6,13-Difluoro-3-methylindazolo[2,3-f ]phenanthridine 12
1-Bromo-7-fluoro-3,10-dimethylacridin-9(10H)-one 17
6-(2-Azido-5-fluorophenyl)-2-fluoro-9-methylphenanthridine 11
(4.0 g, 0.011 mol) was suspended in 1,2,4-trichlorobenzene
(100 mL) and heated at 214 ◦C for 3 h. The solvent was removed
by vacuum distillation and the residue triturated with diethyl
ether to precipitate the product, which was filtered from solution
and recrystallised from chloroform to give 12 as a pale yellow
solid (3.2 g, 87%), mp 247–249 ◦C (Found: C, 75.1; H, 3.8; N,
8.7%. C20H12F2N2 requires C, 75.2; H, 4.1; N, 8.8%); 1H NMR dH
(CDCl3) 8.89 (1 H, dd, J 5.6, 9.2, ArH), 8.33 (1 H, d, J 8.0, ArH),
8.15 (1 H, s, ArH), 8.11 (1 H, dd, J 2.4, 10.0, ArH), 7.94–7.91
(2 H, m, ArH), 7.56 (1 H, dd, J 1.2, 8.0, ArH), 7.47 (1 H, dt, J
2.8, 7.6, ArH), 7.34 (1 H, dt, J 2.8, 8.8, ArH), 2.62 (3 H, s, CH3);
13C NMR dC (CDCl3) 161.2 (CF, J 244), 158.7 (CF, J 239), 146.4
(C), 137.9 (C), 130.7 (CH), 130.2 (CH), 129.1 (C, J 8), 125.5 (C,
J 3), 124.5 (C, J 8), 123.3 (CH), 123.2 (CH), 120.2 (CH, J 9),
119.3 (CH, J 9), 118.5 (CH, J 28), 117.2 (CH, J 24), 116.4 (C,
J 11), 109.1 (CH, J 24), 104.5 (CH, J 25), 30.0 (C), 22.0 (CH3);
m/z (ES-HRMS) 319.1006 (M + 1). Calcd for C20H13F2N2 (M +
1) 319.1047.
1-Bromo-7-fluoro-3-methylacridin-9(10H)-one 16 (30 g, 0.1 mol)
was dissolved in DMF (300 mL) and added dropwise over 30 min
to a suspension of sodium hydride (2.6 g, 0.11 mol) in DMF
(150 mL). After stirring at room temperature for 60 min, dimethyl
sulfate (18.5 g, 0.147 mol) was added and stirring continued for a
further 1 h. The reaction mixture was poured carefully into water
(1 L) and the precipitate collected and dried. The resulting yellow
solid was purified by column chromatography (chloroform) to give
17 as a bright yellow powder (25 g, 80%), mp 262–265 ◦C (Found:
C, 56.3; H, 3.4; N, 4.4%. C15H11BrFNO requires C, 56.3; H, 3.5;
1
N, 4.4%); mmax/cm−1 1637, 1604, 1501, 1271, 815; H NMR dH
[2H6]DMSO 7.83–7.88 (2 H, m, H-5, H-8), 7.69 (1 H, dt, J 9.6,
3.2, H-6), 7.62 (1 H, d, J 0.8, H-2), 7.40 (1 H, d, J 0.8, H-4), 3.87
(3 H, s, NCH3), 2.45 (3 H, s, CH3); m/z (ES) 319.7/321.7 (M + 1).
2-(5-Fluoro-2-nitrophenyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane 20
Potassium acetate (6 g, 0.06 mol), bis(pinacolato)diborane
(5.8 g, 0.022 mol) and dichloro[1,1ꢁ-bis(diphenylphosphino)-
ferrocene]palladium(II) (0.9 g, 3 mol%) were added to a solu-
tion of 5-fluoro-2-nitrophenyltrifluoromethane sulfonate21 (5.9 g,
0.02 mol) in dioxane (60 mL) under a nitrogen atmosphere. The
resulting solution was stirred at 80 ◦C for 20 h. After cooling,
the solvent was removed under reduced pressure and the residue
purified by column chromatography (dichloromethane) to give 20
as a pale cream solid (3.8 g, 70%), mp 79–80 ◦C (from MeOH)
(Found: C, 53.9; H, 5.6; N, 5.1%. C12H15BFNO4 requires C, 53.9;
H, 5.6; N, 5.2%); mmax/cm−1 1578, 1526, 1411, 1346; 1H NMR dH
(CDCl3) 8.21 (1 H, dd, J 4.8, 10.0, H-3), 7.17–7.28 (2 H, m, H-4,
H-6), 1.43 (12 H, s, 4 × CH3).
2-Bromo-6-(4-fluoroanilino)-4-methylbenzonitrile 14
2,6-Dibromo-4-methylbenzonitrile 1318 (60 g, 0.22 mol), 4-
fluoroaniline (27.2 g, 0.24 mol), cesium carbonate (100 g,
0.28 mol), BINAP (2.7 g, 4.3 mmol) and palladium acetate (0.47 g,
2.1 mmol) were dissolved in toluene (800 mL) under nitrogen and
◦
heated at 100 C for 12 h. The solvent was then removed under
vacuum and the residue purified by column chromatography,
initially eluting with 20% chloroform–hexane to remove unreacted
13, increasing to 50% chloroform–hexane to elute 14, and finally
neat chloroform to elute 15. Benzo◦nitrile 14 was obtained as white
needles (43 g, 65%), mp 175–176 C (Found: C, 54.9; H, 3.3; N,
9.1%. C14H10BrFN2 requires C, 55.1; H, 3.3; N, 9.2%); mmax/cm−1
7-Fluoro-1-(5-fluoro-2-nitrophenyl)-3,10-dimethylacridin-
9(10H)-one 21
1
3315 (NH), 2223 (C≡N), 1608, 1568, 1506, 1210, 820; H NMR
dH (CDCl3) 7.21–7.10 (4 H, m, ArH), 6.89 (1 H, d, J 0.4, H-3), 6.67
(1 H, d, J 0.4, H-5), 6.28 (1 H, br s, NH), 2.25 (3 H, s, CH3); m/z
(APCI) 305.0/307.0 (M + 1). The di(4-fluoroanilino)benzonitrile
15 was obtained as a white solid (14.6 g, 20%), mp 170–171 ◦C
(Found: C, 71.5; H, 4.5; N, 12.5%. C20H15F2N3 requires C, 71.6;
H, 4.5; N, 12.5%); mmax/cm−1 3321 (NH), 2201 (C≡N), 1607, 1578,
1511, 1463, 1219, 819; 1H NMR dH (CDCl3) 7.17 (4 H, dd, J 2.4,
6.8, ArH), 7.06 (4 H, dd, J 2.4, 6.8, ArH), 6.18 (2 H, d, J 0.2,
ArH), 6.08 (1 H, br s, NH), 2.11 (3 H, s, CH3); m/z (ES-HRMS)
336.1298 (M + 1). Calcd for C20H16F2N3 (M + 1) 336.1312.
Dichloro[1,1ꢁ -bis(diphenylphosphino)ferrocene]palladium(II )
(90 mg, 10 mol%) was added to a solution of 1-bromo-7-
fluoro-3,10-dimethylacridin-9(10H)-one 17 (0.36 g, 1.1 mmol)
and dioxaborolane 20 (0.45 g, 1.7 mmol) in dioxane (10 mL)
under nitrogen. 2 N sodium carbonate (2 mL) was added and
the resulting solution heated at 80 ◦C for 24 h. The solvent
was removed under vacuum and the residue purified by column
chromatography (chloroform followed by dichloromethane) to
give 21 as a yellow solid (0.2 g, 47%), mp 238–241 ◦C (Found:
C, 66.0; H, 3.7; N, 7.1%. C21H14F2N2 O3 requires C, 66.3; H, 3.7;
N, 7.4%); mmax/cm−1 1607, 1582, 1507, 1358, 1262, 1209; 1H NMR
dH (CDCl3) 8.29 (1 H, dd, J 4.8, 8.8, ArH), 7.99 (1 H, dd, J 3.2,
9.2, ArH), 7.52–7.55 (3 H, m, ArH), 7.21 (1 H, dt, J 2.8, 7.2, 9.2,
ArH), 7.00 (1 H, dd, J 2.8, 8.4, ArH), 6.84 (1 H, d, J 1.2, ArH),
3.98 (3 H, s, NCH3), 2.58 (3 H, s, CH3); m/z (ES) 380.9 (M + 1).
1-Bromo-7-fluoro-3-methylacridin-9(10H)-one 16
Benzonitrile 14 (40 g, 0.13 mol) was suspended in 80% sulfuric acid
(200 mL) and heated at 100 ◦C for 15 h. After cooling, the reaction
mixture was quenched on ice (800 g). The resulting precipitate
was collected, washed with water (200 mL) and allowed to dry.
The yellow solid 16 (34 g, 85%) was used in the next step without
further purification. Physical characteristics of 16: mmax/cm−1 3394
3,11-Difluoro-6,8-dimethyl-8H-quino[4,3,2-kl]acridine 5
1
(NH), 1629 (CO), 1517, 1205, 838; H NMR dH ([2H6]DMSO)
Tin(II) chloride dihydrate (1.6 g, 7.1 mmol) was added to a solution
of acridinone 21 (0.92 g, 2.3 mmol) in ethanol (10 mL), and
the resulting solution heated under reflux for 2 h. 5 M HCl
(10 mL) was then added, and refluxing continued for a further
15 h. After cooling, the ethanol was removed under vacuum, and
11.81 (1 H, br s, NH), 7.81 (1 H, dd, J 4.0, 12.0, ArH), 7.64 (1 H,
ddd, J 4.0, 8.0, 12.0, ArH), 7.55 (1 H, dd, J 4.0, 8.0, ArH), 7.33
(1 H, d, J, ArH), 7.28 (1 H, d, J, ArH), 2.41 (3 H, s, CH3); m/z
(ES) 305.0/307.0 (M + 1).
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 114–120 | 119
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