A tandem radical addition/cyclization process of 1-(2-iodoethyl)indoles and methyl acrylate

Article abstract of DOI:10.1016/S0040-4039(00)01829-3

Benzindolizidine systems are generated in moderate yields by a hexabutylditin mediated consecutive radical addition, cyclization, oxidation process from 1-(2-iodoethyl)indoles and methyl acrylate. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01829-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 10181–10184
A tandem radical addition/cyclization process of
-(2-iodoethyl)indoles and methyl acrylate
1
a,
a,
a
b
Luis D. Miranda, * Raymundo Cruz-Almanza, * Miriam Pav o´ n, Yeni Romero and
c
Joseph M. Muchowski
a
Instituto de Qu ´ı mica, Universidad Nacional Aut o´ noma de M e´ xico, Circuito Exterior,
Ciudad Universitaria Coyoac a´ n M e´ xico D.F. 04510, Mexico
Facultad de Qu ´ı mica, Universidad Aut o´ noma del Estado de M e´ xico, Toluca Edo. de M e´ x. 05000, Mexico
b
c
Roche Bioscience, 3401 Hillview Avenue, Palo Alto, CA 94304-1320, USA
Received 16 October 2000; accepted 19 October 2000
Abstract
Benzindolizidine systems are generated in moderate yields by a hexabutylditin mediated consecutive
radical addition, cyclization, oxidation process from 1-(2-iodoethyl)indoles and methyl acrylate. © 2000
Published by Elsevier Science Ltd.
Keywords: radical cycloaddition; radical addition; hexabutylditin; indole systems.
The alkyl radical addition to double bonds activated by one or more electron attracting
1
groups is a synthetic process, which has considerable utility. The intramolecular oxidative
2
a–f
radical addition to the indole system
and some others heteroaromatic systems has also
2
recently been shown to have preparative importance, and has been used for natural product
synthesis. The one pot coupling of these two processes has, however, rarely been studied.
2
a,c
2b,e,f
We envisage such a process as one in which the stabilized radical 3 (Scheme 1), derived by the
intermolecular addition of the indolylethyl radical 2 to methyl acrylate, would add intramolecu-
larly to C-2 of the indole nucleus to generate benzindolizidine derivatives 5, after rearomatiza-
tion of the tricyclic radical 4. This article describes some of our preliminary results in this area.
In a few preliminary attempts to effect the desired sequence of reactions, tributyltin hydride
and AIBN were added slowly to a benzene solution of 1 and methyl acrylate but in most cases
the major new compound produced was the 3-substituted-1-ethylindole 6 resulting from the
reductive deiodination of the starting material. In contrast, sun-lamp irradiation of a solution
3
(
0.02 M) of the 1-(2-iodoethyl)indoles 1 in degassed refluxing benzene, containing methyl
4
5
acrylate (4 equiv.), and hexabutylditin (2 equiv.) gave the tricyclic indolizidine derivatives 5 as
the major products (Table 1), presumably by a mechanism of the type shown in Scheme 1.
*
Corresponding authors. Tel: (52) 56 22 44 28; fax: (52) 56 16 22 17; e-mail: raymundo@servidor.unam.mx
0
040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01829-3

10182
Scheme 1.
Table 1
a
Tandem addition/cyclization radical process
Entry Substrate
R
Cyclization product
yield (%)
Reduction product
yield (%)
Starting material recovered
(%)
1
2
3
4
5
1a
1b
1c
1d
1e
H
CHO
CO Me
COCO Et 5d (32)
5a (15)
5b (45)
5c (60)
–
–
–
(11)
–
(10)
6b (31)
Traces
–
–
2
2
CN
5e (54)
a
1
5
All compounds were identified by mass spectrometry and H NMR and IR spectroscopy.
The aromatization of 4 may occur by the loss of HI from the iodide 7 (Scheme 2), formed by
4
an atom transfer mechanism which is different to that proposed by Bowman in Bu SnH/AIBN
3
2
g
mediated reactions. Such a process is expected to be catalytic in hexabutylditin, which is
obviously not so in the cases described herein, probably for thermodynamic reasons since, a
primary alkyl radical 2 would be produced from a stabilized benzylic radical 4.
3
In the light of above results, 2-formyl-1-(2-iodoethyl)pyrrol 8 (Scheme 3) was also subjected
to the tandem radical addition/cyclization process, and the indolizidine derivative 9 was isolated
in modest yield as the major product together with a small amount of starting material (Scheme
3
).
Scheme 2.

10183
Scheme 3.
In closing, a tandem radical coupling/oxidative cyclization sequence is described which
provides benzindolizidine derivatives, in one step, from easily accessible starting materials. In
this interesting process, two new carbonꢀcarbon bonds are created in a manner reminiscent of
a Diels–Alder reaction.
Acknowledgements
Financial support from CONACYT (No. 27997E) is gratefully acknowledged. The authors
would also like to thank R. Pati n˜ o, J. P e´ rez, W. Matus and H. Rios for the technical support.
References
1
. (a) Giese, B. Radicals in Organic Synthesis: Formation of CarbonꢀCarbon Bonds; Pergamon: Oxford, 1986. (b)
Curran, D. P. Synthesis 1988, 417. (c) Mothewell, W. B.; Crich, D. Free Radical Chain Reactions in Organic
Synthesis; Academic: New York, 1992.
2. (a) Muchowski, J. M.; Cho, I. S.; Jaime-Figueroa, S.; Artis, R. D. J. Org. Chem. 1994, 59, 2456. (b) Osaki, S.;
Mitoh, H.; Ohmori, H. Chem. Pharm. Bull. 1996, 44, 2020. (c) Ziegler, F. E.; Belema, M. J. Org. Chem. 1997, 62,
1083. (d) Moody, C. J.; Norton, C. L. J. Chem. Soc., Perkin Trans. 1 1997, 2639. (e) Liard, A.; Quiclet-Sire, B.;
Saicic, R. N.; Zard, S. Z. Tetrahedron Lett. 1997, 38, 1759. (f) Kaoudi, T.; Quiclet-Sire, B.; Seguin, S.; Zard, S.
Z. Angew. Chem., Int. Ed. 2000, 39, 732. (g) Bowman, W. R.; Mann, E.; Parr, J. J. Chem. Soc., Perkin Trans. 1
2000, 2991 and references cited therein.
3. Starting materials were prepared as reported before: Miranda, L. D.; Cruz-Almanza, R.; Pav o´ n, M.; Alva, E.;
Muchowski, J. M. Tetrahedron Lett. 1999, 40, 7153–7157.
4. Curran, D. P.; Tamine, J. J. Org. Chem. 1991, 56, 2746. (b) Curran, D. P.; Chen, M.-H. J. Am. Chem. Soc. 1987,
109, 6558. (c) Curran, D. P.; Kim, D. Tetrahedron Lett. 1986, 27, 5821. (d) Keck, E. G.; Byers, J. H. J. Org. Chem.
1985, 50, 5442.
5. Typical Procedure: A solution (0.02 M) of 1-(2-iodoethyl)indoles 1 in degassed benzene, containing methyl acrylate
(
4 equiv.), and hexabutylditin (2 equiv.) was refluxed with sun-lamp irradiation. The reaction was monitored by
TLC analysis, and was terminated when no starting material was present (6–12 h). After this time, the reaction was
cooled, the solvent was removed under reduced pressure and the residue was partitioned between hexane and
acetonitrile. The polar layer was washed with hexane (five times). The solvent was then evaporated and the crude
product was purified by flash column chromatography (hexane–EtOAc). Selected spectral data of final products: 5a
−
1
+
1
IR (CHCl ): w
(cm ) 2652, 1643, 1100; MS (EI) m/z: M =229 (55%); H NMR (CDCl , 200 MHz):
3
max
3
l=7.52–7.58 (m, 1H, H-9), 7.05–7.30 (m, 3H, H-6,7,8), 6.39 (s, 1H, H-10), 405–4.09 (m, 3H, 1-CH and 4-CH ),
2
−
1
3
.77 (s, 3H, OCH ), 2.0–2.32 (m, 4H, 2-CH and 3-CH ); 5b IR (CHCl ): w
(cm ) 2449, 1734, 1647, 1437; MS
3
2
2
3
max
+
1
(
EI) m/z: M =257 (90%); H NMR (CDCl , 300 MHz): l=10.21 (s, 1H), 8.14–8.17 (m, 1H, H-9), 7.29–7.34 (m,
3
3
2
H, H-6,7,8), 435–4.58 (m, 1H, 1-CH), 4.26–4.33 (m, 1H, 4-CH ), 3.94–4.03 (m, 1H, 4-CH ), 3.74 (s, 3H, OCH ),
2 2 3
+
−
1
.10–2.46 (m, 4H, 2-CH and 3-CH ); 5c IR (CHCl ): w
(cm ) 3246, 2947, 1668; MS (EI) m/z: M =287 (20%);
2
2
3
max
1
H NMR (CDCl , 200 MHz): l=8.09–8.19 (m, 1H, H-9), 7.23–7.32 (m, 3H, H-6,7,8), 461–4.65 (m, 1H, 1-CH),
3

10184
4
2
.23–4.33 (m, 1H, 4-CH ), 3.90–4.00 (m, 1H, 4-CH ), 3.88 (s, 3H, OCH ), 3.73 (s, 3H, OCH ), 2.11–2.36 (m, 4H,
2
2
3
3
−
1
+
1
-CH and 3-CH ); 5d IR (CHCl ): w (cm ) 3419, 2925, 2854, 1736, 1442; MS (EI) m/z: M =329 (43%); H
2
2
3
max
NMR (CDCl , 200 MHz): l=7.74–7.82 (m, 1H, H-9), 7.26–7.36 (m, 3H, H-6,7,8), 4.57–4.64 (m, 1H), 4.46 (c, 2H,
3
−
1
J=7.1), 4.22–4.36 (m, 2H), 3.74 (s, 3H, OCH ), 2.20–2.47 (m, 4H), 1.47 (t, 3H, J=7.1); 5e IR (CHCl ): w (cm )
958, 2210, 1647, 1742, 1453; MS (EI) m/z: M =254 (40%); H NMR (CDCl , 200 MHz): l=7.69–7.81 (m, 1H,
3
3
max
+
1
2
3
H-9), 7.27–7.39 (m, 3H, H-6,7,8), 418–4.29 (m, 2H, 1-CH and 4-CH ), 3.93–4.06 (m, 1H, 4-CH ), 3.80 (s, 3H,
2
2
−
1
+
OCH ), 2.04–2.47 (m, 4H, 2-CH and 3-CH ), 9 IR (CHCl ): w (cm ) 1734, 1655; MS (EI) m/z: M =207
40%); H NMR (CDCl , 200 MHz): l=9.47 (s, 1H, CHO), 6.90 (d, 1H, J=4.2 Hz), 6.17 (d, 1H, J=4.2 Hz), 4.4
3
2
2
3
max
1
(
3
(
m, 2H), 3.4 (m, 1H), 3.76 (s, 3H, OCH ), 1.87 (s, 4H, -CH -CH -).
3
2
2
.
.