ORGANIC
LETTERS
2002
Vol. 4, No. 18
3079-3081
Intramolecular Cyclization of Acyl
Radicals onto the Azido Group: A New
Radical Approach to Cyclized Lactams†
Luisa Benati,* Rino Leardini, Matteo Minozzi, Daniele Nanni, Piero Spagnolo,*
Samantha Strazzari,* and Giuseppe Zanardi
Dipartimento di Chimica Organica “A. Mangini”, UniVersita` di Bologna,
Viale Risorgimento 4, I-40136 Bologna, Italy
Received June 14, 2002
ABSTRACT
Aryl- and alkyl-derived azidoacyl radicals, generated from thiolesters by intramolecular homolytic substitution at the sulfur, can undergo five-
and six-membered cyclization onto the azido moiety to give cyclized lactams.
Radical cyclization reactions have become a powerful tool
for the construction of carbocyclic and heterocyclic systems,
even those occurring in natural products.1 Radical cycliza-
tions most often involve carbon-carbon bond formation,
whereas those leading to carbon-nitrogen bond formation
are much less well documented. The reported methodologies
rely on additions of aminyl2 and iminyl3 radicals to CdC
and CdO double bonds or on additions of carbon radicals
to nitrogen atoms of imines.4 However, the synthetic potential
of radical azide reactions has been so far rather poorly
investigated, though the reported studies have revealed
that the azido moiety can act as a valuable radical acceptor
toward carbon- and heteroatom-centered species to yield
an aminyl radical after loss of molecular nitrogen by the
initial triazenyl adduct.2e,f,5 In fact, intramolecular additions
of aryl,6 thiocarbonyl,7 alkyl,8 and vinyl9 radicals have been
recently found to provide useful synthetic routes to N-
heterocycles.
(3) (a) Atmaram, S; Forrester, A. R.; Gill, M.; Thomson, R. H. J. Chem.
Soc., Perkin Trans. 1 1981, 1721. (b) Boivin, J.; Fouquet, E.; Zard, S. Z.
Tetrahedron 1994, 50, 1745. (c) El Kaim, L.; Meyer, C. J. Org. Chem.
1996, 61, 1556. (d) Zard, S. Z. Synlett 1996, 1148. (e) Bowman, W. R.;
Bridge, C. F.; Brookes, P.; Cloonan, M. O.; Leach, D. C. J. Chem. Soc.,
Perkin Trans. 1 2002, 58 and refs therein.
(4) (a) Takano, S.; Suzuki, M.; Ogasawara, K. Heterocycles 1994, 37,
149. (b) Tomaszewski, M. J.; Warkentin, J.; Werstiuk, N. H. Aust. J. Chem.
1995, 48, 291. (c) Bowman, W. R.; Stephenson, P. T.; Young, A. R.
Tetrahedron 1996, 52, 11445. (d) Ryu, I.; Matsu, K.; Minakata, S.; Komatsu,
M. J. Am. Chem. Soc., 1998, 120, 5838 and refs therein.
(5) Dang, H. -S.; Roberts, B. P. J. Chem. Soc., Perkin Trans. 1 1996,
1493.
(6) Benati, L.; Montevecchi, P. C.; Spagnolo, P. Tetrahedron Lett. 1978,
815.
(7) Benati, L.; Montevecchi, P. C. J. Org. Chem. 1981, 46, 4570.
(8) Kim, S.; Joe, G. H.; Do, J. Y. J. Am. Chem. Soc. 1994, 116,
5521.
(9) Montevecchi, P. C.; Navacchia, M. L.; Spagnolo, P. Eur. J. Org.
Chem. 1998, 1219.
† Dedicated to Professor Domenico Spinelli on the occasion of his 70th
birthday.
(1) For leading reviews, including radical cyclizations, see: (a) Moth-
erwell, W. B.; Crich, D. Free-Radical Chain Reactions in Organic Synthesis;
Academic: London, 1992. (b) Curran, D. P.; Porter, N. A.; Giese, B.
Stereochemistry of Radical Reactions; VCH: New York, 1996. (c) Giese,
B.; Kopping, B; Go¨bel, T.; Dickhaut, J.; Thoma, G.; Kulicke, K. J.; Trach,
F. Org. React. 1996, 48, 301. (d) Renaud, P.; Giraud, L. Synthesis 1996,
913. (e) Fallis, A. G.; Brinza, I. M. Tetrahedron 1997, 53, 17543.
(2) (a) Kim, S.; Joe, G. H.; Do, J. Y. J. Am. Chem. Soc. 1993, 115,
3328 and refs therein. (b) Bowman, W. R.; Clark, D. N.; Marmon, R. J.
Tetrahedron 1994, 50, 1275. (c) Maxwell, B. J.; Tsanaktsidis, J. J. Am.
Chem. Soc. 1996, 118, 4276. (d) Bowman, W. R.; Broadhurst, M. J.;
Coghlan, D. R.; Lewis, K. A. Tetrahedron Lett. 1997, 38, 6301. (e) Benati,
L.; Nanni, D.; Sangiorgi, C.; Spagnolo, P. J. Org. Chem. 1999, 64, 7836.
(f) Benati, L.; Leardini, R.; Minozzi, M.; Nanni, D.; Spagnolo, P.; Strazzari,
S.; Zanardi, G.; Calestani, G. Tetrahedron 2002, 58, 3485.
10.1021/ol026366t CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/06/2002