1938
P. H. Bernardo et al.
LETTER
[M – OMe]+ peaks were observed due to 81Br and 79Br
isotopes. HRMS (EI): m/z calcd for C15H1379BrINO3:
460.9124; found: 460.9127. FTIR (KBr): 724 (w), 755 (w),
784 (w), 863 (w), 992 (m), 1042 (m), 1239 (m), 1295 (m),
1420 (m), 1471 (s), 1525 (m), 1599 (m), 1678 (m), 1713 (m),
2853 (m), 2925 (m), 3436 (br) cm–1.
ArH), 9.13 (d, J = 8 Hz, 1 H, ArH). 13C NMR (100 MHz,
CDCl3): d = 56.4 (OMe), 56.7 (OMe), 61.7 (OMe), 74.2
(CH2), 115.1, 118.1, 118.4, 119.9, 121.3, 122.5, 125.4,
128.7, 129.3, 136.7, 152.0, 153.4, 159.5 (CO). MS (EI): m/z
(%) = 379 (90) [M+], 377 (86) [M+], 347 (50), 345 (48), 336
(52), 334 (68), 319 (100), 317 (88), 304 (73). HRMS (EI):
m/z calcd for C17H1679BrNO4: 377.0263; found: 377.0265.
HRMS (EI): m/z calcd for C17H1681BrNO4: 379.0242; found:
379.0252. FTIR (KBr): 758 (w), 1052 (s), 1076 (s), 1224
(m), 1276 (w), 1297 (w), 1363 (w), 1458 (s), 1655 (s), 2824
(w), 2932 (w), 2962 (w), 3435 (br) cm–1. Anal. Calcd for
C17H16BrNO4: C, 53.99; H, 4.26; N, 3.70. Found: C, 53.84;
H, 4.56; N, 3.68.
8-(Nitrophenyl-2-yl)-7,10-dimethoxy-5-methoxymethyl-
phenanthridin-6-one (27): To a rigorously degassed
solution of the 8-bromophenanthridinone 18 (0.1 g, 0.26
mmol) in DMF (10 mL) were added K2CO3 (73 mg, 0.53
mmol), PPh3 (21 mg, 0.082 mmol, 30 mol%), and Pd(OAc)2
(6 mg, 0.026 mmol, 10 mol%). To the reaction mixture was
added nitrophenyl-2-boronic acid (26, 2 equiv). The reaction
mixture was stirred at 150 °C for 16 h under argon. The
reaction mixture was cooled to r.t. and sat. NaHCO3 (10 mL)
was added. The solvent was then removed under reduced
pressure, and the residue was partitioned between CHCl3 (20
mL) and sat. NaHCO3 (20 mL). The aqueous layer was
further extracted with CHCl3 (2 × 20 mL) and the combined
organic layer was dried with MgSO4, filtered, and the
solvent was removed in vacuo to obtain the crude product.
Purification by column chromatography on silica gel gave
the desired product as a yellow solid (0.106 g, 0.25 mmol,
96% yield); Rf 0.34 (EtOAc–hexanes, 1:2); mp 146–148 °C.
1H NMR (400 MHz, CDCl3): d = 3.51 (s, 3 H, OMe), 3.56
(s, 3 H, OMe), 4.02 (s, 3 H, OMe), 5.78 (br s, 2 H, NCH2),
7.18 (s, 1 H, ArH), 7.26 (app. t, J = 7 Hz, 1 H, ArH), 7.50
(app. t, J = 7 Hz, 1 H, ArH), 7.52 (m, 3 H, ArH), 7.69 (app.
t, J = 7 Hz, 1 H, ArH), 8.05 (d, J = 7 Hz, 1 H, ArH), 9.20 (d,
J = 8 Hz, 1 H, ArH). 13C NMR (100 MHz, CDCl3): d = 56.4
(OMe), 56.7 (OCMe), 61.6 (OMe), 74.1 (CH2), 115.1, 116.5,
118.5, 120.3, 122.5, 124.3, 126.1, 128.7, 128.8, 129.3,
132.3, 132.4, 132.5, 132.7, 136.9, 149.2, 151.9, 153.2, 160.2
(CO). MS (EI): m/z (%) = 420 (40) [M+], 405 (25) [M –
OMe]+, 393 (30), 381 (45), 343 (56), 331 (52), 293 (100),
281 (77), 269 (43), 243 (85), 231 (97), 219 (80). HRMS (EI):
m/z calcd for C23H20N2O6: 420.1321; found: 420.1363. Anal.
Calcd for C23H20N2O6: C, 65.71; H, 4.79; N, 6.66. Found: C,
65.30; H, 4.97; N, 6.25.
Intramolecular Cyclization of the Nitrophenylphen-
anthridinone 27 via Microwave-Assisted Cadogan
Reaction: A solution of 8-(nitrophenyl-2-yl)-7,10-dimeth-
oxy-5-methoxymethylphenanthridin-6-one (27, 0.10 g, 0.24
mmol) in triethylphosphite (1 mL) was heated at 174 °C for
1 h in a sealed vessel using the Biotage InitiatorTM EXP
microwave reactor. The reaction mixture was cooled to r.t.
and the solvent was removed in vacuo. The residue was
partitioned between CHCl3 (10 mL) and sat. NaHCO3
(10 mL). The organic layer was dried with MgSO4, filtered,
and the solvent was removed. Purification via column
chromatography on silica gel (EtOAc–hexanes, 1:1) gave
the desired product 25 as a yellow solid (82 mg, 0.21 mmol,
89% yield); Rf 0.21 (EtOAc–hexanes, 1:3). 1H NMR (400
MHz, CDCl3): d = 3.55 (s, 3 H, OMe), 3.90 (s, 3 H, OMe),
4.20 (s, 3 H, OMe), 5.82 (br s, 2 H, NCH2), 7.28–7.36 (m,
2 H, ArH), 7.48 (m, 3 H, ArH), 7.59 (d, J = 8 Hz, 1 H, ArH),
8.42 (d, J = 8 Hz, 1 H, ArH), 8.67 (br s, 1 H, NH), 9.17 (d,
J = 8 Hz, 1 H, ArH). 13C NMR (100 MHz, CDCl3): d = 56.6
(OMe), 60.2 (OMe), 61.6 (OMe), 73.8 (CH2), 110.7, 111.3,
115.3, 118.8, 118.9, 121.0, 122.8, 122.8, 123.7, 125.0,
3-Bromo-N-(2-iodophenyl)-2,5-dimethoxy-N-methoxy-
methylbenzamide (16): To a solution of 3-bromo-N-(2-
iodophenyl)-2,5-dimethoxybenzamide (14, 0.88 g, 1.9
mmol) in anhyd THF (10 mL) under nitrogen were added
MOMCl (0.30 mL, 3.9 mmol) and NaH (0.10 g, 4.1 mmol).
The reaction mixture was stirred for 16 h at 30 °C following
which the reaction mixture was poured into a sat. NaHCO3
solution (20 mL) to quench the reaction. The organic layer
was separated and the aqueous layer was further re-extracted
with CH2Cl2 (3 × 15 mL). The combined organic layers were
dried with MgSO4, filtered and the solvent was removed in
vacuo to yield the crude product. Column chromatography
on silica gel (EtOAc–hexanes, 2:3) gave the desired
compound as a viscous yellow oil which solidified upon
standing (0.93 g, 1.8 mmol, 98% yield). Two distinct sets of
methoxy signals (three methoxy signals per set) in a ratio of
4:1 were observed in the 1H NMR spectrum which suggested
the presence of rotamers, but the aromatic hydrogen signals
overlapped. The 13C NMR spectrum showed distinct sets of
signals for each rotamer; the carbon resonances of each
rotamer are reported below.
Rf 0.72 (EtOAc–hexanes, 2:3); mp 40–42 °C. 1H NMR (300
MHz, CDCl3): d = 3.62 (s, 3 H, OMe), 3.66, 3.78 (s, 3 H,
OMe), 3.80, 3.93 (s, 3 H, OMe), 4.60 (d, J = 10 Hz, 1 H,
CHaHb), 5.87 (d, J = 10 Hz, 1 H, CHaHb), 6.88–6.91 (m, 2 H,
ArH), 7.00–7.08 (m, 1 H, ArH), 7.20 (m, 1 H, ArH), 7.36–
7.39 (m, 1 H, ArH), 7.74 (d, J = 8 Hz, 1 H, ArH). 13C NMR
(75 MHz, CDCl3; rotamer 1): d = 55.6 (OMe), 56.7 (OMe),
62.3 (OMe), 76.6 (CH2), 99.5, 109.5, 117.1, 119.9, 128.8,
129.9, 131.3, 132.7, 139.2, 141.8, 146.1, 155.3, 168.2 (CO).
13C NMR (75 MHz, CDCl3; rotamer 2): d = 55.6 (OMe),
56.7 (OMe), 62.8 (OMe), 76.6 (CH2), 99.5, 111.7, 112.5,
117.6, 120.8, 129.3, 129.9, 131.6, 132.0, 139.7, 147.1,
155.2, 167.8 (CO). MS (EI): m/z (%) = 507 (15) [M+], 505
(15) [M+], 380 (42) [M – I]+, 378 (42) [M – I]+, 245 (97), 243
(100), 45 (92). Two molecular ion peaks [M+] and two [M –
I]+ peaks were observed due to 81Br and 79Br isotopes.
HRMS (EI): m/z calcd for C17H1779BrINO4: 504.9380;
found: 504.9380. FTIR (KBr): 648 (w), 681 (w), 725 (w),
747 (w), 856 (w), 911 (w), 994 (m), 1018 (m), 1044 (s), 1082
(s), 1225 (s), 1278 (m), 1306 (m), 1374 (m), 1420 (s), 1473
(s), 1562 (w), 1598 (m), 1669 (s), 2831 (w), 2937 (m), 3436
(br) cm–1. Anal. Calcd for C17H17BrINO4: C, 40.34; H, 3.39;
N, 2.77. Found: C, 40.66; H, 3.48; N, 2.48.
8-Bromo-7,10-dimethoxy-5-methoxymethyl-
phenanthridin-6-one (18): To a solution of the tertiary
benzamide 16 (0.18 g, 0.35 mmol) in degassed anhyd DMF
(15 mL) were added PPh3 (28 mg, 0.11 mmol), anhyd K2CO3
(97 mg, 0.70 mmol) and Pd(OAc)2 (8 mg, 0.035 mmol). The
reaction mixture was stirred at 100 °C under an argon
atmosphere for 16 h following which the reaction mixture
was cooled to r.t. and filtered through Celite. An aliquot of
acetone (10 mL) was filtered through the Celite, and the
combined filtrates were removed under reduced pressure to
yield the crude product. Purification via column
chromatography on silica gel (EtOAc–hexanes, 1:1) gave
the desired compound as a brown solid (0.12 g, 0.32 mmol,
92% yield); Rf 0.74 (EtOAc–hexanes, 1:1); mp 102–104 °C.
1H NMR (400 MHz, CDCl3): d = 3.51 (s, 3 H, OMe), 3.95
(s, 3 H, OMe), 4.03 (s, 3 H, OMe), 5.77 (s, 2 H, CH2), 7.25–
7.29 (m, 2 H, ArH), 7.49 (s, 1 H, ArH), 7.52–7.58 (m, 1 H,
Synlett 2007, No. 12, 1935–1939 © Thieme Stuttgart · New York