A highly efficient Pd-C catalytic hydrogenation of pyridine nucleus under mild conditions

Article abstract of DOI:10.1016/j.tet.2009.08.011

A synergistic Pd-C catalytic hydrogenation of 4-pyridinecarboxamides straightforward to 4-piperidinecarboxamide hydrochlorides was developed in the presence of ClCH₂CHCl₂. It provided a novel strategy for highly efficient hydrogenati

Full text of DOI:10.1016/j.tet.2009.08.011

Tetrahedron 65 (2009) 8538–8541
Contents lists available at ScienceDirect
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journal homepage: www.elsevier.com/locate/tet
A highly efficient Pd–C catalytic hydrogenation of pyridine
nucleus under mild conditions
*
*
Chuanjie Cheng, Jimin Xu, Rui Zhu, Lixin Xing, Xinyan Wang , Yuefei Hu
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 June 2009
Received in revised form 3 August 2009
Accepted 6 August 2009
Available online 11 August 2009
A synergistic Pd–C catalytic hydrogenation of 4-pyridinecarboxamides straightforward to 4-piper-
idinecarboxamide hydrochlorides was developed in the presence of ClCH2CHCl2. It provided a novel
strategy for highly efficient hydrogenation of pyridine nuclear by using low-cost Pd–C catalyst under
mild conditions.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Hydrogenation
Pyridine nucleus
Pyridinecarboxamides
Piperidinecarboxamide
1. Introduction
advanced into phase II clinical trials as a platelet GP IIb/IIIa antag-
onist with potential to become an oral antithrombotic drug.3
In recent years, piperidinecarboxamides have been gaining in-
creasing importance because they have been recognized as key
pharmacophores in drug discoveries. As shown in Chart 1, the
clinical candidate TAK 220 (1) is a small-molecule CCR5 antagonist,
part of the new class of anti-HIV-1 entry inhibitors.1 BMS-387032
(2), a novel cyclin-dependent kinase 2 inhibitor, is currently in
phase I clinical trials for anticancer therapy.2 Elarofiban (3) has
In our recent project on chemical biology, a variety of 4-piper-
idinecarboxamides (4) were designed as key synthetic precursors.
The investigation showed that they were mainly derived from
4-piperidinecarboxylates by a standard four-step route. As shown
in Scheme 1, this route associated with two extra steps for the
protection and deprotection of the amine group,2,3a,4 even for the
preparation of the most simple 4-piperidinecarboxamide (4a).4c
Although many 4-pyridinecarboxamides (5) are commercially
available products and the catalytic hydrogenation is characterized
by economy, convenience, and environment-friendship, the pre-
paration of 4 by catalytic hydrogenation of 5 in laboratory scale
under mild conditions was an inefficient process, even though the
expensive Pt5 or Rh6 catalysts were employed.
O
O
N
N
NH2
Me
N
N
O
S
Cl
Me
O
TAK 220 (1)
CO2Et
CO2Et
CO2H
CONH2
CONH2
H
N
N
OH
iii
i
ii
iv
HN
S
O
O
O
N
H
N
Boc
N
Boc
N
Boc
N
H
O
HN
N
N
4a
t
Bu
N
H
BMS-387032 (2)
Elarofiban (3)
Scheme 1. Conditions: (i) Boc2O, Et3N; (ii) aq NaOH; (iii) ClCO2iBu, N-methyl-
morpholine, aq NH3; (iv) 4.0 M HCl–EtOAc.
Chart 1.
This problem clearly arose from the fact that the catalyst is
deactivated by the coordination of the metal with the ring nitrogen
of pyridine or piperidine.7 It is well known that the formation of
pyridine salt can completely block the coordination ability of the
* Corresponding authors. Tel.: þ86 10 62795380; fax: þ86 10 62771149.
E-mail addresses: wangxinyan@mail.tsinghua.edu.cn (X. Wang), yfh@mail.
tsinghua.edu.cn (Y. Hu).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.011

C. Cheng et al. / Tetrahedron 65 (2009) 8538–8541
8539
nitrogen and further polarize the pyridine nucleus. As shown in
O
O
Pd-C, H2, ClCH2CHCl2, MeOH
atmospheric pressure, rt
?
R
R
Scheme 2, Adams in 1928 had proved that the pre-formed pyridine
hydrochloride can be hydrogenated directly into piperidine
hydrochloride under extremely mild conditions.8,9 Unfortunately,
4-pyridinecarboxamide hydrochlorides (5$HCl) were rarely used
for this purpose. When we tried to prepare 5$HCl by treatment of 5
with saturated solution of HCl in dry Et2O, we found that it seri-
ously suffered from the poor yields caused by the highly hygro-
scopic properties of those salts.
N
N
R1
N
R1
.
4 HCl
.
NH HCl
5
O
Chemoselective
Pd-Catalyzed
Hydrodechlorination
Highly Efficient
Pd-Catalyzed
Hydrogenation
R
N
R1
N HCl
.
.
5 HCl
Scheme 4.
PtO2 (3 wt%), H2 (1 atm)
Anhydr. EtOH, rt, 10 h
the hydrogenation proceeded in a saturated HCl solution of MeOH
because Pd–C catalyst was completely poisoned within 3 min
(entry 4). To our delight, the desired product 4b$HCl was obtained
as a single product in 99% isolated yield in the presence of
ClCH2CHCl2 (entry 5). This result coincided with that obtained by
using 5b$HCl as a substrate (entry 6).
no reaction in our hands
N
NH
Sat. HCl in Et2O
87%
PtO2 (3 wt%), H2 (1 atm)
Anhydr. EtOH, rt, 1 h
100%
.
.
N HCl
NH HCl
Table 1
Scheme 2.
A highly efficient hydrogenation of 5b into 4b$HCl
O
Herein, we report a novel synergistic Pd–C catalytic hydroge-
nation of 5 straightforward to 4$HCl, in which the key in-
termediates 5$HCl were formed stoichiometrically in situ during
the hydrogenation. By using this method, a series of desired
products 4$HCl were prepared efficiently from 5 under mild con-
ditions in a single flask.
n
Bu HN
10% Pd-C, H2 (1 atm), MeOH, rt
O
N
5b
O
n
Bu HN
.
5b HCl
n
Bu HN
.
4b HCl
+
.
.
NH HCl
N HCl
Yieldb
[%]
2. Results and discussion
Entry Substrate Pd–C Additive
[wt %] [equiv]
Time Ratio of
[h] productsa
Pd–C is the most often used palladium-based catalyst with ad-
vantages of commercial availability, low cost, and easy re-
generation. Comparing with Pt and Rh catalysts, it was a low active
catalyst for the hydrogenation of pyridine nucleus and was rarely
used for this purpose.10 However, it is the most preferred catalyst of
the hydrodechlorination, by which the C–Cl bonds in organo-
chlorides can be cleaved to release HCl.11 In practice, a base (in-
organic bases or tertiary amines) was employed as both promoter
and HCl acceptor in this conversion.12 In our recent study,13 a novel
Pd–C catalytic hydrodechlorination of ClCH2CHCl2 was developed
under mild conditions in the presence of a tertiary benzylamine. As
shown in Scheme 3, it is an amine-controlled highly chemo-
selective process and an exactly equimolar amount of HCl was
produced based on the amine.13
1
2
3
4
5
6
5b
5b
5b
5b
5b
5b$HCl
40
10
10
10
10
10
None
None
15
11
5b:4b¼16:84
5b:4b¼66:34
98
97
37% aq HCl (1.0) 11
Satd HCl in MeOH 15
ClCH2CHCl2 (1.2) 10
5b$HCl:4b$HCl¼60:40 96
5b$HCl:4b$HCl¼100:0 99
5b$HCl:4b$HCl¼0:100 99
None
9.5 5b$HCl:4b$HCl¼0:100 99
a
The ratio was determined by 1H NMR.
Isolated yield was obtained.
b
Thus, a novel synergistic Pd–C catalyzed highly efficient hy-
drogenation of 5b into 4b$HCl was achieved at room temperature
and atmospheric pressure. To the best of our knowledge, this is the
first procedure for highly efficient hydrogenation of pyridine nu-
cleus by Pd–C catalyst under mild conditions. Since 4b$HCl was
obtained as a crystal product, the work-up procedure was as simple
as a filtration.
10% Pd-C (5 wt%), H2 (1 atm)
ClCH2CHCl2, MeOH, rt, 40 min
Table 2
.
Me2NH HCl
PhCH2NMe2
100% conversion
A highly efficient hydrogenation of 5k into 4k$HCl
O
Scheme 3.
10% Pd-C, H2, MeOH, ClCH2CHCl2
Et2N
Thus, an in situ formation of 5$HCl can be expected when 5 is
used as a base in the Pd–C catalytic hydrodechlorination of
ClCH2CHCl2, by which the pyridine nucleus in 5$HCl is polarized to
be more liable to catalytic hydrogenation. Therefore, we may fur-
ther expect that a Pd–C catalytic hydrogenation of 5$HCl will pro-
ceed to directly yield 4$HCl in a single flask (Scheme 4).
To prove our hypothesis, N-butyl-4-pyridinecarboxamide (5b)
was used as a model substrate for the control experiments. As
shown in Table 1, by using 40 wt % of Pd–C catalyst under the
conventional conditions, 5b was hydrogenated for 15 h to give
N-butyl-4-piperidinecarboxamide (4b) in 84% selectivity as a mix-
ture (entry 1). When the loading of Pd–C catalyst was reduced to
10 wt %, the same hydrogenation stopped after 11 h to give 4b in
34% selectivity (entry 2). By addition of 1 equiv of aq HCl (37% so-
lution), a minor improvement was observed (entry 3). It was not
surprised that 5b was quantitatively converted into 5b$HCl when
N
5k
O
O
Et2N
.
5k HCl
Et2N
.
4k HCl
+
.
.
NH HCl
N HCl
Entry Pd–C Pressure
[wt %]
Temperature Time Product ratioa
Yieldb
[ꢀC]
[h]
5k$HCl:4K$HCl [%]
1
2
3
4
5
6
7
10
10
10
10
10
25
50
Atmospheric 25
13
16
15
23
10
17
6
16:84
96
97
99
99
99
99
99
40 psi
50 psi
25
25
4:96
00:100
00:100
00:100
00:100
00:100
Atmospheric 35
Atmospheric 25
Atmospheric 25
Atmospheric 45
The ratio was determined by 1H NMR.
Isolated yield was obtained.
a
b

8540
C. Cheng et al. / Tetrahedron 65 (2009) 8538–8541
However, when N,N-diethylpyridinecarboxamide (5k) was used
To determine the scope and generality of this novel method,
different pyridinecarboxamides (5a–r) were tested with 25 wt % of
Pd–C catalyst under atmospheric pressure (Condition A) or with
10 wt % of Pd–C catalyst under 50 psi hydrogen pressure (Condition
B). As shown in Table 3, 5a–r were hydrogenated into the corre-
sponding piperidinecarboxamide hydrochlorides (4a–r$nHCl) in
practically quantitative yields (entries 1–18). It was clearly observed
that N-monosubstituted amides (5a–j) (entries 1–10) showed much
higher reactivity than N,N-disubstituted amides (5k–p) (entries 11–
16). It was noteworthy that the hydroxyl group stayed intact (entry
6) and the N-benzyl amide tolerated the conditions (entry 8). When
the products with two amino groups, the corresponding dihydro-
chlorides (4e$2HCl and 4o$2HCl) were formed automatically by
as a substrate under the similar conditions, 4k$HCl was obtained as
a mixture in 84% selectivity (Table 2, entry 1). This result may be
caused by the fact that the electron-withdrawing ability of amide
group was decreased by the secondary amine. Thus, the hydroge-
nation was optimized by varying the pressure, temperature, or
catalyst loading. As shown in Table 2, 4k$HCl was obtained as
a single product in 99% yield by simply elevating the pressure
(50 psi, entry 3) or the temperature (35 ꢀC, entry 4). However, for
the consideration of convenient performances in laboratory con-
ditions, we preferred to increase the catalyst loading. Thus, a very
satisfactory result was achieved at room temperature and atmo-
spheric pressure by using 25 wt % of Pd–C catalyst (entry 6).
Table 3
Synergistic catalytic hydrogenation of 5a–r to 4a–r$nHCla
Condition A or Condition B
.
4a-r nHCl
5a-r
Entry
1
Product [4$nHCl]
Timeb [h]
Yieldc [%]
Entry
10
Product [4$nHCl]
Timeb [h]
13(14)
Yieldc [%]
99(98)
O
O
NH2
N
H
11(10)
98(98)
.
.
HCl HN
.
(4a HCl)
HCl HN
.
(4j HCl)
OMe
O
O
O
O
N
H
N
N
N
2
3
5(4)
8(7)
99(98)
99(98)
11
12
17(15)
16(14)
96(96)
99(98)
.
.
HCl HN
.
(4b HCl)
HCl HN
.
(4k HCl)
O
N
H
.
.
HCl HN
.
(4c HCl)
HCl HN
.
(4l HCl)
O
N
4
5
6
7(10)
12(10)
8(7)
96(96)
99(99)
98(97)
13
14
15
16(14)
17(22)
35(26)
98(98)
99(97)
99(98)
H
.
.
HCl HN
.
(4d HCl)
HCl HN
.
(4m HCl)
O
O
.
N
HCl
N
N
H
.
.
HCl HN
.
(4e 2HCl)
HCl HN
.
(4n HCl)
O
O
OH
N
H
N
O
.
.
.
N HCl
HCl HN
.
(4f HCl)
HCl HN
.
(4o 2HCl)
O
N
N
7
8
9(12)
97(97)
16
20(18)
96(96)
H
.
.
HCl HN
.
(4p HCl)
O
HCl HN
.
(4g HCl)
O
O
Bn
.
N
H
HCl HN
NH2
9(7)
5(6)
98(95)
98(97)
17
18
21(19)
46(40)
95(96)
99(98)
.
HCl HN
.
(4h HCl)
.
(4q HCl)
O
O
.
HCl HN
N
N
H
9
.
HCl HN
.
(4i HCl)
.
(4r HCl)
a
Condition A: 10% Pd–C (25 wt %), H2 (1 atm), ClCH2CHCl2 (1.2 equiv) in MeOH at room temperature. Condition B: 10% Pd–C (10 wt %), H2 (50 psi), ClCH2CHCl2 (1.2 equiv) in
MeOH at room temperature.
b
The number in the parenthesis is for Condition B.
The isolated yield was obtained.
c

C. Cheng et al. / Tetrahedron 65 (2009) 8538–8541
8541
using double amount of ClCH2CHCl2 (entries 5 and 15). Two ex-
Acknowledgements
amples of 3-pyridinecarboxamides (5q–r) were also tested and they
worked well but with longer reaction time in comparison with their
4-substituted counterparts (entries 17 and 18). Unfortunately, 2-
pyridinecarboxamide did not undergo a hydrogenation under our
conditions. Finally, the hydrogenation of the parent compound
pyridine was tested under the Condition A. We observed that there
was no absorption of hydrogen in the absence of ClCH2CHCl2, while
96% isolated yield of piperidine hydrochloride was obtained in the
presence of ClCH2CHCl2 in 23 h. These results further indicated that
ClCH2CHCl2 is essential for this novel hydrogenation and the elec-
tron-withdrawing group substituted on the pyridine ring benefited
rate of the hydrogenation.
This work was supported by NNSFC (30600779, 20672066) and
by the Cultivation Fund of the Key Scientific and Technical In-
novation Project, Ministry of Education of China (706003).
Supplementary data
Experimental procedures and full spectroscopic data for 4a–r$
nHCl are given in the Supplementary data. Supplementary data
associated with this article can be found in the online version, at
doi: 10.1016/j.tet.2009.08.011.
References and notes
3. Conclusions
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In conclusion, a highly efficient catalytic hydrogenation of pyr-
idinecarboxamides (5) to piperidinecarboxamide hydrochlorides
(4$HCl) was developed. This novel method in fact is a synergistic
catalytic process, in which the initial Pd–C catalytic hydro-
dechlorination ofClCH2CHCl2 waspromoted by pyridinecarboxamide
(5) to chemoselectively release HCl. Then, pyridinecarboxamide as an
HCl acceptor captured HCl molecule to form the corresponding hy-
drochloride (5$HCl), by which the coordination ability of nitrogen in
pyridine ring was blocked and the pyridine nucleus was polarized.
Finally, pyridinecarboxamide hydrochloride (5$HCl) was hydroge-
nated to the corresponding piperidinecarboxamide hydrochloride
(4$HCl). It provided a novelstrategyforhighlyefficient hydrogenation
of pyridine nucleus by Pd–C catalyst under mild conditions. Since the
key intermediate 5$HCl and the target product 4$HCl were formed in
situ during the hydrogenation in a single flask, the method proceeded
with extremely convenient performance and work-up procedures.
4. Experimental section
4.1. General
4.1.1. A typical procedure for the preparation of N-butyl-4-piper-
idinecarboxamide hydrochloride (4b$HCl). The suspension of N-butyl-
4-pyridinecarboxamide (5b, 178 mg, 1.0 mmol), 10% Pd–C (44.5 mg,
25 wt %), and ClCH2CHCl2 (160 mg, 1.2 mmol) in MeOH (30 mL) was
hydrogenated (on an atmospheric pressure hydrogenator) at room
temperature until the absorption of hydrogen ceased (5 h). After the
Pd–C catalyst was filtered off, solvent was removed on a rotavapor.
The residue was diluted with diethyl ether (10 mL) and 4b$HCl
(220 mg, 99%) was collected as a white crystal by filtration. Usually,
the product was pure enough for any analytical purposes.
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It had mp 106–108 ꢀC (MeOH–Et2O); IR:
n 3353, 3180, 2937,
3.44–3.39 (m, 2H), 3.12–3.07 (m, 2H), 3.04–
1666 cmꢁ1; 1H NMR:
d
2.99 (m, 2H), 2.59–2.50 (m, 1H), 1.99–1.93 (2H), 1.87–1.72 (m, 2H),
1.42–1.37 (m, 2H), 1.26–1.21 (m, 2H), 0.80 (t, 3H, J¼7.22); 13C NMR:
d
175.9, 43.2 (2C), 40.0, 39.1, 30.6, 25.2 (2C), 19.5, 13.2; MS m/z (%):
84 (100); calcd for C10H21ClN2O: C, 54.41; H, 9.59; N, 12.69; found:
C, 54.28; H, 9.67; N, 12.51.
The similar procedure was used to convert the substrates 5a–r
efficiently to the corresponding products 4a–r$nHCl.
13. Cheng, C.; Sun, J.; Xing, L.; Xu, J.; Wang, X.; Hu, Y. J. Org. Chem. 2009, 74, 5671–5674.