Controlling chemoselective transformations of 4-acylpyridines via a Pd-C catalytic hydrodechlorination-hydrogenation

Article abstract of DOI:10.1016/j.tet.2013.12.017

A novel Pd-C catalytic hydrodechlorination-hydrogenation was developed for a multi-step one-pot transformation of 4-acylpyridines. Under the selected conditions, 4-benzoylpyridines and 4-alkanoylpyridines were chemoselectively converted into the corresponding 4-benzylpiperidine hydrochlorides and α-alkyl-4-piperidinemethanol hydrochlorides, respectively. This catalytic method was performed simply by an addition of 1 equiv of ClCH ₂CHCl₂ to the conventional hydrogenation system and directly gave the crystalline piperidine hydrochlorides in practical quantitative yields.

Full text of DOI:10.1016/j.tet.2013.12.017

Tetrahedron 70 (2014) 930e935
Contents lists available at ScienceDirect
Tetrahedron
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Controlling chemoselective transformations of 4-acylpyridines via
a PdeC catalytic hydrodechlorinationehydrogenation
*
*
Chuanjie Cheng, Bo Wang, Nan Liu, Wenwen Chen, Xinyan Wang , Yuefei Hu
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 1 October 2013
Received in revised form 27 November 2013
Accepted 5 December 2013
Available online 13 December 2013
A novel PdeC catalytic hydrodechlorinationehydrogenation was developed for a multi-step one-pot
transformation of 4-acylpyridines. Under the selected conditions, 4-benzoylpyridines and 4-
alkanoylpyridines were chemoselectively converted into the corresponding 4-benzylpiperidine hydro-
chlorides and
a-alkyl-4-piperidinemethanol hydrochlorides, respectively. This catalytic method was
performed simply by an addition of 1 equiv of ClCH2CHCl2 to the conventional hydrogenation system and
directly gave the crystalline piperidine hydrochlorides in practical quantitative yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Chemoselectivity
Palladium
4-Acylpyridines
Hydrodechlorination
Hydrogenation
1. Introduction
prepared starting from 4-benzoylpyridines (5) in a single flask by
a PdeC catalytic hydrogenation.6 Although the hydrogenation
4-Benzylpiperidines (1) have been gaining importance due to
them having been recognized as both key pharmacophores and
intermediates in drug discovery. As shown in Fig.1, many promising
drug candidates contain this structural unit, such as TAK 220 (2),1
ifenprodil (3),2 and eliprodil (4).3
Investigation showed that 4-benzylpiperidines (1) normally
were prepared starting from 4-piperidone4 or 4-methylene-piper-
idine4g,5 by various four-step methods. However, they also could be
method was associated with certain drawbacks related to effi-
ciency, separation, and purification, it represented a streamlined,
inexpensive, and scalable process.
Herein, we report a novel PdeC catalytic hydrodechlorinatione
hydrogenation of 4-acylpyridines. Under the selected pressure or
temperature, the controlling chemoselective transformations were
achieved depending upon the substrate structures. As shown
in Scheme 1, this new catalytic system can be established
simply by adding 1 equiv of ClCH2CHCl2 to the conventional hy-
drogenation system. In a single flask, 4-benzoylpyridines (5) and 4-
alkanoylpyridines (6) were converted into the corresponding
O
O
R
crystalline 4-benzylpiperidine hydrochlorides (1$HCl) and a-alkyl-
4-piperidinemethanol hydrochlorides (7$HCl) in practical quanti-
tative yields.
N
N
NH2
Me
N
NH
O
Cl
4-Benzylpiperidines (1)
TAK 220 (2)
Me
Pd-C, H2 (balloon), MeOH
OH
OH
ClCH2CHCl2, 45 oC, 4-7 h
Ar
N
N
F
NH.HCl
1.HCl
O
R = Ar, 97-99%
Me
OH
Cl
R
Ifenprodil (3)
Eliprodil (4)
N
OH
Pd-C, H2 (40-80 psi), MeOH
ClCH2CHCl2, rt, 4.5-17 h
Fig. 1. 4-Benzylpiperidines (1) and the promising drug candidates 2e4.
5 R = Ar
6 R = Alkyl
Alkyl
R = Alkyl, 97-99%
NH.HCl
7.HCl
* Corresponding authors. Tel./fax: þ86 10 62771149; e-mail addresses: wang-
Scheme 1.
xinyan@mail.tsinghua.edu.cn (X. Wang), yfh@mail.tsinghua.edu.cn (Y. Hu).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.12.017

C. Cheng et al. / Tetrahedron 70 (2014) 930e935
931
2. Results and discussion
8$HCl, 9$HCl, and 10$HCl may be produced when 4-benzoylpyridine
(5)ishydrogenated inthepresenceofClCH2CHCl2. Finally, theywillbe
converted into 4-benzylpiperidine hydrochloride (1$HCl) through
different pathways under mild conditions.
As shown in Scheme 2, the reported hydrogenations6 of 4-
benzoylpyridines (5) in literature have proved to be a three-step
one-pot process: (i) a reduction of the ketone in 5; (ii) a hydro-
genolysis of the CeO bond in 8; (iii) a hydrogenation of the pyridine
nucleus in 9. Since PdeC is a preferred catalyst for the reduction of
aryl ketone and the hydrogenolysis of benzyl alcohol, both step i
and step ii can be carried out smoothly. But, PdeC is a weak catalyst
(compared with Pt-based catalysts) for the hydrogenation of pyri-
dine nucleus in step iii.7 Therefore, development of an efficient
PdeC catalytic hydrogenation of pyridine nucleus is a key issue for
the efficient conversion of 5 into 1.
10% Pd-C (10 wt%), H2 (balloon)
MeOH, rt, 1 h
N
N.HCl
CH2ClCHCl2
CH2ClCH2Cl
99% yield
Deduction
O
Pd-C, H2, MeOH
Ar
Ar
Ar
CH2ClCHCl2
N
NH.HCl
O
OH
5
1.HCl
Ar
Ar
Ar
Ar
i
ii
iii
N
N
N
NH
OH
Ar
OH
5
8
9
1
Ar
Scheme 2.
N.HCl
NH.HCl
9.HCl
N.HCl
8.HCl
10.HCl
It is well known that the N-atoms in the substrate pyridine and
the product piperidine can strongly coordinate with the catalyst to
lead an ineffective hydrogenation of pyridine nucleus.7 However, it
has been well recognized that this problem can be solved easily by
using the isolated pyridine salts as substrates.8 For example, pyridine
hydrochloride can be hydrogenated to give piperidine hydrochloride
in quantitative yield under room temperature and atmospheric
pressure, in which all N-atoms were masked completely as their
amine hydrochlorides. However, this strategy was seldom used9
because preparation of the isolated pyridine salts is a tough task
due to their highly hygroscopic properties.10 Alternatively, the hy-
drogenation of pyridines was typically carried out in the presence of
HOAc, aq HCl or aq H2SO4.11 But low efficiencies were observed in
many cases caused by incomplete formation of pyridine salts, by
which the catalyst could be coordinated by free pyridines and also be
poisoned by free acids. Ideally, the pyridine salts can be formed
stoichiometrically in situ during the catalytic hydrogenation.
Hypothsized Intermediates
Scheme 3.
Thus, 4-benzoylpyridine (5a) was used as a model substrate for
conditional tests. As shown in Table 1, an inseparable mixture was
produced when the suspension of 5a and 10% PdeC (100 wt %) in
MeOH was hydrogenated under the conventional conditions (entry
1). No improvement was observed by addition of aq HCl as an ad-
ditive (entry 2). To our delight, the expected crystalline 1a$HCl was
collected as a single product in 99% yield within 3 h in the presence
of ClCH2CHCl2 (entry 3). The satisfactory result was also obtained
by using 75 wt % of PdeC (entry 4), but a mixture of 1a$HCl and
9a$HCl was obtained by using less than 50 wt % of PdeC (entry 5).
The proportion of 1a$HCl decreased as the amount of PdeC de-
creased (entry 6).
Table 1
Hydrogenation of 5a in the presence of ClCH2CHCl2
OH
O
10% Pd-C, H2 (balloon)
additive, MeOH, rt
+
NH.HCl
NH.HCl
N
5a
9a.HCl
1a.HCl
Entry
10% PdeC
(wt %)
Additive (equiv)
Time
(h)
9a$HCl/1a$HCla
(%)
Yieldb
(%)
1
2
3
4
5
6
100
100
100
75
50
25
None
24
24
3
11
24
40
Inseparable mixture
Inseparable mixture
0:100
0:100
11:89
dc
dc
99
99
99
99
37% aq HCl (1.0)
ClCH2CHCl2 (1.2)
ClCH2CHCl2 (1.2)
ClCH2CHCl2 (1.2)
ClCH2CHCl2 (1.2)
37:63
a
The ratio was measured by 1H NMR.
The isolated yields were obtained.
The substrate 5a was not exhausted.
b
c
In our recent works, an amine promoted PdeC catalytic hydro-
By carefully monitoring the hydrogenation in entry 5 (Table 1),
we found that 5a was reduced into 8a completely in the first 5 min.
Since the pyridine ring in 8a was not conjugated with ketone, its
base strength increased significantly. As shown in Scheme 4, 8a (as
a base) promoted hydrodechlorination of ClCH2CHCl2 then started
to form 8a$HCl. Furthermore, 8a$HCl was converted into the final
product 1a$HCl through two competitive pathways. In path-A, its
pyridine nucleus was hydrogenated first followed by a hydro-
genolysis of the CeO bond. In path-B, its CeO bond was hydro-
genolyzed first followed by a hydrogenation of the pyridine
dechlorination of geminal dichloroalkanes was discovered.12 Its che-
moselectivity was controlled so well that the amine hydrochlorides
were formed stoichiometrically.12a As shown in Scheme 3, we luckily
found that the pyridine hydrochloride can be quantitatively produced
in situ in a PdeC catalytic hydrodechlorination of CH2ClCHCl2 (it was
used specifically for its inexpensive price) when pyridine was used as
an amine. Since no free N-atoms and free HCl molecules were pre-
sented in this process, the catalytic activity of PdeC was never de-
creased. Thus, we hypothesized that three possible intermediates

932
C. Cheng et al. / Tetrahedron 70 (2014) 930e935
O
nucleus. Since the conditional experiments proved that the pure
9a$HCl could be converted into 1a$HCl in only 21% yield under the
same conditions, it indicated that path-A is unfavorable pathway
for the conversion of 8a$HCl into 1a$HCl. This result was caused
clearly by the fact that 9a$HCl is a monoaryl substituted benzyl
alcohol and the hydrogenolysis of its CeO bond is much more
difficult than that of 8a$HCl (as a diaryl substituted benzyl alcohol).
This may be also the reason that 9a$HCl was isolated as a by-
product when low proportions of PdeC were employed (entries 5
and 6, Table 1). Thus, path-B should be the main path and the whole
procedure was a five-step, one-pot process including: (i) a fast re-
duction of the ketone in 5a; (ii) a pyridine-controlled chemo-
selective hydrodechlorination of ClCH2CHCl2; (iii) an in situ
formation of pyridine hydrochloride (8a$HCl); (iv) a hydrogenolysis
of the CeO bond in 8a$HCl; (v) a hydrogenation of pyridine hy-
drochloride (10a$HCl).
10% Pd-C (50 wt%), H2 (balloon)
MeOH, ClCH2CHCl2, 45 oC, 4-6.5 h
97-99%
Ar
Ar
N
NH.HCl
1a-h.HCl
5a-h
Me
NH.HCl
NH.HCl
NH.HCl
NH.HCl
NH.HCl
NH.HCl
NH.HCl
NH.HCl
Me
1a.HCl
1b.HCl
1c.HCl
(4.5 h, 99%)
(4.2 h, 97%)
(4.2 h, 99%)
MeO
Me
MeO
1d.HCl
1e.HCl
1f.HCl
Me
(4.0 h, 97%)
(4.5 h, 97%)
(6.5 h, 97%)
OH
OMe
Me
Me
NH.HCl
MeO
F
1g.HCl
1h.HCl
9i.HCl
o
(6.0 h, 99%)
(6.0 h, 98%)
(25 C, 12 h, 97%)
Scheme 5.
O
5a
OH
Reduction of Ketone
When this method was extended to 4-alkanoylpyridines (6),
interesting results were observed under room temperature and
atmospheric pressure. As shown in Table 3, 4-pyridinemethanol
hydrochloride derivatives (7$HCl) were obtained as major prod-
ucts from the short-chain substrates (entries 1e5) and their pro-
portions increased as the chain length increased. When the chain
length was longer than 6-carbon, the crystalline 7$HCl was ob-
tained as a single product in quantitative yield (entries 6 and 7).
N
N
8a
Formation of pyridine
hydrochloride
Hydrodechlorination
of ClCC2CHCl2
OH
OH
Hydrogenation
of Pyridine Ring
Path-A
N.HCl
NH.HCl
9a.HCl
8a.HCl
Hydrogenolysis
of C-O Bond
Path-B
Hydrogenolysis
of C-O Bond
Table 3
Effect of structures of 6aeg on the hydrogenation
Hydrogenation
of Pyridine Ring
O
OH
10% Pd-C (50 wt%), H2 (balloon)
MeOH, ClCH2CHCl2, rt
NH.HCl
N.HCl
R
R
R
+
N
NH.HCl
7a-g.HCl
NH.HCl
11a-g.HCl
1a.HCl
10a.HCl
6a-g
Scheme 4.
Entry
6, 7, 11
Time (h)
7$HCl/11$HCla (%)
Yieldb (%)
R¼
1
2
3
4
5
6
7
(a) eH
(b) eCH3
(c) eC2H5
(d) eC4H9en
(e) eC5H11en
(f) eC6H13en
(g) eC8H17en
12
12
65:35
65:35
75:25
80:20
93:07
100:00
100:00
99
99
99
99
99
99
99
As shown in Table 2, the intermediate 9a$HCl can be exhausted
by elevating the pressure or temperature when low proportions of
PdeC were used. For an efficient laboratory-scale operation, we
preferred to choose entry 4 as our standard conditions.
8.5
7.5
7.0
6.0
5.5
a
The ratio was measured by 1H NMR.
The isolated yields were obtained.
Table 2
b
Hydrogenation of 5a in the presence of ClCH2CHCl2
10% Pd-C, H2, MeOH, ClCH2CHCl2
5a
9a HCl
+
1a HCl
By carefully monitoring the hydrogenation of 6d (entry 4, Table
Entry
10% PdeC
(wt %)
Pressure
(psi)
Temp
(ꢀC)
Time
(h)
9a$HCl/1a$HCla
(%)
Yieldb
(%)
3), we found that its pathway was similar to that of 5a, and 12d$HCl
was a key intermediate (Scheme 6). Clearly, once 12d$HCl was
hydrogenated into 7d$HCl by the path-A, 7d$HCl will never be
converted into 11d$HCl because it is not a benzyl alcohol and its
1
2
3
4
5
6
7
50
50
50
50
25
25
10
40
80
25
25
35
45
35
45
45
23
11
12
4.5
30
12
22
60:40
0:100
0:100
0:100
0:100
0:100
6:94
99
99
99
99
99
99
99
Balloon
Balloon
Balloon
Balloon
Balloon
OH
OH
Hydrogenation
of Pyridine Ring
Path-A
n-Bu
n-Bu
a
The ratio was measured by 1H NMR.
The isolated yields were obtained.
N.HCl
NH.HCl
b
12d.HCl
7d.HCl
Hydrogenolysis
of C-O Bond
Path-B
Hydrogenolysis
Xof C-O Bond
As shown in Scheme 5, all substrates 5aeh were hydrogenated
Hydrogenation
n-Bu
n-Bu
into the corresponding 1aeh$HCl in practical quantitative yields
under the standard conditions. But, the substrates bearing electron-
withdrawing group on the benzene ring resisted the complete
hydrogenolysis of the CeO bond. Thus, 9i$HCl was obtained as
a single product from the substrate 5i at room temperature.
of Pyridine Ring
N.HCl
NH.HCl
13d.HCl
11d.HCl
Scheme 6.

C. Cheng et al. / Tetrahedron 70 (2014) 930e935
933
hydroxyl group could not be hydrogenolyzed under mild
conditions.
results were obtained when this method was performed at a 5-
g scale.
As shown in Table 4, further experiments proved that the tem-
perature had little influence on the selectivity between path-A and
path-B (entries 1 and 2), but the pressure had significant influence
(entries 3 and 4). When the hydrogenation of 6d carried out at
more than 40 psi (very low pressure, about 2.7 atm), 7d$HCl was
obtained as a single product in 99% yield. The early study results8a
indicated that the formation of pyridine hydrochloride salt may
change the adsorption nature of pyridine nucleus on the catalyst
surface from edgewise to flat. Therefore, when the elevated hy-
drogen pressure was used in our experiments, their flatwise ad-
sorption on the PdeC catalyst surface could be increased and the
hydrogenation was accelerated significantly.
4. Experimental section
4.1. General information and materials
The 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were
recorded in CDCl3. TMS was used as an internal reference and J
values are given in hertz.
4.2. A typical procedure for preparation of 4-substituted pi-
peridine hydrochlorides
A suspension of 5a (366 mg, 2.0 mmol), 10% PdeC (183 mg,
50 wt %), and ClCH2CHCl2 (320 mg, 2.4 mmol) in MeOH (30 mL) was
hydrogenated on an atmospheric pressure hydrogenator (or bal-
loon) at 45 ꢀC until the absorption of hydrogen ceased (4.5 h). After
the PdeC catalyst was filtered off, the solvent was removed on
a rotavapor. The residue was diluted with diethyl ether (10 mL) to
give the desired product 1a$HCl (419 mg, 99%) as a white crystal.
The product was collected simply by a filtration and usually was
pure enough for any analytical purposes.
Table 4
Effects of the pressure and temperature on the hydrogenation of 6d
10% Pd-C (50 wt%), H2
MeOH, ClCH2CHCl2
6d
7d HCl
+
11d HCl
Entry Temp (ꢀC) Pressure (psi) Time (h) 7d$HCl/11d$HCla (%) Yieldb (%)
1
2
3
4
45
55
25
25
Balloon
Balloon
40
6.5
4.5
6.5
5.5
80:20
77:23
100:0
100:0
99
99
99
99
80
A similar procedure was used for the hydrogenation of 5bei to
give the corresponding products 1bei$HCl.
a
The ratio was measured by 1H NMR.
The isolated yields were obtained.
b
4.2.1. 4-Benzylpiperidine hydrochloride (1a$HCl). White crystal, mp
180e181 ꢀC (MeOHeEt2O) (lit.13a 177e179 ꢀC). 1H NMR
d 7.33e7.25
As shown in Scheme 7, the different 4-alkanoylpyridines were
(m, 2H), 7.23e7.15 (m, 3H), 3.35e3.25 (m, 2H), 2.86e2.77 (m, 2H),
selectively hydrogenated into the corresponding 7aeh$HCl as
single products in practical quantitative yields. When 2-
alkanoylpyridine (6i) was used as a substrate, 7i$HCl was ob-
tained in similar excellent yields.
2.53 (d, J¼6.9 Hz, 2H), 1.85e1.70 (m, 3H), 1.44e1.25 (m, 2H); 13C
NMR
d 140.0, 129.4, 128.6, 126.4, 44.1, 41.5, 35.1, 28.2.
4.2.2. 4-(4-Methylbenzyl)piperidine hydrochloride (1b$HCl). White
crystal, mp 218e220 ꢀC (MeOHeEt2O) (lit.13b 209e211 ꢀC). 1H NMR
O
OH
d
7.12e7.05 (m, 4H), 3.35e3.25 (m, 2H), 2.87e2.77 (m, 2H), 2.48 (d,
10% Pd-C (50 wt%), H2 (40-80 psi)
MeOH, ClCH2CHCl2, rt, 4.5-17 h
J¼6.9 Hz, 2H), 2.20 (s, 3H), 1.81e1.72 (m, 3H), 1.39e1.24 (m, 2H); 13
C
R
R
N
NH.HCl
7a-h.HCl
97-99%
NMR
d 136.8, 135.5, 129.2, 129.0, 43.9, 41.2, 35.2, 28.2, 20.4.
6a-h
4.2.3. 4-(2-Methylbenzyl)piperidine hydrochloride (1c$HCl). White
crystal, mp 205e207 ꢀC (MeOHeEt2O) (lit.6b 202e204 ꢀC). 1H NMR
OH
OH
Me
OH
Et
H
NH.HCl
NH.HCl
NH.HCl
7c.HCl, 97%
(80 psi, 6.0 h)
d
7.17e7.05 (m, 4H), 2.33e3.23 (m, 2H), 2.82e2.72 (m, 2H), 2.49 (d,
J¼6.87 Hz, 2H), 2.19 (s, 3H), 1.77e1.68 (m, 3H), 1.44e1.26 (m, 2H);
13C NMR
138.2, 136.9, 130.4, 130.3, 126.6, 125.9, 44.1, 38.7, 34.0,
28.3, 18.6.
7a.HCl, 98%
(80 psi, 8 h)
7b.HCl, 99%
(80 psi, 7.5 h)
OH
d
OH
OH
n-Bu
n-C
H
n-C H
6 13
5
11
NH.HCl
NH.HCl
NH.HCl
7d.HCl, 99%
7e.HCl, 97%
4.2.4. 4-(2-Methoxylbenzyl)piperidinehydrochloride(1d$HCl). White
crystal, mp 172e174 ꢀC (MeOHeEt2O) (lit.4f 175e177 ꢀC). 1H NMR
7f.HCl, 97%
(40 psi, 6.5 h)
(40 psi, 4.5 h)
(40 psi, 5.0 h)
OH
OH
OH
d
7.07 (d, J¼8.2 Hz, 2H), 6.83 (d, J¼8.6 Hz, 2H), 3.69 (s, 3H), 3.33e3.23
Ph
n-Bu
HCl.HN
n-C
H
17
8
2
(m, 2H), 2.83e2.73 (m, 2H), 2.49 (d, J¼6.5 Hz, 2H),1.77e1.65 (m, 3H),
NH.HCl
NH.HCl
1.37e1.20 (m, 2H); 13C NMR
d 157.2, 132.6, 130.4, 113.9, 55.4, 44.0,
7g.HCl, 97%
(40 psi, 4.5 h)
7h.HCl, 99%
(60 psi, 17 h)
7i.HCl, 98%
(50 psi, 6.5 h)
40.5, 35.2, 28.1.
Scheme 7.
4.2.5. 4-(3-Methoxylbenzyl)piperidine hydrochloride (1e$HCl). White
crystal, mp 150e152 ꢀC (MeOHeEt2O), (lit.6b 138e140 ꢀC). 1H NMR
3. Conclusions
d
7.21 (t, J¼7.6 Hz, 1H), 6.81e6.70 (m, 3H), 3.72 (s, 3H), 3.33e3.23 (m,
2H), 2.87e2.76 (m, 2H), 2.49 (d, J¼6.9 Hz, 2H), 1.80e1.69 (m, 3H),
In conclusion, a novel PdeC catalytic hydrodechlorinatione
hydrogenation was developed by a simple addition of 1 equiv of
ClCH2CHCl2 into the conventional hydrogenation system. Under the
selected temperature and pressure, the controlling transformations
of 4-benzoylpyridines and 4-alkanoylpyridines were achieved to
1.42e1.24 (m, 2H); 13C NMR
d 158.9, 141.8, 129.7, 122.2, 114.8, 111.7,
55.3, 44.0, 41.5, 35.0, 28.2.
4.2.6. 4-(3,5-Dimethylbenzyl)piperidinehydrochloride(1f$HCl). White
crystal, mp 184e186 ꢀC (MeOHeEt2O). IR 3442, 2955, 1588 cmꢁ1
1H NMR
6.64e6.55 (m, 2H), 6.53e6.47 (m, 1H), 3.23e3.18 (m, 2H),
2.65e2.55 (m, 2H), 2.24 (d, J¼5.8 Hz, 2H), 1.99 (s, 6H), 1.57e1.48 (m,
3H), 1.28e1.24 (m, 2H); 13C NMR
139.8, 137.5, 127.4, 127.0, 43.9, 41.7,
35.2, 28.3, 20.8; MS m/z (%) 204 (11.7), 203 (MꢁHCl, 100.0), 202
n
;
give the corresponding 4-benzylpiperidine hydrochlorides and
a
-
d
alkyl-4-piperidinemethanol hydrochlorides. Since this multi-step
one-pot reaction gave all products as crystalline salts, the work-
up procedure was as simple as a filtration. The same excellent
d

934
C. Cheng et al. / Tetrahedron 70 (2014) 930e935
(52.4). Calcd for C14H22ClN: C, 70.13; H, 9.25; N, 5.84; Found: C, 70.02;
H, 9.28; N, 5.77.
J¼6.2 Hz, 3H); 13C NMR
d 70.4, 44.1, 44.0, 40.2, 28.2, 24.6, 24.3, 19.1;
MS m/z (%) 130 (1.8), 129 (MꢁHCl, 17.1), 30 (100.0). Calcd for
C7H16ClNO: C, 50.75; H, 9.73; N, 8.46; Found: C, 50.66; H, 9.85; N,
8.44.
4.2.7. 4-(3,4-Dimethylbenzyl)piperidine hydrochloride (1g$HCl).
White crystal, mp 218e219 ꢀC (MeOHeEt2O); IR
n
3420, 2909,
1586 cmꢁ1
;
1H NMR
d
6.77e6.73 (m, 2H), 6.69e6.66 (m, 1H),
4.3.3.
crystal, mp 106e108 ꢀC (MeOHeEt2O). IR
1578cmꢁ1;1HNMR
2.42e2.29(m, 3H), 2.95e2.83(m, 2H),1.97e1.89
a-Ethyl-4-pyridinemethanol hydrochloride (7c$HCl). White
3.26e3.21 (m, 2H), 2.69e2.60 (m, 2H), 2.26 (d, J¼6.54 Hz, 2H), 1.94
n
3394, 3068, 2959,
(s, 3H), 1.91 (s, 3H); 1.59e1.50 (m, 3H), 1.34e1.25 (m, 2H); 13C NMR
d
d
137.3, 136.2, 133.7, 130.4, 129.5, 126.7, 43.9, 41.3, 35.3, 28.3, 19.1,
(m, 1H), 1.82e1.73 (m, 1H), 1.71e1.57 (m, 1H), 1.53e1.30 (m, 4H), 0.83
18.7; MS m/z (%) 204 (11.1), 203 (MꢁHCl, 100.0), 202 (44.8). Calcd
for C14H22ClN: C, 70.13; H, 9.25; N, 5.84; Found: C, 69.93; H, 9.18; N,
5.96.
(t, J¼7.2 Hz, 3H); 13C NMR
d 75.6, 44.2, 44.1, 38.3, 25.8, 25.1, 23.8, 9.4;
MS m/z (%) 143 (MꢁHCl, 75.1), 84 (100.0). Calcd for C8H18ClNO: C,
53.47; H, 10.10; N, 7.80; Found: C, 53.52; H, 10.14; N, 7.78.
4.2.8. 4-(2,4-Dimethoxylbenzyl)piperidine hydrochloride (1h$HCl).
4.3.4.
crystal, mp 112e114 ꢀC (MeOHeEt2O). IR
1H NMR
3.46e3.43 (m, 3H), 3.02e2.91 (m, 2H), 2.05e1.95 (m, 1H),
1.89e1.81 (m, 1H), 1.76e1.62 (m, 1H), 1.59e1.25 (m, 8H), 1.91e1.82
(m, 3H); 13C NMR
74.1, 44.3, 44.2, 38.9, 32.8, 27.5, 25.2, 23.8, 22.4,
138; MS m/z (%) 171 (MꢁHCl, 19.7), 82 (100.0). Calcd for
10H22ClNO: C, 57.82; H, 10.67; N, 6.74; Found: C, 57.75; H, 10.79; N,
a
-Butyl-4-pyridinemethanol hydrochloride (7d$HCl). White
White crystal, mp 178e180 ꢀC (MeOHeEt2O). IR
n
3449, 2932, 1611,
n
3392, 2954, 1579 cmꢁ1
;
1506 cmꢁ1; 1H NMR
d
6.83e6.80 (m,1H), 6.36e6.28 (m, 2H), 3.61 (s,
d
3H), 3.60 (s, 3H), 3.28e3.22 (m, 2H), 2.75e2.56 (m, 2H), 2.28 (d,
J¼6.5 Hz, 2H), 1.63e1.58 (m, 3H), 1.33e1.24 (m, 2H); 13C NMR
d
d
158.8, 158.2, 131.4, 120.4, 104.8, 98.6, 55.44, 55.36, 44.0, 35.2, 33.9,
28.3; MS m/z (%) 235 (MꢁHCl, 31.2), 151 (100.0). Calcd for
C
C
14H22ClNO2: C, 61.87; H, 8.16; N, 5.15; Found: C, 61.68; H, 8.18; N,
6.72.
5.21.
4.3.5.
a
-Pentyl-4-pyridinemethanol hydrochloride (7e$HCl). White
3393, 3070, 2951,
3.51e3.35 (m, 3H), 2.98e2.84 (m, 2H),
2.01e1.89 (m, 1H), 1.87e1.76 (m, 1H), 1.69e1.58 (m, 1H), 1.55e1.32
(m, 5H), 1.29e1.20 (m, 5H), 0.89e0.75 (m, 3H); 13C NMR
74.0, 44.2,
44.1, 38.9, 33.1, 31.4, 25.2, 24.9, 23.7, 22.3, 13.7; MS m/z (%) 185
(MꢁHCl, 10.8), 84 (100.0). Calcd for C11H24ClNO: C, 59.57; H, 10.91;
N, 6.32; Found: C, 59.68; H, 10.79; N, 6.47.
4.2.9.
a
-(4-Fluorophenyl)-4-piperidinemethanol hydrochloride (1i$HCl).
3339, 2950,
7.32e7.28 (m, 2H), 7.12e7.03 (m, 2H),
4.40 (d, J¼8.2 Hz, 1H), 3.47e3.42 (m, 1H), 3.35e3.25 (m, 1H), 2.96e2.75
(m, 2H), 2.08e2.15 (m, 1H), 1.97e1.85 (m, 1H), 1.55e1.28 (m, 3H); 13
NMR 163.8, 160.6, 137.5, 128.7, 128.5, 115.5, 115.2, 76.6, 43.9, 43.8, 40.1,
25.1, 25.0; MS m/z (%) 209 (MꢁHCl, 32), 30 (100.0); Calcd for
12H17ClFNO: C, 58.66; H, 6.97; N, 5.70; Found: C, 58.67; H, 7.12; N,
crystal, mp 108e110 ꢀC (MeOHeEt2O); IR
n
White crystal, mp 248e250 ꢀC (dec, MeOHeEt2O). IR
n
1580 cmꢁ1 1H NMR
; d
2813, 2718,1509 cmꢁ1; 1H NMR
d
d
C
d
C
5.55.
4.3.6.
crystal, mp 98e100 ꢀC (MeOHeEt2O); IR
2955 cmꢁ1;1H NMR
3.51e3.35(m, 3H), 3.01e2.86(m, 2H), 2.01e1.94
(m,1H),1.87e1.77 (m,1H),1.68e1.17 (m, 12H), 0.83 (t, J¼6.00 Hz, 3H);
13C NMR
74.0, 44.2, 38.9, 33.1, 31.4, 28.8, 25.2, 23.7, 22.3,13.7; MS m/z
a
-Hexyl-4-pyridinemethanol hydrochloride (7f$HCl). White
n
3394, 3370, 3064,
d
4.3. A typical procedure for preparation of
pyridinemethanol hydrochlorides
a-substituted-4-
d
(%) 199 (MꢁHCl, 5.5), 82 (100); Anal. Calcd for C12H26ClNO: C, 61.12; H,
The suspension of 6d (326 mg, 2.0 mmol), 10% PdeC (163 mg,
50 wt %), and ClCH2CHCl2 (320 mg, 2.4 mmol) in MeOH (30 mL) was
hydrogenated on a Parr-Hydrogenator (40 psi, about 2.7 atm) at
room temperature until the absorption of hydrogen ceased (4.2 h).
After the PdeC catalyst was filtered off, the solvent was removed on
a rotavapor. The residue was diluted with diethyl ether (10 mL) to
give the desired product 7d$HCl (410 mg, 99%) as a white crystal.
The product was collected simply by a filtration and usually was
pure enough for any analytical purposes.
11.11; N, 5.94. Found: C, 61.28; H, 11.07; N, 5.87.
4.3.7.
crystal, mp 107e108 ꢀC (MeOHeEt2O). IR
2955 cmꢁ1 1H NMR
3.48e3.30 (m, 3H), 2.95e2.80 (m, 2H),
a-Octyl-4-pyridinemethanol hydrochloride (7g$HCl). White
n
3392, 3366, 3067,
;
d
1.94e1.86 (m, 1H), 1.77e1.68 (m, 1H), 1.59e1.48 (m, 2H), 1.47e1.32
(m, 4H), 1.28e1.15 (m, 11H), 0.79 (t, J¼5.8 Hz, 3H); 13C NMR
d 73.9,
44.1, 44.0, 33.6, 31.9, 29.7, 29.4, 25.8, 25.4, 23.5, 22.6, 13.9; MS m/z
(%) 227 (MꢁHCl, 7.9), 84 (100.0). Calcd for C14H30ClNO: C, 63.73; H,
11.46; N, 5.31; Found: C, 63.47; H, 11.32; N, 5.29.
A similar procedure was used for the hydrogenation of 6aec and
6eei to give the corresponding products 7aec$HCl and 7eei$HCl.
4.3.8.
White crystal, mp 170e171 ꢀC (MeOHeEt2O). IR
1578 cmꢁ1 1H NMR
7.29e7.11 (m, 5H), 3.42e3.29 (m, 3H),
2.89e2.66 (m, 3H), 2.59e2.46 (m, 1H), 1.91e1.82 (m, 1H), 1.72e1.56
(m, 3H), 1.51e1.35 (m, 3H); 13C NMR
142.5, 128.7, 126.0, 73.2, 44.1,
a
-(2-Phenylethyl)-4-pyridinemethanol hydrochloride (7h$HCl).
4.3.1. 4-Pyridinemethanol hydrochloride (7a$HCl). White crystal,
mp 128e130 ꢀC (MeOHeEt2O). IR
n 3261, 2937, 2888, 2821, 2731,
n
3628, 3382, 2947,
2509 cmꢁ1; 1H NMR
d
3.40 (t, J¼10.7 Hz, 4H), 2.93 (t, J¼12.4 Hz, 2H),
;
d
1.88 (d, J¼14.1 Hz, 2H), 1.81e1.68 (m, 1H), 1.25e1.42 (m, 2H); 13C
d
NMR
d 65.5, 43.8, 35.4, 25.1; MS m/z (%) 117 (18.5), 116 (56.1), 115
44.0, 39.0, 35.3, 31.7, 25.2, 23.5; MS m/z (%) 219 (MꢁHCl, 2.7), 128
(100.0). Calcd for C14H22ClNO: C, 65.74; H, 8.67; N, 5.48; Found: C,
65.68; H, 8.44; N, 5.41.
(MꢁHCl, 43.1), 30 (100.0). Calcd for C6H14ClNO: C, 47.52; H, 9.31; N,
9.24; Found: C, 47.17; H, 9.41; N, 9.11.
4.3.2.
crystal, mp 108e110 ꢀC (MeOHeEt2O). IR
2496, 1602 cmꢁ1; 1H NMR
3.58e3.42 (m, 1H), 3.42e3.30 (m, 2H),
a
-Methyl-4-pyridinemethanol hydrochloride (7b$HCl). White
4.3.9.
crystal, mp 132e134 ꢀC (MeOHeEt2O); IR
1486 cmꢁ1 1H NMR
3.76e3.52 (m, 1H), 3.41e3.32 (m, 1H),
3.14e2.86 (m, 2H), 1.92e1.79 (m, 3H), 1.62e1.20 (m, 9H), 0.83 (s,
3H); 13C NMR
71.4, 70.7, 61.3, 60.6, 45.1, 44.7, 32.0, 31.4, 27.4, 26.7,
25.3, 22.1, 21.9, 21.6, 21.4, 13.4; MS m/z (%) 171 (MꢁHCl, 0.05), 84
a
-Butyl-2-pyridinemethanol hydrochloride (7i$HCl). White
n
3404, 2968, 2812, 2722,
n
3423, 2956, 2869,
d
;
d
2.83e3.01 (m, 2H), 2.02e1.95 (m, 1H), 1.84e1.79 (m, 1H), 1.62e1.52
(m, 1H), 1.50e1.35 (m, 2H), 1.15e1.05 (m, 3H); 1H NMR (CD3OH)
d
d
3.55e3.50 (m, 1H), 3.42e3.35 (m, 2H), 2.98e2.85 (m, 2H),
2.07e2.00 (m, 1H), 1.84e1.78 (m, 1H), 1.55e1.43 (m, 3H), 1.14 (d,

C. Cheng et al. / Tetrahedron 70 (2014) 930e935
935
2295e2309; (b) Furman, B.; Dziedzic, M. Tetrahedron Lett. 2003, 44,
8249e8252; (c) Vice, S.; Bara, T.; Bauer, A.; Evans, C. A.; Ford, J.; Josien, H.;
McCombie, S.; Miller, M.; Nazareno, D.; Palani, A.; Tagat, J. J. Org. Chem. 2001, 66,
2487e2492.
(100.0). Calcd for C10H22ClNO: C, 57.82; H, 10.67; N, 6.74; Found: C,
57.94; H, 10.48; N, 6.87.
6. (a) Armitage, M.; Bret, G.; Choudary, B. M.; Kingswood, M.; Loft, M.; Steve, M.;
Smith, S.; Urquhart, M. W. J. Org. Process Res. Dev. 2012, 16, 1626e1634; (b) Agai,
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Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21072112 and 21221062).
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Supplementary data
These data include 1H NMR and 13C NMR spectra for all products
1aei$HCl and 7aei$HCl described in this article. Supplementary
data related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.12.017.
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