A short synthesis of lennoxamine using a radical cascade

Article abstract of DOI:10.1021/ol051563o

(Chemical Equation Presented) A short synthesis of lennoxamine has been achieved by using a radical cascade involving aryl radical-induced 7-endo cyclization and homolytic aromatic substitution.

Full text of DOI:10.1021/ol051563o

ORGANIC
LETTERS
2005
Vol. 7, No. 20
4389-4390
A Short Synthesis of Lennoxamine
Using a Radical Cascade
Tsuyoshi Taniguchi, Keiko Iwasaki, Masahiko Uchiyama, Osamu Tamura, and
Hiroyuki Ishibashi*
DiVision of Pharmaceutical Sciences, Graduate School of Natural Science and
Technology, Kanazawa UniVersity, Kakuma-machi, Kanazawa 920-1192, Japan
isibasi@p.kanazawa-u.ac.jp
Received July 4, 2005
ABSTRACT
A short synthesis of lennoxamine has been achieved by using a radical cascade involving aryl radical-induced 7-endo cyclization and homolytic
aromatic substitution.
Lennoxamine (1), an isoindolobenzazepine alkaloid, was
isolated from Chilean Berberis darwinii (Figure 1).1 Owing
to its unique tetracyclic ring system, the alkaloid 1 has
attracted much attention from synthetic chemists, and efforts
have culminated in the total synthesis of 1.2
of the carbonyl group.3 For example, treatment of enamide
2a with Bu3SnH in the presence of 1,1′-azobis(cyclohexane-
carbonitrile) (V-40) in boiling toluene causes aryl radical
cyclization to give 6-exo cyclization product 3a along with
a small amount of 7-endo cyclization product 4a, whereas
enamide 2b undergoes 7-endo aryl radical cyclization to
afford benzazepine 4b exclusively (Scheme 1).3b As an
Scheme 1
Figure 1. Structure of lennoxamine (1).
We recently reported that regioselectivity of aryl radical
cyclization onto enamides can be shifted by positional change
(1) Natural 1 was isolated as a racemate, see: Valencia, E.; Freyer, A.
J.; Shamma, M.; Fajardo, V. Tetrahedron Lett. 1984, 25, 599.
(2) Quite recently (+)-1 was synthesized, see: (a) Comins, D. L.;
Schilling, S.; Zhang, Y. Org. Lett. 2005, 7, 95. For the recent syntheses of
racemic 1, see: (b) Sahakitpichan, P.; Ruchirawat, S. Tetrahedron 2004,
60, 4169. (c) Kim, G.; Kim, J. H.; Kim, W.-J.; Kim, Y. A. Tetrahedron
Lett. 2003, 44, 8207. (d) Koseki, Y.; Katsura, S.; Kusano, S.; Sakata, H.;
Sato, H.; Monzene, Y.; Nagasaka, T. Heterocycles 2003, 59, 527. (e) Fuchs,
J. R.; Funk, R. L. Org. Lett. 2001, 3, 3923. (f) Ruchirawat, S.; Sahakitpichan,
P. Tetrahedron Lett. 2000, 41, 8007. (g) Couture, A.; Deniau, E.;
Grandclaudon, P. Hoarau, C. Tetrahedron 2000, 56, 1491. (h) Koseki, Y.;
Kusano, S.; Sakata, H.; Nagasaka, T. Tetrahedron Lett. 1999, 40, 2169. (i)
Ishibashi, H.; Kawanami, H.; Ikeda, M. J. Chem. Soc., Perkin Trans. 1
1997, 817.
application of the latter process, we envisioned the synthesis
of lennoxamine (1) using a radical cascade involving 7-endo
(3) (a) Ishibashi, H.; Kato, I.; Takeda, Y.; Kogure, M.; Tamura, O. Chem.
Commun. 2000, 1527. (b) Taniguchi, T.; Ishita, A.; Uchiyama, M.; Tamura,
O.; Muraoka, O.; Tanabe, G.; Ishibasi, H. J. Org. Chem. 2005, 70, 1922.
See also: (c) Kamimura, A.; Taguchi, Y.; Omata, Y.; Hagihara, M. J. Org.
Chem. 2003, 68, 4996.
10.1021/ol051563o CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/03/2005

aryl radical cyclization and homolytic aromatic substitution
(Scheme 3).4,5 We report herein a concise synthesis of 1
according to this strategy.
Our investigation began with preparation of enamide 7
(Scheme 2). Amine 56 was treated with acetaldehyde in THF
Table 1. Radical Reaction of Enamide 7
yieldb (%)
entry
conditions (equiv)a
1
9
1
2
3
4
5
6
Bu3SnH (1.5), V-40 (2.0), toluene
Bu6Sn2 (2.0), hν, toluene
Bu6Sn2 (2.0), hν, chlorobenzene
Bu6Sn2 (2.0), V-40 (2.0), hν, chlorobenzene
Bu6Sn2 (2.0), hν, 1,2-dichlorobenzene
Me6Sn2 (2.0), hν, 1,2-dichlorobenzene
16
18
25
26
40
41
32
0
0
0
0
Scheme 2
0
a All reactions were carried out in refluxing solvent (7 mM). b Isolated
yield.
The use of ditin instead of Bu3SnH might prevent the
formation of 9, and several experiments were carried out to
improve the yield of product 1 by using ditin under
photochemical conditions.9
Irradiation of a mixture of 7 and Bu6Sn2 (2.0 equiv) with
a sun lump in boiling toluene, as expected, gave no com-
pound 9, but only a 18% yield of the requisite lennoxamine
(1) was obtained (entry 2). The dehalogenated product of 7
was also obtained in entry 2. We assumed that an abstraction
of a benzylic hydrogen atom from toluene used as a solvent
might occur, and chlorobenzene was therefore used as a
solvent to give lennoxamine (1) in 25% yield (entry 3).
Recently, Beckwith et al. have suggested that the radical
species generated from a radical initiator such as V-40 plays
an important role in the hydrogen atom abstraction for the
rearomatization of an intermediary cyclohexadienyl radicals.5c
Hence, 2 equiv of V-40 were added, but no improvement in
the yield of the product 1 was observed (entry 4).
Finally, a more satisfactory result was obtained by carrying
out the reaction using high boiling 1,2-dichlorobenzene as a
solvent. These conditions gave lennoxamine (1) in 40% yield
(entry 5). Using Me6Sn2 instead of Bu6Sn2 gave a similar
result (41%) (entry 6).
in the presence of molecular sieves 4A at 10 °C7 to give
imine 6, which was then treated with 2,3-dimethoxybenzoyl
chloride in the presence of triethylamine to afford enamide
7 in 54% yield from 5.
When enamide 7 was treated with Bu3SnH (1.5 equiv) in
the presence of V-40 (2.0 equiv) in boiling toluene using a
slow addition technique, lennoxamine (1) (mp 227-228 °C,
lit.2b mp 226-227 °C) and 7-endo cyclization product 9 were
obtained in 16 and 32% yields, respectively (Scheme 3)
Scheme 3
In conclusion, three-step synthesis of lennoxamine (1) from
amine 5 has been achieved in 22% overall yield. The present
synthesis of 1 clearly demonstrates the usefulness of the
radical cascade process involving a homolytic aromatic
substitution for the synthesis of nitrogen-containing poly-
cyclic compounds.
(Table 1, entry 1). Formation of 1 may involve 7-endo
cyclization of the aryl radical generated from 7 followed by
homolytic aromatic substitution of the resulting R-amidoyl
radical 8 onto the dimethoxyphenyl group.8 Formation of 9
might be due to the reduction of R-amidoyl radical 8 with
Bu3SnH.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research from the Ministry of Educa-
tion, Culture, Sports, Science and Technology of Japan.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 7, 1, and 9.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(4) For reviews on radical cascades, see: (a) McCarroll, A. J.; Walton,
J. C. Angew. Chem., Int. Ed. 2001, 40, 2225. (b) J. Chem. Soc., Perkin
Trans. 1 2001, 3215. For a radical cascade involving endo-selective aryl
radical cyclization onto enamide, see: (c) Ishibashi, H.; Ishita, A.; Tamura,
O. Tetrahedron Lett. 2002, 43, 473. See also, ref 3b.
OL051563O
(5) For recent references on homolytic aromatic substitution, see: (a)
Ohno, H.; Iwasaki, H.; Eguchi, T.; Tanaka, T. Chem. Commun. 2004, 2228.
(b) Bennasar, M.-L.; Roca, T.; Ferrando, F. Tetrahedron Lett. 2004, 45,
5605. (c) Beckwith, A. L. J.; Bowry, V. W.; Bowman, W. R.; Mann, E.;
Parr, J.; Storey, J. M. D. Angew. Chem., Int. Ed. 2004, 43, 95 and references
therein.
(6) Tietze, L. F.; Schirok, H. J. Am. Chem. Soc. 1999, 121, 10264.
(7) Garc´ıa, A.; Rodr´ıguez, D.; Castedo, L.; Saa´, C.; Dom´ınguez, D.
Tetrahedron Lett. 2001, 42, 1903.
(8) For an example of radical addition of an R-amidoyl radical onto an
aromatic ring, see: Gribble, G. W.; Fraser, H. L.; Badenock, J. C. Chem.
Commun. 2001, 805.
(9) For examples of homolytic aromatic substitution using irradiation of
ditin with sunlamp, see: (a) Marion, F.; Courillion, C.; Malacria, M. Org.
Lett. 2003, 5, 5095. (b) Bennasar, M.-L.; Roca, T.; Griera, R.; Bosch, J. J.
Org. Chem. 2001, 66, 7547. (c) Bowman, W. R.; Bridge, C. F.; Cloonan,
M. O.; Leach, D. C. Synlett 2001, 765. (d) Josien, H.; Ko, S.-B.; Bom, D.;
Curran, D. P. Chem. Eur. J. 1998, 4, 67. See also ref 5b.
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