New light-induced iminyl radical cyclization reactions of acyloximes to isoquinolines

Article abstract of DOI:10.1021/ol061258i

An efficient photochemical approach for the unusual generation of six-membered heterocyclic rings is reported. Iminyl radicals, generated by the irradiation of acyloximes, participate in intramolecular cyclization processes and in intermolecular addition-intramolecular cyclization sequences.

Full text of DOI:10.1021/ol061258i

ORGANIC
LETTERS
2006
Vol. 8, No. 16
3521-3523
New Light-Induced Iminyl Radical
Cyclization Reactions of Acyloximes to
Isoquinolines
Rafael Alonso, Pedro J. Campos, Ba´rbara Garc´ıa, and Miguel A. Rodr´ıguez*
Departamento de Qu´ımica, UniVersidad de La Rioja, Grupo de S´ıntesis Qu´ımica de La
Rioja, Unidad Asociada al C.S.I.C., Madre de Dios, 51, 26006 Logron˜o, Spain
miguelangel.rodriguez@dq.unirioja.es
Received May 23, 2006
ABSTRACT
An efficient photochemical approach for the unusual generation of six-membered heterocyclic rings is reported. Iminyl radicals, generated by
the irradiation of acyloximes, participate in intramolecular cyclization processes and in intermolecular addition
sequences.
−intramolecular cyclization
The behavior of iminyl radicals generated from S-arylimines,
oxime benzoates, xanthyl hydrazones, S-benzothiazole sul-
fenylimines, and N-benzotriazolimines for the synthesis of
diverse pyrrolidine systems has been reported.1 The reactions
can be promoted by both thermal and photochemical
methods. More recently, the groups of Zard2 and Narasaka3
reported the photochemical radical cyclization of γ,δ-
unsaturated ketone oxime derivatives to give 3,4-dihydro-
2H-pyrroles. Although intramolecular cyclization between
an iminyl radical and an olefin seems an attractive strategy
to construct nitrogen heterocycles, as far as we know, these
photochemical processes have not been utilized in the
preparation of six-membered heterocyclic rings. In this letter,
we report our results from investigations in this area.
In the context of our studies on the photochemistry of
compounds containing a carbon-nitrogen double bond,4 we
focused our attention on acyloximes. Acyloximes can be used
as photoinitiators for UV-curable coatings.5 When they are
irradiated, nitrogen-oxygen bond cleavage occurs, and this
initiates the polymerization process.6 The simplicity of the
iminyl radical formation prompted us to investigate the ability
of these systems to generate six-membered heterocyclic rings.
We started our investigation of the reaction conditions by
irradiating a solution of 2-phenylbenzaldehyde O-acetyl-
oxime7 (1, 0.5 mmol) in 50 mL of hexane, with a 400 W
mercury lamp through Pyrex, under an Ar atmosphere, until
the acetyloxime was consumed. After the usual workup
procedure, we isolated the desired six-membered ring
(4) See, for example: (a) Ortega, M.; Rodr´ıguez, M. A.; Campos, P. J.
Tetrahedron 2005, 61, 11686. (b) Soldevilla, A.; Sampedro, D.; Campos,
P. J.; Rodr´ıguez, M. A. J. Org. Chem. 2005, 70, 6976. (c) Sampedro, D.;
Caro, M.; Campos, P. J.; Rodr´ıguez, M. A. J. Org. Chem. 2005, 70, 6705.
(d) Sampedro, D.; Soldevilla, A.; Rodr´ıguez, M. A.; Campos, P. J.; Olivucci,
M. J. Am. Chem. Soc. 2005, 127, 441.
(5) For reviews on photoinitiated polymerization, see: (a) Fouassier, J.
P. Photoinitiation, Photopolymerization and Photocuring: Fundamentals
and Applications; Carl Hanser Verlag: Munich, 1995. (b) Roffey, C. G.
Photogeneration of ReactiVe Species for UV Curing; J. Wiley: New York,
1997. (c) Neckers, D. C.; Jager, W. Photoinitiation for Polymerization:
UV & EB at the Millenium, Sita Series in Surface Coatings Technology 7;
J. Wiley: New York, 1999. (d) Photoinitiated Polymerization; ACS
Symposium Series 847, Belfield, K. D., Crivello, J. V., Eds.; American
Chemical Society: Washington, DC, 2003.
(1) For a review, see: Fallis, A. G.; Brinza, I. M. Tetrahedron 1997,
53, 17543.
(2) Gagosz, F.; Zard, S. Synlett 1999, 1978.
(3) (a) Uchiyama, K.; Hayashi, Y.; Narasaka, K. Tetrahedron 1999, 55,
8915. (b) Mikami, T.; Narasaka, K. Chem. Lett. 2000, 338. (c) Kitamura,
M.; Mori, Y.; Narasaka, K. Tetrahedron Lett. 2005, 46, 2373.
(6) Okada, T.; Kawanisi, M.; Nozaki, H. Bull. Chem. Soc. Jpn. 1969,
42, 2981.
10.1021/ol061258i CCC: $33.50
© 2006 American Chemical Society
Published on Web 07/01/2006

phenanthridine (2) in 19% yield.8 In addition to 2, nitrile 3
(47%) was also obtained (Scheme 1). The yields of 2 and 3
Scheme 2
Scheme 1
The same approach was employed in the irradiation of
2-ethynylbenzaldehyde O-acetyloxime (14). The reaction led
to the formation of isoquinoline in 64% yield (Scheme 3).9
were dependent on the solvent employed (Table 1, entries
1-5). The use of tert-butyl alcohol afforded the highest yield
of 2 (58%, entry 5).
Scheme 3
Table 1. Synthesis of Phenanthridines by Irradiation of
O-Acyloximes
We also investigated the intermolecular attack of the
iminyl radical on a carbon-carbon triple bond. We chose
benzophenone O-acetyloxime (15) as the starting material
because, after an initial addition reaction, one of the phenyl
groups could sequentially participate in an annulation
process. Irradiation was initially performed in the presence
of tolane. As shown in Scheme 4, a tandem (cascade)
Scheme 4
a Yields of isolated product.
We also explored the effect on the yield of the reaction
of ketone O-acyloximes. Irradiation of 2-phenylacetophenone
or 2-phenylbenzophenone O-acetyloxime in tert-butyl alcohol
gave the corresponding phenanthridine in 91 and 40% yield,
respectively (Table 1, entries 6 and 7).
We subsequently focused our attention on evaluating the
participation of unsaturated systems other than phenyl. We
assayed the irradiation of 2-vinylbenzaldehyde O-acetyl-
oximes. As indicated in Scheme 2, irradiation of compounds
bearing a carbon-carbon double bond (8, 10, and 12) is
useful for the preparation of six-membered heterocyclic
compounds.8
intermolecular addition/intramolecular cyclization took place,
with isoquinoline 16 formed in 76% yield. This reaction
sequence was also applied to dimethyl acetylenedicarbox-
ylate, which led to the formation of 17.
In summary, we have developed an efficient photochemi-
cal approach for the unusual generation of six-membered
heterocyclic rings from iminyl radicals, generated from
acyloximes, through intramolecular cyclization or intermo-
(7) 2-Phenylbenzaldehyde oxime, prepared according to Cullen, K. E.;
Sharp, J. T. J. Chem. Soc., Perkin Trans. 1 1993, 2961, was used as
precursor.
(8) The addition of nitrogen-centered radical should form an azacyclo-
hexadienyl radical, from which a hydrogen atom may be abstracted by
another radical to gain aromaticity: Parsons, A. F. An Introduction to Free
Radical Chemistry; Blackwell: Oxford, 2000; p 68.
(9) The addition of nitrogen-centered radical should generate an iso-
quinolyl radical, which may evolve by hydrogen atom abstraction since
the use of 2-propanol-d7 as solvent led to 4-deuteroisoquinoline, while the
use of methanol-d1 led to nondeuterated isoquinoline.
3522
Org. Lett., Vol. 8, No. 16, 2006

lecular addition/intramolecular cyclization sequences. A
systematic and extensive study of the scope and limitations
of this process is currently under investigation in our
laboratory and will be reported in due course.
R.A. and B.G. thank the Comunidad Auto´noma de La Rioja
for their fellowships.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank the Spanish Ministerio de
Educacio´n y Ciencia (CTQ2004-03134) and the Comunidad
Auto´noma de La Rioja (ACPI2005/06) for financial support.
OL061258I
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