4.4.8. 1-(1,2,2,4,4-Pentamethyl-3-oxo-1,2,3,4-tetrahydroquino-
lin-6-yl)-3-(4-(trifluoromethyl)phenyl)urea (3c)
mmol), and the resulting mixture was refluxed for 12 h.20 The
reaction was cooled and filtered through Celite. The Celite was
washed with ethanol (3 × 5 mL), and the filtrate was concentrated
o
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Brown solid (0.28 g, 0.67 mmol, 78%), mp 198-199 C; IR
under vacuum at 45 C to give a brown solid. Recrystallization
(nujol): 3328, 1720, 1656 cm-1; 1H NMR (400 MHz, DMSO-d6):
8.78 (s, 1H, NH), 8.52 (s, 1H, NH), 7.54 (d, J = 8.5 Hz, 2H,
ArH), 7.32-7.24 (complex, 4H, ArH), 6.79 (d, J = 8.6 Hz, 1H,
ArH), 2.82 (s, 3H, NCH3), 1.38 (s, 6H, C(CH3)2), 1.19 (s, 6H,
C(CH3)2); 13C NMR (CDCl3): 213.7, 151.8, 143.1, 140.1,
131.4, 129.6, 125.4 (q, J = 3.5 Hz), 124.1 (q, J = 272.5 Hz),
120.8 (q, J = 32.0 Hz), 118.1, 117.1, 115.3, 113.7, 63.1, 46.5,
30.2, 22.2 (2C) ; MS(ESI): m/z 420 (M+H+). Anal. Calcd. for
C22H24F3N3O2: C, 63.00; H, 5.77; N, 10.02. Found: C, 63.12; H,
5.59; N, 10.29.
of the solid from ether-pentane gave pure 3g (92 mg (0.25 mmol,
o
84%) as a brown solid, mp 135-137 C. IR (nujol): 3297, 1713,
1
1642, 1601, 1502 cm-1; H NMR (400 MHz, DMSO-d6): 8.26
(s, 1H, NH), 8.00 (s, 1H, NH), 7.38-7.22 (complex, 2H, ArH),
7.05 (d, J = 8.2 Hz, 2H, ArH), 6.76 (d, J = 8.6 Hz, 1H, ArH),
6.50 (d, J = 8.2 Hz, 2H, ArH), 4.76 (br s, 2H, NH2), 2.77 (s, 3H,
NCH3), 1.37 (s, 6H, C(CH3)2), 1.18 (s, 6H, C(CH3)2); 13C NMR
(101 MHz, DMSO-d6): 213.8, 152.6, 143.2, 139.5, 132.4,
129.5, 128.2, 120.0, 117.4, 114.7, 113.7, 113.5, 63.1, 46.5, 30.2,
22.2, 22.1; MS(ESI): m/z 367 (M+H+). Anal. Calcd. for
C21H26N4O2: C, 68.83; H, 7.15; N 15.29. Found: C, 68.66; H,
7.26; N, 15.07.
4.4.9. 1-(1,2,2,4,4-Pentamethyl-3-oxo-1,2,3,4-tetrahydroquino-
lin-6-yl)-3-(4-trifluoromethyl)phenyl)thiourea (3d)
4.5. Synthesis of 4a-f (series 4)
o
Brown solid (0.25 g, 0.58 mmol, 67%), mp 149-151 C; IR
(nujol): 3291, 3206, 1716, 1615, 1324 cm-1; 1H NMR (400 MHz,
CDCl3): 7.88 (s, 1H, NH), 7.65 (s, 1H, NH), 7.61 (d, J = 9.1
Hz, 2H, ArH), 7.59 (d, J = 9.1 Hz, 2H, ArH), 7.22 (dd, J = 8.5,
2.6 Hz, 1H, ArH), 7.15 (d, J = 2.4 Hz, 1H, ArH), 6.86 (d, J = 8.5
Hz, 1H, ArH), 2.90 (s, 3H, NCH3), 1.48 (s, 6H, C(CH3)2), 1.32 (s,
6H, C(CH3)2); 13C NMR (101 MHz, CDCl3): 214.0, 179.8,
145.3, 141.1, 132.3, 127.8 (q, J = 32.6 Hz), 127.7 (br), 126.1 (q,
J = 2.7 Hz), 125.6, 124.1, 123.9 (q, J = 272.0 Hz), 122.7, 115.0,
64.4, 47.6, 31.1, 23.6, 23.0; MS(ESI): m/z 436 (M+H+). Anal.
Calcd. for C22H24F3N3OS: C, 60.67; H, 5.55; N, 13.09. Found:
C, 60.94; H, 5.23; N, 13.28.
4.5.1. General procedure to synthesize 4a-f (series 4)
To a stirred solution of 18 (0.2 g, 0.86 mmol) in THF (10
mL) was added portion-wise lithium aluminum hydride (65.0 mg,
o
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1.72 mmol) at 0 C. The mixture was stirred at 23 C for 4 h,
o
quenched with saturated Na2SO4 at 0 C, filtered through Celite
and extracted with EtOAc (20 mL). The organic extract was
washed with water, saturated NaCl, dried (Na2SO4), filtered and
concentrated to give 19 as a brown oil. The oil was dissolved in
o
THF (5 mL), and the solution was added dropwise at 23 C to a
solution of an iso(thio)cyanate (0.86 mmol) in THF (5 mL).
When TLC analysis indicated the disappearance of 19, the
reaction mixture was concentrated under vacuum and purified by
column chromatography (EtOAc in hexanes gradient).
Concentration of the major fraction and crystallization from
DCM/ether mixture (2:8) afforded 4a-f.
4.4.10. 1-(1,2,2,4,4-Pentamethyl-3-oxo-1,2,3,4-tetrahydroquino-
lin-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea (3e)
o
Brown solid (0.27 g, 0.62 mmol, 72%), mp 191-192 C; IR
(nujol): 3318, 1716, 1648 cm-1; 1H NMR (400 MHz, DMSO-d6):
9.01 (s, 1H, NH), 8.61 (s, 1H, NH), 7.65 (d, J = 8.8 Hz, 2H,
ArH), 7.61 (d, J = 8.8 Hz, 2H, ArH), 7.32 (d, J = 2.4 Hz, 1H,
ArH), 7.30 (dd, J = 8.5, 2.4 Hz, 1H, ArH), 6.80 (d, J = 8.6 Hz,
1H, ArH), 2.79 (s, 3H, NCH3), 1.39 (s, 6H, C(CH3)2), 1.19 (s,
6H, C(CH3)2); 13C NMR (101 MHz, DMSO-d6): 213.7, 152.1,
141.8, 140.0, 138.7, 131.6, 129.6, 121.1, 119.6 (q, J = 255.2 Hz),
118.6, 117.9, 115.2, 113.7, 63.1, 46.5, 30.2, 22.1 (2C); MS(ESI):
m/z 436 (M+H+). Anal. Calcd. for C22H24F3N3O3: C, 60.68; H,
5.56; N, 9.65. Found: C, 60.79; H, 5.76; N, 9.83.
4.5.2.
1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydro-
quinolin-6-yl)-3-(4-nitrophenyl)urea (4a)
Yellow solid (0.27 g, 0.69 mmol, 80%), mp 215-217 oC; IR
(nujol): 3473, 3251, 1659, 1556 cm-1; 1H NMR (400 MHz,
DMSO-d6): 9.27 (s, 1H, NH), 8.51 (s, 1H, NH), 8.17 (d, J =
8.8 Hz, 2H, ArH), 7.67 (d, J = 8.8 Hz, 2H, ArH), 7.27 (s, 1H,
ArH), 7.11 (d, J = 8.6 Hz, 1H, ArH), 6.51 (d, J = 8.8 Hz, 1H,
ArH), 5.17 (d, J = 6.4 Hz, 1H, OH), 3.23 (d, J = 6.4 Hz, 1H,
CHOH), 2.71 (s, 3H, NCH3), 1.26 (s, 3H, CH3), 1.23 (s, 3H,
CH3), 1.16 (s, 3H, CH3), 1.06 (s, 3H, CH3); 13C NMR (101 MHz,
DMSO-d6): 151.5, 146.2, 140.0, 139.8, 132.1, 128.0, 124.5,
117.9, 117.1, 116.5, 111.4, 78.2, 57.7, 37.2, 30.9, 28.8, 26.5,
22.9, 17.6; MS(ESI): m/z 399 (M+H+). Anal. Calcd. for
C21H26N4O4: C, 63.30; H, 6.58; N, 14.06. Found: C, 63.62; H,
6.81; N, 14.16.
4.4.11. 1-(1,2,2,4,4-Pentamethyl-3-oxo-1,2,3,4-tetrahydroquino-
lin-6-yl)-3-(4-(trifluoromethoxy)phenyl)thiourea (3f)
o
Brown solid (0.24 g, 0.52 mmol, 60%), mp 83-85 C; IR
(nujol): 3291, 3213, 1716, 1501 cm-1; 1H NMR (400 MHz,
DMSO-d6): 9.76 (s, 1H, NH), 9.72 (s, 1H, NH), 7.56 (d, J =
8.8 Hz, 2H, ArH), 7.30 (coincident d, J = 8.8 Hz, 2H, ArH and
dd, J = 8.7, 2.1 Hz, 1H, ArH), 7.24 (d, J = 2.1 Hz, 1H, ArH), 6.83
(d, J = 8.7 Hz, 1H, ArH), 2.81 (s, 3H, NCH3), 1.37 (s, 6H,
C(CH3)2), 1.21 (s, 6H, C(CH3)2); 13C NMR (101 MHz, DMSO-
d6): 213.5, 178.9, 143.8, 142.0, 138.3, 130.8, 129.1, 124.6,
123.3, 120.5, 120.2, 119.5 (q, J = 255.7 Hz), 113.3, 63.2, 46.4,
30.3, 22.4, 22.1; MS(ESI): m/z 452 (M+H+). Anal. Calcd. for
C22H24F3N3O2S: C, 58.52; H, 5.36; N, 9.31. Found: C, 58.29; H,
5.12; N, 9.07.
4.5.3.
1-(3-Hydroxy-1,2,2,4,4-pentamethyl-1,2,3,4-tetrahydro-
quinolin-6-yl)-3-(4-nitrophenyl)thiourea (4b)
Yellow solid (0.22 g, 0.53 mmol, 62%), mp 161-163 oC; IR
(nujol): 3444, 1645, 1377 cm-1; 1H NMR (400 MHz, DMSO-d6):
δ 10.1 (s, 1H, NH), 10.0 (s, 1H, NH), 8.17 (d, J = 8.7 Hz, 2H,
ArH), 7.81 (d, J = 8.7 Hz, 2H, ArH), 7.23 (s, 1H, ArH), 7.13 (d, J
= 8.7 Hz, 1H, ArH), 6.54 (d, J = 8.8 Hz, 1H, ArH), 5.21 (d, J =
6.3 Hz, 1H, OH), 3.23 (d, J = 6.4 Hz, 1H, CHOH), 2.74 (s, 3H,
NCH3), 1.25 (s, 6H, C(CH3)2), 1.15 (s, 3H, CH3), 1.09 (s, 3H,
CH3); 13C NMR (101 MHz, DMSO-d6): δ 177.9, 146.0, 141.4,
141.3, 131.5, 127.4, 123.7, 122.2, 121.3, 120.5, 110.9, 77.9, 57.9,
37.1, 31.0, 28.5, 26.8, 22.9, 17.9; MS(ESI): m/z 415 (M+H+).
Anal. Calcd. for C21H26N4O3S: C, 60.85; H, 6.32; N, 13.52.
Found: C, 60.58; H, 6.42; N, 13.71.
4.4.12.
1-(4-Aminophenyl)-3-(1,2,2,4,4-pentamethyl-3-oxo-
1,2,3,4-tetrahydroquinolin-6-yl)urea (3g)
To a stirred suspension of 3a (120 mg, 0.30 mmol) and iron
powder (electrolytic, 106 mg, 1.88 mmol, ≥100 mesh) in
ethanol:water (4:1, 6.0 mL) was added NH4Cl (48 mg, 0.90