debromo derivatives of 9 (1, X ) H2) were formed as the
byproducts in small amount.
from 1-(2′-bromobenzyl)-1,2-dihydroiso-quinolines 18 adds
to the double bond at the 3 position or prefers an aryl-aryl
coupling similar to the radical cyclizations of analogous
systems, such as 1,2,3,4-tetrahydro- and 3,4-dihydroisoquno-
lines, which give aporphines and dehydroaporphines. A
sparingly soluble 2′-bromopapaverine15 methiodide 17 was
converted to its 1,2-dihydro derivative 18a by treatment with
LiAlH4 in DME at 0 °C for 2 h (88%) or almost quantita-
tively with Bu3SnH (3 mol equiv) in a boiling toluene
containing DMF (1:1) for 4 h. When this bromide 18a was
heated with AIBN (1 mol equiv) and Bu3SnH (2 mol equiv)
in toluene-DMF (3:1) for 4 h, the desired pavine alkaloid,
(()-N-methylpavine 19a [(()-argemonine],16 was obtained
as the only cyclization product in 78% isolated yield, and
no aporphine was detected. Although attempts to execute a
one-pot transformation of the salt 17 to 19a by adding all of
the reagents at once failed, the step-by-step treatment of a
boiling suspension of 17 in DMF-toluene (1:3) with Bu3SnH
(1 mol equiv) for 1 h and successively with AIBN (1 mol
equiv) and Bu3SnH (2 mol equiv) for 4 h gave 19a in 62%
isolated yield. Treatment of 16 with Bu3SnH (1 equiv) in
CH3CN at 0 °C for 5 min and then ClCOOMe or ClCOOEt
(1.2 equiv) at 0-20 °C for 3 h gave carbamate 18b or 18c
(87% or 90%, respectively), which was then subjected to
radical cyclization using AIBN (0.1 mol equiv) andBu3SnH
(2 mol equiv) to give methoxy- and ethoxycarbonylpavines
19b or 19c17 in isolated yields of 62% and 64%, respectively.
In these reactions, aporphines, 20b and 20c, were formed as
byproducts in less than 1/10 product ratios, owing to an aryl-
aryl coupling probably induced by the steric effect of a more
bulky N-substituent.8 These product ratios (94:6 for 19b and
20b and 90:10 for 19c and 20c) both changed to 80:20, when
1 mol equiv of AIBN was used.
Nor- and homosalts, 10 and 11, were also subjected to
the one-pot radical cyclization [AIBN (1 mol equiv) and
Bu3SnH (3mol equiv), toluene-CH3CN (4:1), 4 h] to give
dibenzo[b,g]indolizidine 14a (49%) and dibenzo[a,h]-1-
azabicyclo[5.4.0]undecane 15a (33%) (Scheme 3), accom-
Scheme 3
panied by the 1,2-dihydro derivatives of the debrominated
reactants. Their 8-oxo derivatives, 14b and 15b, were
obtained in better yields (74% and 72%, respectively) by
the radical cyclization [AIBN (0.1 mol equiv) and Bu3SnH
(2 mol equiv), benzene, 4 h] of isocarbostyrils 12 and 13,
which were prepared in 70% and 87% yields from the salts
10 and 11, respectively.
Next, we describe the synthesis of pavine alkaloid (Scheme
4), which has a unique dibenzo-9-azabicyclo-[3.3.1]nonane
structure.14 It is of interest whether an aryl radical generated
In summary, we have demonstrated a new and convenient
method for synthesis of protoberberine18 and pavine alkaloids
based on an intramolecular aryl radical addition.
Supporting Information Available: Characterization
data for compounds 4-22. This material is available free of
Scheme 4
OL006213A
(14) Go¨zler, B. In The Alkaloids; Brossi, A., Ed.; Academic Press:
Orlando, 1987; Vol. 31, pp 317-389.
(15) Anderson, O. Liebigs Ann. 1854, 95, 235-240.
(16) (a) Pyman, F. I.; Reynolds, W. C. J. Chem. Soc. 1910, 97, 1320-
1328. (b) Battersby, A. R.; Binks, R. J. Chem. Soc. 1955, 2888-2896. (c)
Stermitz, F. R.; Lwo, S.-Y.; Kallos, G. J. Am. Chem. Soc. 1963, 85, 1551-
1552 (d) Rice, K. C.; Ripka, W. C.; Reden, J.; Brossi, A. J. Org. Chem.
1980, 45, 601-607. (e) Nomoto, T.; Takayama, H. J. Chem. Soc., Chem.
Commun. 1982, 1113-1115.
(17) Baker, A. C.; Battersby, A. R. J. Chem. Soc. C 1967, 1317-1323.
(18) For the synthesis of protoberberine alkaloids by radical cyclization,
see: (a) Takano, S.; Suzuki, M.; Ogasawara, K. Heterocycles 1990, 31,
1151-1156. (b) Takano, S.; Suzuki, M.; Kijima, A.; Ogasawara, K.
Tetrahedron Lett. 1990, 31, 2315-2318. (c) Dai-Ho, G.; Mariano, P. S. J.
Org. Chem. 1998, 52, 704-707. (d) Nimgirawath, S.; Ronghousabury, O.-
A. Aust. J. Chem. 1994, 47, 951-955. (e) Ishibashi, S.; Kawakami, H.;
Nakagawa, H.; Ikeda, M. J. Chem. Soc., Perkin Trans. 1 1997, 2291-
2295.
Org. Lett., Vol. 2, No. 16, 2000
2537