EtOH (5 mL). The reaction mixture was stirred for 1 h at 10 ◦C. A
solution of 5% H2SO4 in EtOH was added dropwise, the mixture
was poured on water (20 mL) extracted into EtOAc, washed with
brine (15 mL) and dried over MgSO4. The title compound was
obtained as a white solid and used without further purification
(0.130 g, 80%): Rf 0.81 (MeOH/DCM 1 : 99); mp 183–185 ◦C; IR
(cm-1) 2559, 1600, 1568, 1505, 1445, 1407, 1334, 1245, 1191, 1116,
1151, 1074, 1018, 894; lmax (EtOH)/nm 314, 438; 1H NMR (300
MHz, CDCl3) d 3.57 (1H, s, SH), 7.21 (1H, d, J = 7.9 Hz, H-Ar),
7.36 (1H, ap t, J = 7.9 Hz, H-Ar), 7.52 (1H, d, J = 8.6 Hz, H-Ar),
7.61 (1H, d, J = 7.9 Hz, H-Ar), 8.05 (1H, s, H-Ar), 8.14 (1H, d,
J = 8.6 Hz, H-Ar); 13C NMR (75 MHz, CDCl3) d 123.8, 125.5,
128.1, 129.4, 129.7, 131.5, 132.7, 134.7, 138.4, 139.6, 142.2, 146.1;
MS (EI) m/z = 299.0 [M(35Cl)]+, 301.0 [M(37Cl)]+; HRMS calcd
for C12H7NO2Cl2 [M(35Cl)]+ 298.9569, found 298.9569.
NH4Cl and the product was extracted into EtOAc. The combined
organic layers were washed with brine and dried over MgSO4. The
solvent was removed in vacuo to give the crude product that was
purified by medium pressure chromatography.
8-(7-Methyldibenzo[b,d]thiophen-4-yl)-2-morpholin-4-yl-4H-
chromen-4-one (21)
Following Method E: 6-bromo-3-methyldibenzo[b,d]thiophene
(0.072 g, 0.259 mmol), PdCl2(dppf) (0.021 g, 0.026 mmol), KOAc
(0.153 g, 1.56 mmol) and bis(pinacolato)diboron (0.099 g, 0.389
mmol) in THF (7 mL) at reflux for 24 h. The crude product was pu-
rified by medium pressure chromatography (EtOAc/MeOH 95 : 5)
to yield 4,4,5,5-tetramethyl-2-(7-methyldibenzo[b,d]thiophen-4-
yl)-1,3,2-dioxaborolane. The boronate (0.030 g, 0.093 mmol), 19
(0.037 g, 0.097 mmol), PdCl2(dppf) (8.0 mg, 0.009 mmol) and
Cs2CO3 (0.091 g, 0.279 mmol) in THF (5 mL) was heated at reflux
for 16 h. The crude product was purified by medium pressure
chromatography (DCM/MeOH 9 : 1) to yield the title compound
as a white solid (0.027 g, 58%): Rf 0.12 (EtOAc); mp 258–
6-Chloro-2-nitrodibenzo[b,d]thiophene (4)
A mixture of 2¢,3¢-dichloro-5-nitro-[1,1¢-biphenyl]-2-thiol (1.40
g, 4.6 mmol) and Cs2CO3 (2.30 g, 6.9 mmol) in acetonitrile
(10 mL) was heated by microwave irradiation at 130 ◦C for 8 min.
The mixture was diluted with DCM and washed with water. The
organic layer was dried over MgSO4 and concentrated in vacuo to
give the title compound as cream needles which were used without
further purification (1.10 g, 91%): Rf 0.78 (DCM/petrol 1 : 4); mp
199–201 ◦C; IR (cm-1) 1570, 1504, 1398, 1338, 1243, 1192, 1192,
1147, 1112, 1022, 896, 815, 781; lmax (EtOH)/nm 254, 271, 304,
328; 1H NMR (300 MHz, CDCl3) d 7.52–7.61 (2H, m, H-Ar), 8.04
(1H, d, J = 8.8 Hz, H-Ar), 8.19 (1H, d, J = 7.5 Hz, H-Ar), 8.38
(1H, d, J = 8.8 Hz, H-Ar), 9.04 (1H, s, H-Ar); 13C NMR (75 MHz,
CDCl3) d 117.9, 120.7, 122.0, 123.7, 126.9, 127.0, 128.1, 128.3,
129.0, 130.2, 136.6, 146.1; MS (EI) m/z = 263.0 [M(35Cl)]+, 265.0
[M(37Cl)]+; HRMS calcd for C12H6NClSO2 [M(35Cl)]+ 262.9802,
found 262.9802.
◦
260 C; IR (cm -1) 2853, 1618, 1560, 1405, 1244, 1116, 985, 780;
1
lmax (EtOH)/nm 237; H NMR (300 MHz, CDCl3) d 2.44 (3H,
s, Me), 3.03 (4H, m, morpholine-CH2), 3.44 (4H, m, morpholine-
CH2), 5.23 (1H, s, H-3), 7.22 (1H, ap t, J = 7.6 Hz, H-Ar), 7.28–7.53
(4H, m, H-Ar), 7.74 (1H, d, J = 7.4 Hz, H-Ar), 8.01 (1H, d, J =
8.1 Hz, H-Ar), 8.09 (1H, d, J = 8.1 Hz, H-Ar), 8.21 (1H, d, J = 7.8
Hz, H-Ar); 13C NMR (75 MHz, CDCl3) d 22.1; 31.3; 44.9; 66.2;
87.4; 121.4; 121.9; 124.9; 125.3; 126.6; 126.9; 127.5; 127.9; 129.0;
131.6; 133.5; 133.9; 136.5; 137.9; 139.8; 150.9; 162.5; MS (ES+)
m/z 428.61 [M+H]+; Anal. Calcd for 3C26H21NO3S∑2CH2Cl2: C,
66.16, H, 4.65, N, 2.89. Found: C, 66.20, H, 4.60, N, 2.62%.
8-(9-Methoxydibenzo[b,d]thiophen-4-yl)-2-morpholin-4-yl-4H-
chromen-4-one (22a)
Following Method F: 2-morpholin-4-yl-8-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)-4H-chromen-4-one
20
(0.10
g,
Substituted dibenzothiophen-4-yl chromenone derivatives (21,
22a–f, 23a–c, 24)
0.28 mmol), 4-bromo-1-methoxydibenzo[b,d]thiophene 2a
(0.09 g, 0.28 mmol), Pd(PPh3)4 (5.0 mg, 0.002 mmol), 2 M
Na2CO3 (0.6 mL) and DME (4 mL). The reaction mixture was
heated under microwave irradiation at 175 ◦C for 1 h. The crude
product was purified using medium pressure chromatography
(MeOH/DCM 5 : 95) to give the title compound as a white solid
(0.040 g, 40%): Rf 0.45 (MeOH/DCM 3 : 97); mp 266–267 ◦C;
lmax (EtOH)/nm 282, 316; IR (cm-1) 1641, 1579, 1428, 1260,
Typical procedure. Method E:
A mixture of the sub-
stituted 6-bromo-dibenzo[b,d]thiophene (1, 2b, 1.0 eq.),
bis(pinacolato)diboron (1.5 eq.), PdCl2(dppf) (10 mol%), KOAc
(6.0 eq.) and THF was heated at reflux for 16 h. EtOAc was
added and the combined organic phase was washed with water
and brine and dried over MgSO4. The solvent was removed
in vacuo to give the crude product that was purified by medium
pressure chromatography. In a Schlenk tube, a degassed solution of
the boronate (1.0 eq.), 2-morpholin-4-yl-4-oxo-4H-chromen-8-yl
trifluoromethanesulfonate 19 (1.05 eq.), PdCl2(dppf) (10 mol%),
Cs2CO3 (3.0 eq.) in THF (5 mL) was heated to reflux for 16 h.
Water (10 mL) was added and the reaction mixture was extracted
into DCM. the combined extracts were dried over MgSO4 and
concentrated in vacuo. The crude product was purified by medium
pressure chromatography.
Method F: A mixture of the substituted halo dibenzothio-
phenes (2a, 2c–f, 3a–c, 1.0 eq.), 2-morpholin-4-yl-8-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-chromen-4-one 20 (1.0
eq.), Pd(PPh3)4 (5 mol%), 2 M aqueous Na2CO3 and DME was
heated under microwave irradiation at 175 ◦C for 45–60 min. The
resulting mixture was poured into a saturated aqueous solution of
1
1124, 1053, 992, 795; H NMR (300 MHz, CDCl3) d 3.08–3.11
(4H, m, morpholine-CH2), 3.49–3.53 (4H, m, morpholine-CH2),
4.14 (3H, s, OMe), 5.54 (1H, s, H-3), 6.93–7.00 (1H, m, H-Ar),
7.40–7.60 (5H, m, H-Ar), 7.79 (1H, d, J = 7.7 Hz, H-Ar), 8.28
(1H, d, J = 8.5 Hz, H-Ar), 8.75 (1H, d, J = 8.5 Hz, H-Ar); 13C
NMR (75 MHz, CDCl3) d 45.0, 55.8, 66.0, 87.3, 106.2, 115.2,
124.0, 124.9, 125.0, 125.5, 125.9, 126.2, 127.3, 127.9, 129.2, 130.9,
133.6, 136.1, 139.4, 141.2, 151.1, 157.1, 162.5, 177.2; MS (ES+)
m/z = 444.2 [M + H]+; HRMS calcd for C26H21NO4S [M + H]+
444.1264, found 444.1262. Anal. Calcd for C26H21NO4S: C, 69.35,
H, 4.73, N, 3.10. Found: C, 69.43, H, 4.72, N, 3.04%.
Enzyme inhibition assay
Compounds 21, 22a–f, 23a–c and 24 were measured for inhibition
of the DNA-PK enzyme as detailed in reference 26. Mammalian
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The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 6066–6074 | 6073
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