D. Castagnolo et al. / Bioorg. Med. Chem. 17 (2009) 5716–5721
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5.2. Microwave irradiation experiments
C19H18ClN3O: C, 67.15; H, 5.34; N, 12.37. Found: C, 67.28; H,
5.35; N, 12.39.
Microwave irradiation was conducted using a CEM Discover
Synthesis Unit (CEM Corp., Matthews, NC). The machine consists
of a continuous focused microwave power delivery system with
operator selectable power output (0–300 W). The temperature of
the contents of the vessels was monitored using a calibrated infra-
red temperature sensor mounted under the reaction vessel. All
experiments were performed using the stirring option whereby
the contents of the vessels were stirred by means of a rotating
magnetic plate located below the floor of the microwave cavity
and a Teflon-coated magnetic stir bar in the vessel.
Compound 5e: Yield: 50%. 1H NMR (CDCl3): d (ppm) 7.91 (2H, d,
J = 8.53 Hz, Ph), 7.44 (2H, d, J = 8.53 Hz, Ph), 7.29–7.23 (4H, m, Ph),
4.10 (2H, m, CH2NCH2), 3.55 (2H, m, CH2NCH2), 2.95 (2H, m,
CH2SCH2), 2.63 (2H, m, CH2SCH2), 1.27 (3H, s, CH3). 13C NMR
(CDCl3): d (ppm) 165.67, 161.61, 149.41, 138.71, 138.06, 133.57,
132.21, 132.12, 131.80, 130.05, 129.75, 129.65, 129.19, 128.83,
120.05, 103.77, 57.76, 53.78, 28.66. MS: m/z 432–434 (M+1)+;
454–456 (M+Na)+; 470–472 (M+K)+; 887–885 (2M+Na)+. Anal.
Calcd for C21H19Cl2N3OS: C, 58.34; H, 4.43; N, 9.72. Found: C,
58.46; H, 4.44; N, 9.74.
Compound 5f: Yield: 50%. 1H NMR (CDCl3): d (ppm) 7.96 (2H, d,
J = 8.63 Hz, Ph), 7.46 (2H, d, J = 8.63 Hz, Ph), 7.33–7.26 (4H, m, Ph),
3.96 (2H, m, CH2NCH2), 3.41 (2H, m, CH2NCH2), 2.69 (2H, m,
CH2N(CH3)CH2), 2.49 (2H, m, CH2N(CH3)CH2), 2.33 (3H, s, NCH3),
1.32 (3H, s, CH3). 13C NMR (CDCl3): d (ppm) 164.75, 161.77,
149.33, 138.49, 138.20, 133.41, 131.77, 129.53, 128.63, 120.12,
102.74, 55.85, 55.66, 55.17, 51.21, 45.81, 15.78. MS: m/z 429–431
(M+1)+; 451–453 (M+Na)+; 881–879 (2M+Na)+. Anal. Calcd for
C22H22Cl2N4O: C, 61.54; H, 5.16; N, 13.05. Found: C, 61.68; H,
5.18; N, 13.10.
5.3. Synthesis of pyrazolones 5a–k
Compound 1 or 3 (1 equiv/mol) was dissolved in anhydrous
DMF or DME in a sealed vessel equipped with a magnetic stirring
bar. The appropriate amine was added (1.2 equiv/mol) to the solu-
tion and the vessel was placed in a microwave oven and heated
(160 °C, 10 min) under microwave irradiation. After cooling, a sat-
urated solution of NH4Cl was added and the aqueous phase was ex-
tracted with AcOEt (3 Â 10 mL). The combined organic layers were
washed with a saturated solution of NH4Cl and H2O, dried over
anhydrous Na2SO4, filtered, and evaporated to dryness to afford
crude compounds 5a–k, which were purified by flash chromatog-
raphy (CH2Cl2/MeOH 99:1 for compounds 5b, 5f, and 5i–k; petro-
leum ether/EtOAc 8:2 for compounds 5a, 5c, 5e, and 5g) to afford
the final products (25–70% yield).
Compound 5g: Yield: 50%. 1H NMR (CDCl3): d (ppm) 7.94 (2H, d,
J = 8.50 Hz, Ph), 7.48 (2H, d, J = 8.50 Hz, Ph), 7.32–7.26 (4H, m, Ph),
4.00 (2H, m, CH2OCH2), 3.95 (2H, m, CH2OCH2), 3.73 (2H, m,
CH2NCH2), 3.37 (2H, m, CH2NCH2), 1.34 (3H, s, CH3). 13C NMR
(CDCl3): d (ppm) 164.77, 161.65, 149.34, 138.72, 138.05, 132.94,
131.83, 129.67, 128.88, 128.63, 120.21, 102.82, 67.59, 67.40,
55.66, 51.79, 15.76. MS: m/z 416–418 (M+1)+; 438–440 (M+Na)+;
855–853 (2M+Na)+. Anal. Calcd for C21H19Cl2N3O2: C, 60.59; H,
4.60; N, 10.09. Found: C, 60.83; H, 4.62; N, 10.13.
Compound 5a: Yield: 70%. 1H NMR (CDCl3): d (ppm) 7.91 (2H, d,
J = 8.04 Hz, Ph), 7.44 (2H, d, J = 8.35 Hz, Ph), 7.32–7.28 (4H, m, Ph),
7.04 (1H, t, J = 7.30 Hz, Ph), 4.12 (2H, m, CH2NCH2), 3.55 (2H, m,
CH2NCH2), 2.96 (2H, m, CH2SCH2), 2.64 (2H, m, CH2SCH2), 1.29
(3H, s, CH3). 13C NMR (CDCl3): d (ppm) 165.43, 161.66, 149.02,
139.40, 138.60, 133.70, 131.80, 131.60, 129.90, 129.50, 129.20,
129.15, 124.10, 123.90, 119.20, 104.02, 57.73, 57.71, 28.81. MS:
m/z 398–400 (M+1)+; 420–422 (M+Na)+; 817–819. Anal. Calcd for
C21H20ClN3OS: C, 63.39; H, 5.07; N, 10.56. Found: C, 63.58; H,
5.08; N, 10.59.
Compound 5h: Yield: 26%. 1H NMR (CDCl3): d (ppm) 7.99 (2H, d,
J = 8.50 Hz, Ph), 7.47 (2H, d, J = 8.50 Hz, Ph), 7.34–7.24 (4H, m, Ph),
3.57 (3H, s, CH3NCH3), 3.07 (3H, s, CH3NCH3), 1.35 (3H, s, CH3). 13
C
NMR (CDCl3): d (ppm) 165.99, 161.90, 148.91, 138.49, 138.27,
133.23, 131.92, 129.41, 128.63, 128.56, 120.08, 102.18, 46.75,
43.58, 15.62. MS: m/z 374–376 (M+1)+; 396–398 (M+Na)+; 412–
414 (M+K)+. Anal. Calcd for C19H17Cl2N3O: C, 60.97; H, 4.58; N,
11.23. Found: C, 61.15; H, 4.59; N, 11.26.
Compound 5b: Yield: 60%. 1H NMR (CDCl3): d (ppm) 7.91 (2H, d,
J = 7.71 Hz, Ph), 7.41 (2H, d, J = 7.52 Hz, Ph), 7.27–7.26 (4H, m, Ph),
7.01 (1H, t, J = 7.00 Hz, Ph), 3.92 (2H, m, CH2NCH2), 3.35 (2H, m,
CH2NCH2), 2.65 (2H, m, CH2N(CH3)CH2), 2.43 (2H, m,
CH2N(CH3)CH2), 2.27 (3H, s, NCH3), 1.28 (3H, s, CH3). 13C NMR
(CDCl3): d (ppm) 164.56, 161.81, 148.95, 139.52, 138.34, 133.54,
131.80, 129.45, 128.74, 128.71, 128.67, 128.61, 128.57, 123.90,
119.31, 102.95, 55.96, 55.86, 55.09, 51.10, 55.67, 15.81. MS: m/z
395–397 (M+1)+; 417–419 (M+Na)+; 433–435 (M+K)+, 811–813
(2M+Na)+. Anal. Calcd for C22H23ClN4O: C, 66.91; H, 5.87; N,
14.19. Found: C, 67.11; H, 5.71; N, 14.23.
Compound 5i: Yield: 55%. 1H NMR (CDCl3): d (ppm) 8.02 (2H, d,
J = 8.53 Hz, Ph), 7.51 (2H, d, J = 8.53 Hz, Ph), 7.39 (2H, d, J = 8.53 Hz,
Ph), 7.33 (2H, d, J = 8.53 Hz, Ph), 3.95 (2H, m, CH2NCH2), 3.40 (2H,
m, CH2NCH2), 1.88–1.74 (6H, m, CH2CH2CH2), 1.38 (3H, s, CH3).
13C NMR (CDCl3): d (ppm) 165.18, 161.80, 149.39, 138.45, 133.95,
131.55, 129.23, 128.82, 128.44, 119.89, 102.56, 56.54, 52.50,
29.69, 27.46, 27.24, 23.54. MS: m/z 414–416 (M+1)+. Anal. Calcd
for C22H21Cl2N3O: C, 63.77; H, 5.11; N, 10.14. Found: C, 62.37; H,
5.13; N, 10.19.
Compound 5j: Yield: 56%. 1H NMR (CDCl3): d (ppm) 7.99 (2H, d,
J = 8.85 Hz, Ph), 7.46 (2H, d, J = 8.83 Hz, Ph), 7.36 (2H, d, J = 8.63 Hz,
Ph), 7.28 (2H, d, J = 8.63 Hz, Ph), 3.95 (2H, m, CH2NCH2), 3.48 (1H,
m, CH2NCH2), 3.23 (1H, m, CH2NCH2), 1.87 (4H, m,
CH2CH(CH3)CH2), 1.49–1.46 (1H, m, CHCH3), 1.33 (3H, s, CH3),
1.01 (3H, d, J = 5.76 Hz, CH3). 13C NMR (CDCl3): d (ppm) 165.18,
161.82, 149.36, 138.34, 133.37, 129.95, 129.18, 128.47, 120.01,
102.63, 55.65, 51.83, 35.39, 29.86, 21.35, 15.67. MS: m/z 428–430
(M+1)+; 450–452 (M+Na)+. Anal. Calcd for C23H24Cl2N3O: C,
64.49; H, 5.41; N, 9.81. Found: C, 64.37; H, 5.35; N, 9.97.
Compound 5c: Yield: 30%. 1H NMR (CDCl3): d (ppm) 7.95 (2H, d,
J = 8.05 Hz, Ph), 7.48 (2H, d, J = 8.05 Hz, Ph), 7.36–7.32 (4H, m, Ph),
7.08 (1H, t, J = 7.30 Hz, Ph), 4.02 (2H, m, CH2OCH2), 3.96 (2H, m,
CH2OCH2), 3.74 (2H, m, CH2NCH2), 3.38 (2H, m, CH2NCH2), 1.35
(3H, s, CH3). 13C NMR (CDCl3): d (ppm) 164.39, 161.74, 148.92,
139.44, 138.54, 133.16, 131.85, 129.60, 128.66, 124.02, 119.29,
103.10, 67.68, 67.35, 55.60, 51.72, 15.83. MS: m/z 382–384
(M+1)+; 404–406 (M+Na)+; 785–787 (2M+Na)+. Anal. Calcd for
C21H20ClN3O2: C, 66.05; H, 5.28; N, 11. Found: C, 66.76; H, 5.30;
N, 11.04.
Compound 5k: Yield: 56%. 1H NMR (CDCl3): d (ppm) 7.97 (2H, d,
J = 8.73 Hz, Ph), 7.46 (2H, d, J = 8.46 Hz, Ph), 7.36–7.30 (4H, m, Ph),
3.56 (3H, s, N–CH3), 3.38–3.34 (2H, m, CH3CH2CH2NCH3), 1.69–1.66
(2H, m, CH3CH2CH2), 1.36 (3H, s, CH3), 0.81 (3H, t, J = 7.32, CH2CH3).
13C NMR (CDCl3): d (ppm) 165.55, 161.74, 152.73, 148.84, 138.22,
133.74, 131.87, 129.37, 128.49, 127.95, 119.96, 102.74, 60.20,
57.54, 44.11, 40.99, 29.64, 21.94, 21.24, 15.66, 11.13, 10.47. MS:
m/z 402–404 (M+1)+; 424–426 (M+Na)+. Anal. Calcd for
Compound 5d: Yield: 25%. 1H NMR (CDCl3): d (ppm) 8.01 (2H, d,
J = 8.04 Hz, Ph), 7.48 (2H, d, J = 8.04 Hz, Ph), 7.37–7.34 (4H, m, Ph),
7.09 (1H, t, J = 7.29 Hz, Ph), 3.58 (3H, s, CH3NCH3), 3.08 (3H, s,
CH3NCH3), 1.37 (3H, s, CH3). 13C NMR (CDCl3): d (ppm) 165.64,
162.00, 148.51, 139.65, 138.32, 133.45, 131.96, 129.37, 128.60,
123.76, 119.12, 102.44, 46.76, 43.51, 15.69. MS: m/z 340–342
(M+1)+; 362–364 (M+Na)+; 701–703 (2M+Na)+. Anal. Calcd for