1,4-pentadienyl-3-sulfonamides: frameworks for disfavored radical cascade cyclizations.

Article abstract of DOI:10.1021/ol0166449

[reaction: see text]. 1,4-pentadienyl-3-sulfonamides afford products including those resulting from disfavored 5-endo-trig reactions when subjected to radical cyclization conditions. Products resulting from pathways featuring 4-exo-trig cyclizations are also detected, even when the 4-exo-trig reaction leads to a highly strained bicyclo[3.2.0] ring system.

Full text of DOI:10.1021/ol0166449

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3405-3407
1,4-Pentadienyl-3-sulfonamides:
Frameworks for “Disfavored” Radical
Cascade Cyclizations
Sacha Bommezijn, Concepcion Gonzalez Martin, Alan R. Kennedy,
Dimitrios Lizos, and John A. Murphy*
Department of Pure and Applied Chemistry, UniVersity of Strathclyde,
295 Cathedral Street, Glasgow G1 1XL, U.K.
john.murphy@strath.ac.uk
Received August 24, 2001
ABSTRACT
1,4-Pentadienyl-3-sulfonamides afford products including those resulting from disfavored 5-endo-trig reactions when subjected to radical
cyclization conditions. Products resulting from pathways featuring 4-exo-trig cyclizations are also detected, even when the 4-exo-trig reaction
leads to a highly strained bicyclo[3.2.0] ring system.
The outcome of radical cyclization reactions can usually be
predicted by applying the rules that were announced by
Baldwin1 25 years ago (and subsequently developed by
Beckwith2 in specific relation to radical cases). The examples
in Baldwin’s original papers focused especially on the
disfavored nature of 5-endo-trig reactions. 5-Endo-trig radical
cyclizations are rare,3,4 and steric and electronic factors are
frequently present3 that help to mitigate the unfavorable
factors. We now report a novel specific series of sulfon-
amides that flout the 5-endo-trig guideline, where there is
no obvious rationalization for this behavior.
Dienes 15 were treated with tributyltin hydride and AIBN
and afforded6 the expected products 2. However, the yield
of 2 was very low, and further investigation revealed that a
second type of product was present as a mixture of
3018. (q) Nonami, Y.; Baran, J.; Sosnicki, J.; Mayr, H.; Masuyama, A.;
Nojima, M. J. Org. Chem. 1999, 64, 4060. (r) Reimann, H.; Sarre, O. Z.
Can. J. Chem. 1971, 49, 344. (s) Lo¨ffler, H. P.; Schro¨der, G. Tetrahedron
Lett. 1970, 2119. (t) Lo¨ffler, H. P. Chem. Ber. 1971, 104, 1981.
(1) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734 and 736.
(2) Beckwith, A. L. J. Tetrahedron 1981, 37, 3073. Beckwith, A. L. J.;
Easton, J. C.; Serelis, A. K. J. Chem. Soc., Chem. Commun. 1980, 482.
(3) For illustrative examples, see: (a) Gao, J.; Rusling, J. F. J. Org. Chem.
1998, 63, 218. (b) Schmalz, H. G.; Siegel, S.; Bats, J. W. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 2383. (c) Crich, D.; Yao, Q. J. Chem. Soc., Chem.
Commun. 1993, 1265. (d) Crich, D.; Yao, Q. Tetrahedron 1994, 50, 12305.
(e) Mendenhall, G. D.; Protasiewicz, J. D.; Brown, C. E.; Ingold, K. U.;
Lusztyk, J. J. Am. Chem. Soc. 1994, 116, 1718. (f) Tanner, D. D.; Rahimi,
P. M. J. Org. Chem. 1979, 44, 1674. (g) Yamamoto, Y.; Ohno, M.; Eguchi,
S. J. Am. Chem. Soc. 1995, 117, 9653. (h) Ishibashi, H.; Nakamura, N.;
Sato, T.; Takeuchi, M.; Ikeda, M. Tetrahedron Lett. 1991, 32, 1725. (i)
Baker, S. R.; Burton, K. I.; Parsons, A. F.; Pons, J. F.; Wilson, M. J. Chem.
Soc., Perkin Trans. 1 1999, 427. (j) Cassayre, J.; Dauge, D.; Zard, S. Z.
Synlett 2000, 4, 471. (k) Chatgilialoglu, C.; Gimisi, T.; Spada, G. P. Chem.
Eur. J. 2000, 5, 2866. (l) Sannigrahi, M.; Mayhew, D. L.; Clive, D. L. J.
J. Org. Chem. 1999, 64, 2776. (m) Capella, L.; Montevecchi, P. C.;
Navacchia, M. L. J. Org. Chem. 1996, 61, 6783. (n) Journet, M.; Rouillard,
A.; Cai, D.; Larsen, R. D. J. Org. Chem. 1997, 62, 8630. (o) Bogen, S.;
Gulea, M.; Fensterbank, L.; Malacria, M. J. Org. Chem. 1999, 64, 4920.
(p) Wilt, J. A.; Maravetz, L. L.; Zawadzki, J. F. J. Org. Chem. 1966, 31,
(4) (a) Julia, M.; Le Goffic, F. Bull. Soc. Chim. Fr. 1965, 1550. (b) Pines,
H.; Sih, N. C.; Rosenfield, D. B. J. Org. Chem. 1966, 31, 2255. (c) Bradney,
M. A. M.; Forbes, A. D.; Wood, J. J. Chem. Soc., Perkin Trans. 2 1973,
1655. (d) Nonami, Y.; Baran, J.; Sosnicki, J.; Mayr, H.; Masuyama, A.;
Nojima, M. J. Org. Chem. 1999, 64, 4060. (e) Reimann, H.; Sarre, O. Z.
Can. J. Chem. 1971, 49, 344. (f) Lo¨ffler, H. P.; Schro¨der, G. Tetrahedron
Lett. 1970, 2119. (g) Lo¨ffler, H. P. Chem. Ber. 1971, 104, 1981.
(5) Compounds 1, 7, 15, 16, and 24 were prepared by Mitsunobu coupling
of the corresponding 1,4-dien-3-ols with the appropriate sulfonamide. In
the cases of 7, 15, 16, and 24 the desired product was contaminated by the
isomeric 2,4-dienyl-1-sulfonamides. The latter isomers were removed by
Diels-Alder reaction with 4-phenyl-1,3,4-triazoline-2,5-dione followed by
chromatographic separation to leave the pure desired products.
(6) A mixture of tributyltin hydride (1.5 equiv) and AIBN (0.25 equiv)
in solution in benzene was added by syringe pump over 7-12 h to the
substrate (10 mM in benzene) while heating under reflux. Treatment with
iodine and DBU, filtration, and chromatography afforded the products;
see: Curran, D. P.; Chang, C.-T. J. Org. Chem. 1989, 54, 3140.
10.1021/ol0166449 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/12/2001

Scheme 1
diastereoisomers. This structure was assigned as 6, and this
strained bicyclo[3.2.0] intermediate 12. (To our knowledge,
this is the first example of a radical cyclization to form the
four-membered ring of a bicyclo[3.2.0] system). Fragmenta-
tion of this radical, 12, produces the somewhat stabilized
indolinyl intermediate 13, which yields 14 by loss of the
sulfinyl radical and then tautomerizes to indole 10. Variation
of the sulfonamide group as in 7b,c altered the relative yield
of the products: “normal” product 8b, (12%), 8c (0%),
5-endo product 9b, (29%), 9c (25%), and indole 10 (24%
from 7b, 31% from 7c).
was confirmed by selective crystallization of one of the
isomers 6* and subsequent single-crystal X-ray structure
determination.
Two pathways were considered for formation of cyclo-
pentene 6: (a) 5-endo-trig cyclization of intermediate 3 to
afford the cyclopropylcarbinyl radical 4, which following
fragmentation and hydrogen atom abstraction afforded 6, or
(b) a fragmentation-cyclization pathway via 5. Although
the fragmentation to a vinyl radical, 5, would not be favored
on energetic grounds, slow progress through an unfavorable
equilibrium might, in principle, afford 5, which should then
cyclize in a favorable 5-exo-trig mode onto the activated
alkene to yield the observed product 6 following hydrogen
atom abstraction. To distinguish between the two possible
mechanisms and to explore the scope of the reaction,
substrate 7a was prepared and subjected to radical cycliza-
tion. This afforded both the product expected from 5-exo-
trig cyclization followed by reductive termination, 8a (as a
mixture of isomers) and the 5-endo product 9a, the latter
being the predominant product. Intriguingly, it also afforded
the indole 10 (20%). This product can be rationalized by a
second cyclization (4-exo-trig) of 11 cis to afford the highly
The formation of products 9 in these reactions cannot occur
by a fragmentation route as discussed for the substrate (1)
and clearly demonstrates that the normally disfavored 5-endo-
trig pathway is in operation. To test the generality of the
reaction, the seven- and eight-membered ring dienes 15 and
16 were then prepared. Cyclization of 15 led to the tricycle
17 (50%). If tetracyclic radicals 19 and 20 were formed, their
reversal to 18 was too rapid to permit reduction by tributyltin
hydride. By contrast, however, the eight-membered substrate
16 afforded not only the simple tricyclic product 21 (20%)
but also the two products resulting from transannular
cyclization, 22 (37%) and the indole 23 (10%). This con-
3406
Org. Lett., Vol. 3, No. 21, 2001

Scheme 2
jugated product must arise by tautomerism of the initially
formed isomer.
studies to substrates with activated radical acceptor sites and
alternative radical-chain carriers is currently under investiga-
tion.
All of the examples reported above feature an aryl ring;
to see if this was a prerequisite for the 5-endo cyclization,
chloroamide (24) was prepared and treated with tributyltin
hydride under the normal conditions. This afforded the
expected monocyclic pyrrolidine product (25, 48%) as the
principal product. However, the bicyclic amide (26, 15%),
resulting from 5-endo cyclization, was also formed.
Acknowledgment. We thank the EPSRC, the EU COST
D12 initiative, the University of Strathclyde for funding and
EPSRC Mass Spectrometry Service, Swansea, for mass
spectra. We are grateful to the Ministerio de Educacion y
Ciencia (Spain) for a Fellowship to C.G.M., and we thank
Dr. Louis Fensterbank for helpful discussions
It is clear that the dienesulfonamide substrates examined
in this study constitute a class of compounds that undergo
normally disfavored radical cyclizations with unusual ease.
The examples studied in this communication all feature
unactivated alkenes and use tributyltin hydride, which
features a relatively weak Sn-H bond. Extension of the
Supporting Information Available: NMR spectra for all
products and crystallographic information files (in CIF
format) for compound 6*. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0166449
Org. Lett., Vol. 3, No. 21, 2001
3407