A convenient synthesis of (1 H-azol-1-yl)piperidines

Article abstract of DOI:10.1055/s-0031-1291126

A convenient preparation of 3- and 4-(1H-azol-1-yl)piperidines by arylation of azoles (i.e., pyrazoles, imidazoles, and triazoles) with 3- and 4-bromopyridines and subsequent reduction of the pyridine ring was developed. The method was extended to benzo analogues of the title compounds. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1291126

PAPER
▌2041
paper
A Convenient Synthesis of (1H-Azol-1-yl)piperidines
Azolylpiperidines
Nadiia V. Shevchuk,a Kostiantyn Liubchak,a Kostiantyn G. Nazarenko,a Aleksandr A. Yurchenko,a
Dmitriy M. Volochnyuk,a,b Oleksandr O. Grygorenko,*b,c Andrey A. Tolmachevb
a
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Street 5, Kyiv 02660, Ukraine
b
Enamine Ltd., Alexandra Matrosova Street, 23, Kyiv 01103, Ukraine
c
Kyiv National Taras Shevchenko University, Volodymyrska Street, 64, Kyiv 01601, Ukraine
Fax +38(44)5024832; E-mail: gregor@univ.kiev.ua
Received: 22.03.2012; Accepted after revision: 18.04.2012
In this work, we have turned our attention to the synthesis
of (1H-azol-1-yl)piperidines 5–10 (Figure 2). These scaf-
folds have been already used in the discovery of tyrosine
kinase inhibitors,5,6 CCR5 antagonists,7,8 factor Xa inhib-
itors,9 and many other biologically active compounds.10–13
Several approaches to the synthesis of compounds 5–10
have been reported in the literature. In particular, com-
pounds of general formula 5 were prepared from the cor-
responding piperidine-derived precursors 114,5,10 or 127,11
(Scheme 1). Analogous procedures were used for the
preparation of 6, using 3-substituted isomers of 11 and 12
as the starting materials.4,10c,11c In the preparation of 7 and
8, the imidazole ring was constructed in the key step, start-
ing from a 3- or 4-aminopiperidine precursor.12 Alterna-
tively, 8 were prepared from the 3-isomer of 11 ana-
logously to 5.10d,e,13 Compounds 9 were also prepared
from the piperidine derivatives analogous to 12.8 A single
report on a different method commencing from 3-pyridyl-
hydrazine and a β-dicarbonyl compound as the precursors
of 6 can be also mentioned (Scheme 2).9
Abstract: A convenient preparation of 3- and 4-(1H-azol-1-yl)pi-
peridines by arylation of azoles (i.e., pyrazoles, imidazoles, and tri-
azoles) with 3- and 4-bromopyridines and subsequent reduction of
the pyridine ring was developed. The method was extended to ben-
zo analogues of the title compounds.
Key words: nitrogen heterocycles, azoles, piperidine, hydrogena-
tion, molecular rigidity
Over the entire history of medicinal chemistry, heterocy-
clic compounds have remained a major pool of new che-
motypes for drug discovery. Considerable efforts were put
towards exploring aromatic heterocycles, as they are easy
to synthesize, provide conformationally restricted tem-
plates for constructing the molecules of potential drug
candidates, and ensure efficient binding to biological tar-
gets. Recent tendencies to move away from two-dimen-
sional scaffolds provided by sp2-rich ring systems1 have
turned the attention of chemists to their aliphatic counter-
parts. In this respect, templates combining the advantages
of both aromatic and aliphatic heterocycles, in particular
via their connection by a single C–C bond, are particularly
promising.2 Nature provides a number of such molecules,
e.g. alkaloids nicotine (1), cytisine (2), or anabasine (3)
(Figure 1).3 Synthetic compounds of biological relevance
are also rich in analogous examples, among which the sig-
nal transduction inhibitor Crisotinib (4) can be men-
tioned.4
R3
R1
R1
R1
N
N
R2
HN
R2
R2
HN
N
N
N
N
N
R3
HN
5
7
9
R3
R1
R1
R1
N
N
R2
R2
R2
N
N
N
N
NH
N
R3
O
N
N
N
N
N
N
H
H
H
H
6
8
10
N
N
F
1
2
3
Figure 2
Cl
N
O
R3
N
R1
R2
Cl
LG
N
NH
H2N
N
R2
R3
O
O
4
+
+
5
N
Figure 1
R1
N
H
N
H
NH2
PG
11
N
PG
SYNTHESIS 2012, 44, 2041–2048
Advanced online publication: 31.05.2012
12
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1291126; Art ID: SS-2012-Z0299-OP
© Georg Thieme Verlag Stuttgart · New York
Scheme 1

2042
N. V. Shevchuk et al.
PAPER
ploying copper(I) catalysts.14–26 A number of copper-
based catalytic systems were described in the literature,
varying in copper source, ligand, base, and solvent. To
find the optimal conditions for the arylation, we studied
reaction of 3-bromopyridine (13) and imidazole (15a) us-
ing different catalytic systems (Table 1). Copper(I) io-
dide, which has almost unlimited shelf stability and is
readily available, was used as the copper(I) source. Fur-
thermore, only inexpensive and readily available copper-
stabilizing ligands [i.e., N,N′-dimethylethylenediamine
(DMEDA), 8-oxyquinoline, 1,10-phenanthroline, and L-
proline] were checked. It was found that using N,N-di-
methylformamide and dimethyl sulfoxide as the solvents
gave the best yields of product 21a, presumably due to
their higher polarity as well as the higher temperature that
could be achieved. N,N′-Dimethylethylenediamine
showed the most promising results as the copper-stabiliz-
ing ligand. Finally, although cesium carbonate was slight-
ly better in most of the preliminary experiments, we chose
less expensive potassium carbonate as the optimal base
for the reaction.
R3
R2
R2
NH2
N
HN
O
O
N
R1
R3
N
+
6
R1
N
Scheme 2
In this work, we considered the latter idea, but as starting
materials of the type 11 or 12 are not readily available
commercially in bulk quantities, this limits their use for
the multigram preparations of 5–10. Contrary to the liter-
ature methods, our retrosynthetic analysis of 5–10 led to
3- and 4-bromopyridines (Scheme 3).
R2
R2
R2
Br
X
X
X
X
X
+
N
N
R1
R1
X
R1
N
N
H
HN
N
The above described conditions [CuI (5 mol%), DMEDA
(10 mol%), K2CO3, DMF, reflux, 6–12 h] (Table 1, entry
9) were successfully applied to arylation of other azoles
15b–h with 13 (Table 2). In most cases, the corresponding
3-(1H-azol-1-yl)pyridines 19, 21, and 23 were obtained in
moderate to good yields (62–92%, except 19c and 21d).
The method was also extended to 4-bromopyridine (14),
as well as 4-bromoisoquinoline (16) and 3-bromoquino-
line (17).
Scheme 3
Table 1 Arylation of Imidazole with 3-Bromopyridine (reflux,a 6 h)
Entry Solvent
Ligand
Base
Yieldb (%)
1
2
toluene
toluene
toluene
toluene
toluene
toluene
MeCN
MeCN
DMF
DMEDAc
K2CO3
Cs2CO3
K2CO3
Cs2CO3
K2CO3
Cs2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
K2CO3
K2CO3
K2CO3
Cs2CO3
0
3
DMEDA
It should be noted that the following reactivity of azoles
15a–h was observed in these transformations:
3
8-hydroxyquinoline
8-hydroxyquinoline
1,10-phenanthroline
1,10-phenanthroline
DMEDA
0
4
0
15e ≈ 15f ≈ 15a > 15b ≈ 15c > 15h >> 15d >> 15g
5
18
15
0
These results show that the reactivity of 15 is governed
mainly by steric factors, although basicity of the azole an-
ion also has some importance (e.g., in the case of 15h).
6
7
3-(1H-Azol-1-yl)pyridines 18–23 obtained in the above
reactions were subjected to catalytic hydrogenation (5%
Pd/C, MeOH, 100 atm, 80 °C, 24 h) to give the corre-
sponding products 5–10 in 72–95% yields (Table 2). It
should be noted that catalytic hydrogenation reaction of
(1H-azol-1-yl)pyridines was described previously on pyr-
idine oxide derivatives in the presence of platinum(IV)
oxide catalyst.9 In the case of benzo analogues 24–27, the
hydrogenation was carried out under milder conditions
(5% Pd/C, MeOH, 30 atm, monitored by TLC): careful
control of the reaction was necessary in these cases in or-
der to avoid reduction of the second aromatic ring.
8
1,10-phenanthroline
DMEDA
0
9
72
81
71
15
53
69
79
10
11
12
13
14
15
DMF
DMEDA
DMF
DMEDA
DMF
8-hydroxyquinoline
1,10-phenanthroline
L-proline
DMF
DMSO
DMSO
L-proline
In conclusion, a convenient method for the synthesis of 3-
and 4-(1H-azol-1-yl)piperidines 5–10 as well as their ben-
zo analogues 28–31 was developed. The corresponding
products are obtained by a two-step procedure using inex-
pensive starting materials, reagents, and catalysts in 9–
86% overall yields. The method was used for the prepara-
tion of up to 100 g of the title compounds in a single run.
a 150 °C in the case of DMSO as the solvent.
b The yields were detected by NMR.
c DMEDA = N,N′-dimethylethylenediamine.
Arylation of pyrazoles and imidazoles with 3- and 4-bro-
mopyridines has been documented in the literature. Look-
ing for a convenient method that might allow multigram
preparations, we turned our attention to procedures em-
Synthesis 2012, 44, 2041–2048
© Georg Thieme Verlag Stuttgart · New York

PAPER
Azolylpiperidines
Yield (%)
2043
Table 2 Two-Step Synthesis of (1H-Azol-1-yl)piperidines 5–10 and Their Benzo Analogues 28–31
Entry
Bromide
Azole
Product of the 1st step
Final product
1st stepa
2nd stepb Total
N
N
N
N
N
N
Br
1
87
95
81
78
83
50
52
N
H
N
NH
NH
NH
13
21a
8a
15a
N
N
N
N
N
N
H
2
3
62
67
N
15b
8b
21b
N
N
N
N
N
N
H
N
15c
21c
8c
N
N
N
N
N
N
H
4
31
81
25
NH
NH
N
15d
21d
8d
N
N
N
N
N
5
6
N
92
89
94
91
87
81
N
H
19a
6a
15e
N
N
N
N
N
N
N
H
N
N
N
NH
19b
6b
15f
N
N
7
8
13
82
72
93
9
N
H
N
N
NH
6c
19c
15g
N
N
N
N
N
N
N
N
N
NH
76
H
23
1a
15h
N
N
N
N
N
NH
Br
N
9
10
11
15a
15e
15h
72
87
72
90
83
92
65
72
66
14
7a
20
N
N
N
N
NH
N
18
5a
N
N
N
NH
N
N
N
N
22
9a
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2041–2048

2044
N. V. Shevchuk et al.
PAPER
Table 2 Two-Step Synthesis of (1H-Azol-1-yl)piperidines 5–10 and Their Benzo Analogues 28–31 (continued)
Entry
Bromide
Azole
Product of the 1st step
Final product
Yield (%)
1st stepa
2nd stepb Total
Br
N
N
N
N
12
15a
94
89
75
71
71
63
N
NH
N
16
24
28
13
15e
N
N
N
N
N
NH
29
25
Br
N
N
N
N
14
15
15a
15e
94
90
66
78
62
70
N
N
NH
17
26
30
N
N
N
N
N
NH
27
31
a CuI (5 mol%), DMEDA (10 mol%), K2CO3, DMF, reflux, 6–12 h.
b For the preparation of 5–10: 5% Pd/C, MeOH, 100 atm, 80 °C, 24 h; 28–31: 5% Pd/C, MeOH, 30 atm, 30 °C, monitored by TLC.
The solvents were purified according to the standard procedures.
All the starting materials were purchased from Acros, Merck, Flu-
ka, and UORSY. Analytical TLC was performed using Polychrom
SI F254 plates. Column chromatography was performed using Kie-
3-(2-Methyl-1H-imidazol-1-yl)pyridine (21b)29
White crystals; yield: 6.76 g (62%); mp 85–86 °C.
1H NMR (CDCl3): δ = 2.34 (s, 3 H, CH3), 6.98 (s, 1 H), 7.03 (s, 1
H), 7.42 (dd, J = 5.0, 8.0 Hz, 1 H), 7.62 (dd, J = 1.5, 8.0 Hz, 1 H),
8.59 (s, 1 H), 8.63 (d, J = 4.5 Hz, 1 H).
selgel Merck 60 (230–400 mesh) as the stationary phase. 1H and 13
C
NMR spectra were recorded on a Bruker 170 Avance 500 spectrom-
eter [500 MHz (1H), 125 MHz (13C)] with TMS (1H, 13C) as an in-
ternal standard. Elemental analyses were performed at the
Laboratory of Organic Analysis, Institute of Organic Chemistry,
National Academy of Sciences of Ukraine. Mass spectra were re-
corded on an Agilent 1100 LCMSD SL instrument [chemical ion-
ization (APCI)] and Agilent 5890 Series II 5972 GCMS instrument
[electron impact ionization (EI)].
13C NMR (CDCl3): δ = 13.7 (CH3), 120.4 (CH), 123.7 (CH), 128.5
(CH), 132.7 (CH), 134.7 (C), 144.8 (C), 146.6 (CH), 149.3 (CH).
MS (APCI): m/z = 160 (M + H+).
Anal. Calcd for C9H9N3: C, 67.90; H, 5.70; N, 26.40. Found: C,
67.94; H, 5.47; N, 26.59.
3-(2-Ethyl-1H-imidazol-1-yl)pyridine (21c)
White crystals; yield: 8.22 g (67%); mp 105–106 °C; bp 140–145
°C/0.08 mbar.
1H NMR (CDCl3): δ = 1.11 (t, J = 7.5 Hz, 3 H), 2.51 (q, J = 7.5 Hz,
2 H), 6.86 (s, 1 H), 6.93 (s, 1 H), 7.32 (dd, J = 4.6, 7.7 Hz, 1 H), 7.52
(dd, J = 1.2, 7.8 Hz, 1 H), 8.42–8.49 (m 1 H), 8.52 (d, J = 4.6 Hz, 1
H).
13C NMR (CDCl3): δ = 12.2 (CH3), 20.4 (CH2), 120.4 (CH), 123.8
(CH), 128.3 (CH), 132.9 (CH), 134.3 (C), 146.7 (CH), 149.3 (CH),
149.8 (C).
(1H-Azol-1-yl)pyridines 18–27; General Procedure
CuI (5 mmol), DMEDA (10 mmol), and K2CO3 (20 mmol) were
added to a soln of 15 (0.1 mol) and the corresponding bromide (0.1
mol) in DMF (100 mL). The resulting mixture was stirred at reflux
under an argon atmosphere for 12 h, then cooled, filtered, and evap-
orated. The residue was dissolved in MeOH (200 mL), and 10 M aq
HCl (20 mL) was added. The resulting mixture was evaporated to
dryness, and the residue was recrystallized (MeOH, 25 mL) to give
the product as its hydrochloride.
MS (APCI): m/z = 174 (M + H+).
To obtain the product as a free base, a soln of NaOMe (0.2 mol) in
MeOH (100 mL) was added to a suspension of the hydrochloride
(0.1 mol) in MeOH (100 mL). The mixture was stirred for 0.5 h,
then filtered and evaporated to dryness to give the product (>95%
by LC-MS). An analytical sample was prepared by distillation in
vacuo.
Anal. Calcd for C10H11N3: C, 69.34; H, 6.40; N, 24.26. Found: C,
69.38; H, 6.27; N, 24.35.
3-(2-Isopropyl-1H-imidazol-1-yl)pyridine (21d)
Colorless oil; yield: 5.86 g (31%); bp 145–150 °C/0.13 mbar.
3-(1H-Imidazol-1-yl)pyridine (21a)
1H NMR (CDCl3): δ = 1.16 (d, J = 6.9 Hz, 6 H), 2.82 (q, J = 6.8 Hz,
1 H), 6.87 (s, 1 H), 6.69 (s, 1 H), 7.41 (dd, J = 4.8, 6.4 Hz, 1 H),
7.57–7.64 (m, 1 H), 8.52 (d, J = 2.3 Hz, 1 H), 8.61 (d, J = 4.8 Hz, 1
H).
White crystals; yield: 13.4 g (87%); mp 54–55 °C (Lit.33 56–58 °C);
bp 131–134 °C/18.7 mbar.
Spectral and physical data are available in the literature.21,29
Synthesis 2012, 44, 2041–2048
© Georg Thieme Verlag Stuttgart · New York

PAPER
Azolylpiperidines
2045
13C NMR (CDCl3): δ = 21.8 (CH3), 25.8 (CH), 120.4 (CH), 124.0
(CH), 128.0 (CH), 133.7 (CH), 134.6 (C), 147.1 (CH), 149.6 (CH),
153.7 (C).
4-(1H-1,2,4-Triazol-1-yl)pyridine (22)31
White crystals; yield: 10.58 g (72%); mp 113–115 °C (Lit.33 120–
120.5 °C).
1H NMR (DMSO-d6): δ = 8.09 (d, J = 5.6 Hz, 2 H), 8.38 (s, 1 H),
8.83 (d, J = 4.9 Hz, 2 H), 9.67 (s, 1 H).
13C NMR (DMSO-d6): δ = 114.2 (CH), 144.4 (CH), 144.5 (C),
150.0 (CH), 153.9 (CH).
MS (APCI): m/z = 147 (M + H+).
MS (APCI): m/z = 188 (M + H+).
Anal. Calcd for C11H13N3: C, 70.56; H, 7.00; N, 22.44. Found: C,
70.35; H, 7.14; N, 22.51.
3-(1H-Pyrazol-1-yl)pyridine (19a)
White crystals; yield: 14.2 g (92%); mp 47–48 °C (Lit.20 50 °C); bp
140–142 °C/18.7 mbar.
Anal. Calcd for C7H6N4: C, 57.53; H, 4.14; N, 38.34. Found: C,
57.80; H, 4.02; N, 38.18.
Spectral and physical data are available in the literature.30
4-(1H-Imidazol-1-yl)isoquinoline (24)
3-(4-Methyl-1H-pyrazol-1-yl)pyridine (19b)
White crystals; yield: 18.3 g (94%); mp 67–68 °C.
Colorless oil; yield: 14.1 g (89%).
1H NMR (DMSO-d6): δ = 7.27 (s, 1 H), 7.63 (d, J = 8.0 Hz, 1 H),
7.67 (s, 1 H), 7.81 (t, J = 7.0 Hz, 1 H), 7.89 (t, J = 7.3 Hz, 1 H), 8.09
(s, 1 H), 8.30 (d, J = 7.9 Hz, 1 H), 8.61 (s, 1 H), 9.45 (s, 1 H).
13C NMR (DMSO-d6): δ = 121.4 (CH), 122.5 (CH), 128.5 (CH),
128.9 (C), 128.9 (CH), 129.3 (C), 129.9 (CH), 131.5 (C), 132.8
(CH), 139.1 (CH), 139.9 (CH), 153.5 (CH).
1H NMR (CDCl3): δ = 2.13 (s, 3 H), 7.33 (dd, J = 4.8, 8.0 Hz, 1 H),
7.54 (s, 1 H), 7.71 (s, 1 H), 7.97 (d, J = 8.1 Hz, 1 H), 8.47 (d, J = 3.8
Hz, 1 H), 8.91 (s, 1 H).
13C NMR (CDCl3): δ = 8.9 (CH3), 118.9 (C), 125.2 (CH), 125.9
(CH), 140.1 (CH), 142.7 (CH), 147.0 (CH).
MS (APCI): m/z = 160 (M + H+).
MS (APCI): m/z = 196 (M + H+).
Anal. Calcd for C9H9N3: C, 67.90; H, 5.70; N, 26.40. Found: C,
68.00; H, 5.63; N, 26.37.
Anal. Calcd for C12H9N3: C, 73.83; H, 4.65; N, 21.52. Found: C,
73.88; H, 5.00; N, 21.12.
3-(3,5-Dimethyl-1H-pyrazol-1-yl)pyridine (19c)
4-(1H-Pyrazol-1-yl)isoquinoline (25)
Colorless oil; yield: 2.26 g (13%).
White crystals; yield: 17.3 g (89%); mp 65–66 °C (Lit.27 67–71 °C).
1H NMR (CDCl3): δ = 2.28 (s, 3 H), 2.32 (s, 3 H), 6.02 (s, 1 H), 7.38
(qd, J = 0.6, 4.6 Hz, 1 H), 7.78 (dq, J = 1.5, 8.3 Hz, 1 H), 8.56 (dd,
J = 1.2, 4.8 Hz, 1 H), 8.71 (d, J = 2.1 Hz, 1 H).
13C NMR (CDCl3): δ = 12.4, 13.5, 107.8, 123.7, 131.8, 136.6, 139.7,
145.5, 148.1, 150.1.
1H NMR (DMSO-d6): δ = 6.58–6.72 (m, 1 H), 7.73–7.97 (m, 3 H),
7.97–8.08 (m, 1 H), 8.23–8.41 (m, 2 H), 8.64 (s, 1 H), 9.43 (s, 1 H).
13C NMR (DMSO-d6): δ = 107.6, 122.8, 128.4, 128.7, 129.1, 130.8,
132.2, 132.3, 138.9, 142.1, 153.1.
MS (APCI): m/z = 196 (M + H+).
MS (APCI): m/z = 174 (M + H+).
Anal. Calcd for C12H9N3: C, 73.83; H, 4.65; N, 21.52. Found: C,
73.68; H, 4.69; N, 21.63.
Anal. Calcd for C10H11N3: C, 69.34; H, 6.40; N, 24.26. Found: C,
69.26; H, 6.34; N, 24.40.
3-(1H-Imidazol-1-yl)quinoline (26)
3-(1H-1,2,4-Triazol-1-yl)pyridine (23)
White crystals; yield: 18.2 g (94%); mp 151–152 °C (Lit.28 149 °C).
White solid; yield: 11.97 g (82%); mp 80–81 °C (Lit.33 82–83 °C).
1H NMR (DMSO-d6): δ = 7.06–7.48 (m, 1 H), 7.71 (t, J = 7.2 Hz, 1
H), 7.80 (t, J = 7.2 Hz, 1 H), 7.94–8.07 (m, 2 H), 8.03 (d, J = 8.3 Hz,
1 H), 8.10 (d, J = 8.3 Hz, 1 H), 8.43–8.61 (m, 1 H), 9.31 (s, 1 H).
13C NMR (DMSO-d6): δ = 119.0, 125.7, 127.9, 128.3, 128.5, 129.3,
130.0, 130.9, 131.0, 136.6, 144.7, 146.5.
1H NMR (CDCl3): δ = 7.48 (d, J = 4.0 Hz, 1 H), 8.04 (d, J = 7.0 Hz,
1 H), 8.15 (s, 1 H), 8.63 (s, 1 H), 8.66 (s, 1 H), 9.00 (s, 1 H).
1H NMR (D2O): δ = 7.38 (dd, J = 4.7, 8.0 Hz, 1 H), 7.86 (d, J = 8.0
Hz, 1 H), 8.02 (s, 1 H), 8.34 (d, J = 4.6 Hz, 1 H), 8.56 (d, J = 2.0 Hz,
1 H).
MS (APCI): m/z = 196 (M + H+).
13C NMR (CDCl3): δ = 124.2 (CH), 127.6 (CH), 133.7 (C), 141.0
(CH), 141.3 (CH), 149.4 (CH), 153.19 (CH), 153.21 (CH).
MS (APCI): m/z = 147 (M + H+).
Anal. Calcd for C12H9N3: C, 73.83; H, 4.65; N, 21.52. Found: C,
73.81; H, 4.80; N, 21.39.
Anal. Calcd for C7H6N4: C, 57.53; H, 4.14; N, 38.34. Found: C,
57.71; H, 4.30; N, 37.99.
3-(1H-Pyrazol-1-yl)quinoline (27)
White crystals; yield: 17.5 g (90%); mp 123–124 °C (Lit.28 128 °C).
1H NMR (DMSO-d6): δ = 6.67 (s, 1 H), 7.67 (t, J = 7.3 Hz, 1 H),
7.67 (t, J = 7.2 Hz, 1 H), 7.89 (s, 1 H), 7.97–8.13 (m, 2 H), 8.64–
8.82 (m, 2 H), 9.51 (d, J = 2.5 Hz, 1 H).
13C NMR (DMSO-d6): δ = 109.0 (CH), 123.2 (CH), 127.9 (C),
128.1 (CH), 128.7 (CH), 128.9 (CH), 129.3 (CH), 129.6 (CH),
133.5 (C), 142.3 (CH), 143.2 (CH), 146.2 (C).
4-(1H-Imidazol-1-yl)pyridine (20)32
White solid; yield: 12.32 g (85%); mp 114–115 °C (Lit.33 115–116
°C).
1H NMR (DMSO-d6): δ = 7.22 (s, 1 H), 7.80 (d, J = 4.5 Hz, 2 H),
8.00 (s, 1 H), 8.64 (s, 1 H), 8.68 (d, J = 4.5 Hz, 2 H).
13C NMR (DMSO-d6): δ = 114.3 (CH), 117.7 (CH), 130.8 (CH),
MS (APCI): m/z = 196 (M + H+).
136.1 (CH), 143.5(C), 151.8 (CH).
Anal. Calcd for C12H9N3: C, 73.83; H, 4.65; N, 21.52. Found: C,
73.69; H, 4.55; N, 21.76.
MS (APCI): m/z = 146 (M + H+).
Anal. Calcd for C8H7N3: C, 66.19; H, 4.86; N, 28.95. Found: C,
66.07; H, 4.94; N, 28.63.
(1H-Azol-1-yl)piperidines 5–10; General Procedure
A suspension of 5% Pd/C (0.78–0.94 g, 1 g per 10 g of the substrate)
in a soln of (1H-azol-1-yl)pyridine 18–23 (0.05 mol) in MeOH (200
mL) was hydrogenated at 100 atm and 80 °C for 24 h. The catalyst
was filtered off, and the filtrate was evaporated to dryness to give
5–10. An analytical sample was prepared by distillation in vacuo.
4-(1H-Pyrazol-1-yl)pyridine (18)
White crystals; yield: 12.8 g (87%); mp 83–84 °C (Lit.33 84 °C).
Spectral and physical data are available in the literature.30
© Georg Thieme Verlag Stuttgart · New York
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2046
N. V. Shevchuk et al.
PAPER
3-(1H-Imidazol-1-yl)piperidine (8a)
13C NMR (CDCl3): δ = 25.7 (CH2), 31.4 (CH2), 46.1 (CH2), 52.3
(CH2), 58.9 (CH), 104.9 (CH), 127.2 (CH), 138.7 (d, J = 2.0 Hz,
CH).
Colorless oil; yield: 7.17 g (95%); bp 144–146 °C/0.13 mbar.
1H NMR (CDCl3): δ = 1.47–1.94 (m, 4 H), 2.12–2.21 (m, 1 H), 2.59
(dt, J = 1.9, 11.5 Hz, 1 H), 2.78 (t, J = 10.7 Hz, 1 H), 2.96–3.07 (m,
1 H), 3.22–3.33 (m, 1 H), 4.00 (dt, J = 4.0, 11.0 Hz, 1 H), 6.94 (s, 1
H), 7.02 (s, 1 H), 7.53 (s, 1 H).
13C NMR (CDCl3): δ = 25.7 (CH2), 32.2 (CH2), 46.0 (CH2), 53.4
(CH2), 54.9 (CH), 117.2 (CH), 129.0 (CH), 135.5 (CH).
MS (APCI): m/z = 152 (M + H+).
GC/MS: tR = 7.63 min; MS (EI): m/z (%) = 151 (M+, 20), 95 (26),
MS (APCI): m/z = 152 (M + H+).
GC/MS: tR = 6.15 min; MS (EI): m/z (%) = 121 (13), 95 (28), 83
(100), 82 (76), 81 (40), 68 (92).
Anal. Calcd for C8H13N3: C, 63.54; H, 8.67; N, 27.79. Found: C,
63.60; H, 8.77; N, 27.63.
3-(4-Methyl-1H-pyrazol-1-yl)piperidine (6b)
Colorless oil; yield: 7.51 g (91%).
1H NMR (CDCl3): δ = 1.44–1.65 (m, 1 H), 1.68–1.96 (m, 3 H), 2.03
(s, 3 H), 2.08–2.25 (m, 1 H), 2.61 (dt, J = 2.5, 11.8 Hz, 1 H), 2.89
(t, J = 10.2 Hz, 1 H), 2.94–3.03 (m, 1 H), 3.24–3.35 (m, 1 H), 4.07
(tt, J = 4.4, 10.8 Hz, 1 H), 7.18 (s, 1 H), 7.27 (s, 1 H).
82 (100), 68 (25).
Anal. Calcd for C8H13N3: C, 63.54; H, 8.67; N, 27.79. Found: C,
63.68; H, 8.43; N, 27.89.
3-(2-Methyl-1H-imidazol-1-yl)piperidine (8b)
Colorless oil; yield: 6.68 g (81%).
13C NMR (CDCl3): δ = 8.9 (CH3), 25.8 (CH2), 31.4 (CH2), 46.1
1H NMR (CDCl3): δ = 1.52–1.75 (m, 2 H), 1.75–1.90 (m, 1 H),
(CH2), 52.4 (CH2), 58.4 (C), 115.4 (CH), 125.9 (CH), 138.9 (CH).
MS (APCI): m/z = 166 (M + H+).
2
1.90–2. 15 (m, 2 H), 2.58 (t, J = 11.8 Hz, 1 H), 2.70 (t, 2J = 11.0
Hz, 1 H), 2.97–3.09 (m, 2 H), 3.12–3.22 (m, 2 H), 3.86–4.00 (m, 1
H), 6.87 (s, 1 H), 6.88 (s, 1 H).
13C NMR (CDCl3): δ = 13.2 (CH3), 26.0 (CH2), 32.2 (CH2), 45.9
(CH2), 52.8 (CH2), 53.8 (CH), 115.5 (CH), 127.2 (CH), 149.9 (C).
MS (APCI): m/z = 166 (M + H+).
GC/MS: tR = 6.97 min; MS (EI): m/z (%) = 135 (8), 109 (22), 95
(36), 83 (100), 82 (65), 68 (54), 39 (29).
Anal. Calcd for C9H15N3: C, 65.42; H, 9.15; N, 25.43. Found: C,
65.55; H, 8.99; N, 25.46.
3-(3,5-Dimethyl-1H-pyrazol-1-yl)piperidine (6c)
Colorless oil; yield: 6.44 g (72%).
Anal. Calcd for C9H15N3: C, 65.42; H, 9.15; N, 25.43. Found: C,
65.21; H, 9.29; N, 25.50.
1H NMR (CDCl3): δ = 1.48–1.62 (m, 1 H), 1.74–1.87 (m, 1 H),
1.86–1.99 (m, 1 H), 2.00–2.10 (m, 1 H), 2.17 (s, 3 H), 2.18 (s, 3 H),
2.37–2.55 (br s, 1 H), 2.65 (td, J = 2.7, 12.0 Hz, 1 H), 2.94–3.01 (m,
1 H), 3.01–3.12 (m, 2 H), 3.95 (tt, J = 4.8, 9.8 Hz, 1 H), 5.72 (s, 1 H).
13C NMR (CDCl3): δ = 10.7 (CH3), 13.5 (CH3), 25.9 (CH2), 31.1
(CH2), 45.9 (CH2), 51.7 (CH2), 54.9 (CH), 104.6 (CH2), 138.1 (C),
147.0 (C).
3-(2-Ethyl-1H-imidazol-1-yl)piperidine (8c)
Colorless oil; yield: 6.98 g (78%).
1H NMR (CDCl3): δ = 1.28 (t, J = 9.5 Hz, 3 H), 1.50–1.92 (m, 4 H),
1.94–2.09 (m, 1 H), 2.56 (dt, J = 2.5, 12.2 Hz, 1 H), 2.61–2.77 (m,
3 H), 2.98–3.07 (m, 1 H), 3.07–3.18 (m, 1 H), 3.86–4.01 (tt, J = 3.5,
11.4 Hz, 1 H), 6.85 (d, J = 1.2 Hz, 1 H), 6.90 (d, J = 1.2 Hz, 1 H).
13C NMR (CDCl3): δ = 12.2 (CH3), 20.2 (CH2), 26.0 (CH2), 32.5
(CH2), 45.9 (CH2), 52.9 (CH2), 53.1 (CH), 75.9 (CH2), 115.5 (CH),
127.2 (CH), 148.7 (C).
MS (APCI): m/z = 180 (M + H+).
Anal. Calcd for C10H17N3: C, 67.00; H, 9.56; N, 23.44. Found: C,
67.21; H, 9.63; N, 23.16.
MS (APCI): m/z = 180 (M + H+).
3-(1H-1,2,4-Triazol-1-yl)piperidine (10a)
White crystals; yield: 7.07 g (93%); mp 45–50 °C.
1H NMR (DMSO-d6): δ = 1.84–1.97 (m, 2 H, CH2), 1.97–2.10 (m,
1 H), 2.13–2.25 (m, 1 H), 2.84–2.99 (m, 1 H), 3.17–3.34 (m, 2 H),
3.49–3.58 (m, 1 H), 4.78–4.91 (m, 1 H), 8.31 (s, 1 H), 9.07 (s, 1 H).
Anal. Calcd for C10H17N3: C, 67.00; H, 9.56; N, 23.44. Found: C,
67.20; H, 9.33; N, 23.47.
3-(2-Isopropyl-1H-imidazol-1-yl)piperidine (8d)
White amorphous solid; yield: 7.82 g (81%).
1H NMR (CDCl3): δ = 1.24 (t, J = 6.8 Hz, 6 H), 1.50–1.72 (m, 2 H),
1.77 (d, 2J = 12.7 Hz, 1 H), 2.00 (d, 2J = 12.7 Hz, 1 H), 2.52 (t, 2J =
11.5 Hz, 1 H), 2.69 (t, 2J = 11.5 Hz, 1 H), 2.92–3.02 (m, 2 H), 3.02–
3.14 (m, 1 H), 3.92–4.01 (m, 1 H), 6.79 (s, 1 H), 6.87 (s, 1 H).
13C NMR (CDCl3): δ = 21.8 (CH3), 22.0 (CH3), 25.9 (CH), 26.1
(CH2), 32.7 (CH2), 45.9 (CH2), 52.9 (CH), 53.2 (CH2), 115.3 (CH),
127.1 (CH), 152.4 (C).
13C NMR (DMSO-d6): δ = 20.5 (CH2), 28.3 (CH2), 42.7 (CH2), 45.8
(CH2), 53.7 (CH), 143.2 (CH), 148.9 (CH).
MS (APCI): m/z = 153 (M + H+).
GC/MS: tR = 6.75 min; MS (EI): m/z (%) = 96 (6), 83 (100), 82 (38),
68 (33), 43 (20), 41 (15).
Anal. Calcd for C7H12N4: C, 55.24; H, 7.95; N, 36.81. Found: C,
55.44; H, 7.72; N, 36.84.
MS (APCI): m/z = 194 (M + H+).
GC/MS: tR = 8.18 min; MS (EI): m/z (%) = 193 (M+, 28), 83 (100),
56 (50), 43 (75), 39 (51).
4-(1H-Imidazol-1-yl)piperidine (7a)
White crystals; yield: 6.80 g (90%); mp 153–154 °C.
1H NMR (CDCl3): δ = 1.77 (dq, J = 3.4, 12.0 Hz, 3 H), 2.02 (d, J =
12.0 Hz, 2 H), 2.69 (dt, J = 2.0, 12.2 Hz, 2 H), 3.23–3.11 (m, 2 H),
3.97 (tt, J = 3.9, 12.0 Hz, 1 H), 6.93 (d, J = 1.1 Hz, 1 H), 7.00 (d, J =
1.1 Hz, 1 H), 7.51 (s, 1 H).
13C NMR (CDCl3): δ = 34.7 (CH2), 45.7 (CH2), 55.2 (CH), 116.6
(CH), 129.1 (CH), 135.2 (d, J = 2 Hz, CH).
Anal. Calcd for C11H19N3: C, 68.35; H, 9.91; N, 21.74. Found: C,
68.20; H, 10.04; N, 21.76.
3-(1H-Pyrazol-1-yl)piperidine (6a)
Colorless oil; yield: 7.09 g (94%).
1H NMR (CDCl3): δ = 1.49–1.66 (m, 1 H), 1.74–1.86 (m, 1 H),
1.87–2.07 (m, 2 H), 2.11–2.25 (m, 1 H), 2.63 (dt, J = 2.7, 12.0 Hz,
1 H), 2.92 (t, J = 10.9 Hz, 1 H), 2.95–3.06 (m, 1 H), 3.27–3.39 (m,
1 H), 4.08–4.24 (m, 1 H), 6.18–6.25 (m, 1 H), 7.42 (d, J = 1.5 Hz, 1
H), 7.47 (d, J = 1.5 Hz, 1 H).
MS (APCI): m/z = 152 (M + H+).
Anal. Calcd for C8H13N3: C, 63.54; H, 8.67; N, 27.79. Found: C,
63.31; H, 8.79; N, 27.90.
Synthesis 2012, 44, 2041–2048
© Georg Thieme Verlag Stuttgart · New York

PAPER
Azolylpiperidines
2047
4-(1H-Pyrazol-1-yl)piperidine (5a)
White crystals; yield: 6.31 g (83%); mp 53–54 °C; bp 108–110
°C/0.67 mbar.
1H NMR (DMSO-d6): δ = 1.65–1.85 (m, 3 H), 1.85–2.00 (m, 2 H),
2.52–2.64 (m, 2 H), 2.92–3.11 (m, 2 H), 4.09–4.28 (dt, J = 4.2, 11.6
Hz, 1 H), 6.22 (t, J = 2.0 Hz, 1 H), 7.42 (d, J = 1.5 Hz, 1 H), 7.73 (d,
J = 1.9 Hz, 1 H).
1H NMR (DMSO-d6): δ = 3.07–3.12 (br m, 2 H), 3.34–3.43 (m, 1
H), 3.43–3.53 (m, 1 H), 4.58–4.68 (m, 1 H), 5.98 (s, 1 H), 6.50 (t,
J = 7.3 Hz, 1 H), 6.55 (d, J = 7.8 Hz, 1 H), 6.70–7.00 (m, 3 H), 7.24
(s, 1 H), 7.71 (s, 1 H).
13C NMR (DMSO-d6): δ = 33.9 (CH2), 46.4 (CH2), 49.9 (CH), 113.9
(CH), 116.4 (CH), 117.9 (C), 118.6 (CH), 127.5 (CH), 128.6 (CH),
129.7 (CH), 136.6 (CH), 144.7 (C).
13C NMR (DMSO-d6): δ = 32.2 (CH2), 45.7 (CH2), 59.5 (CH), 105.0
(CH), 127.7 (CH), 138.4 (CH).
MS (APCI): m/z = 152 (M + H+).
MS (APCI): m/z = 200 (M + H+).
Anal. Calcd for C12H13N3: C, 72.33; H, 6.58; N, 21.09. Found: C,
72.25; H, 6.69; N, 21.06.
Anal. Calcd for C8H13N3: C, 63.54; H, 8.67; N, 27.79. Found: C,
63.65; H, 8.77; N, 27.58.
3-(1H-Pyrazol-1-yl)-1,2,3,4-tetrahydroquinoline (31)
White crystals; yield: 7.76 g (78%); mp 94–95 °C.
4-(1H-1,2,4-Triazol-1-yl)piperidine (9a)
1H NMR (DMSO-d6): δ = 3.09–3.20 (m, 1 H), 3.20–3.34 (m, 1 H),
3.34–3.49 (m, 1 H), 3.49–3.59 (m, 1 H), 4.67 (s, 1 H), 5.94 (s, 1 H),
6.25 (s, 1 H), 6.45–6.60 (m, 2 H), 6.85–7.03 (m, 2 H), 7.49 (s, 1 H),
7.74 (s, 1 H).
13C NMR (DMSO-d6): δ = 33.2 (CH2), 46.1 (CH2), 54.4 (CH), 105.5
(CH), 113.9 (CH), 116.4 (CH), 118.2 (C), 127.4 (CH), 128.8 (CH),
129.8 (CH), 138.9 (CH), 144.8 (C).
White crystals; yield: 7.08 g (92%); mp 63–64 °C.
1H NMR (CDCl3): δ = 1.75–1.90 (br m, 3 H), 1.92 (dq, J = 3.9, 11.2
Hz, 2 H), 2.24–2.11 (m, 2 H), 2.77 (t, J = 11.5 Hz, 2 H), 4.28 (tt, J =
4.2, 11.5 Hz, 1 H), 7.94 (s, 1 H), 8.10 (s, 1 H).
13C NMR (CDCl3): δ = 33.4 (CH2), 45.2 (CH2), 57.9 (CH), 140.7 (d,
J = 3 Hz, CH), 151.5 (d, J = 2 Hz, CH).
MS (APCI): m/z = 200 (M + H+).
MS (APCI): m/z = 153 (M + H+).
Anal. Calcd for C12H13N3: C, 72.33; H, 6.58; N, 21.09. Found: C,
72.51; H, 6.67; N, 20.82.
Anal. Calcd for C7H12N4: C, 55.24; H, 7.95; N, 36.81. Found: C,
55.40; H, 7.88; N, 36.68.
(1H-Azol-1-yl)quinolines and -isoquinolines 28–31; General
Procedure
Supporting Information for this article is available online at
A suspension of 5% Pd/C (0.98 g) in a soln of 24–27 (0.05 mol) in
MeOH (200 mL) was hydrogenated at 30 atm and 30 °C (monitored
by TLC). The catalyst was filtered off, and the filtrate was evapo-
rated to dryness to give 28–31. The crude 28 and 29 were triturated
with 10 M aq HCl and evaporated to dryness. The hydrochlorides
thus obtained were recrystallized (MeOH).
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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References
(1) (a) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem.
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4-(1H-Imidazol-1-yl)-1,2,3,4-tetrahydroisoquinoline Hydro-
chloride (28·HCl)
White crystals; yield: 8.83 g (75%); mp 203–204 °C.
1H NMR (DMSO-d-): δ = 3.79–4.03 (m, 2 H), 3.35 (d, 2J = 16.0 Hz,
1 H), 4.45 (d, 2J = 16.0 Hz, 1 H), 6.23 (s, 1 H), 7.06 (d, J = 7.3 Hz,
1 H), 7.31–7.40 (m, 1 H), 7.40–7.51 (m, 2 H), 7.77 (d, J = 1.2 Hz, 1
H), 7.88 (d, J = 1.4 Hz, 1 H), 9.27 (s, 1 H), 10.30–11.50 (br s, 2 H).
13C NMR (DMSO-d6): δ = 43.6 (CH2), 44.5 (CH2), 53.1 (CH), 121.0
(CH), 121.5 (CH), 127.7 (CH), 128.3 (CH), 128.8 (CH), 129.4 (C),
129.8 (CH), 130.9 (C), 137.1 (CH).
(3) Wink, M. In Modern Alkaloids: Structure, Isolation,
Synthesis and Biology; Fattorusso, E.; Taglialatela-Scafati,
O., Eds.; Wiley–VCH: Weinheim, 2008.
MS (APCI): m/z = 200 (M + H+).
(4) Cui, J. J.; Tran-Dube, M.; Shen, H.; Nambu, M.; Kung, P.-
P.; Pairish, M.; Jia, L.; Meng, J.; Funk, L.; Botrous, I.;
McTigue, M.; Grodsky, N.; Ryan, K.; Padrique, E.; Alton,
G.; Timofeevski, S.; Yamazaki, S.; Li, Q.; Zou, H.;
Christensen, J.; Mroczkowski, B.; Bender, S.; Kania, R. S.;
Edwards, M. P. J. Med. Chem. 2011, 54, 6342.
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Spencer, K. B.; Young, J.; Pan, B.-S.; Marshall, C. G.; Lu,
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Anal. Calcd for C12H14ClN3: C, 61.15; H, 5.99; Cl, 15.04; N, 17.83.
Found: C, 61.29; H, 5.88; Cl, 15.00; N, 17.83.
4-(1H-Pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline Hydrochlo-
ride (29·HCl)
White crystals; yield: 8.36 g (71%); mp 223–224 °C.
1H NMR (DMSO-d6): δ = 3.69–3.86 (m, 2 H), 4.35 (d, 2J = 16.0 Hz,
1 H), 4.45 (d, 2J = 16.0 Hz, 1 H), 6.01 (t, J = 6.0 Hz, 1 H), 6.35 (t,
J = 2.1 Hz, 1 H), 6.91 (d, J = 7.7 Hz, 1 H), 7.22–7.31 (m, 1 H), 7.31–
7.42 (m, 2 H), 7.55 (d, J = 1.4 Hz, 1 H), 8.06 (d, J = 1.9 Hz, 1 H),
9.31–10.7 (br s, 2 H).
13C NMR (DMSO-d6): δ = 44.0 (CH2), 44.9 (CH2), 54.6 (CH), 106.2
(CH), 127.3 (CH), 127.6 (CH), 128.3 (CH), 128.8 (CH), 129.7 (C),
131.2 (CH), 132.7 (C), 140.3 (CH).
MS (APCI): m/z = 200 (M + H+).
(6) Cho, S. Y.; Han, S.-Y.; Ha, J. D.; Ryu, J. W.; Lee, C. O.;
Jung, H.; Kang, N. S.; Kim, H. R.; Koh, J. S.; Lee, J. Bioorg.
Med. Chem. Lett. 2010, 20, 4223.
Anal. Calcd for C12H14ClN3: C, 61.15; H, 5.99; Cl, 15.04; N, 17.83.
Found: C, 61.00; H, 6.04; Cl, 15.57; N, 17.39.
(7) Shen, D.-M.; Shu, M.; Mills, S. G.; Chapman, K. T.;
Malkowitz, L.; Springer, M. S.; Gould, S. L.; DeMartino, J.
A.; Siciliano, S. J.; Kwei, G. Y.; Carella, A.; Carver, G.;
3-(1H-Imidazol-1-yl)-1,2,3,4-tetrahydroquinoline (30)
White crystals; yield: 6.56 g (66%); mp 103–105 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2041–2048

2048
N. V. Shevchuk et al.
PAPER
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