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M. Nowak et al. / Tetrahedron 71 (2015) 9463e9473
(d, 1H, J¼8.8, 5AreH), 7.89 (dd, 1H, J¼2.5, 9.2, 9AreH), 7.77 (d, 1H,
J¼8.8, 6AreH), 7.13 (d, 1H, J¼2.0, 5DMB-H), 6.96 (dd, 1H, J¼2.0, 8.3,
1 or 2DMB-H), 6.91 (d, 1H, J¼8.3, 1 or 2DMB-H), 5.23 (s, 2H, CH2),
48.9; 19F NMR (DMSO-d6):
d
ꢁ124.11 to ꢁ125.06 (m); HRMS (ESI-
LC/MS) m/z calcd for C31H30FN4O3: 525.2296; found [MþH]þ:
525.2296.
3.75 (s, 3H, Me), 3.71 (s, 3H, Me); 13C NMR (DMSO-d6):
d 160.2,
150.3, 149.0, 148.8, 148.5, 134.6, 133.1, 131.3, 130.4, 129.0, 128.9,
128.6, 127.4, 120.5, 119.9, 114.8, 112.3, 111.9, 55.6, 55.5, 49.1; HRMS
(ESI-LC/MS) m/z calcd for C21H18BrN2O3: 425.0495; found [MþH]þ:
425.0495.
5.11.3. Methyl {[2-(3,4-dimethoxybenzyl)-1-oxo-1,2dihydrobenzo[f]
quinazolin-8-yl]-sulfanyl}propanoate (16c). Pale yellow solid, yieꢁld1:
75%, Rf (AcOEt/Hex 10:1)¼0.68; mp 175e177 ꢀC; IR (KBr cm
)
1735, 1656; 1H NMR (CDCl3):
d
9.88 (d, 1H, J¼9.0, 10AreH), 8.33 (s,
1H, 3AreH), 8.05 (d, 1H, J¼8.8, 5AreH), 7.84 (d, 1H, J¼1.5, 7AreH),
7.75 (d, 1H, J¼8.8, 6AreH), 7.70e7.68 (m, 1H, 9AreH), 6.97e6.95 (m,
2H, DMB-H), 6.85 (d, 1H, J¼8.1, DMB-H), 5.25 (s, 2H, CH2), 3.87 (s,
3H, Me), 3.86 (s, 3H, Me), 3.69 (s, 3H, CH2CH2COOMe), 3.32 (t, 2H,
CH2CH2COOMe), 2.70 (t, 2H, CH2CH2COOMe); 13C NMR (CDCl3):
5.10.3. 6-Bromo-3-(3,4-dimethoxybenzyl)benzo[h]quinazolin-4(3H)-
one (19b). Pale yellow solid, yield: 45%, Rf (PE/AcOEt 3:1)¼0.7; mp
182e185 ꢀC; IR (KBr cmꢁ1) 1670; 1H NMR (DMSO-d6):
d 8.98 (d, 1H,
J¼8.2, 10AreH), 8.86 (s, 1H, 3AreH), 8.36 (s, 1H, 5AreH), 8.26 (d, 1H,
J¼8.3, 7AreH), 7.97e7.94 (m, 1H, 8AreH), 7.88e7.85 (m, 1H,
9AreH), 7.12 (d, 1H, J¼1.9, 5DMB-H), 6.96 (dd, 1H, J¼1.9, 8.3, 1 or
2DMB-H), 6.91 (d,1H, J¼8.3,1 or 2DMB-H), 5.20 (s, 2H, CH2), 3.75 (s,
d
172.2, 161.1, 149.8, 149.6, 146.9, 135.2, 135.0, 132.9, (130.1)ꢂ2,
(129.3)ꢂ2, (128.2)ꢂ2,128.1, (127.8)ꢂ2,126.6,121.0, 116.1, (111.8)ꢂ2;
HRMS (ESI-LC/MS) m/z calcd for C25H25N2O5S: 465.1479; found
[MþH]þ: 465.1479.
3H, Me), 3.72 (s, 3H, Me); 13C NMR (DMSO-d6):
d 159.0, 149.1, 148.8,
148.6, 146.0, 133.3, 131.0, 130.5, 128.8, 126.8, 125.1, 124.9, (120.5)ꢂ2,
118.6, 112.3, 112.0, (55.6)ꢂ2, 49.1; HRMS (ESI-LC/MS) m/z calcd for
5.11.4. 3-Benzyl-6-(4-methylpiperazin-1-yl)benzo[h]quinazolin-
C
21H18BrN2O3: 425.0495; found [MþH]þ: 425.0495.
4(3H)-one (20a). White solid, yield: 62%, Rf (MeOH/PE 10:2)¼0.34;
mp 171e173 ꢀC; IR (KBr cmꢁ1) 1660; 1H NMR (CDCl3):
d 8.98 (dd,
5.11. General procedure for the palladium-catalyzed CeN and
CeS bonds formations. Synthesis of compound 16aec, 20aec,
21aec
1H, J¼1.1, 8.0, 10AreH), 8.24 (s, 1H, 2AreH), 8.20 (d, 1H, J¼7.8,
7AreH), 7.82 (s,1H, 5AreH), 7.73e7.67 (m, 2H, 8, 9AreH), 7.40e7.30
(m, 5H, Bn-H), 5.28 (s, 2H, CH2), 3.34 (br s, 4H, Pip-H), 2.94 (br s, 4H,
Pip-H), 2.57 (s, 3H, Me); 13C NMR (CDCl3):
d 161.1, 145.2, 143.8,
The reaction was carried out under an argon atmosphere in an
oven dried resealable Schlenk flask. A resealable Schlenk flask was
charged with bromobenzoquinazolinone 15 or 19a,b (0.12 mmol),
freshly distilled 1,4-dioxane (3 mL) and Pd(OAc)2 (15 mol %),
XantPhos (15 mol %), KOt-Bu (0.18 mmol), and the appropriate
amine (0.35 mmol) for synthesis of aminobenzoquinazolinones
16a,b and 20aec or Pd(OAc)2 (30 mol %), XantPhos (30 mol %),
DIPEA (0.24 mmol), the appropriate mercaptan (0.24 mmol) for
synthesis of sulfanylbenzoquinazolinones 16c and 21aec. The
whole mixture was stirred and heated at 90e100 ꢀC for 20 h. After
this time the reaction mixture was cooled and diluted with chlo-
roform (5 mL). The solid was filtered off, washed with chloroform
(2 mL) and the filtrate concentrated. The product was purified by
flash chromatography.
136.0, 132.0, 131.4, 129.2, 129.0, (128.5)ꢂ2, 128.3, 127.2, 125.7, 123.7,
119.2, 109.8, (55.2)ꢂ2, (52.0)ꢂ2, 50.1; HRMS (ESI-LC/MS) m/z calcd
for C24H25N4O: 385.2023; found [MþH]þ: 385.2023.
5.11.5. 3-Benzyl-6-[4-(2-fluorophenyl)piperazin-1-yl)benzo[h]quina-
zolin-4(3H)-one (20b). Yellow solid, yield: 67%, Rf (DCM/PE/AcOEt
6:1:0.5)¼0.52; mp 205e208 ꢀC; IR (KBr cmꢁ1) 1667; 1H NMR
(CDCl3):
d
9.01 (dd, 1H, J¼1.0, 8.2, 10AreH), 8.31 (d, 1H, J¼7.7,
7AreH), 8.28 (s, 1H, 2AreH), 7.88 (s, 1H, 5AreH), 7.76e7.69 (m, 2H,
8, 9AreH), 7.41e7.31 (m, 6H, DMB-H or 2-FPP-H), 7.16e7.05 (m, 3H,
DMB-H or 2-FPP-H), 5.30 (s, 2H, CH2), 3.51e3.46 (m, 8H, 2-FPP-H);
13C NMR (CDCl3):
d 161.1, 157.0, 155.0, 150.0, 149.0, 145.3, 143.5,
135.9, 132.1, 131.3, 129.4, 129.2, 129.1, 128.5, 128.3, 127.3, 125.7,
124.9, 123.8, 122.1, 120.3, 119.2, 116.7, 116.6, 109.9, (52.8)ꢂ2, (51.5)ꢂ
2, 50.1. 19F NMR (DMSO-d6):
d
ꢁ122.55 to ꢁ122.62 (m); HRMS (ESI-
5.11.1. 2-(3,4-Dimethoxybenzyl)-8-[4-(4-fluorophenyl)piperazin-1-
yl]benzo[f]quinazolin-1(2H)-one (16a). Lemon solid, yield: 86%, Rf
(AcOEt/Hex 3:1)¼0.42; mp 210e213 ꢀC; IR (KBr cmꢁ1) 1659; 1H
LC/MS) m/z calcd for C29H26FN4O: 465.2085; found [MþH]þ:
465.2085.
NMR (CDCl3):
d
9.87 (d, 1H, J¼9.4, 10AreH), 8.23 (s, 1H, 3AreH),
5.11.6. 3-(3,4-Dimethoxybenzyl-6-[4-(4-fluorophenyl)piperazin-1-yl)
benzo[h]quinazolin-4(3H)-one (20c). Yellow solid, yield: 67%, Rf
(AcOEt/DCM 2:1)¼0.74; mp 165e168 ꢀC; IR (KBr cmꢁ1) 1657; 1H
8.02 (d, 1H, J¼8.8, 5 or 6AreH), 7.67 (d, 1H, J¼8.8, 5 or 6AreH),
7.52 (dd, 1H, J¼2.3, 9.4, 9AreH), 7.30e7.28 (m, 1H, 7AreH),
7.02e6.94 (m, 6H, 4-FPP-H, DMB), 6.84 (d, 1H, J¼8.1, DMB), 5.25 (s,
2H, CH2), 3.86 (s, 6H, (Me)ꢂ2), 3.59e3.53 (m, 4H, 4-FPP-H),
NMR (CDCl3):
d
8.99 (d, 1H, J¼7.9, 10AreH), 8.30 (d, 1H, J¼8.2,
7AreH), 8.25 (s, 1H, 2AreH), 7.85 (s, 1H, 5AreH), 7.74e7.68 (m, 2H,
8, 9AreH), 7.02e6.96 (m, 6H, DMB-H, 4-FPP-H), 6.84 (d, 1H, J¼8.0,
DMB-H), 5.22 (s, 2H, CH2), 3.87 (s, 3H, Me), 3.86 (s, 3H, Me),
3.37e3.33 (m, 4H, 4-FPP-H); 13C NMR (CDCl3):
d 161.4, 149.7, 149.4,
(148.7)ꢂ2, 145.9, 135.0, 134.0, (128.8)ꢂ2, 128.7, 128.6, 126.6, 120.8,
120.4, 118.8, 118.7, 116.3, 116.0, 115.8, 111.7, (56.2)ꢂ2, 50.8, 49.9,
3.42e3.37 (m, 8H, 4-FPP-H); 13C NMR (CDCl3):
d 161.2, 158.5, 149.7,
(49.1)ꢂ2; 19F NMR (DMSO-d6):
d
ꢁ123.75 to ꢁ125.04 (m); HRMS
149.4, 149.2, 145.1, 143.7, 132.1, 131.5, 129.1, 128.5, 127.3, 125.7, 122.8,
121.0, 119.2, 118.3, 118.2, 115.9, 115.7, 111.8, 111.7, 109.6, 56.2, 56.1,
(ESI-LC/MS) m/z calcd for C31H30FN4O3: 525.2296; found [MþH]þ:
525.2296.
53.1, 53.0, (50.9)ꢂ2, 49.9; 19F NMR (CDCl3):
ꢁ124.7 to ꢁ124.2 (m);
d
HRMS (ESI-LC/MS) m/z calcd for C31H30FN4O3: 525.2296; found
[MþH]þ: 525.2296.
5.11.2. 2-(3,4-Dimethoxybenzyl)-8-[4-(2-fluorophenyl)piperazin-1-
yl]benzo[f]quinazolin-1(2H)-one (16b). Pale yellow solid, yield: 35%,
Rf (AcOEt/Hex 3:1)¼0.40; mp 211e214 ꢀC; IR (KBr cmꢁ1) 1657; 1H
5.11.7. 3-Benzyl-6-(propylsulfanyl)benzo[h]quinazolin-4(3H)-one
NMR (DMSO-d6):
d
9.87 (d, 1H, J¼8.4, 10AreH), 8.80 (s, 1H, 3AreH),
(21a). Beige solid, yield: 62%, Rf (DCM/AcOEt/PE 1:1:1)¼0.68; mp
8.31 (d, 1H, J¼8.8, 5AreH), 8.08 (d, 1H, J¼7.9, 9AreH), 7.78e7.67 (m,
4H, 6AreH, 2-FPP-H), 7.59e7.54 (m, 1H, 2-FPP-H), 7.14 (d, 1H, J¼1.8,
7AreH), 6.97e6.91 (m, 3H, DMB-H), 5.25 (s, 2H, CH2), 3.76e3.74 (m,
4H, 2-FPP-H), 3.72e3.71 (m, 4H, 2-FPP-H), 3.29 (s, 6H, Me); 13C
164e167 ꢀC; IR (KBr cmꢁ1) 1657; 1H NMR (CDCl3):
d 9.00 (d, 1H,
J¼8.1, 10AreH), 8.41 (d, 1H, J¼8.2, 7AreH), 8.29 (s, 1H, 2 or 5AreH),
8.17 (s, 1H, 2 or 5AreH), 7.78e7.75 (m, 1H, 8AreH), 7.73e7.70 (m,
1H, 9AreH), 7.41e7.31 (m, 5H, Bn-H), 5.29 (s, 2H, CH2), 3.12 (t, 2H,
J¼7.3, CH2CH2CH3), 1.83e1.77 (m, 2H, CH2CH2CH3), 1.10 (t, 3H, J¼7.3,
NMR (DMSO-d6):
d 160.4, 155.4, 154.1, 150.1, 149.3, 148.7, 148.6,
148.5, 135.6, 131.5, 130.2, 130.1, 129.1, 128.8, 128.5, 126.6, 126.4,
CH2CH2CH3); 13C NMR (CDCl3):
d 160.8, 151.4, 145.8, 145.0, 135.9,
126.0, 125.3, 122.8, 120.4, 116.5, 116.4, 114.7, 112.2, 111.9, (55.5)ꢂ2,
135.8, 134.8, 130.1, 129.6, 129.2, 128.6, 128.3, 127.5, 125.6, 124.8,