H, 6.5; N, 13.4. Calcd for C10H14N2O3: C, 57.1; H, 6.7;
N, 13.3%.
0.042 mmol) and anisole (0.022 cm3, 0.21 mmol) were dis-
solved in TFA (0.6 cm3). After stirring at 80 °C for 12 h, the
mixture was poured into sat. aqueous NaHCO3 and the mixture
was extracted with EtOAc twice. The combined extracts were
washed with H2O and brine, dried over Na2SO4, and concen-
trated in vacuo. The crude product (21a) was dissolved in 1,4-
dioxane (0.4 cm3), then 3 N NaOH (0.083 cm3, 0.25 mmol) was
added. After stirring at 40 °C for 12 h, NH4Cl (22 mg,
0.42 mmol) was added and the mixture was stirred at rt for 1 h.
The mixture was concentrated in vacuo and the residue was chro-
matographed on silica gel (CHCl3–MeOH = 9 : 1) to afford the
title compound 6a (5.8 mg, 49%) as a white solid: mp >300 °C;
IR (neat): νmax/cm−1 1703 (CvO); δH (500 MHz; DMSO-d6;
Me4Si) 7.48 (1H, dd, J 7.6, 7.6 Hz), 7.58 (2H, dd, J 7.6, 7.6
Hz), 7.78 (1H, s), 7.85 (2H, d, J 7.6 Hz), 8.17 (1H, d, J 8.6 Hz),
8.28 (1H, s), 8.53 (1H, d, J 8.6 Hz), and 8.70 (1H, s); δC
(125 MHz; DMSO-d6) 118.7, 121.0, 121.6 (2C), 123.3, 126.49,
126.53, 127.9, 128.2 (2C), 129.0 (2C), 130.4, 131.4, 131.7,
133.0, 139.1, and 167.8; HRMS (FAB) m/z Calcd for
C18H11N2O2 [M − H]− 287.0826, found 287.0820.
Representative procedure for gold-catalysed three-component
annulation and cyclisation cascade reactions of 17a–d with 18 and
19a,b: synthesis of dimethyl 2-(4-methoxybenzyl)-4-(4-methoxy-
phenyl)-2,3-dihydro-1H-benzo[g]indazole-1,7-dicarboxylate (20b).
Under argon atmosphere, the mixture of 17b (20 mg,
0.069 mmol), a hydrazine 18 (5.8 mg, 0.028 mmol), para-
formaldehyde 19a (1.7 mg, 0.055 mmol as HCHO), IPrAuCl
(2.1 mg, 3.5 μmol), and AgOTf (0.9 mg, 3.5 μmol) in AcOH
(0.35 cm3) was stirred at 35 °C for 2 h, then the additional
hydrazine 18 (5.8 mg, 0.028 mmol) and paraformaldehyde 19a
(1.7 mg, 0.055 mmol as HCHO) were added. After stirring at
35 °C for 2 h, further hydrazine 18 (5.8 mg, 0.028 mmol) and
paraformaldehyde 19a (1.7 mg, 0.055 mmol as HCHO) were
added and stirred for 2 h. The reaction mixture was poured into
sat. aqueous NaHCO3 and the mixture was extracted with EtOAc
twice. The combined extracts were washed with H2O and brine,
dried over Na2SO4, and concentrated in vacuo. The residue was
chromatographed on silica gel (hexane–EtOAc = 10 : 1 to 2 : 1)
to afford the title compound 20b [11.5 mg, 33% (41% rsm)] as a
yellow oil: IR (neat): νmax/cm−1 1716, 1609 (CvO), 1251
(OCH3); δH (500 MHz; CDCl3; Me4Si, 50 °C) 3.75 (3H, s), 3.79
(2H, br s), 3.79 (3H, s), 3.86 (3H, s), 3.99 (3H, s), 4.34 (2H, br
s), 6.76 (2H, d, J 8.6 Hz), 7.00 (2H, d, J 8.6 Hz), 7.19 (2H, d,
J 8.6 Hz), 7.37 (2H, d, J 8.6 Hz), 7.81 (1H, s), 8.01–8.07 (2H,
m), and 8.63 (1H, s); δC (100 MHz; CDCl3) 52.3, 53.6, 55.2,
55.4, 57.7, 61.7, 113.5 (2C), 114.4 (2C), 124.8, 125.6, 125.8,
127.2, 127.5, 128.3, 129.2 (2C), 130.1, 131.1 (2C), 131.2,
131.5, 133.6, 136.2, 137.3, 157.0, 159.1, 159.5, and 167.1;
HRMS (FAB) m/z Calcd for C30H29N2O6 (MH+) 513.2020,
found 513.2011.
3-Isopropyl-4-(thiophen-2-yl)-1H-benzo[g]indazole-7-carboxylic
acid (6e). The mixture of 20e (65 mg, 0.12 mmol) and DDQ
(83 mg, 0.37 mmol) in CH2Cl2–H2O (5 : 1, 1.2 cm3) was stirred
at rt for 18 h. The resulting mixture was diluted with CHCl3,
washed with H2O, and dried over Na2SO4. The solvent was
removed in vacuo and the residue was chromatographed on silica
gel (CHCl3) to afford the title compound 21e (36.8 mg, 73%) as
a white solid: mp 135–136 °C; IR (neat): νmax/cm−1 1746, 1714
(CvO), 1262 (OCH3); δH (500 MHz; CDCl3; Me4Si) 1.21 (6H,
d, J 6.9 Hz), 2.99–3.04 (1H, m), 4.00 (3H, s), 4.20 (3H, s),
7.14–7.16 (2H, m), 7.45 (1H, d, J 4.6 Hz), 7.79 (1H, s), 8.20
(1H, dd, J 8.6, 1.7 Hz), 8.65 (1H, s), and 9.11 (1H, d, J 8.6 Hz);
δC (125 MHz; CDCl3) 22.0 (2C), 27.1, 52.3, 55.2, 123.1, 123.5,
125.9, 126.1, 126.3, 126.8, 126.9, 128.0, 128.5, 130.1, 131.1,
132.7, 138.8, 139.5, 152.5, 157.8, and 166.7; HRMS (FAB) m/z
Calcd for C22H21N2O4S (MH+) 409.1217, found 409.1215.
The mixture of 21e (30 mg, 0.073 mmol) and 3 N NaOH
(15 cm3, 0.44 mmol) in 1,4-dioxane was stirred at 40 °C for
12 h. After addition of NH4Cl (39 mg, 0.73 mmol), the mixture
was stirred at rt for 1 h, then concentrated in vacuo. The residue
was chromatographed on silica gel (CHCl3–MeOH = 9 : 1) to
afford the title compound 6e (19.9 mg, 81%) as a white solid:
mp >300 °C; IR (neat): νmax/cm−1 1681 (CvO); δH (500 MHz;
DMSO-d6; Me4Si) 1.15 (6H, d, J 6.9 Hz), 3.09–3.14 (1H, m),
7.23 (1H, dd, J 4.9, 3.7 Hz), 7.31 (1H, d, J 3.7 Hz), 7.62 (1H,
s), 7.70 (1H, d, J 4.9 Hz), 8.17 (1H, d, J 8.6 Hz), 8.56 (1H, d,
J 8.6 Hz), and 8.67 (1H, s); δC (125 MHz; DMSO-d6) 22.7
(2C), 26.3, 116.0, 121.9, 122.9, 124.0, 126.3 (2C), 127.3,
127.45, 127.51, 128.7, 130.4, 130.6, 138.9, 140.3, 150.3, and
167.3; HRMS (FAB) m/z Calcd for C19H15N2O2S [M − H]−
335.0860, found 335.0865.
Dimethyl 3-isopropyl-2-(4-methoxybenzyl)-4-(thiophen-2-yl)-
2,3-dihydro-1H-benzo[g]indazole-1,7-dicarboxylate (20e). Under
argon atmosphere, the mixture of 17c (40 mg, 0.15 mmol), a
hydrazine 18 (35 mg, 0.17 mmol), isobutyraldehyde 19b
(0.027 cm3 μL, 0.30 mmol), IPrAuCl (4.7 mg, 7.5 μmol), and
AgOTf (1.9 mg, 7.5 μmol) in AcOH (1.5 cm3) was stirred at
50 °C for 7 h. The reaction mixture was poured into sat. aqueous
NaHCO3 and the mixture was extracted with EtOAc twice. The
combined extracts were washed with H2O and brine, dried over
Na2SO4, and concentrated in vacuo. The residue was chromato-
graphed on silica gel (hexane–EtOAc = 4 : 1) to afford the
title compound 20e (67.6 mg, 85%) as a yellow oil: IR (neat):
νmax/cm−1 1717, 1612 (CvO); δH (400 MHz; CDCl3; Me4Si)
0.53 (3H, d, J 6.8 Hz), 0.61 (3H, d, J 6.8 Hz), 1.55–1.63 (1H,
m), 3.77 (1H, d, J 12.2 Hz), 3.79 (3H, s), 3.86 (3H, s), 3.99 (3H,
s), 4.12 (1H, d, J 12.2 Hz), 4.36 (1H, d, J 3.4 Hz), 6.84 (2H, d,
J 8.5 Hz), 7.11 (1H, dd, J 4.8, 3.4 Hz), 7.21 (1H, d, J 3.7 Hz),
7.34–7.38 (3H, m), 7.90 (1H, s), 8.00–8.07 (2H, m), and 8.61
(1H, s); δC (100 MHz; CDCl3) 16.0, 20.1, 30.9, 52.2, 53.3, 55.2,
62.6, 72.4, 113.4 (s, 2H), 124.9, 125.5, 125.7, 125.9, 126.0,
127.6, 127.7, 127.8, 128.5, 129.6, 131.1, 131.2, 131.6 (s, 2H),
133.6, 137.6, 141.3, 157.1, 159.2, and 167.0; HRMS (FAB) m/z
Calcd for C30H31N2O5S (MH+) 531.1948, found 531.1946.
Methyl 3-bromo-4-[3-(dimethylamino)acryloyl]benzoate (24).
The mixture of 22 (5.53 g, 21.5 mmol) in dimethylformamide
dimethylacetal (23) (17.3 cm3, 129 mmol) was stirred at 85 °C
for 8 h in an open vessel. After cooling to rt, the reaction
mixture was concentrated in vacuo and the residue was recrystal-
lized from EtOAc–Et2O to afford the title compound 24 (5.77 g,
Deprotection and aromatisation of 20: 4-phenyl-1H-benzo[g]-
indazole-7-carboxylic acid (6a). Compound 20a (20 mg,
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 4907–4915 | 4913