Intramolecular reactions of 2-indolylacyl Radicals: Access to 1,2-fused ring indole derivatives

Article abstract of DOI:10.1021/ol036455l

The generation of 2-indolylacyl radicals from the corresponding phenyl selenoesters under reductive conditions and their behavior in intramolecular addition reactions to carbon-carbon double bonds located at the indole nitrogen have been studied.

Full text of DOI:10.1021/ol036455l

ORGANIC
LETTERS
2004
Vol. 6, No. 5
759-762
Intramolecular Reactions of 2-Indolylacyl
Radicals: Access to 1,2-Fused Ring
Indole Derivatives
M.-Llu1ısa Bennasar,* Toma`s Roca, and Francesc Ferrando
Laboratory of Organic Chemistry, Faculty of Pharmacy, UniVersity of Barcelona,
Barcelona 08028, Spain
bennasar@ub.edu
Received December 18, 2003
ABSTRACT
The generation of 2-indolylacyl radicals from the corresponding phenyl selenoesters under reductive conditions and their behavior in
intramolecular addition reactions to carbon−carbon double bonds located at the indole nitrogen have been studied.
Radical reactions have long been recognized as important
tools in organic synthesis,1 often being used as key steps in
the construction of complex natural products.2 In particular,
the addition of functionalized acyl radicals3 to multiple C-C
bonds constitutes a useful method for the synthesis of acyclic
and cyclic ketones. The reaction of selenoesters with stannyl
and tris(trimethylsilyl)silyl radicals is one of the most
practical ways to generate these radical intermediates,3
although other protocols and precursors can be used.4 Our
interest in the chemistry of functionalized indoles as common
substructures of many natural and medicinal compounds5 led
us to explore the reactivity and synthetic possibilities of
indolylacyl radicals. Thus, with Boger’s work on benzoyl
radicals in mind,6 2- and 3-indolylacyl radicals were gener-
ated from the corresponding phenyl selenoesters under
reductive conditions and allowed to intermolecularly react
with alkene acceptors, providing easy access to 2-7 and
3-acylindoles8 (Scheme 1). Our efforts were then focused
Scheme 1
(1) (a) Curran, D. P. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 715-777 and 779-
831. (b) Giese, B.; Kopping, B.; Go¨bel, T.; Dickhaut, J.; Thoma, G.; Kulicke,
K. J.; Trach, F. Org. React. 1996, 48, 301-856. (c) Renaud, P., Sibi, M.
P., Eds. Radicals in Organic Synthesis; Wiley-VCH: Weinheim, 2001.
(2) (a) Koert, U. Angew. Chem., Int. Ed. Engl. 1996, 35, 405-407. (b)
McCarroll, A. J.; Walton, J. C. Angew. Chem., Int. Ed. 2001, 40, 2224-
2248.
(3) For reviews on acyl radical chemistry, see: (a) Ryu, I.; Sonoda, N.;
Curran D. P. Chem. ReV. 1996, 96, 177-194. (b) Chatgilialoglu, C.; Crich,
D.; Komatsu, M.; Ryu, I. Chem. ReV. 1999, 99, 1991-2069.
(4) For recent examples of the generation of acyl radicals from thiolesters,
see: (a) Crich, D.; Yao, Q. J. Org. Chem. 1996, 61, 3566-3570. (b) Ozaki,
S.; Adachi, M.; Sekiya, S.; Kamikawa, R. J. Org. Chem. 2003, 68, 4586-
4589. (c) Benati, L.; Calestani, G.; Leardini, R.; Minozzi, M.; Nanni, D.;
Spagnolo, P.; Strazzari, S. Org. Lett. 2003, 5, 1313-1316. From acyl
hydrazides, see: (d) Braslau, R.; Anderson, M. O.; Rivera, F.; Jime´nez,
A.; Haddad, T.; Axon, J. R. Tetrahedron 2002, 58, 5513-5523. (e) Bath,
S.; Laso, N. M.; Lo´pez-Ruiz, H.; Quiclet-Sire, B.; Zard, S. Z. Chem.
Commun. 2003, 204-205.
on the intramolecular version of the above radical reactions,
as a general approach to a great variety of polycyclic indolyl
ketones.9 We herein report our preliminary results concerning
this new indole annulation procedure, using 2-indolylacyl
(5) Sundberg, R. J. Indoles; Academic Press: New York, 1996; pp 105-
134.
(6) Boger, D. L.; Mathvink, R. J. J. Org. Chem. 1992, 57, 1429-1443.
(7) Bennasar, M.-L.; Roca, T.; Griera, R.; Bosch, J. Org. Lett. 2001, 3,
1697-1700.
(8) Bennasar, M.-L.; Roca, T.; Griera, R.; Bassa, M.; Bosch, J. J. Org.
Chem. 2002, 67, 6268-6271.
10.1021/ol036455l CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/30/2004

Table 1. Radical Cyclization of Indoles 1-6a
Figure 1.
radicals in cyclization reactions upon alkene acceptors located
at the indole nitrogen.10
With the aim of studying the scope of this cyclization
process for the construction of isolated or fused rings, indole
selenoesters 1-6 (Figure 1), which carry different alkenyl,
cyclohexenyl, or tetrahydropyridyl moieties at the nitrogen,
were selected as radical precursors. These compounds were
prepared from the respective carboxylic acids,11 following
the procedure reported by Batty and Crich.12 The results of
the radical reactions, performed in all cases under standard
reductive conditions (n-Bu3SnH, AIBN, benzene, reflux, slow
addition), are depicted in Table 1.
Consistent with empirical rules for alkyl radical cycliza-
tions,1b as well as previous results with benzoyl radicals,6
the 5-hexenoyl radical derived from 1a showed a strong
preference for the formation of the five-membered ring
through the exo mode to give 7 as the only isolable product
in 84% yield (entry 1).13 Compound 7 has the pyrrolo[1,2-
a]indole skeleton characteristic of mytomycins,14 a group of
metabolites from Streptomyces that have attracted much
attention due to their antitumoral and antibacterial activity.
Significantly, cyclization of the 6-heptenoyl radical15 derived
from 1b was also totally exo regioselective, leading to
pyrido[1,2-a]indole 8 in 70% yield (entry 2). No evidence
of radical reduction (i.e., formation of an aldehyde) coming
from direct hydrogen abstraction from the hydride or an
eventual [1,5]-hydrogen atom transfer was observed. In
contrast to the benzoyl series, the formation of a seven-
a n-Bu3SnH (1.1 mol), AIBN (10 mol %), C6H6, 0.06 M, reflux, syringe
pump. b Isolated yield of chromatographically pure material.
(9) For recent examples of intramolecular reactions of acyl radicals
generated from alkyl phenyl selenoesters, see: (a) Double, P.; Pattenden,
G. J. Chem. Soc., Perkin Trans. 1 1998, 2005-2007. (b) Evans, P. A.;
Raina, S.; Ahsan, K. Chem. Commun. 2001, 2504-2505 and references
therein. (c) Allin, S. M.; Barton, W. R. S.; Bowman, W. R.; McInally, T.
Tetrahedron Lett. 2001, 42, 7887-7890.
(10) For related cyclizations involving 2-indolyl radicals, see: Dobbs,
A. P.; Jones, K.; Veal, K. T. Tetrahedron 1998, 54, 2149-2160.
(11) See the Supporting Information for complete details.
(12) Batty, D.; Crich, D. Synthesis 1990, 273-275.
(13) Tetracycle 7 has been prepared by cyclization of a 2-indolylacyl
radical generated from an alkynylthiol ester. See ref 4c.
(14) Remers, W. A.; Dorr, R. T. In Alkaloids: Chemical and Biological
PerspectiVes; Pelletier, S. W., Ed.; Wiley: New York, 1988; Vol. 6, pp
1-74.
(15) For a recent study on cyclization of 6-heptenyl radicals, see: Bailey,
W.; Longstaff, S. C. Org. Lett. 2001, 3, 2217-2219.
membered ring did not occur from 1c, only aldehyde 9
(Figure 2) being isolated in 70% yield. Reduction to 9 was
also observed when the poorer hydrogen-atom donor tris-
(trimethylsilyl)silane16 was used as the radical mediator.
We were also interested in the possibility of promoting a
cascade reaction from selenoester 1a, involving a cyclization
process followed by an intermolecular addition of the
intermediate cyclopentylmethyl radical A to an external
electron-deficient alkene (Scheme 2).17 To this end, 1a was
treated with n-Bu3SnH-AIBN in the presence of different
(16) Chatgilialoglu, C. Acc. Chem. Res. 1992, 25, 188-194.
Org. Lett., Vol. 6, No. 5, 2004
760

trans-fused tetracycle 16 was isolated as the major product
in 75% yield along with minor amounts (10%) of the spiro
compound 15 (entry 5). As the exo-endo product ratio was
not significantly affected by the hydride concentration, we
assumed that it reflected the kinetic composition of the
initially formed radical adducts A and B rather than the
equilibration between these intermediates through an in-
tramolecular rearrangement (Scheme 3).19 On the other hand,
the trans configuration of 16 is the result of the stereose-
lective axial hydrogen abstraction of the bridgehead radical
B from the hydride.18,20
Figure 2.
amounts of methyl acrylate. The best yields (45%) of the
desired 2-substituted pyrrolo[1,2-a]indole 12 were obtained
when the reaction was performed in the presence of 5
equivalents of alkene. However, minor amounts (20%) of
7, coming from the direct reduction of the radical A, were
also formed. Confirming the fast 5-exo cyclization, the simple
alkene-addition product was not detected in any assay.
Scheme 3
Scheme 2. Radical Cyclization-Intermolecular Addition
Cascade Reaction
Disappointingly, the 2-indolylacyl radical derived from 4b,
with an additional carbon atom in the connecting chain,
underwent reduction to aldehyde 11 (Figure 2) under the
reaction conditions, thus indicating that both 6-exo and
7-endo ring closure were too slow for the radical chain to
be productive.
With the aim of extending the above regioselective 6-endo
cyclizations to the construction of fused azacyclic systems,
we next turned our attention to selenoesters 5 and 6, in which
a double bond of the same substitution pattern as 4a is
included in a 4- or 3-substituted 1,2,5,6-tetrahydropyridine
moiety.21
Rather surprisingly, in both cases the crude cyclization
product was shown by 1H NMR to be a nearly equimolecular
mixture of the corresponding spiro (17 and 19) and fused
piperidine compounds (18 and 20), from which pure regio-
isomers were isolated in yields depicted in Table 1 (entries
6 and 7). As in the above carbocyclic series, the 6-endo
cyclization products 18 and 20 were exclusively obtained
The formation of fused rings via an exo cyclization mode
was investigated from selenoesters 2 and 3a,b, bearing a
2-cyclohexenyl moiety directly attached to the indole nitro-
gen or separated by one or two methylene groups. In these
series, we expected the cyclization of the 2-acyl radical to
the cyclic alkene to occur in a cis manner owing to steric
constraints imposed by the ring system.18 Subsequent reduc-
tion of the cyclic radical adduct at the R-position of the ring
junction would account for the formation of the final
products. Indeed, clean 5- and 6-exo cyclizations took place
from 2 and 3a to give stereoselectively the cis-fused
tetracycles 13 and 14 (entries 3 and 4, 70%). Tetracycle 14
could be quantitatively transformed into the thermodynami-
cally more stable trans-fused tetracycle 16 (see below) by
treatment with MeONa in MeOH. In contrast, 7-exo cycliza-
tion did not occur from 3b, and only aldehyde 10 (Figure 2)
was isolated from the reaction mixtures.
(19) For a discussion, see: Chatgilialoglu, C.; Ferreri, C.; Lucarini, M.;
Venturini, A.; Zavitsas, A. A. Chem. Eur. J. 1997, 3, 376-387. See also
ref 6.
(20) Beckwith, A. L. J.; Gream, G. E.; Struble, D. L. Aust. J. Chem.
1972, 25, 1081-1105.
The higher alkene substitution present in the 2-indolylacyl
radical derived from 4a retarded the usually favored 5-exo
cyclization mode in benefit of the 6-endo mode. Thus, the
(21) In the literature, there are several reports of alkyl and aryl radical
cyclizations upon azacyclic systems, most of them 1,4,5,6-tetrahydropy-
ridines, to give heterocycles bearing the nitrogen atom in the new ring
formed. See inter alia: (a) Mangeney, P.; Hamon, L.; Raussou, S.; Urbain,
N.; Alexakis, A. Tetrahedron 1998, 54, 10349-10362. (b) Zhang, W.
Tetrahedron 2001, 57, 7237-7262. (c) Zhang, W.; Pugh, G. Tetrahedron
2003, 59, 3009-3018. For radical cyclizations upon 1,4,5,6-tetrahidropy-
ridines where a carbocycle is created, see: (d) Ripa, L.; Hallberg, A. J.
Org. Chem. 1998, 63, 84-91. (e) Clive, D. L. J.; Yeh, V. S. C. Tetrahedron
Lett. 1999, 40, 8503-8507.
(17) For similar 5-exo cyclizations-intermolecular additions, see: (a)
Boger, D. L.; Mathvink, R. J. J. Am. Chem. Soc. 1990, 112, 4003-4008.
(b) Tsunoi, S.; Ryu, I.; Fukushima, H.; Tanaka, M.; Komatsu, M.; Sonoda,
N. Synlett 1995, 1249-1251.
(18) Curran, D. P.; Porter, N. A. Giese, B. Stereochemistry of Radical
Reactions; WCH: Weinheim, 1996.
Org. Lett., Vol. 6, No. 5, 2004
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as trans-fused stereoisomers due to the stereoselective
reduction of the intermediate radical adducts. The different
exo-endo regioselectivity exhibited by 2-indolylacyl radicals
derived from 5 and 6 with respect to 4a deserves comment.
It seems reasonable to assume that, as a consequence of the
inclusion of a nitrogen atom in the preexisting ring, the
6-endo pathway is kinetically decelerated.
Acknowledgment. Financial support from the “Ministerio
de Ciencia y Tecnolog´ıa” (MCYT), Spain (Project No.
BQU2000-0785), and MCYT-FEDER (Project No. BQU2003-
04967-C02-02) is gratefully acknowledged. We also thank
the DURSI (Generalitat de Catalunya) for Grant No.
2001SGR00084. F.F. thanks the University of Barcelona for
a grant.
In summary, a new indole annulation procedure based on
intramolecular reactions of 2-indolylacyl radicals has been
developed. When appropriate carbon-carbon double bonds
connected to the indole nitrogen are used as acceptors, the
procedure provides straightforward access to cyclic ketones
fused to the 1,2-position of the indole nucleus, which should
be of interest for the synthesis of natural products and
medicinal compounds.
Supporting Information Available: Experimental pro-
cedures and characterization data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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