Synthesis of aminocyclobutanes through ring expansion of N-vinyl-β-lactams

Article abstract of DOI:10.1021/ol900118d

Both eight-membered enamide rings and fused [4.2.0]aminocyclobutane- containing δ-lactams can be accessed from N-vinyl-β-lactams. The eight-membered rings are made through a [3,3] sigmatropic rearrangement. At elevated temperature, the eight-membered lact

Full text of DOI:10.1021/ol900118d

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
ayudin@chem.utoronto.ca
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

Scheme 1
.
Synthesis of ꢀ-Lactam Starting Materials
Table 1. Substrate Scope of the [3,3] Sigmatropic
Rearrangement
Upon thermal activation, we observed the formation of
eight-membered enamide rings via a [3,3] sigmatropic
rearrangement. As shown in Table 1, electron-rich, -poor,
and -neutral enamide substituents are tolerated (entries 1-4).
Various aromatic heterocycles such as furan, thiophene and
pyrrole also participate in this chemistry (entries 7-9). The
ꢀ-lactam component can be modified to contain an allene,
instead of an olefin, to participate in the formal [3,3]
sigmatropic rearrangement leading to a conjugated triene ring
system (entry 10). When the R group is an alkyl substituent
(entries 5 and 6), the initial product is an imine that
tautomerizes to the enamide product.
Entry 8 of Table 1 indicates that a fused cyclobutane
δ-lactam product 8c has been formed as a byproduct. Despite
the low yield, 8c sparked our interest. The reaction was
initially studied through a cascade sequence involving
coupling 2-bromoprop-1-ene and ꢀ-lactam A (Scheme 2)
under thermal cooper-catalyzed cross-coupling conditions.
The product of N-vinylation was found to undergo a formal
[3,3] sigmatropic rearrangement without concomitant tau-
tomerization to the enamide form. This behavior is particu-
larly noticeable when R and R1 ) alkyl, rather than aryl,
groups (entries 5 and 6, Table 1). In this case, the imine
lifetime is long enough that deprotonation R to the carbonyl
can occur to produce a 6π electron system that can undergo
the electrocyclization to produce the fused cyclobutane
δ-lactam. The reaction yields are highest when N-vinyl-ꢀ-
lactam is used as the starting material without isolation of
the intermediate product of the [3,3] sigmatropic rearrange-
ment. Cs2CO3 and a copper source, such as CuI or CuCl,
were found to be essential for the reaction. This sequence
represents a rare thermal method to produce fused cyclobu-
tane δ-lactams as most methods employ photochemistry to
make the fused cyclobutane δ-lactams.12
Table 2 shows the scope of the reaction. The substrates
initially tested were those of entries 1-3. The reaction
(10) (a) Harried, S. S; Lee, C. P.; Yang, G.; Lee, T. I. H.; Myles, D. C.
J. Org. Chem. 2003, 68, 6646. (b) Trost, B. M.; Rudd, M. T. Org. Lett.
2003, 5, 4599. (c) Barton, D. H. R.; Bashiardes, G.; Pourrey, J. L.
Tetrahedron Lett. 1983, 24, 1605. (d) Blaskovicova, M.; Gaplovsky, A.;
Blasko, J. Molecules 2007, 11, 188. (e) Kamiya, N.; Chikami, Y.; Ishii, Y.
Synlett 1990, 675.
a Yields of isolated products obtained under microwave heat
(160-200 °C).
(11) Jiang, L.; Job, G. E.; Klapers, A.; Buchwald, S. L. Org. Lett. 2003,
5, 3667.
(12) (a) Chen, P.; Chen, Y.; Carroll, P. J.; Sieburth, S. M. Org. Lett.
2006, 8, 3367. (b) Commins, D. L.; Zheng, X.; Goehring, R. R. Org. Lett.
2002, 4, 1611. (c) Chiba, T.; Takada, Y.; Kaneko, C.; Kiuchi, F.; Tsuda,
Y. Chem. Pharm. Bull. 1990, 38, 3317. (d) Chiba, T.; Takada, Y.; Naito,
T.; Kaneko, C. Chem. Pharm. Bull. 1990, 38, 2335. (e) Kaneko, C.;
Ychiyama, K.; Sato, M.; Katagiri, N. Chem. Pharm. Bull. 1986, 34, 3658.
(f) Naito, T.; Kaneko, C. Chem. Pharm. Bull. 1985, 33, 5328. (g) Kaneko,
C.; Katagiri, N.; Uchiyama, K.; Yamada, T. Chem. Pharm. Bull. 1985, 33,
4160.
worked well in each case with moderate levels of diaste-
reoselectivity. The reaction with the geminally disubstituted
enamides worked particularly effectively (entries 4 through
6). The crude material did not require any purification. In
entry 7, a trisubstituted olefin was employed to afford a
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Org. Lett., Vol. 11, No. 6, 2009

Table 2. Cyclobutane Formation: The Substrate Scope
a Yields of isolated products obtained under microwave heat (160-200 °C). b See the Supporting Information.
tricyclic system with three contiguous stereocenters. When
aryl groups were used at the geminal position the reaction
selectivity was not as high as with geminal alkyl substituents:
both the fused cyclobutane δ-lactam product and the eight-
membered ring product of the sigmatropic rearrangement
were isolated. The cyclopropyl, cyclobutyl, and cyclohexyl
carbocycles at the geminal position can also be used. Lastly,
spirocyclic compounds can be made from tetrasubstituted
olefins that are exocyclic to the carbocycle (entry 14).
In summary, we have developed a versatile class of
stable ꢀ-lactam intermediates that can undergo ring
expansion to afford 8-membered enamide rings. The
[3,3] sigmatropic rearrangement of these ꢀ-lactams pro-
ceeds without any relative stereochemical requirement
imposed on the starting material unlike the ring-strain
releasing [3,3] sigmatropic rearrangements that require a
syn relative stereochemistry between the reacting olefins.13
Most importantly, we have also demonstrated that ꢀ-lac-
tams can undergo ring expansion/ring closure in a domino
fashion to produce highly substituted fused cyclobutane
δ-lactams with high levels of diastereoselectivity. Catalytic
asymmetric synthesis of fused cyclobutane δ-lactams is
currently underway.
Scheme 2. Mechanism of Cyclobutane Formation
(13) (a) Brown, J. M.; Golding, B. T.; Stofko, J. J. J. Chem. Soc., Chem.
Commun. 1973, 319b. (b) Vogel, E. Ann. 1958, 615, 1. (c) Alcaide, B.;
Rodr´ıguez-Ranera, C.; Rodr´ıguez-Vicente, A. Tetrahedron Lett. 2001, 42,
3081.
Org. Lett., Vol. 11, No. 6, 2009
1283

Acknowledgment. This work was supported by the
Natural Science and Engineering Research Council of
Canada (NSERC). We thank Professor William Reynolds
(University of Toronto) for NMR assistance, Dr. Alan
Lough (University of Toronto) for his contribution to
X-ray analysis and Professor Robert Batey (University of
Toronto), Mr. Farhad Nowrouzi (University of Toronto),
Mr. Petar Duspara (University of Toronto), and Dr. Chris
Smith (University of Toronto) for the use of their
microwave reactor.
Supporting Information Available: Crystallographic
data, NMR spectra, and experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL900118D
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Org. Lett., Vol. 11, No. 6, 2009