol% Pd(OAc)2, 3 mol% DavePhos, 1.2
mmol t-BuONa, 3 mL toluene, 120 °C, 12 h, argon atmosphere, isolated
yields.
2
3
85
89
A wide variety of functional groups including cyclopropyl,
alkoxy, and N, N-dimethylamino afforded the desired products in
moderate to good yields (Table 2, entries 2-6). While the group
of N-phenylamino was an exception, the corresponding product
could only be obtained in trace yield (Table 2, entry 7). We
speculated there were two reasons: (i) the competition between

4
Tetrahedron
process is quite easy, efficient and suitable for many kinds of
substitutes. Thus, the simplicity of this short and clean procedure
and generally satisfactory yields render this method particularly
attractive which will provide a convenient alternative and useful
methodology in developing complex piperidine scaffolds of
biological and pharmaceutical interest.
4
5
82
84
Acknowledgments
We are grateful to the Natural Science Foundation of China
(21172200), Research Program of Fundamental and Advanced
Technology of Henan Province (122300413203), and
Technology Research and Development Funds of Zhengzhou
(141PRCYY516) for financial support.
6
30
References and notes
7 b
50
80
60
80
83
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Schramm, V. L.; Tyler, P. C. J. Med. Chem. 2008, 51, 948-956; b)
Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108, 3988-
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Rev. 2010, 39, 4402-4421 d) Horton, D. A.; Bourne, G. T.; Smythe,
M. L. Chem. Rev. 2003, 103, 893-930.
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2. Vitaku, E.; Smith, D. T.; Njardarson, J. T. J. Med. Chem. 2014, 57,
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3. a) Greenlee, W. J.; Huang, Y.; Kelly, J. M.; Mccombie, S. W.;
Stamford, A. W.; Wu, Y. U.S. 20030114517A1, 2003; b)
Brotherton-Pleiss, C. E.; Kertesz, D. J.; Yang, M. WO 2008071587,
2008; c) Coates, D. A.; Gelbert, L. M.; Knobeloch, J. M.; Magana,
A. D. D.; Gonzalez, A. D. P.; Catalina, M. F. D. P.; Herranz, A. I.
M. U.S. 20100160340, 2010.
9
Boc
N
4. Imaeda, Y.; Miyawaki, T.; Sakamoto, H.; Itoh, F.; Konishi, N.;
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N
N
N
5. Ruiz-Castillo, P.; Buchwald, S. L. Chem. Rev. 2016, 116, 12564-
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Chem. Int. Ed. 2002, 114, 3820-3823.
a
Reaction conditions: 1.0 mmol chloride derivatives, 1.3 mmol 4-(N-Boc-N-
methyl)aminopiperidine, 3 mol% Pd(OAc)2, 3 mol% DavePhos, 1.2 mmol t-
BuONa, 3 mL toluene, 120 °C, 12 h, argon atmosphere, isolated yields. b
Starting from 4-chloropyridine hydrochlodide, and 2.4 mmol t-BuONa was
used.
10. Stamford, A. W.; Dong, Y. H.; Mc Combie, S. W. WO
2002049648, 2002.
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2413-2416; b) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald,
S. L. J. Am. Chem. Soc. 1999, 121, 9550-9561; c) Pickett, T. E.;
Richards, C. J. Tetrahedron Lett. 2001, 42, 3767-3769.
13. a) Urgaonkar, S.; Verkade, J. G. J. Org. Chem. 2004, 69, 9135-
9142; b) Stauffer, S. R.; Lee, S.; Stambuli, J. P.; Hauck, S. I.;
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Lastly, the deprotection process of Boc was also investigated,
and the results were shown in Scheme 1. As we could see, this
simple condition worked well for most kinds of derivatives
whether electron-donating or electron-withdrawing groups to
obtain the desired products in good yields.
Scheme 1. Deprotection process of 1-heteroaryl-4-(N-methyl-N-
Boc)aminopiperidine
Conclusion
In conclusion, an efficient and mild synthetic procedure for
the synthesis of 1-heteroaryl-4-(N-methyl)aminopiperidine
starting from corresponding chloride derivatives was described.
The key amination step proceeded well and most of the coupling
products are obtained in good to excellent yields under the
optimized reaction conditions by using the commercially
available DavePhos as ligand. In addition, the deprotection

5
Highlights
.A facile and efficient strategy for the construction
of 1-heteroaryl-4-aminopiperidine has been
developed.
.A broad range of 1-heteroaryl-4-(N-Boc-N-
methyl)aminopiperidine can be prepared from
relative heteroaryl chlorides.
.The deprotection process is easy-handled and
wide applicability.