April 2002
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6.89—6.92 (3H, m, aromatic protons), 7.07—7.27 (5H, m, aromatic pro-
tons). FAB-MS m/z: 390 (Mϩϩ1). Anal. Calcd for C16H14F3NO5S: C, 49.36;
H, 3.62; N, 3.60. Found: C, 49.39; H, 3.82; N, 3.53.
General Procedure for the Coupling Reaction of N-Methylbenz-
anilides 1 Using Bidentate Ligands (Runs 6—27 in Table 1 and Runs
over, other bidentate ligands were also effective for the cou-
pling reaction of 1a and 1d using equimolar Pd(OAc)2 as
shown in Table 3.
Consequently, our novel combination system consisting of
equimolar Pd(OAc)2, DPPP, and Bu3P and two molar equiva- 1—11 in Table 3) Reaction of 1 (0.3 mmol) with Pd(OAc)2, a bidentate
ligand, and/or Bu3P and a base in dry solvent (8 ml) was carried out using
Pd(OAc)2, a bidentate ligand, and/or Bu3P in the ratios indicated in Tables 1
and 3, and 2 mol equivalents of a base under reflux. The reaction mixture
was diluted with ether and the precipitates were removed by filtration. The
filtrate was washed with brine. The residue dissolved in hexane–AcOEt
(4 : 1) was subjected to column chromatography on silica gel. In the cases of
1a—c, elution with hexane–AcOEt (4 : 1) gave the cyclized product (2a)2a)
and further elution with hexane–AcOEt (3 : 1) gave the starting material
lents of a base is very efficient and powerful for the intramo-
lecular aryl–aryl coupling reaction of not only triflate-amides
(1a, d, 3), but also halo-amides (1b, c). Mechanistic and syn-
thetic studies of benzo[c]phenanthridine alkaloids are cur-
rently under way using our novel method.12)
Experimental
Melting points were measured on a micro melting point hot-stage appara- (1a). In the case of 1d, elution with hexane–AcOEt (4 : 1) gave 8-methoxy-
tus (Yanagimoto) and are given uncorrected. IR spectra were recorded from N-methylphenanthridine-6(5H)-one (2b) as colorless needles, mp 134—
1
samples in KBr pellets with JASCO A-102 or JASCO FT/IR 350 spec- 134.5 °C (from hexane). IR cmϪ1: 1650. H-NMR (60 MHz) d: 3.79 (3H, s,
trophotometer, and 1H-NMR spectra were recorded in deuteriochloroform NCH3), 3.95 (3H, s, OCH3), 6.87—7.48 (4H, m, aromatic protons), 7.98
on a Hitachi R-1500 (60 MHz) unless otherwise stated. NMR data are re- (1H, d, Jϭ8.1 Hz, C9-H), 8.02 (1H, d, Jϭ8.1 Hz, C10-H), 8.20 (1H, s, C7-H).
ported in parts per million downfield from tetramethylsilane as an internal FAB-MS m/z: 240 (Mϩϩ1). Anal. Calcd for C15H13NO2: C, 75.30; H, 5.48;
standard (d 0.0) and coupling constants are given in Hertz. Mass spectra N, 5.85. Found: C, 75.13; H, 5.71; N, 5.91.
were obtained on a VG-70SE spectrometer. Column chromatography was
2-Trifluoromethanesulfonyloxy-5-methoxy-N-methyl-N-(1-naphthyl)-
carried out on silica gel (Merck, silica gel 60, No. 9385). All experiments benzamide (3) A mixture of salicylic acid (1.1 g, 8.0 mmol), N-methyl-1-
were carried out in an argon atmosphere and the extract was washed with naphthylamine (1.56 g, 9.5 mmol), P2O5 (0.34 g, 2.4 mmol) in dry xylene
brine, dried over anhydrous MgSO4, then filtered, and the filtrate was evapo- (30 ml) was refluxed for 8 h. The reaction mixture was diluted with ether
rated to dryness under reduced pressure, unless otherwise noted. Pd(OAc)2 and then, washed with 10% HCl, aqueous 5% NaHCO3 solution and brine.
was treated with boiling benzene and the mixture was filtered while hot. The The residue in hexane–AcOEt (4 : 1) was subjected to column chromatogra-
hot filtrate was then concentrated to dryness to give purified Pd(OAc)2.13)
phy on silica gel. Elution with hexane–AcOEt (4 : 1) gave 2-hydroxy-N-
2-Trifluoromethanesulfonyloxy-N-methyl-N-phenylbenzamide (1a) To
methyl-N-(1-naphthyl)benzamide (1.1 g, 50%) as a colorless oil. IR cmϪ1
a mixture of 2-hydroxy-N-methyl-N-phenylbenzamide5) (0.97 g, 4.3 mmol) (CHCl3): 3050, 1650. H-NMR (60 MHz) d: 3.52 (3H, s, NCH3), 6.14 (1H,
1
and dry NEt3 (1.30 g, 12.8 mmol) in dry CH2Cl2 (14 ml) at Ϫ15 °C was
dt, Jϭ6.3, 1.8 Hz, C3-H), 6.52 (1H, m, aromatic proton), 6.81—7.21 (4H, m,
added triflic anhydride (1.81 g, 6.4 mmol) in dry CH2Cl2 (4 ml). The whole aromatic protons), 7.35—8.07 (5H, m, aromatic protons), 11.17 (1H, s, OH).
was stirred for 30 min at the same temperature. The mixture was diluted FAB-MS m/z: 278 (Mϩϩ1).
with CH2Cl2 (20 ml) and washed with aqueous sat. NaHCO3 (20 ml) and
brine (20 ml). The organic layer was dried over anhydrous Na2SO4. The
To a mixture of 2-hydroxy-5-methoxy-N-methyl-N-(1-naphthyl)benz-
amide (0.56 g, 2.02 mmol) and dry NEt3 (0.61 g, 6.06 mmol) in dry CH2Cl2
residue dissolved in hexane–AcOEt (2 : 1) was subjected to column chro- (15 ml) at Ϫ21 °C was added triflic anhydride (0.85 g, 3.03 mmol) in dry
matography on silica gel. Elution with hexane–AcOEt (2 : 1) gave 1a (1.45 g, CH2Cl2 (5 ml). The whole was stirred for 1 h at the same temperature. The
94%) as colorless needles, mp 69—70 °C (from hexane). IR cmϪ1: 1650, mixture was diluted with CH2Cl2 (20 ml) and washed with aqueous sat.
1
1150. H-NMR (60 MHz) d: 3.49 (3H, s, NCH3), 7.16—7.34 (9H, m, aro-
NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4.
matic protons). FAB-MS m/z: 360 (Mϩϩ1). Anal. Calcd for C15H12F3NO4S: The residue dissolved in hexane–AcOEt (3 : 1) was subjected to column
C, 50.14; H, 3.37; N, 3.90. Found: C, 49.91; H, 3.57; N, 4.06.
chromatography on silica gel. Elution with hexane–AcOEt (3 : 1) gave 3
General Procedure for the Coupling Reaction of 2-Trifluoromethane- (0.70 g, 85%) as colorless oil. IR cmϪ1 (CHCl3): 1660, 1150. 1H-NMR
sulfonyloxy-N-methyl-N-phenylbenzamide (1a) (Runs 1—5 in Table 1) (60 MHz) d: 3.56 (3H, s, NCH3), 6.95—8.06 (11H, m, aromatic protons).
Reaction of 1a (0.3 mmol) with Pd(OAc)2, PPh3, and a base in dry solvent FAB-MS m/z: 410.0674 (Calcd for C19H14F3NO4S: 410.0674).
(8 ml) was carried out using Pd(OAc)2 and PPh3 in a ratio 1 : 2 and 2 mol
General Procedure for the Coupling Reaction of 2-Trifluoromethane-
equivalent of a base under reflux and under the reaction conditions indicated sulfonyloxy-5-methoxy-N-methyl-N-(1-naphthyl)benzamide (3) to N-
in Table 1. The reaction mixture was diluted with ether, and the precipitates Methylbenzo[c]phenanthridine-6(5H)-one (4) (Runs 1—3 in Table 2)
were removed by filtration. The filtrate was washed with brine. The residue Reaction of 3 (0.3 mmol) in dry DMF (8 ml) was carried out using
dissolved in hexane–AcOEt (4 : 1) was subjected to column chromatography Pd(OAc)2, DPPP, and Bu3P in the ratio indicated in the Table 2 and 2 mol
on silica gel. Elution with hexane–AcOEt (4 : 1) gave the hydrolysis product, equivalents of a base under reflux. The reaction mixture was diluted with
2-hydroxy-N-methyl-N-phenylbenzamide, and then, the cyclized product ether and the precipitates were removed by filtration. The filtrate was washed
(2a).2a) Elution with hexane–AcOEt (3 : 1) gave the starting material (1a).
2-Trifluoromethanesulfonyloxy-5-methoxy-N-methyl-N-phenylbenz-
with 1 N HCl, aqueous sat. NaHCO3 solution and brine. The residue dis-
solved in hexane–AcOEt (4 : 1) was subjected to column chromatography on
amide (1d) A mixture of 2-hydroxy-5-methoxybenzoic acid (2.0 g, 11.9 silica gel. Elution with hexane–AcOEt (4 : 1) gave 4 as pale yellow needles,
mmol), N-methylaniline (1.66 g, 15.5 mmol), P2O5 (0.56 g, 3.96 mmol) in mp 148—148.5 °C (from hexane) (lit.14) mp 148—149 °C). IR cmϪ1: 1650.
dry xylene (40 ml) was refluxed for 6 h. The reaction mixture was diluted
1H-NMR (60 MHz) d: 4.02 (3H, s, NCH3), 7.42—7.91 (6H, m, aromatic
with AcOEt and then, washed with 10% HCl, aqueous 5% NaHCO3 solution protons), 8.13—8.40 (3H, m, aromatic protons), 8.57 (1H, dd, Jϭ7.6,
and brine. The residue in hexane–AcOEt (3 : 1) was subjected to column 1.7 Hz, C7-H). Anal. Calcd for C18H13NO: C, 83.38; H, 5.05; N, 5.40. Found:
chromatography on silica gel. Elution with hexane–AcOEt (3 : 1) gave 2-hy- C, 83.64; H, 5.22; N, 5.10.
droxy-5-methoxy-N-methyl-N-phenylbenzamide (1.84 g, 60%) as a colorless
1
amorphous solid. IR cmϪ1: 3300—3650, 1580. H-NMR (60 MHz) d: 3.20
Acknowledgements This research was supported by a Grant-in-Aid for
(3H, s, NCH3), 3.49 (3H, s, OCH3), 6.17 (1H, m, OH), 6.79—6.83 (2H, m, Scientific Research (No. 11672103) from the Ministry of Education, Cul-
aromatic protons) 7.05—7.41 (4H, m, aromatic protons). FAB-MS m/z: ture, Sports, Science and Technology, Japan. The authors are indebted to the
258.1130 (Calcd for C15H16NO3: 253.1130).
To mixture of 2-hydroxy-5-methoxy-N-methyl-N-phenylbenzamide
(0.80 g, 3.11 mmol) and dry NEt3 (0.94 g, 9.33 mmol) in dry CH2Cl2 (16 ml) References and Notes
SC-NMR Laboratory of Okayama University for the NMR experiments.
a
at Ϫ21 °C was added triflic anhydride (1.31 g, 4.66 mmol) in dry CH2Cl2
(4 ml). The whole was stirred for 1.5 h at the same temperature. The mixture
was diluted with CH2Cl2 (20 ml) and washed with aqueous sat. NaHCO3 and
brine. The organic layer was dried over anhydrous Na2SO4. The residue dis-
solved in hexane–AcOEt (3 : 1) was subjected to column chromatography on
silica gel. Elution with hexane–AcOEt (3 : 1) gave 1d (0.97 g, 80%) as color-
less needles, mp 100—103 °C (from hexane–benzene). IR cmϪ1: 1650,
1145. 1H-NMR (60 MHz) d: 3.49 (3H, s, NCH3), 3.73 (3H, s, OCH3),
1) a) Tsuji J., “Palladium Reagents and Catalysts,” John Wiley & Sons
Inc. New York, 1995, pp. 125—252; b) Li J. J., Gribble G. W., “Palla-
dium in Heterocyclic Chemistry,” Pergamon , Oxford, 2000; c) Knight
D. W., “Comprehensive Organic Synthesis,” Vol. 3, ed. by Trost B. M.,
Fleming I., Pergamon, Oxford, 1991, pp. 481—520; d) Cabri W., Can-
diani I., Acc. Chem. Res., 28, 2—7 (1995); e) Miyaura N., Suzuki A.,
Chem. Rev., 95, 2457—2483 (1995); f) Beletskaya I. P., Cheorakov A.
V., ibid., 100, 3009—3066 (2000); g) Ames D. E., Opalko A., Tetrahe-
Harayama, Takashi
