M. A. Chowdhury et al. / Bioorg. Med. Chem. 16 (2008) 8882–8888
8887
5.3.1. 4-[2-(4-Methanesulfonylphenyl)-5-trifluoromethyl-2H-
pyrazol-3-yl]-1-methyl-1,2,3,6-tetrahydropyridine (11a)
Yield, 99%; white solid; mp 153–155 °C; IR (film) 1317, 1165
fluxed for 3 h using a modified literature method.19 The reaction
mixture was cooled to 25 °C prior to evaporated to dryness in
vacuo. A solution of saturated NaCO3 (20 mL) was added and
the mixture was extracted with EtOAc (3 ꢁ 25 mL). The com-
bined organic extracts were washed successively with water
and then brine, and the EtOAc fraction was dried (MgSO4). Filtra-
tion and removal of the solvent from the organic fraction in va-
cuo afforded the impure product which was purified by silica gel
column chromatography. Elution with EtOAc/methanol (1:1, v/v)
furnished the respective 1,2,3,6-tetrahydropyridine product 13a
or 13b. Some physical and spectroscopic data for 13a and 13b
are listed below.
(SO2) cmꢀ1 1H NMR (CDCl3 + DMSO-d6) d 2.25–2.29 (m, 2H, tetra-
;
hydropyridyl H-3), 2.37 (s, 3H, NMe)ß 2.56 (t, 2H, J = 5.5 Hz, tetra-
hydropyridyl H-2), 3.02–3.06 (m, 2H, tetrahydropyridyl H-6), 3.09
(s, 3H, SO2Me), 5.82–5.86 (m, 1H, tetrahydropyridyl H-5) 6.59 (s,
1H, pyrazole H-4), 7.76 (d, 2H, J = 8.5 Hz, phenyl H-2, H-6), 8.05
(d, J = 8.5 Hz, 2H, phenyl H-3, H-5); MS (M+H)+ 386.09. Anal. Calcd
for C17H18F3N3O2S: C, 52.98; H, 4.71; N, 10.90. Found: C, 52.94; H,
4.93; N, 11.09.
5.3.2. 4-[5-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-3-
trifluoromethylpyrazol-1-yl]benzenesulfonamide (11b)
Yield, 90%; white solid; mp 243–245 °C; IR (film) 3322 (broad
5.5.1. 4-[2-(4-Methanesulfonylphenyl)-5-trifluoromethyl-2H-
pyrazol-3-yl]-1,2,3,6-tetrahydropyridine (13a)
NH2), 1325, 1145 (SO2) cmꢀ1
;
1H NMR (CDCl3 + DMSO-d6) d
Yield, 55%; brown solid; mp 88–91 °C; IR (film) 3337 (NH),
1320, 1160 (SO2) cmꢀ1; 1H NMR (CDCl3) d 2.11–2.23 (m, 2H, tetra-
hydropyridyl H-3), 2.65 (br s, 1H, tetrahydropyridyl NH that ex-
changes with D2O), 2.98 (t, 2H, J = 5.5 Hz, tetrahydropyridyl H-2),
3.08 (s, 3H, SO2Me), 3.42–3.51 (m, 2H, tetrahydropyridyl H-6),
5.90–5.98 (m, 1H, tetrahydropyridyl H-5) 6.58 (s, 1H, pyrazole H-
4), 7.77 (d, 2H, J = 8.5 Hz, phenyl H-2, H-6), 8.04 (d, J = 8.5 Hz, 2H,
phenyl H-3, H-5); MS (M+H)+ 372.08. Anal. Calcd for
2.13–2.19 (m, 2H, tetrahydropyridyl H-3), 2.26 (s, 3H, NMe)ß 2.47
(t, 2H, J = 5.5 Hz, tetrahydropyridyl H-2), 2.93–2.96 (m, 2H, tetra-
hydropyridyl H-6), 5.78–5.79 (m, 1H, tetrahydropyridyl H-5),
6.58 (s, 1H, pyrazole H-4), 7.28 (s, 2H, SO2NH2 that exchanges with
D2O), 7.58 (d, 2H, J = 8.5 Hz, phenyl H-3, H-5), 7.95 (d, J = 8.5 Hz,
2H, phenyl H-2, H-6); MS (M+H)+ 387.12. Anal. Calcd for
C16H17F3N4O2S: C, 49.73; H, 4.43; N, 14.50. Found: C, 49.55; H,
4.75; N, 14.40.
C
16H16F3N3O2Sꢂ1/3H2O: C, 50.92; H, 4.45; N, 11.13. Found: C,
51.26; H, 4.72; N, 10.85.
5.4. General procedure for the synthesis of N-ethoxycarbonyl-
1,2,3,6-tetrahydropyridines (12a–b)
5.5.2. 4-[5-(1,2,3,6-Tetrahydropyridin-4-yl)-3-
trifluoromethylpyrazol-1-yl]benzenesulfonamide (13b)
Yield, 33%; brown solid; IR (film) 3320 (broad NH), 1350, 1150
(SO2) cmꢀ1; 1H NMR (CDCl3 + DMSO-d6) d 1.71–1.82 (m, 2H, tetra-
hydropyridyl H-3), 2.06 (t, 2H, J = 5.5 Hz, tetrahydropyridyl H-2),
2.50–2.61 (m, 2H, tetrahydropyridyl H-6), 5.35–5.45 (m, 1H, tetra-
hydropyridyl H-5), 6.15 (s, 1H, pyrazole H-4), 6.80 (s, 2H, SO2NH2
that exchanges with D2O), 7.18 (d, 2H, J = 8.5 Hz, phenyl H-3, H-
5), 7.56 ppm (d, J = 8.5 Hz, 2H, phenyl H-2, H-6); 13C NMR
(DMSO-d6) d 27.9 (tetrahydropyridyl C-3), 42.0 (tetrahydropyridyl
C-2 or C-6), 44.6 (tetrahydropyridyl C-6 or C-2), 104.9 (pyrazole C-
4), 123.0 (pyrazole C-5), 124.8 (CF3), 125.3 (phenyl C-3, C-5), 126.9
(phenyl C-2, C-6), 132.2 (tetrahydropyridyl C-5), 141.5 (phenyl C-
4), 142.1 (tetrahydropyridyl C-4), 143.9 (phenyl C-1), 146.5 (pyra-
zole C-3); MS (M+H)+ 373.08.
Ethyl chloroformate (2.23 mL, 23.37 mmol) was added drop
wise to a stirred solution of a N-methyl-1,2,3,6-tetrahydropyridine
11a or 11b (7.79 mmol) in 1,2-dichloroethane (30 mL) at 25 °C fol-
lowing a procedure analogous to a literature method.19 The reac-
tion was allowed to proceed at reflux with stirring for 12 h, and
the solvent was removed in vacuo to afford the crude product.
Purification by silica gel column chromatography using EtOAc/hex-
anes (2:1, v/v) as eluent furnished the respective N-ethoxycar-
bonyl-1,2,3,6-tetrahydropyridine 12a or 12b. Some physical and
spectroscopic data for 12a and 12b are listed below.
5.4.1. 4-[2-(4-Methanesulfonylphenyl)-5-trifluoromethyl-2H-
pyrazol-3-yl]-1-ethoxycarbonyl-1,2,3,6-tetrahydropyridine (12a)
Yield, 95%; viscous oil; IR (film) 1693 (CO), 1325, 1153 (SO2)
cmꢀ1 1H NMR (CDCl3) d 1.27 (t, 3H, J = 7.1 Hz, CH2CH3), 2.11–
;
5.6. 4-[2-(4-Methanesulfonylphenyl)-5-trifluoromethyl-2H-
pyrazol-3-yl]-1-nitroso-1,2,3,6-tetrahydropyridine (14)
2.29 (m, 2H, tetrahydropyridyl H-3), 3.12 (s, 3H, SO2Me), 3.51–
3.65 (m, 2H, tetrahydropyridyl H-2), 4.02–4.12 (m, 2H, tetrahydro-
pyridyl H-6), 4.17 (q, 2H, J = 7.1 Hz, CH2CH3), 5.82–6.02 (m, 1H, tet-
rahydropyridyl H-5) 6.62 (s, 1H, pyrazole H-4), 7.74 (d, 2H,
J = 8.5 Hz, phenyl H-2, H-6), 8.07 (d, J = 8.5 Hz, 2H, phenyl H-3, H-
5); MS (M+Na)+ 466.09.
4-[2-(4-Methanesulfonylphenyl)-5-trifluoromethyl-2H-pyra-
zol-3-yl]-1,2,3,6-tetrahydropyridine (13a, 0.83 g, 2.24 mmol) was
added to a solution of NaOMe (2.24 mmol, 0.5 mL of a 25% w/v
solution in MeOH) and diethyl ether (10 mL) with stirring at
25 °C. Acetonitrile (10 mL) was then added to the reaction mixture
to increase the solubility of 13a. This mixture was purged with dry
nitrogen gas for 5 min, and then the reaction was allowed to pro-
ceed under an atmosphere of nitric oxide (40 psi internal pressure)
with stirring at 25 °C for 48 h. Removal of the solvents in vacuo
gave a the dark brown residue that was purified by silica gel col-
umn chromatography using a EtOAc/hexane (1:1, v/v) as eluent
to yield the N-nitroso product (14) in 53% yield, mp 190–192 °C;
5.4.2. 4-[2-(4-Sulfamoylphenyl)-5-trifluoromethyl-2H-pyrazol-
3-yl]-1-ethoxycarbonyl-1,2,3,6-tetrahydropyridine (12b)
Yield, 60%; viscous oil; IR (film) 3310 (broad NH2), 1708 (CO),
1377, 1160 (SO2) cmꢀ1 1H NMR (CDCl3) d 1.25 (t, 3H, J = 7.3 Hz,
;
CH2CH3), 2.13–2.21 (m, 2H, tetrahydropyridyl H-3), 3.54 (t, 2H,
J = 5.5 Hz, tetrahydropyridyl H-2), 4.04–4.10 (m, 2H, tetrahydropyr-
idylH-6), 4.13 (q, 2H, J = 7.3 Hz, CH2CH3), 5.49 (s, 2H, SO2NH2 thatex-
changes with D2O), 5.85–5.94 (m, 1H, tetrahydropyridyl H-5), 6.59
(s, 1H, pyrazole H-4), 7.63 (d, 2H, J = 8.5 Hz, phenyl H-2, H-6), 8.01
(d, J = 8.5 Hz, 2H, phenyl H-3, H-5); MS (M+Na)+ 467.05.
IR (film) 1320, 1160 (SO2) cmꢀ1 1H NMR (CDCl3) d 2.45–2.55 (m,
;
2H, tetrahydropyridyl H-3), 3.12 (s, 3H, SO2Me), 4.30–4.38 (m,
2H, tetrahydropyridyl H-6), 4.43 (t, 2H, J = 5.5 Hz, tetrahydropyr-
idyl H-2), 5.95–6.0 (m, 1H, tetrahydropyridyl H-5) 6.66 (s, 1H, pyr-
azole H-4), 7.73 (d, 2H, J = 8.5 Hz, phenyl H-2, H-6), 8.09 (d,
J = 8.5 Hz, 2H, phenyl H-3, H-5); MS (M+Na)+ 423.02. Anal. Calcd
for C16H15F3N4O3S: C, 48.00; H, 3.78; N, 13.99. Found: C, 48.07;
H, 4.03; N, 13.81.
5.5. General Procedure for the synthesis of 1,2,3,6-
tetrahydropyridines (13a–b)
A solution of a N-ethoxycarbonyl-1,2,3,6-tetrahydropyridine
12a or 12b (6 mmol) in hydrochloric acid (10 N, 10 mL) was re-