Synthesis of 1-(pyrrolidin-2-ylmethyl)-1H-azoles and their piperidine-derived homologues

Article abstract of DOI:10.2478/s11532-013-0344-y

A convenient preparation of 1-(pyrrolidin-2-yl)-1H-pyrazoles, -imidazoles, and -1H-1,2,4-triazoles, 1-(piperidin-2-yl)-1H-pyrazoles and -1H-1,2,4-triazoles, and 1-(piperidin-3-yl)-1H-1,2,4-triazoles by alkylation of azoles (viz. pyrazoles, imidazoles, and triazoles) with N-Cbz-prolinol mesylate or its analogues and subsequent deprotection is reported. The two-step method allows for synthesis of the title compounds in 16-65% yields. The utility of the procedure has been demonstrated by multigram preparation of a 15-member building block mini-library for the lead-oriented synthesis of compound libraries. These building blocks perfectly fit the definition of low-molecular-weight hydrophilic three-dimensional templates, which leave much room for the lead-oriented synthesis of the compound libraries. [Figure not available: see fulltext.]

Full text of DOI:10.2478/s11532-013-0344-y

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Central European Journal of Chemistry
Synthesis of 1-(pyrrolidin-2-ylmethyl)-1H-azoles
and their piperidine-derived homologues
Research Article
Sergey Zhersh1,2, Oleksandr V. Karpenko1, Vasyl Ripenko1,
Andrey A. Tolmachev1,2, Oleksandr O. Grygorenko2*
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Received 10 July 2013; Accepted 2 September 2013
Abstract:ꢀ
A convenient preparation of 1-(pyrrolidin-2-yl)-1H-pyrazoles, -imidazoles, and -1H-1,2,4-triazoles, 1-(piperidin-2-yl)-1H-pyrazoles
and -1H-1,2,4-triazoles, and 1-(piperidin-3-yl)-1H-1,2,4-triazoles by alkylation of azoles (viz. pyrazoles, imidazoles, and triazoles) with
1-Cbz-prolinol mesylate or its analogues and subsequent deprotection is reported. The two-step method allows for synthesis of the
title compounds in 16–65% yields. The utility of the procedure has been demonstrated by multigram preparation of a 15-member
EXLOGLQJꢀEORFNꢀPLQLꢁOLEUDU\ꢀIRUꢀWKHꢀOHDGꢁRULHQWHGꢀV\QWKHVLVꢀRIꢀFRPSRXQGꢀOLEUDULHVꢂꢀ7KHVHꢀEXLOGLQJꢀEORFNVꢀSHUIHFWO\ꢀğWꢀWKHꢀGHğQLWLRQꢀRIꢀ
low-molecular-weight hydrophilic three-dimensional templates, which leave much room for the lead-oriented synthesis of the compound
libraries.
Keywords: $]ROHVꢀľꢀ6DWXUDWHGꢀQLWURJHQꢀKHWHURF\FOHVꢀľꢀ0ROHFXODUꢀULJLGLW\ꢀľꢀ/HDGꢁRULHQWHGꢀV\QWKHVLVꢀľꢀ$ON\ODWLRQ
© Versita Sp. z o.o.
nicotine 1 and anabasine 2, Fig. 2). Other examples
comprise of synthesis of compounds of established
1. Introduction
Contemporary drug discovery relies heavily on the biological activity, e.g. inhibitors of deacetylases (3)
careful choice of chemotypes that can serve as the [10], tyrosine kinases (4) [11], or thrombin-activated
starting points for the design and synthesis of compound ¿EULQRO\VHꢀ ꢁ5) [12]. In this work, we have focused on
libraries. The so-called lead-likeness methodology the scaffolds 6 – 11 obtained by linking the azole and
for drug design, which relies on a number of concepts pyrrolidine (or piperidine) heterocyclic rings by a single
such as privileged structures, three-dimensional methylene unit (Table 1). Some examples of biologically
molecular shape, conformational restriction, and relevant compounds derived from these templates are
control of physicochemical properties of the potential given in Fig. 2. Recently, derivatives of 7 have attracted
lead compounds, have received much attention in the additional attention as enantioselective catalysts [13,14]
chemical literature recently [1–4]. The need for the “lead- and chiral ionic liquids [15–19].
oriented synthesis” [5] has guided the efforts of organic
chemists towards novel low-molecular-weight hydrophilic
three-dimensional scaffolds.
2. Experimental procedures
Among the numerous possible ways to design such
structures we have turned our attention to the approach 2.1. General
shown schematically in Fig. 1: a highly polar aromatic 7KHꢀ VROYHQWVꢀ ZHUHꢀ SXUL¿HGꢀ DFFRUGLQJꢀ WRꢀ WKHꢀ VWDQGDUGꢀ
heterocycle is mounted onto
a three-dimensional procedures. Compounds 13, 17, and 18 were prepared
VDWXUDWHGꢀWHPSODWHꢀEHDULQJꢀDQꢀHDVLO\ꢀPRGL¿DEOHꢀIXQFWLRQDOꢀ according to the methods reported in the literature [20].
group (such as amino) [6–9]. The use of this approach is All other starting materials were purchased from Acros,
encountered among natural compounds (e.g. alkaloids Merck, Fluka, and UkrOrgSyntez. All the chiral starting
* E-mail: gregor@univ.kiev.ua
67

Synthesis of 1-(pyrrolidin-2-ylmethyl)-1H-azoles
and their piperidine-derived homologues
materials were used as racemates. Analytical TLC was (CH2Cl2 – MeOH – Et3N (9 : 1 : 0.1)) to give 6 – 11
performed using Polychrom SI F254 plates. Column (Table 1ꢃꢄꢀ 7Rꢀ REWDLQꢀ WKHꢀ ¿QDOꢀ FRPSRXQGVꢀ DVꢀ
chromatography was performed using Kieselgel Merck dihydrochlorides, 6 – 11 (0.05 mol) were taken up in
60 (230–400 mesh) as the stationary phase. 1H and 13
NMR spectra were recorded on a Bruker 170 Avance
C
10% HCl in dioxane (50 mL) and evaporated to dryness.
1-(Pyrrolidin-2-ylmethyl)-1H-pyrazole (6a): yield
1
500 spectrometer (at 499.9 MHz for Protons and 58 g (44%). Yellowish liquid. H NMR (CDCl3), į 7.47
124.9 MHz for Carbon-13). Chemical shifts are reported (s, 1H), 7.42 (s, 1H), 6.20 (s, 1H), 4.15 (dd, J = 13.6 Hz
1
LQꢀ SSPꢀ GRZQ¿HOGꢀ IURPꢀ 706ꢀ ꢁ H, 13C) as an internal and 4.8 Hz, 1H), 3.99 (dd, J = 13.6 Hz and 7.9 Hz, 1H),
standard. Elemental analyses were performed at 3.49–3.56 (m, 1H), 2.91–2.96 (m, 1H), 2.83–2.89 (m,
the Laboratory of Organic Analysis, Department of 1H), 2.14 (s, 1H), 1.79–1.90 (m, 1H), 1.64–1.79 (m,
Chemistry, Kyiv National Taras Shevchenko University. 2H), 1.36–1.44 (m, 1H). 13C NMR (CDCl3), į 139.5,
Mass spectra were recorded on an Agilent 1100 LCMSD 129.7, 105.3, 58.6, 57.1, 46.4, 29.0, 25.2. Anal. calcld.
SL instrument (chemical ionization (CI)) or Agilent 5890 for C8H13N3 C 63.55, H 8.67, N 27.79. Found C 63.94,
Series II 5972 GCMS instrument (electron impact H 8.30, N 27.96. MS (APCI): 152 (MH+).
ionization (EI)).
4-Methyl-1-(pyrrolidin-2-ylmethyl)-1H-pyrazole
(6b):yield106g(65%).Yellowishliquid. 1HNMR(CDCl3),
2.2. General procedure for the synthesis of 6–11 į 7.22 (s, 1H), 7.14 (s, 1H), 4.03 (dd, J = 13.6 Hz and
To a suspension of NaH (0.12 mol) in DMF (200 mL), 4.4 Hz, 1H), 3.87 (dd, J = 13.6 Hz and 7.7 Hz, 1H),
compound 14, 15, or 16 (0.1 mol) in DMF (100 mL) 3.42–3.48 (m, 1H), 2.87–2.92 (m, 1H), 2.78–2.84 (m,
was added. After the hydrogen evolution was complete, 1H), 2.28 (s, 1H), 1.99 (s, 3H), 1.75–1.84 (m, 1H), 1.62–
compound 13, 17, or 18 was added, and the resulting 1.73 (m, 2H), 1.30–1.39 (m, 1H). 13C NMR (CDCl3), į
mixture was heated at 60°C (14) or 100°C (15 or 16) for 139.7, 128.5, 115.7, 58.5, 56.8, 46.3, 28.9, 25.1, 8.8.
8 h, then cooled and evaporated in vacuo. The residue Anal. calcld. for C9H15N3 C 65.42, H 9.15, N 25.43.
was quenched with H2O (1000 mL) and EtOAc (300 mL). Found C 65.63, H 8.94, N 25.11. MS (APCI): 166 (MH+).
The organic phase was separated, and aqueous phase
3,5-Dimethyl-1-(pyrrolidin-2-ylmethyl)-1H-
was extracted with EtOAc (2×300 mL). The combined pyrazole (6c) dihydrochloride: yield 29 g (19%).
1
organic extracts were washed with brine (2×400 mL), White powder. Mp 178–179 °C. H NMR (DMSO-d6), į
dried over Na2SO4, and evaporated to dryness. The 10.59 (br s, 1H), 9.93 (br s, 1H), 9.83 (br s, 1H), 6.12
UHVLGXHꢀ ZDVꢀ SXUL¿HGꢀ E\ꢀ FROXPQꢀ FKURPDWRJUDSK\ꢀ (s, 1H), 4.58 (dd, J = 14.7 Hz and 7.5 Hz, 1H), 4.44 (dd,
(Hexanes–EtOAc(1:1)asaneluent)andthendissolved J = 14.7 Hz and 5.7 Hz, 1H), 3.86–3.95 (m, 1H), 3.21–
in MeOH (400 mL). 10% Pd-C (2–3 g) was added, and 3.28 (m, 1H), 3.07–3.14 (m, 1H), 2.35 (s, 3H), 2.20 (s,
the mixture was hydrogenated at 1 bar until the reaction 3H), 1.91–2.04 (m, 2H), 1.80–1.89 (m, 1H), 1.64–1.72
was complete (NMR control, usually 1 day). The catalyst (m, 1H). 13C NMR (DMSO-d6), į 146.4, 143.2, 106.7,
ZDVꢀ ¿OWHUHGꢀ RIIꢂꢀ WKHꢀ ¿OWUDWHꢀ ZDVꢀ HYDSRUDWHGꢂꢀ DQGꢀ WKHꢀ 58.9, 47.9, 44.9, 28.0, 22.8, 12.6, 11.3. Anal. calcld. for
FUXGHꢀSURGXFWꢀZDVꢀSXUL¿HGꢀE\ꢀFROXPQꢀFKURPDWRJUDSK\ꢀ C10H19Cl2N3 C 47.63, H 7.59, Cl 28.12, N 16.66. Found
C 47.50, H 7.74, Cl 27.89, N 16.38. MS (APCI): 180
(MH+).
1-(Pyrrolidin-2-ylmethyl)-1H-imidazole
(7a):
yield 82 g (54%). White amorphous solid. 1H NMR
(D2O), į 7.83 (s, 1H), 7.29 (s, 1H), 7.14 (s, 1H), 4.49
(dd, J = 14.7 Hz and 4.5 Hz, 1H), 4.41 (dd, J = 14.7 Hz
and 8.9 Hz, 1H), 4.00–4.07 (m, 1H), 3.41–3.46 (m,
1H), 3.32–3.38 (m, 1H), 2.24–2.30 (m, 1H), 2.03–2.18
Figure 1. Scaffolds for lead-oriented synthesis By combining
saturated and aromatic nitrogen heterocycles.
N
N
R
H2N
Cl
N
O
N
O
N
N
NH2
O
R
N
NH
OH
N
N
NH
H
N
O
N
N
N
N
Cl
HO
F
3, R= H, Me, CF3
1
2
4
5
Figure 2. %LRORJLFDOO\ꢀDFWLYHꢀGHULYDWLYHVꢀRIꢀWKHꢀVFDIIROGVꢀGHğQHGꢀLQꢀ)LJꢁꢀ1 (the scaffolds are shown in red).
68

S. Zhersh et al.
Table 1. Synthesis of 1-(pyrrolidinylmethyl)-1H-azoles and their piperidine-derived homologues 6 – 11. Conditions: ꢂLꢃꢀ1D+ꢀꢂꢄꢀHTꢃꢅꢀ'0)ꢅꢀꢆꢇŞ&ꢀ
ꢀ
ꢀꢀꢀꢀꢀꢀRUꢀꢄꢇꢇŞ&ꢅꢀꢈbKꢉꢀꢂLLꢃꢀ+2ꢅꢀꢄꢇꢊꢀ3Gꢋ&ꢅꢀ0H2+ꢅꢀꢄꢀDWPꢅꢀUWꢅꢀPRQLWRUHGꢀE\ꢀ105ꢁ
Entry No.
Substrate
Azole
Product
Yield, %
OMs
N
N
1
44
N
N
N
N
H
14a
N
H
Cbz
6a
13
2
3
ꢆꢌ
N
N
N
H
14b
N
H
6b
N
N
19
N
N
H
N
H
6c
14c
N
N
N
N
N
4
5
6
ꢌꢍ
43
ꢄꢆ
N
H
N
H
15a
7a
N
N
N
H
H
7b
7c
15b
N
N
N
N
H
N
H
15c
N
N
7
17
N
N
N
H
N
H
7d
8a
15d
N
N
N
N
8
ꢌꢆ
23
22
ꢎꢆ
N
H
N
H
16a
N
N
N
N
9
N
N
H
N
H
8b
16b
N
N
N
Cl
10
11
N
H
N
N
H
14a
Cbz
17
9a
N
N
N
H
14c
N
N
H
9b
69

Synthesis of 1-(pyrrolidin-2-ylmethyl)-1H-azoles
and their piperidine-derived homologues
ContinuedTable 1. Synthesis of 1-(pyrrolidinylmethyl)-1H-azoles and their piperidine-derived homologues 6 – 11. Conditions: ꢂLꢃꢀ 1D+ꢀ ꢂꢄꢀ HTꢃꢅꢀ '0)ꢅꢀ
ꢀ
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢆꢇŞ&ꢀRUꢀꢄꢇꢇŞ&ꢅꢀꢈbKꢉꢀꢂLLꢃꢀ+2ꢅꢀꢄꢇꢊꢀ3Gꢋ&ꢅꢀ0H2+ꢅꢀꢄꢀDWPꢅꢀUWꢅꢀPRQLWRUHGꢀE\ꢀ105ꢁ
Entry No.
Substrate
Azole
Product
Yield, %
N
N
N
N
N
12
22
N
H
N
H
16a
10a
N
N
N
N
N
N
13
14
15
ꢆꢇ
ꢌꢎ
ꢍꢌ
N
H
N
H
16b
10b
N
OMs
N
N
N
N
H
N
N
H
16a
Cbz
18
11a
N
N
N
N
N
N
H
N
H
16b
11b
(m, 2H), 1.79–1.87 (m, 1H). 13C NMR (D2O), į 138.0, (m, 2H), 2.87–2.95 (m, 1H), 1.94 (br s, 1H), 1.77–1.92
128.5, 120.1, 60.4, 47.3, 45.9, 27.6, 22.8. Anal. calcld. (m, 2H), 1.69–1.77 (m, 1H), 1.36–1.44 (m, 1H), 1.31
for C8H13N3 C 63.55, H 8.67, N 27.79. Found C 63.42, (d, J = 7.0 Hz, 3H). 1.29 (d, J = 7.0 Hz, 3H). 13C NMR
H 8.76, N 27.65. MS (APCI): 152 (MH+).
(CDCl3), į 153.1, 127.2, 119.0, 59.1, 50.9, 46.4, 29.3,
2-Methyl-1-(pyrrolidin-2-ylmethyl)-1H-imidazole 26.0, 25.1, 22.1, 22.0. Anal. calcld. for C11H19N3 C 68.35,
(7b): yield 71 g (43%). Yellowish liquid. 1H NMR H 9.91, N 21.74. Found C 68.07, H 10.02, N 21.70. MS
(DMSO-d6), į 7.05 (s, 1H), 6.70 (s, 1H), 3.71–3.80 (m, (APCI): 194 (MH+).
2H), 3.28 (quint, J = 6.7 Hz, 1H), 3.09 (br s, 1H), 2.79 (t,
1-(Pyrrolidin-2-ylmethyl)-1H-1,2,4-triazole (8a):
1
J = 6.7 Hz, 2H), 2.29 (s, 3H), 1.65–1.77 (m, 2H), 1.55– yield 56.6 g (56%). Yellowish liquid. H NMR (CDCl3),
1.64 (m, 1H), 1.28–1.36 (m, 1H). 13C NMR (DMSO-d6), į 8.15 (s, 1H), 7.90 (s, 1H), 4.17 (dd, J = 13.8 Hz and
į 144.3, 126.4, 120.4, 58.9, 50.8, 46.4, 29.5, 25.6, 13.4. 3.6 Hz, 1H), 4.05 (dd, J = 13.8 Hz and 8.0 Hz, 1H),
Anal. calcld. for C9H15N3 C 65.42, H 9.15, N 25.43. 3.37 (quint, J = 6.6 Hz, 1H), 2.92 (td, J = 6.6 Hz and
Found C 65.17, H 9.49, N 25.36.
MS (EI): 165 (M+), 96, 70.
1.0 Hz, 2H), 2.34 (br s, 1H), 1.88–1.94 (m, 1H), 1.67–
1.80 (m, 2H), 1.40–1.47 (m, 1H). 13C NMR (CDCl3), į
2-Ethyl-1-(pyrrolidin-2-ylmethyl)-1H-imidazole 151.7, 143.5, 57.4, 54.7, 46.4, 28.9, 25.3. Anal. calcld.
(7c): yield 23.5 g (16%).White amorphous solid. 1H for C7H12N4 C 55.24, H 7.95, N 36.81. Found C 54.99,
NMR (D2O), į 7.18 (s, 1H), 7.02 (s, 1H), 4.29–4.38 (m, H 8.17, N 36.52. MS (APCI): 153 (MH+).
2H), 3.91 (quint, J = 7.4 Hz, 1H), 3.39–3.44 (m, 1H),
3,5-Dimethyl-1-(pyrrolidin-2-ylmethyl)-1H-1,2,4-
3.27–3.33 (m, 1H), 2.77 (q, J = 7.3 Hz, 2H), 2.19–2.25 triazole (8b): yield 35 g (23%). Yellowish liquid. 1H NMR
(m, 1H), 2.00–2.17 (m, 2H), 1.74–1.82 (m, 1H), 1.28 (t, (CDCl3), į 3.89 (dd, J = 13.7 Hz and 4.9 Hz, 1H), 3.79
J = 7.3 Hz, 3H). 13C NMR (D2O), į 150.6, 125.6, 120.4, (dd, J = 13.7 Hz and 7.8 Hz, 1H), 3.49 (quint, J = 6.8 Hz,
59.8, 46.3, 45.8, 27.7, 22.6, 19.2, 11.2. Anal. calcld. 1H), 2.81–2.90 (m, 2H), 2.34 (s, 3H), 2.23 (s, 3H),
for C10H17N3 C 67.00, H 9.56, N 23.44. Found C 67.32, 2.18 (br s, 1H), 1.78–1.85 (m, 1H), 1.61–1.77 (m, 2H),
H 9.47, N 23.15. MS (APCI): 180 (MH+).
1.32–1.40 (m, 1H). 13C NMR (CDCl3), į 159.4, 152.6,
2-Isopropyl-1-(pyrrolidin-2-ylmethyl)-1H- 58.0, 53.1, 46.4, 29.1, 25.3, 13.9, 12.1. Anal. calcld.
imidazole (7d): yield 14.5 g (17%). Yellowish liquid. for C9H16N4 C 59.97, H 8.95, N 31.08. Found C 59.96,
1H NMR (CDCl3), į 6.93 (s, 1H), 6.86 (s, 1H), 3.86 (dd, H 8.61, N 31.33. MS (EI): 180 (M+), 111, 70.
J = 13.8 Hz and 5.4 Hz, 1H), 3.77 (dd, J = 13.8 Hz and
2-(1H-pyrazol-1-ylmethyl)piperidine (9a): yield
7.8 Hz, 1H), 3.34 (quint, J = 6.4 Hz, 1H), 2.94–3.06 24.4 g (22%). Yellowish liquid. 1H NMR (CDCl3), į 7.51
70

S. Zhersh et al.
N
OTs
Boc
1. Pyrazole,
NaH, MeCN
1. Imidazole,
NaH, MeCN
N
N
N
2. HCl, H2O
2. TFA, CH2Cl2
N
NH
NH
7a
12
6a
Scheme 1. ꢄꢋꢂ3\UUROLGLQ\OPHWK\OꢃꢋꢄH-azoles reported in the literature.
(s, 1H), 7.40 (s, 1H), 6.22 (s, 1H), 4.10 (dd, J = 13.6 Hz (m, 2H), 2.52–2.59 (m, 1H), 2.01 (d, J = 14.8 Hz, 1H),
and 4.1 Hz, 1H), 3.94 (dd, J = 13.6 Hz and 8.7 Hz, 1.89 (d, J = 12.5 Hz, 1H), 1.72–1.81 (m, 1H), 1.41 (qd,
1H), 2.97–3.04 (m, 2H), 2.55 (td, J = 11.5 Hz and J = 12.5 Hz and 3.5 Hz, 1H). 13C NMR (D2O), į 144.6,
2.5 Hz, 1H), 2.04 (br s, 1H), 1.79 (d, J = 11.5 Hz, 1H), 142.1, 53.6, 45.9, 44.1, 33.5, 25.2, 21.3. Anal. calcld. for
1.60 (t, J = 14.0 Hz, 2H), 1.27–1.46 (m, 2H), 1.14 (qd, C8H16Cl2N4 C 40.18, H 6.74, N 23.43. Found C 39.87,
J = 11.8 Hz and 3.4 Hz, 1H). 13C NMR (CDCl3), į 139.8, H 6.51, N 23.62. MS (APCI): 167 (MH+).
130.1, 105.2, 58.1, 56.5, 46.6, 30.1, 26.0, 24.3. Anal.
3-[(3,5-Dimethyl-1H-1,2,4-triazol-1-yl)methyl]
calcld. for C9H15N3 C 65.42, H 9.15, N 25.43. Found piperidine (11b): yield 87.6 g (45%). Yellowish liquid. 1H
C 65.73, H 9.06, N 25.62.
MS (APCI): 166 (MH+).
NMR (CDCl3), į 3.70–3.82 (m, 2H), 2.86 (t, J = 13.6 Hz,
2H), 2.50 (td, J = 11.8 Hz and 2.1 Hz), 2.30 (s, 3H),
2-[(3,5-Dimethyl-1H-pyrazol-1-yl)methyl] 2.22 (s, 3H), 1.97 (br s, 1H), 1.56–1.71 (m, 3H), 1.31–
1
piperidine (9b): yield 12 g (26%). Yellowish liquid. H 1.40 (m, 1H), 1.04–1.13 (m, 1H). 13C NMR (CDCl3), į
NMR (CDCl3), į 5.73 (s, 1H), 3.78–3.88 (m, 2H), 2.97– 159.2, 152.1, 51.4, 50.2, 46.8, 37.6, 28.8, 25.5, 13.7,
3.06 (m, 2H), 2.56 (td, J = 11.8 Hz and 2.5 Hz, 1H), 11.9. Anal. calcld. for C10H18N4 C 61.82, H 9.34, N 28.84.
2.48 (br s, 1H), 2.20 (s, 3H), 2.18 (s, 3H), 1.72–1.80 (m, Found C 61.64, H 9.48, N 29.08. MS (APCI): 195 (MH+).
1H), 1.53–1.60 (m, 2H), 1.25–1.47 (m, 2H), 1.10–1.20
(m, 1H). 13C NMR (CDCl3), į 147.7, 139.5, 104.7, 56.7,
54.1, 46.6, 30.2, 26.0, 24.4, 13.5, 11.2. Anal. calcld.
for C11H19N3 C 68.35, H 9.91, N 21.74. Found C 68.26,
H 10.15, N 21.51. MS (APCI): 194 (MH+).
3. Results and discussion
Only a few reports on the synthesis of compounds
6 – 11 can be found in the literature: namely, the
preparation of compounds 6a [13] and 7a [14,18] has
been documented (Scheme 1). Both compounds were
obtained by alkylation of the corresponding azole anions
with N-Boc-prolinol tosylate (12). For the preparation
of compounds 6 – 8, we have used an analogous
method commencing from N-Cbz-prolinol mesylate (13)
(Table 1), which is more reactive than N-Boc-prolinol
tosylate, is shelf-stable and can be easily obtained on
a hundred gram scale [20]. Azoles 14 – 16 were used
to generate anions for the reaction with 13 (Table 1,
Entries 1–9).
It was found that anions of pyrazoles 14a–c were
more reactive towards alkylation with 13 than anions
of imidazoles 15a–d or 1,2,4-triazoles 16a,b. Whereas
13 and anions of 14a–c reacted smoothly in DMF
already at 60°C, in the case of 15a–d or 16a,b, the
reaction was successful only at 100°C. It should be
noted that in the case of 16, the alkylation proceeded
regioselectively at N-1 atom of the heterocycle. The
corresponding Cbz derivatives were not characterized
but subjected to catalytic hydrogenation (10% Pd-C,
MeOH, 1 atm, rt) to give pure 6 – 8 in 16–65% overall
yields.
2-(1H-1,2,4-triazol-1-ylmethyl)piperidine
(10a):
1
yield 24.7 g (22%). Yellowish liquid. H NMR (CDCl3),
į 8.04 (s, 1H), 7.89 (s, 1H), 4.08 (dd, J = 13.6 Hz and
4.2 Hz, 1H), 3.99 (dd, J = 13.6 Hz and 8.3 Hz, 1H),
2.93–3.00 (m, 2H), 2.52 (td, J = 11.7 Hz and 2.6 Hz,
1H), 1.75–1.79 (m, 2H), 1.52–1.61 (m, 2H), 1.24–1.40
(m, 2H), 1.06–1.16 (m, 1H). 13C NMR (CDCl3), į 152.3,
143.7, 55.8, 55.5, 46.5, 30.0, 25.9, 24.2. Anal. calcld.
for C8H14N4 C 57.81, H 8.49, N 33.70. Found C 58.06,
H 8.49, N 34.01. MS (APCI): 167 (MH+).
2-[(3,5-Dimethyl-1H-1,2,4-triazol-1-yl)methyl]
piperidine (10b): yield 19 g (60%). Yellowish liquid. 1H
NMR (CDCl3), į 3.81–3.90 (m, 2H), 2.98–3.04 (m, 2H),
2.57 (td, J = 11.6 Hz and 1.7 Hz, 1H), 2.38 (s, 3H), 2.29
(s, 3H), 2.03 (br s, 1H), 1.79 (d, J = 13.5 Hz, 1H), 1.56–
1.62 (m, 2H), 1.28–1.46 (m, 2H), 1.11–1.21 (m, 1H). 13
C
NMR (CDCl3), į 159.5, 152.6, 56.1, 53.7, 46.5, 30.0,
25.8, 24.1, 13.7, 11.9. Anal. calcld. for C10H18N4 C 61.82,
H 9.34, N 28.84. Found C 61.89, H 9.07, N 29.10. MS
(APCI): 195 (MH+).
3-(1H-1,2,4-triazol-1-ylmethyl)piperidine
(11a)
dihydrochloride: yield 150 g (52%). White powder. Mp
198–200 °C. 1H NMR (D2O), į 9.65 (s, 1H), 8.69 (s, 1H),
4.48–4.52 (m, 2H), 3.46 (t, J = 11.7 Hz, 2H), 2.91–3.00
71

Synthesis of 1-(pyrrolidin-2-ylmethyl)-1H-azoles
and their piperidine-derived homologues
Table 2. 3K\VLFRFKHPLFDOꢀSDUDPHWHUVꢀRIꢀN-methyl derivatives of the
amines 6 – 11.
9a,b and 10a,b were obtained in 22–60% yields. The
PHWKRGꢀ ZDVꢀ HTXDOO\ꢀ HI¿FLHQWꢀ IRUꢀ WKHꢀ SUHSDUDWLRQꢀ RIꢀ
1-(pyrrolidin-2-yl)-1H-1,2,4-triazoles 11a,b (45–52%
yields) starting from mesylate 18 [20] and anions of
16a,b (Table 1, Entries 14 and 15).
Parameter
Value range
ꢄꢆꢌĮꢎꢇꢏ
Molecular weight (MW)
Calculated logarithm of octanol-water
Compounds 6 – 11 were obtained as rather
hygroscopic liquids or oils, therefore any aqueous
work-up should be avoided during their isolation and/
RUꢀ SXUL¿FDWLRQꢄꢀ ,Qꢀ VRPHꢀ FDVHVꢂꢀ WKHꢀ FRPSRXQGVꢀ ZHUHꢀ
isolated as dihydrochlorides; 10% HCl in dioxane was
used for that purpose. Although the synthetic scheme
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products in a single run.
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Number of H-bond donors
Number of H-bond acceptors
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ꢎꢄꢁꢇĮꢑꢍꢁꢇ
Analysis of the physicochemical properties of the
simplest (N-methyl) derivatives of the amines 6 – 11
(Table 2ꢃꢀVKRZHGꢀWKDWꢀWKHVHꢀEXLOGLQJꢀEORFNVꢀSHUIHFWO\ꢀ¿Wꢀ
WKHꢀGH¿QLWLRQꢀRIꢀORZꢇPROHFXODUꢇZHLJKWꢀK\GURSKLOLFꢀWKUHHꢇ
dimensional templates [21]. They provide an opportunity
for the lead-oriented synthesis of the compound libraries
even if the strictest current criteria of lead-likeness are
considered[5] (Fig. 3).
4. Conclusions
A convenient approach to multigram synthesis of
1-(pyrrolidin-2-yl)-1H-pyrazoles,
-imidazoles,
and
-1H-1,2,4-triazoles, 1-(piperidin-2-yl)-1H-pyrazoles and
-1H-1,2,4-triazoles, and 1-(piperidin-3-yl)-1H-1,2,4-
triazoles was developed. The method allowed for the
preparation of the target compounds in 16–65% yields.
The building blocks obtained comply with the strictests
GH¿QLWLRQVꢀ RIꢀ WHPSODWHVꢀ IRUꢀ OHDGꢇRULHQWHGꢀ V\QWKHVLVꢀ RIꢀ
3K\VLFRFKHPLFDOꢀ SDUDPHWHUVꢀ RIꢀ N-methyl derivatives
of the amines 6 – 11 (black dots within the ellipse),
shown together with the lead-likeness criteria as given
by Churcher et al. [ꢌ] (dark grey rectangle). The white
arrow shows that there is much room for the design of
compound libraries.
Figure 3.
As was described previously by our group [20], the compound libraries.
the mesylate of benzyl 2-(hydroxymethyl)piperidine-
1-carboxylate is not stable enough to be isolated.
Therefore the corresponding chloride 17 was used in the Acknowledgements
reaction with the azole anions (Table 1, Entries 10–13).
This change did not affect the outcome of the reaction The authors thank Prof. Igor V. Komarov for his help
sequence described above: the corresponding products with Instant Jchem calculations.
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