E
V. Lellek et al.
Letter
Synlett
30 min of stirring at 0 °C, the reaction was quenched with drop-
wise addition of 30 wt% aqueous solution of NaOH (53.3 g, 0.4
mol, 4 equiv) over 1 h. The resulting heterogeneous mixture
was warmed briefly to 45–55 °C and then cooled to 25 °C. The
reaction mixture was stirred overnight to afford a suspension
which was filtered. The collected solid was washed with water
(60 mL) to afford crude product as wet solids. The wet solid in
EtOH (35 mL) was heated at reflux for 30 min, cooled to 25 °C,
stirred at this temperature for 1 h, and filtered. The collected
solid was washed with EtOH (4–6 mL) and dried for 24 h at 65 °C
under vacuum (2 mbar) to afford pyrazoles 14 or 7.
2.34 (d, J = 0.6 Hz, 3 H, CH3-C5). 13C NMR (150 MHz, CDCl3): δ =
128.7 (1′ and 3′), 127.9 (4′), 125.6 (2′), 102.1 (4), 11.8 (CH3), C3
and C5 missing. MS (LR-APCI+): m/z calcd for C10H10N2: 158.1;
found: 158.9 [M + H]+.
Analytical Data for Compound 17b
1H NMR (600 MHz, CDCl3): δ = 7.75 (dt, J = 7.0, 1.5 Hz, 2 H, 2′),
7.43 (tt, J = 7.1, 1.4 Hz, 2 H, 3′), 7.39 (tt, J = 7.3, 1.5 Hz, 1 H, 4′),
6.25 (br s, 1 H, 1), 2.27 (s, 3 H, CH3-C5). 13C NMR (150 MHz,
CDCl3): δ = 145.4 (3), 143.8 (5), 130.4 (1′ phenyl), 128.7 (4′ phe-
nyl), 128.6 (3′ phenyl), 127.4 (2′ phenyl), 92.8 (4), 11.3 (Me). MS
(LR-APCI+): m/z calcd for C10H9BrN2: 236.0; found: 236.8 [M +
H]+, 238.8 [M + 2 + H]+.
Analytical Data for Compound 14a
1H NMR (600 MHz, CDCl3): δ = 8.42 (br s, 1 H, 1). 7.72 (dt, J = 7.0,
1.2 Hz, 2 H, 2′ phenyl), 7.44 (tt, J = 7.2, 1.1 Hz, 2 H, 3′ phenyl),
7.39 (tt, J = 7.4, 1.2 Hz, 1 H, 4′ phenyl), 2.72 (t, J = 6.1 Hz, 2 H, 4),
2.70 (t, J = 6.2 Hz, 2 H, 7), 1.87–1.80 (m, 4 H, 6 and 5). 13C NMR
(150 MHz, CDCl3): δ = 145.0 (7a), 143.2 (3), 129.2 (4′ phenyl),
129.1 (1′ phenyl), 129.0 (3′ phenyl), 127.4 (2′ phenyl), 114.0
(3a), 22.9 (5), 21.9 (6), 21.7 (7), 21.5 (4). MS (LR-APCI+): m/z
calcd for C13H14N2: 198.1; found: 199.0 [M + H]+.
General Procedure for Preparation of Pyrazoles 7, 14a and
21a–o by Oxidation of Pyrazolines 13 and 20a–p with
Oxygen
A solution of pyrazoline HCl salt 20 or 13 (2 mmol) in DMSO (10
mL) under 1 atm of pure O2 gas was heated at 85 °C for 1–2 h or
until the consumption of the starting material. The reaction
solution was cooled to ambient temperature and poured into
water (200 mL) with stirring to afford a suspension. The suspen-
sion was stirred at ambient temperature for 1 h, and solids were
collected by filtration and washing with water. The solids were
dried under vacuum at 45 °C overnight to afford pyrazoles 7,
14a, and 21.
Procedure for the Synthesis of 3,5-Substituted Pyrazole 17a
by Catalytic Reduction of 4-Bromopyrazol 17b
A suspension of hydrazine hydrochloride (6.85 g, 0.1 mol,
1 equiv) in MeOH (30 mL) is warmed under argon atmosphere
to 55 °C. Acetone (5.80 g, 0.1 mol, 1 equiv) is mixed with the
stirred suspension, then, within 30 min neat benzaldehyde
(10.61 g, 0.1 mol, 1 equiv) is added dropwise to the reaction
mixture. After 10 min of stirring the resulting orange solution is
cooled to 0 °C. Bromine (31.96 g, 0.2 mol, 2 equiv) is added
dropwise to the reaction mixture while stirring at temperature
lower than 15 °C. After more than 30 min of the continuing stir-
ring at 0–5 °C the reaction is quenched by slowly (over 1 h)
adding of the 30% aqueous NaOH solution (53.33 g, 0.4 mol, 4
equiv). The resulting heterogeneous mixture is extracted with
ethyl acetate (100 mL). From the separated organic layer solvent
is removed. The residue, pyrazole 17b, is submitted to a cata-
lytic hydrogenation at 4 bar/80 °C with 5% wet Pd on activated
charcoal (3 g, 1.4 mmol, 0.014 equiv) in EtOH (50 mL). After 10–
20 h of hydrogenation, the reaction mixture is cooled, filtered
over Celite, the cake is washed with EtOH (50 mL), and from
combined mother liquors containing the product solvent is
removed in vacuo. The isolated material is hydrobromide salt of
pyrazole 7a which is converted into free base by the basic
extraction work-up in ethyl acetate/10% w/w aqueous solution
of sodium carbonate.
Analytical Data for Pyrazole 7
1H NMR (300 MHz, CDCl3): δ = 13.33 und 13.00 (br s, NH two
tautomers), 7.61–7.67 (m, 4 H, 2′, 3′, 5′, and 6′ phenyl), 4.55 (s, 2
H, 4), 3.63 (t, J = 5.7 Hz, 2 H, 7), 2.85–2.91 (m, 5 H, MeSO2, and
6). 13C NMR (75 MHz, CDCl3): δ = 142.37 (3), 141.21 (7a), 135.17
(1′ phenyl), 129.74 (q, J = 32.6 Hz, 4′ phenyl), 126.41 (2′ and 6′
phenyl), 125.85 (q, J = 3.9 Hz, 3′ and 5′ phenyl), 124.10 (q, J =
287.5 Hz, CF3), 109.61 (3a), 43.09 (4), 42.86 (6), 36.93 (MeSO2),
22.77 (7). 19F NMR (282 MHz, CDCl3): δ = –62.60. MS (LR-APCI+):
m/z calcd for C14H14F3N3O2S: 345.1; found: 346.1 [M + H]+.
Analytical Data for Pyrazoline 13
1H NMR (300 MHz, DMSO-d6): δ = 7.87 (s, 2′, 3′ 5′, and 6′phe-
nyl), 4.80 (br d, J = 10.27 Hz, 1 H, 3), 3.91 4.07 (m, 2 H, 4 and 6),
3.62–3.78 (m, 1 H, 3a), 3.08 (br t, J = 11.65 Hz, 1 H, 4), 3.01 (s, 3
H, MeSO2), 2.85–3.01 (m, 2 H, 6), 2.65–2.79 (m, 2 H, 7). 13C NMR
(75 MHz, DMSO-d6): δ = 172.67 (7a), 138.98 (br s, 1′ phenyl),
130.01 (q, J = 31.7 Hz, 3′ and 5′ phenyl), 129.95 (2′ and 6′ phe-
nyl), 126.90 (q, J = 3.3 Hz, 3′ and 5′ phenyl), 124.49 (q, J = 272.6
Hz, CF3), 63.54 (3), 51.92 (3a), 49.01 (4), 44.82 (6), 37.34
(MeSO2), 27.96 (7). MS (LR-APCI+): m/z calcd for C14H16N3O2S:
347.1; found: 348.1 [M
C14H16N3O2S·HCl: 9.25%; found: 9.79%.
+
H]+; titration Cl–: calcd for
Analytical Data for Compound 17a
1H NMR (600 MHz, CDCl3): δ = 7.71 (d, J = 7.1 Hz, 2 H, 2′), 7.44 (t,
J = 7.5 Hz, 2 H, 3′), 7.31 (tt, J = 7.4, 1.2 Hz, 1 H, 4′), 6.36 (s, 1 H, 4),
(16) Detailed procedures along with full analytical data are available
in the Supporting Information.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–E