1
and 32b (32a : 32b 1 : 0.21 by H NMR spectroscopy) as a white
(1R*,2R*,3R*/S*)-1-(Benzylthio)-2-chloro-N-(4-fluorophenyl)-3-
methylcyclopropanecarboxamide 56a, (1R*,2R*,3S*/R*)-
1-(benzylthio)-2-chloro-N-(4-fluorophenyl)-3-
methylcyclopropanecarboxamide 56b & 2-(benzylthio)-3-
chloro-N-(4-fluorophenyl)pent-2-enamide 57
solid (0.20 g, 94%), mp 98–100 ◦C; (Found C, 54.77; H, 4.30; N,
10.66. C18H17ClN3O2SF requires C, 54.89; H, 4.35; N, 10.67%);
max/cm-1 (KBr) 3298 (NH), 3029 (CH), 1668 (CO), 1552 (N N),
=
n
1514, 1407, 1226, 1038 (SO);
(3R*,4R*,5R*)-3-(Benzylthio)-4-chloro-N-(4-fluorophenyl)-4,5-
dihydro-5-methyl-3H-pyrazole-3-carboxamide 44a and (3R*,4R*,
5S*)-3-(benzylthio)-4-chloro-N-(4-fluorophenyl)-4,5-dihydro-5-
methyl-3H-pyrazole-3-carboxamide 44b (1 : 0.1 mixture of di-
astereomers) (0.37 g, 1.0 mmol) was heated at reflux in toluene
(30 mL) for 2 h. Following removal of the solvent by evaporation
under reduced pressure, the crude product was obtained as a pale
Major diastereomer 32a. dH (300 MHz, CDCl3) 1.52 [3H, d,
J 7.5, C(5)CH3], 4.07 (1H, d, A of AB system, JAB 12.8, SCH2),
4.45 (1H, d, B of AB system, JAB 12.8, SCH2), 4.75 [1H, d, J 3.6,
C(4)H], 5.25 [1H, dq, J 3.6, 7.5, C(5)H], 7.04-7.13 (2H, m, ArH)‡,
7.31-7.40 (5H, m, ArH)‡, 7.49-7.64 (2H, m, ArH)‡, 8.90 (1H, br s,
NH).
dC (75.5 MHz, DMSO-d6) (signals for major diastereomer 32a
only detected) 15.8 [CH3, C(5)CH3], 54.1, (CH2, SCH2), 61.3 [CH,
C(5)H], 90.0 [CH, C(4)H], 107.1 [C, C(3)], 115.6 [CH, d, 2JCF 22,
1
brown oil (56a : 56b : 57 1 : 0.8 : 0.6 by H NMR spectroscopy).
Purification by column chromatography using hexane–ether (gra-
dient elution 0–2% ether) as eluent gave 56a and 56b as a clear oil
and a 1 : 0.8 mixture (by 1H NMR spectroscopy) of diastereomers
(0.12 g, 35%); nmax/cm-1 (KBr) 3281 (NH), 3067 (CH), 2930 (CH),
1652 (CO), 1510;
3
aromatic C(3¢)H], 124.1 [CH, d, JCF 8, aromatic C(2¢)H], 128.7,
129.1, 130.9 (3 ¥ CH, 3 ¥ aromatic CH), 131.2, 134.0 (2 ¥ C, 2 ¥
aromatic C), 159.4 [C, d, 1JCF 244, aromatic C(4¢)], 162.4 (C, CO).
Minor diastereomer 32b. dH (300 MHz, CDCl3) 1.87 [3H, d,
J 7.3, C(5)CH3], 4.05 (1H, d, A of AB system, JAB 12.8, SCH2),
4.48 (1H, d, B of AB system, JAB 12.8, SCH2), 4.78-4.82 [1H,
m, C(5)H], 5.32 [1H, d, J 5.5, C(4)H], 7.04-7.13 (2H, m, ArH)‡,
7.31-7.40 (5H, m, ArH)‡, 7.49-7.64 (2H, m, ArH)‡, 9.14 (1H, br s,
NH).
Major diastereomer 56a: dH (300 MHz, CDCl3) 1.36 [3H, d, J
6.6, C(3)CH3], 2.14 [1H, dq, J 8.1, 6.3, C(3)H], 3.91 (1H, d, A of
AB system, JAB 12.6, one of SCH2), 3.97 (1H, d, B of AB system,
J
AB 12.6, one of SCH2), 4.22 [1H, d, J 8.1, C(2)H], 6.90-7.34 (9H,
m, ArH)§, 9.05 (1H, br s, NH); dC (75.5 MHz, CDCl3) 7.9 [CH3,
C(3)CH3], 26.8 [CH, C(3)H], 34.8 (CH2, SCH2), 36.6 [C, C(1)],
44.2 [CH, C(2)H], 166.5 (C, CO).
Minor diastereomer 56b: dH (300 MHz, CDCl3) 1.20 [3H, d,
J 6.3, C(3)CH3], 1.88 [1H, dq, J 9.9, 6.6, C(3)H], 3.96 (2H, s,
SCH2), 4.22 [1H, d, J 6.0, C(2)H], 6.90-7.34 (9H, m, ArH)§, 8.91
(1H, br s, NH); dC (75.5 MHz, CDCl3) 9.2 [CH3, C(3)CH3], 33.8
[CH, C(3)H], 35.9 (CH2, SCH2), 38.2 [C, C(1)], 43.5 [CH, C(2)H],
163.7 (C, CO).
HRMS (ES+): Exact mass calculated for C18H18NO2S35ClF
[(M+H)+–N2], 366.0731. Found 366.0727; m/z (ES+) 396.2
{[(C18H17N3O2S37ClF)+H+], 2%}, 394.2 {[(C18H17N3O2S35-
ClF)+H+], 8%}, 368.2 {[(C18H17NO2S37ClF)+H+], 18%}, 366.2
{[(C18H17NO2S35ClF)+H+], 40%}, 220.2 (100%).
N-(4-Fluorophenyl)-5-methyl-1H-pyrazole-3-carboxamide 38
The aromatic signals were not distinguished in the 13C NMR
spectrum for the two diastereomers and were seen at dC 113.7
[CH, d, 2JCF 21, aromatic C(3¢)H], 119.5 [CH, d, 3JCF 8, aromatic
C(2¢)H], 125.8, 125.9, 127.0, 127.1, 127.3 (5 ¥ CH, 5 ¥ aromatic
CH), 131.7, 135.3, 135.5 (3 ¥ C, 3 ¥ aromatic C), 157.6 [C, d, 1JCF
243, aromatic C(4¢)].
An excess of an ethereal solution of diazoethane [pre-
pared from N-ethyl-N-nitrosourea (0.77 g, 6.6 mmol)] was
added to
a
solution of N-(4-fluorophenyl)-Z-3-chloro-2-
(benzenesulfinyl)propenamide 13 (0.30 g, 0.9 mmol) in ether
(30 mL) cooled in an ice-salt bath while stirring. The reaction
solution was allowed to return slowly to room temperature while
stirring for 4 h. The solvent was removed by evaporation at
reduced pressure to give 38 as a yellow oil. Following purification
by column chromatography using hexane–ethyl acetate (gradient
elution 5–40% ethyl acetate) as eluent, the pyrazole 38 was obtained
as an off-white solid (0.10 g, 49%), mp 196–197 ◦C; (Found
C, 60.18; H, 4.67; F, 8.91. C11H10FN3O requires C, 60.27; H,
4.60; F, 8.67%); nmax/cm-1 (KBr) 3380 (NH), 3193 (NH), 3121,
2986 (CH), 1662 (CO), 1555, 1509, 1412, 1218; dH (300 MHz,
DMSO-d6) 2.34 [3H, s, C(5)CH3], 6.54 [1H, s, C(4)H], 7.13-7.27
(2H, m, ArH), 7.81-7.93 (2H, m, ArH), 10.09 (1H, br s, NH of
carboxamide), 13.12 [1H, br s, N(1)H]; dC (75.5 MHz, DMSO-d6)
HRMS (ES+): Exact mass calculated for C18H18NOS35ClF
(M+H)+, 350.0782. Found 350.0777; m/z (ES+) 352.1
{[(C18H17NOS37ClF)+H+], 38%}, 350.1 {[(C18H17NOS35ClF)+H+],
100%}, 90.9 (14%).
57 was also isolated from this reaction as a white solid (0.02 g,
5%) as a single stereoisomer; nmax/cm-1 (KBr) 3245 (NH), 3068
(CH), 2972 (CH), 1641 (CO), 1507; dH (300 MHz, CDCl3) 1.20
[3H, t, J 7.3, C(5)H3], 2.80 [2H, q, J 7.3, C(4)H2], 3.97 (2H, s,
SCH2), 6.93-7.06 (2H, m, ArH), 7.20-7.40 (7H, m, ArH), 7.83
(1H, br s, NH); dC (75.5 MHz, CDCl3) 13.4 [CH3, C(5)H3],
2
32.3 [CH2, C(4)H2], 38.4 (CH2, SCH2), 116.0 [CH, d, JCF 22,
3
aromatic C(3¢)H], 121.9 [CH, d, JCF 8, aromatic C(2¢)H], 126.1
2
10.7 [CH3, C(5)CH3], 105.0 [CH, C(4)H], 115.4 [CH, d, JCF 22,
[C, C(2)], 128.0, 129.2, 129.3 (3 ¥ CH, 3 ¥ aromatic CH), 133.8,
137.5 (2 ¥ C, 2 ¥ aromatic C), 153.6 [C, C(3)], 159.9 [C, d,
1JCF 244, aromatic C(4¢)], 163.3 (C, CO); HRMS (ES+): Exact
mass calculated for C18H18NOS35ClF (M+H)+, 350.0782. Found
350.0796; m/z (ES+) 352.0 {[(C18H17NOS37ClF)+H+], 38%}, 350.0
{[(C18H17NOS35ClF)+H+], 100%}.
3
aromatic C(3¢)H], 122.2 [CH, d, JCF 8, aromatic C(2¢)H], 135.6
(C, aromatic C), 140.6, 147.2 [2 ¥ C, C(3) & C(5)], 158.4 [C, d, 1JCF
239, aromatic C(4¢)], 160.9 (C, CO); HRMS (ES+): Exact mass
calculated for C11H11N3OF [M+H]+, 220.0886. Found 220.0897;
m/z (ES+) 220.2 {[(C11H10N3OF)+H+], 100%}, 272.1.
§ The aromatic signals were indistinguishable for the two diastereomers in
the 1H NMR spectrum.
‡ The aromatic signals were indistinguishable for the two diastereomers.
This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2735–2748 | 2745
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