Synthesis of 8-Oxoberbines and Related Benzolactams by
Pd(OAc)2-Catalyzed Direct Aromatic Carbonylation
February 2013
E53
3264 (NH), 1730 (CO), 1638, 1598, 1502, 1490 cm−1; 1H‐NMR: δ
2.75–3.10 (m, 4H, 5‐, 6a‐ and 13b‐H), 3.47 (d, J = 15.1, 3.5 Hz, 1H,
13a‐H), 4.94 (br. d, J = 13.2 Hz, 1H, 13a‐H), 5.25 (br. d, J = 8.2 Hz,
1H, 6b‐H), 6.09, 6.17 (each s, each 1H, OCH2O), 6.72, 6.89 (each
d, J = 8.1 Hz, 1H, 11, 12‐H), 7.09, 7.14 (each t, J = 7.0 Hz, each
1H, 2‐ and 3‐H), 7.16, 7.53 (each d, J = 7.0 Hz, each 1H, 1‐ and
4‐H), 9.98 (br. s, 1H, NH) ppm; EI‐MS (70 eV): m/z 332
(M+, 50.7), 317 (12.5), 301 (27.2), 213 (83.9), 199 (11.2), 171
(100), 135 (28.5), 115 (12.5); HR‐MS: calcd for C20H16N2O3
332.1162; Found 332.1143.
(10,11‐Methylenedioxy)‐8‐oxobenz[g]indolo[2,3‐a]quinolizidine
(8b). A colorless oil (22% in Method B); Rf 0.45 (3% methanol–
dichloromethane); IR (neat): 3258 (NH), 1710 (CO), 1634, 1598,
1502, 1466 cm−1; 1H‐NMR δ 2.82–3.10 (m, 4H, 5‐, 5‐, 6a‐H, 13b‐
H), 3.20 (dd, J = 15.5, 4.0 Hz, 1H, 13a‐H), 4.96 (br, d, J = 13.5
Hz, 1H, 13a‐H), 5.22 (br. d, J = 12.7 Hz, 1H, 6a‐H), 6.65 (each s,
each 1H, 12‐H), 7.12, 7.20 (each t, J = 7.6 Hz, 2‐ and 3‐H), 7.38,
7.56 (each d, J = 7.6 Hz, each 1H, 1‐ and 4‐H), 7.63 (s, 1H, 9‐H),
8.07 (br. s, 1H, NH) ppm; EI‐MS (70 eV): m/z 332 (M+, 46.3),
184 (22.1), 171 (25), 129 (25.4), 96 (100). HR‐MS: calcd for
C20H16N2O3 332.1162; Found 332.1180.
Vol. 4, p 77; (b) Santavy F. In The Alkaloids; Manske, R. H. F., Ed.;
Academic Press: New York, 1970; Vol. 12, p 333; (c) Santavy, F. In
The Alkaloids; Manske, R. H. F.; Rodrigo, R. G. A., Eds.; Academic
Press: New York, 1979; Vol. 17, p 385; (d) Bhakuni, D. S.; Jain S. In
The Alkaloids; Brossi, A., Ed.; Academic Press: Orlando, FL, 1986;
Vol. 28, p 95; (e) Hanaoka M. In The Alkaliids; Brossi, A., Ed.; Academic
Press: Orlando, FL, 1988; Vol. 33; p 141.
[4] Synthesis of 8‐oxoberbines with Pd(0), see: (a) Pandey, G. D.;
Tiwari, K. P. Synth Commun 1979, 9, 895; (b) Pandey, C. D.; Tiwari, K.
P. Tetrahedron 1981, 37, 1213; (c) Orito, K.; Miyazawa, M.; Kanbayashi,
R.; Tokuda, M.; Suginome, H. J Org Chem 1999, 64, 6583. With Co2
(CO)8 and Fe3(CO)12, see: (d) Trifonov, L. S.; Orehovats, A. S.; Tetrahe-
dron Lett 1985, 26, 3159.
[5] (a) Leitaoda‐Cunha, E. V.; Fechine, I. M.; Guedes, D. N.;
Barbosa‐Filho, J. M.; de Silva, M. S. In The Alkaloids; Cordell, G. A.,
Ed.; Elsevier Academic Press: Amsterdam, 2005; Vol. 62, p 1; (b) Matu-
lenko, M. A.; Meyers, A. I. J Org Chem 1996, 61, 573.
[6] (a) Whaley, W. M.; Govindachari, T. R. Inorg React 1951, 6,
74; (b) Deulofeu, V.; Comin, J.; Vernengo, M. J. In The Alkaloids;
Manske, R. H. F., Ed.; Academic Press: New York, 1963; Vol. 10, p 401.
[7] For ortho‐palladation products with Pd(OAc)2 of benzylic
amines and β‐phenethylamines having hydrogen on their nitrogen atoms,
see: (a) Fuchita, Y.; Tsuchiya, H. Polyhedron 1993, 12, 2079; Inorg Chim
Acta 1993, 209, 229; (b) Vicente, J.; Saura‐Llamas, I.; Palin, M. J.; Jones,
P. G.; Ramírez de Arellano, M. C. Organometallics 1997, 16, 826.
[8] (a) Liang, C. D. Tetrahedron Lett 1986, 27, 1971; (b) Sonoda,
M.; Kakiuchi, F.; Chatani, N.; Murai, S. Bull Chem Soc Jpn 1997, 70,
3117; (c) Ie, Y.; Chatani, N.; Ogo, T.; Marshall, D. R.; Fukuyama, T.;
Kakiuchi, F.; Murai, S. J Org Chem 2000, 65, 1475.
12‐Bromo‐2,3,10,11‐tetramethoxy‐8‐oxoberbine (10a). From
9a [22]; colorless crystals (76%); Rf 0.6 (3% methanol–
dichloromethane); mp 166–167.5°C (ethanol); IR (Nujol): 1649
1
(CO), 1594, 1561, 1510 cm−1; H‐NMR: δ 2.70–3.06 (m, 4H, 5‐
and 13‐H), 3.52 (dd, J = 16.1, 4.0 Hz, 1H, 6a‐H), 3.90 (s, 3H,
OMe), 3.92 (s, 6H, 2 OMe), 3.94 (s, 3H, OMe), 4.82 (dd, J = 13.5,
4.0 Hz, 1H, 13a‐H), 4.93 (dd, J = 8.1, 3.0 Hz, 1H, 6b‐H), 6.70,
6.75, 7.73 (each s, each 1H, 1‐, 4‐ and 9‐H) ppm; EI‐MS (70 eV):
m/z 449, 447 (M+, 79 and 100), 434, 432 (23 and 30), 418, 416 (22
and 19), 258, 256 (24 and 23), 230, 228 (43 and 43), 190 (13), 149
(16). Anal. Calcd. for C21H22NO5Br: C, 56.27; H, 4.95; N, 3.12;
Br, 17.82. Found: C, 56.07; H, 5.19; N, 3.07; Br, 17.87.
12‐Bromo‐2,3,10,11‐tetramethoxy‐8‐oxoberbine (10b). From
9b [22] colorless crystals (78%); Rf 0.6 (3% methanol–
dichloromethane); mp 220–221°C (ethanol); IR (Nujol): 1651,
1607, 1524 cm−1; 1H‐NMR: δ 2.68 (dd, J = 16.3, 13.4 Hz,
1H, 5b‐H), 2.78 (t, J = 11.7 Hz, 1H, 5a‐H), 2.92, 2.98 (AB type,
J = 11.7 Hz, 2H, 13‐H), 3.46 (dd, J = 16.6, 3.7 Hz, 1H, 13a‐H),
3.90, 3.93 (each s, each 3H), 4.79 (dd, J = 13.5, 3.7 Hz, 1H,
13a‐H), 4.92 (br. d, J = 8.2 Hz, 1H, 6b‐H), 6.11 (s, 2H, OCH2O),
6.69, 6.71, 7.59 (each s, each 1H, 1, 4‐ and 9‐H) ppm; EI‐MS (70
eV): m/z 433, 431 (M+, 88 and 100), 418, 416 (30 and 36), 402,
400 (29 and 25), 244, 242 (34 and 34), 214, 212 (52 and 53), 190
(18), 133 (45). Anal. Calcd. for C21H18NO5Br: C, 55.57; H, 4.20;
N, 3.24; Br, 18.48. Found: C, 55.61; H, 4.24; N, 3.00; Br, 18.66.
[9] A catalytic version of the Method C carbonylation of 1d with
Pd(OAc)2·2 PPh3 [20] (20 mol %) in the presence of oxygen (70 mol
%) gave 2d 18 h later in a similar selectivity (72%) to that of Method
C, when the initial dark‐reddish color of the reaction mixture due to the
Pd(II) ion was kept during the carbonylation. Similar carbonylation of
1d with Pd(PPh)4 (20 mol%)‐AcOH (40 mol %), Pd2(dba)3 (10 mol %)‐
PPh3 (40 mol %)‐AcOH (40 mol %), or Pd(OH)2 (20%) on carbon or
Pd(acac)2 (20 mol %) with PPh3 (40 mol %) and AcOH (40 mol %) also
produced 2d in 50–70%. However, an identical treatment for carbonyla-
tion of 1d with Pd2(dba)3 (5 mol %) gave no benzolactams but a mixture
of 6,7,3′,4′‐bis(methylenedioxy)‐1‐benzylisoquinoline and its 3,4‐dihydro
derivative in a ratio of 1:9 almost quantitatively.
[10] (a) Monteiro H. J. In The Alkaloids; Manske, R. H. F., Ed.;
Academic Press: New York, 1968; Vol. 11, p 145; (b) Toke, L.; Szantay,
C. Heterocycles 4, 251 (1976); (c) Szantay, C.; Blasko, G.; Honty, K.;
Dornyei, G. In The Alkaloids; Brossi, A., Ed.; Academic Press: Orlando,
1986; Vol. 27, p 131, 407; (d) Chen F.‐E.; Huang, J. Chem Rev 2005,
105, 4671.
[11] ( )‐Nuevamine, which is one of the isoquinoline alkaloids
having a five‐membered benzolactam, could not be obtained by the
method A or C, but formed by the method (B) with 3 equiv of palla-
dium(II) acetate in boiling toluene almost as a single product (>95%) in
73% isolated yield, mp 206.2–208.9°C (methanol). For isolation and syn-
thesis of the alkaloid, see; (a) Moniot, J. L.; Hindenlang, D. M. Shamma,
M. J Org Chem 1979, 44, 4347; (b) Valencia, E.; Freyer, A. J.; Shamma,
M. Tetrahedron Lett 1984, 25, 599; (c) Alonso, R.; Castedo, L.; Domin-
guez, D. Tetrahedron Lett 1985, 26, 2925; (d) Moreau, A.; Couture, A.;
Deniau, E.; Grandclaudon, P.; Lebrun, S. Tetrahedron 2004, 60, 6169;
(e) Wakchaure, R. B.; Easwar, S.; Puranik, V.; Argade, N. P. Tetrahedron
2008, 64, 1786.
Acknowledgments. The authors thank the Akiyama Foundation
for generous financial support and N. E. ChemCat, Co. Ltd., for
the generous donation of palladium catalysts.
[12] (a) Wada, Y.; Nagasaki, H.; Tokuda, M.; Orito, K. J Org Chem
2007, 72, 2008; (b) Yamashita, S.; Kurono, N.; Senboku, H.; Tokuda, M.;
Orito, K. Eur J Org Chem 2009, 1173.
REFERENCES AND NOTES
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet