MacNeil et al.
mL, 24.07 mmol), 1,4-dioxane (1.56 mL, 18.29 mmol), THF (20
mL)], standard workup followed by flash column chromatography
(20% EtOAc/hexane) afforded 18b (1.1872 g, 83%) as an orange
Experimental Section
General Procedure A. Palladium-Mediated Aryl Amina-
tions. A thick-walled, screw-capped glass tube was charged with
a mixture of the aryl bromide, substituted aniline (1.2 equiv),
NaOtBu (1.4 equiv), Pd2(dba)3 (0.22-0.87 mol %), BINAP
(0.68-1.52 mol %), and toluene (0.25-0.5 M) and purged with
argon. The tube was sealed, and the contents were heated with
stirring for the time indicated. After cooling to rt, standard workup
followed by flash column chromatography (EtOAc/hexanes) af-
forded the product.
1
oil: IR (neat) νmax 1632 cm-1; H (250 MHz, CDCl3) δ 7.26 (t, J
) 7.5 Hz, 1H), 7.17-6.84 (m, 7H), 3.27-3.01 (m, 3H), 3.16 (s,
3H), 2.68-2.24 (m, 1H), 2.24 (s, 3H), 1.0 (t, J ) 7.0 Hz, 3H),
0.90 (t, J ) 7.0 Hz, 3H); 13C NMR (62.9 MHz, CDCl3) δ 169.1,
147.8, 146.5, 134.3, 130.6, 128.7, 127.4, 127.2, 125.9, 125.3, 124.2,
118.8, 118.0, 42.3, 40.6, 38.0, 17.6, 13.0, 12.0; MS (EI) m/z (rel
intensity) 296 (M+, 66), 224 (100), 209 (27); HRMS calcd for
C19H24N2O 296.1889, found 296.1894.
Representative Example: N,N-Diethyl-2-(3-methoxyanili-
no)benzamide (10b). Following general procedure A using the
following materials [1b (2.0700 g, 8.08 mmol), 2a (1.09 mL, 9.70
mmol), NaOtBu (1.0874 g, 11.31 mmol), Pd2(dba)3 (0.0199 g, 0.020
mmol), BINAP (0.0393 g, 0.060 mmol), toluene (20 mL) at
100-110 °C for 20 h], standard workup followed by acid/base wash
and flash column chromatography (10% EtOAc/hexane) afforded
10b (1.4550 g, 60%) as colorless crystals: mp 58-60 °C (hexanes);
General Procedure C. LDA-Mediated Cyclization to 10H-
acridin-9-ones (4) and 5-Methyl-5,11-dihydro-dibenzo[b,f]azepin-
10-ones (20). LDA (2.5-3.5 equiv) was prepared using a solution
of n-BuLi in hexanes and HNiPr2 in THF (∼0.5 M) at 0 °C (ice/
salt bath) and was added dropwise via cannula to a solution of the
amide in THF (∼0.5 M) precooled to 0 °C. The resulting solution
was stirred for the time indicated and quenched, either at 0 °C or
rt, with a satd aq NH4Cl solution. Standard workup followed by
flash column chromatography (EtOAc/hexanes) afforded the product.
1-Methoxy-10-methyl-9,10-dihydro-9-acridinone (4a). Fol-
lowing general procedure C using the following materials [3b
(0.2755 g, 0.88 mmol), n-BuLi (1.32 mL, 1.67 M, 2.20 mmol),
HNiPr2 (0.29 mL, 2.20 mmol), THF (10 mL) (15 min at 0 °C)],
standard workup followed by flash column chromatography (60%
EtOAc/hexane) afforded 4a (0.1920 g, 91%): yellow crystals, mp
1
IR (thin film) νmax 747, 1288, 1476, 1603, 3344 cm-1; H (250
MHz, CDCl3) δ 7.43 (d, J ) 8.2 Hz, 1H), 7.26-7.13 (m, 2H),
6.92-6.86 (m, 2H), 6.69-6.63 (m, 2H), 6.49 (dd, J ) 1.7, 8.2 Hz,
1H), 3.77 (s, 3H), 3.44 (bs, 4H), 1.17 (bs, 6H); 13C NMR (62.9
MHz, CDCl3) δ 170.5, 160.6, 143.7, 141.1, 130.0, 129.8, 127.1,
125.5, 119.9, 117.7, 110.8, 106.6, 104.0, 55.2, 13.5; MS (FAB)
m/z (rel intensity) 298 (M+, 100), 225 (90); HRMS calcd for
C18H22N2O2 298.1681, found 298.1691. Anal. Calcd for C18H22N2O2
(M+): C, 72.43; H, 7.43; N, 9.42. Found: C, 72.67; H, 7.32; N,
9.37.
164-166 °C (aq EtOH) [lit.40 mp 162-164 °C]; H (200 MHz,
1
CDCl3) δ 8.49 (dd, J ) 1.6, 8.2 Hz, 1H), 7.66-7.57 (m, 1H), 7.53
(d, J ) 8.5 Hz, 1H), 7.38 (d, J ) 8.8 Hz, 1H), 7.27-7.18 (m, 1H),
7.00 (d, J ) 8.8 Hz, 1H), 6.69 (d, J ) 8.2 Hz, 1H), 4.01 (s, 3H),
3.78 (s, 3H).
N,N-Diethyl-2-(2-toluidino)benzamide (17b). Following general
procedure A using the following materials [1b (1.5144 g, 5.91
mmol), 16a (0.76 mL, 7.09 mmol), NaOtBu (0.7946 g, 8.27 mmol),
Pd2(dba)3 (0.0180 g, 0.020 mmol), BINAP (0.0306 g, 0.049 mmol),
toluene (15 mL) at 90-100 °C for 24 h], standard workup, and
acid/base wash followed by flash column chromatography (10%
EtOAc/hexane) afforded 17b (1.4200 g, 85%) as a brown oil: IR
5-Methyl-10,11-dihydro-5H-dibenzo[b,f]azepin-10-one (20a)
and 4,10-Dimethyl-9,10-dihydro-9-acridinone (21a). Following
general procedure C using the following materials [18b (0.1485 g,
0.50 mmol), n-BuLi (0.75 mL, 1.67 M, 1.25 mmol), HNiPr2 (0.17
mL, 1.25 mmol), THF (5 mL) (1 h at 0 °C)], standard workup
followed by flash column chromatography (5 f 20% EtOAc/
hexanes) afforded 20a (0.1004 g, 89%) and 21a (0.0030 g, <5%).
20a: light yellow crystals; mp 102-104 °C (hexanes) [lit.41 mp
1
(neat) νmax 3355, 1625 cm-1; H (250 MHz, CDCl3) δ 7.27-7.11
(m, 6H), 6.92 (t, J ) 7.3 Hz, 1H), 6.83 (dt, J ) 1.2, 7.3 Hz, 1H),
3.46 (bs, 4H), 2.24 (s, 3H), 1.19 (t, J ) 6.8 Hz, 6H); 13C NMR
(62.9 MHz, CDCl3) δ 170.5, 142.2, 140.3, 130.8, 129.7, 128.8,
127.0, 126.4, 124.0, 122.0, 119.1, 118.8, 116.3, 17.7, 13.5; MS
(EI) m/z (rel intensity) 282 (M+, 50), 209 (100), 180 (22); HRMS
calcd for C18H22N2O 282.1732, found 282.1731.
1
102-103 °C (aq EtOH)]; H (200 MHz, CDCl3) δ 8.14 (dd, J )
1.8, 7.9 Hz, 1H), 7.49 (ddd, J ) 1.8, 6.9, 8.7 Hz, 1H), 7.30-7.08
(m, 5H), 6.95 (dt, J ) 0.9, 7.5 Hz, 1H), 3.88 (s, 2H), 3.55 (s, 3H).
21a: light yellow crystals; mp 89-91 °C (aq EtOH) [lit.42 mp
92 °C (EtOH)]; 1H (200 MHz, CDCl3) δ 8.43 (dd, J ) 8.1, 1.6 Hz,
1H), 8.36 (dd, J ) 7.9, 1.5 Hz, 1H), 7.72 (ddd, J ) 8.6, 7.0, 1.8
General Procedure B. N-Methylation. A solution of the
N-arylanthranilamide in THF (0.1-0.3 M) was cooled to 0 °C under
an argon atmosphere and treated with a solution of n-BuLi in
hexanes (1.0-1.1 equiv). The reaction mixture was stirred for 15
min and treated sequentially with MeI (5 equiv) and 1,4-dioxane
(3.5 equiv). Following additional stirring (as indicated), the reaction
mixture was either quenched with satd aq NH4Cl at 0 °C or warmed
to rt before quenching. Standard workup followed by flash column
chromatography afforded the desired product.
(38) See ref 12d for application of the method to an industrial-scale synthesis
of oxcarbezepine, an important dibenzo[b,f]azepinone widely prescribed for the
treatment of epilepsy.
(39) For potential applications in light-emitting diodes, see: Chen, Y.; Sheu,
R.-B.; Wu, T.-Y. J. Polym. Sci Part A: Polym. Chem. 2003, 41, 725–731.
(40) Gibbons, S.; Craven, L.; Dunlop, C.; Gray, A. I.; Hartley, T. G.;
Waterman, P. G. Phytochemistry 1997, 44, 1109–1114.
(41) Ueda, I.; Sato, Y.; Maeno, S.; Umio, S. Chem. Pharm. Bull. Jpn. 1978,
26, 3058–3070.
(42) Mahamoud, A.; Galy, J.-P.; Vincent, E.-J.; Galy, A.-M.; Barbe, J.
J. Heterocycl. Chem. 1982, 19, 503–507.
(43) Gaussian 03, ReVision B.05: Frisch, M. J.; Trucks, G. W.; Schlegel,
H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.;
Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi,
J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson,
G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa,
J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo,
J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli,
C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.;
Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.;
Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.;
Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.;
Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople,
J. A. Gaussian, Inc., Wallingford, CT, 2004.
N,N-Diethyl-2-[3-methoxy(methyl)anilino]benzamide (3b). Fol-
lowing general procedure B using the following materials [10b
(0.6605 g, 2.21 mmol), n-BuLi (1.33 mL, 1.67 M, 2.21 mmol),
MeI (0.69 mL, 11.06 mmol), 1,4-dioxane (0.72 mL, 8.41 mmol),
THF (10 mL)], standard workup followed by flash column
chromatography (10% EtOAc/hexane) afforded 3b (0.6150 g, 89%)
1
as a yellow oil: IR (neat) νmax 1609 cm-1; H (250 MHz, CDCl3)
δ 7.41-7.20 (m, 4H), 7.06 (t, J ) 8.1 Hz, 1H), 6.34-6.25 (m,
3H), 3.74 (s, 3H), 3.23 (s, 3H), 3.13-3.07 (m, 2H), 2.96-2.91
(m, 2H), 0.99-0.94 (m, 6H); 13C NMR (62.9 MHz, CDCl3) δ 168.8,
160.0, 150.0, 145.0, 135.8, 129.7, 129.0, 128.2, 127.6, 125.4, 107.4,
102.5, 100.8, 54.7, 42.5, 40.3, 38.0, 13.5, 11.9; MS (EI) m/z (rel
intensity) 312 (M+, 28), 240 (30), 169 (100); HRMS calcd for
C19H24N2O2 312.1838, found 312.1830.
N,N-Diethyl-2-(2-dimethylanilino)benzamide (18b). Following
general procedure B using the following materials [17b (1.3595 g,
4.81 mmol), n-BuLi (2.97 mL, 1.70 M, 5.06 mmol), MeI (1.50
9718 J. Org. Chem. Vol. 73, No. 24, 2008