ORGANIC
LETTERS
2009
Vol. 11, No. 6
1281-1284
Synthesis of Aminocyclobutanes
through Ring Expansion of
N-Vinyl-ꢀ-Lactams
Lawrence L. W. Cheung and Andrei K. Yudin*
Department of Chemistry, UniVersity of Toronto, 80 St. George Street,
Toronto M5S 3H6, Canada
Received January 9, 2009
ABSTRACT
Both eight-membered enamide rings and fused [4.2.0]aminocyclobutane-containing δ-lactams can be accessed from N-vinyl-ꢀ-lactams. The
eight-membered rings are made through a [3,3] sigmatropic rearrangement. At elevated temperature, the eight-membered lactam undergoes
electrocyclization to furnish fused cyclobutane δ-lactams in a diastereoselective manner.
As part of a program aimed at synthesis of stereochemically
complex cyclobutanes, we evaluated the possibility of their
construction from ꢀ-lactams. The latter are structural con-
stituents in a number of biologically active molecules and
are valuable intermediates in chemical synthesis.1 The ring
strain embedded in the four-membered ring of a ꢀ-lactam is
an attractive structural feature that has been exploited in
numerous ring-opening and ring-expansion reactions.1 Com-
pared to cyclobutanes, ꢀ-lactams have received more atten-
tion and are generally easier to make. We sought a method
that transposes the strain of a ꢀ-lactam into that of a
cyclobutane. There are many ways to prepare ꢀ-lactams,
including ester-enolate imine cycloaddition,2 olefin-iso-
cyanate cycloaddition,3 Kinugasa reaction,4 and the Staudinger
reaction.5 In comparison, there are not many general methods
to make cyclobutanes, the most popular process being the
photochemical [2 + 2] cycloaddition. However, the latter
reaction has inherent drawbacks such as dimerization of
starting materials and formation of product mixtures resulting
from lack of regio- and stereoselectivity.6 In this paper, we
report that ring scission of ꢀ-lactams can give rise to
diversely substituted aminocyclobutanes7 via sigmatropic ring
opening/electrocyclic ring closure sequence.
The ꢀ-lactam starting materials can be prepared on a
multigram scale in three steps that include a single purifica-
tion (Scheme 1). The synthesis begins with a cycloaddition
between isoprene and chlorosulfonyl isocyanate8 to afford
the N-chlorosulfonyl ꢀ-lactam that is cleanly reduced to the
corresponding N-H ꢀ-lactam with aqueous sodium sulfite.9
The ꢀ-lactam is then cross coupled with an appropriate
vinyl10 iodide under copper catalysis11 to give the corre-
sponding N-vinyl-ꢀ-lactam.
(1) (a) Alcaide, B.; Almendros, P. Synlett 2002, 3, 381. (b) Alcaide, B.;
Almendros, P.; Aragoncillo, C. Chem. ReV. 2007, 107, 4437. (c) Alcaide,
B.; Almendros, P. Curr. Med. Chem. 2004, 29, 1921.
(2) (a) Gilman, H.; Speeter, H. J. Am. Chem. Soc. 1943, 65, 2255. (b)
Hart, D. J.; Ha, D. C. Chem. ReV. 1989, 89, 1447.
(5) (a) Staudinger, H Justus Liebigs Ann. Chem. 1907, 356, 51. (b)
Palomo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Eur. J. Org. Chem.
1999, 3223. (c) France, S.; Taggi, A. E.; Lectka, T. Acc. Chem. Res. 2004,
37, 592.
(6) Rappoport, Z.; Liebman, J. F. The chemistry of cyclobutanes; John
Wiley & Sons: Chichester, 2005.
(3) (a) Grai, R. Justus Liebigs Ann. Chem. 1963, 661, 111. (b) Hoffmann,
H.; Diehr, H. J. Tetrahedron Lett. 1963, 4, 1875. (c) Friedrich, H. J.
Tetrahedron Lett. 1971, 12, 2981.
(7) For utility of aminocyclobutane derivatives in drug discovery, see:
Allan, R. D.; Hanrahan, J. R.; Hambley, T. W.; Johnston, G. A. R.; Mewett,
K. N.; Mitrovic, A. D. J. Med. Chem. 1990, 33, 2905.
(4) (a) Kinugasa, M.; Hashimoto, S. J. Chem. Soc., Chem. Commun.
1972, 466. (b) Pal, R.; Ghosh, S. C.; Chandra, K.; Basak, A. Synlett 2007,
2321.
(8) Moriconi, E. J.; Meyer, W. C. Tetrahedron Lett. 1968, 35, 3823.
(9) Durst, T.; O’Sullivan, M. J. J. Org. Chem. 1970, 35, 2043.
10.1021/ol900118d CCC: $40.75
Published on Web 02/24/2009
2009 American Chemical Society