C O M M U N I C A T I O N S
Table 2. Alkylative Ring Expansion of MCP 1a (Q ) Pyrid-2-yl)
The amide nitrogen atom, which is generally considered non-
nucleophilic, was incorporated into the newly formed ring under
neutral conditions. Through hetero-aryl MCP amides bearing one
o-nitrogen atom, the alkylative ring expansion with aryl aldimines
and aldehydes was achieved, resulting in the exclusive formation
of γ′-amino- or -hydroxy-alkylated pyrrol-2-ones. Currently, we
are studying further applications of a variety of MCP substrates
with Lewis acids including chiral variants.
entry
4
X
Y
equiv of MgI2
[1] (M)
8
yielda (%)
1
2
3
4
5
6
7
8
a
a
b
b
c
d
e
f
NTs 4-Br
NTs 4-Br
NTs 2,4-dimethyl
NTs 2,4-dimethyl
NTs 4-OMe
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
0.05
0.1
0.05
0.1
0.1
0.1
0.1
0.1
0.1
0.1
aa
aa
ab
ab
ac
ad
ae
af
45
53
54
68
71
72
76
62
72
81
Acknowledgment. We thank NSERC (Canada) and the Uni-
versity of Toronto for funding this research. W.H. thanks the
University of Toronto for financial support.
NTs
H
NTs 2-CF3
Supporting Information Available: Details of all experimental
procedures and analytical data (PDF). This material is available free
O
O
O
H
9
10
g
h
3,4-OCH2O
4-CF3
ag
ah
a In each case, the nonalkylated product 7a was isolated in 10-30%
yield.
References
(1) For methylenecyclopropanes, see: (a) Lautens, M.; Han, W. J. Am. Chem.
Soc. 2002, 124, 6312. (b) Monti, H.; Rizzotto, D.; Le´andri, G. Tetrahedron
1998, 54, 6725. (c) Yamago, S.; Nakamura, M.; Wang, X. Q.; Yanagawa,
M.; Tokumitsu, S.; Nakamura, E. J. Org. Chem. 1998, 63, 1694. (d)
Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. (e) Binger,
P.; Bu¨ch, H. M. Top. Curr. Chem. 1987, 135, 77. (f) Trost, B. M. Angew.
Chem., Int. Ed. Engl. 1986, 25, 1. For cyclopropanes, see: (g) Bertozzi,
F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4, 3147. (h) Wender, P.
A.; Gamber, G. G.; Hubbard, R. D.; Zhang, L. J. Am. Chem. Soc. 2002,
124, 2876 and references therein. (i) Han, Z.; Uehira, S.; Tsuritani, T.;
Shinokubo, H.; Oshima, K. Tetrahedron 2001, 57, 987. (j) Alper, P. B.;
Meyers, C.; Lerchner, A.; Siegel, D. R.; Carreira, E. M. Angew. Chem.,
Int. Ed. 1999, 38, 3186. (k) Lee, P. H.; Lee, J. Tetrahedron Lett. 1998,
39, 7889 and references therein. (l) Hudlicky, T.; Reed, J. W. In
ComprehensiVe Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, 1991; Vol. 5, pp 946-947. (m) Ohta, T.; Takaya, H. In ref 1l,
Vol. 5, pp 1185-1205. (n) Danishefsky, S. Acc. Chem. Res. 1979, 12,
66. (o) de Meijere, A. Angew. Chem., Int. Ed. Engl. 1979, 25, 1. (p)
Stevens, R. V. Acc. Chem. Res. 1977, 10, 193. (q) Turro, N. J. Acc. Chem.
Res. 1969, 2, 25. For cyclopropenes, see: (r) Delgado, A.; Castedo, L.;
Mascaren˜as, J. L. Org. Lett. 2002, 4, 3091. (s) Boger, D. L.; Brotherton,
C. E. J. Am. Chem. Soc. 1984, 106, 805.
Table 3. Alkylative Ring Expansion of MCP 1k (Q ) Isoxazol-3-yl)
entry
4
X
Y
equiv of MgI2
[1] (M)
8
yielda (%)
1
2
3
4
5
6
7
8
c
i
b
b
b
j
NTs 4-OMe
NTs 3,4-OCH2O
1.1
1.1
1.1
1.1
3.0
1.1
1.1
1.1
1.1
0.3
3.0
1.1
0.1
0.1
0.05
0.1
0.1
0.1
0.2
0.2
0.2
0.2
0.1
0.2
kc
ki
kb
kb
kb
kj
38
53
55
65
74
48
61
68
73
29b
82
67
O
O
O
O
O
O
O
O
O
O
H
H
H
2-CF3
2-CF3
4-CF3
3,4-OCH2O
3,4-OCH2O
3,4-OCH2O
4-OMe
j
kj
h
g
g
g
k
kh
kg
kg
kg
kk
9
10
11
12
a In most cases, the nonalkylated product 7k was isolated in 10-30%
yield. b The major product was 7k which was isolated in 65% yield.
(2) It is unusual that the amide nitrogen was incorporated instead of the
carbonyl oxygen of the activating group (CONHQ) in these types of
rearrangements. For a comparison see: Seebach, D. Angew. Chem., Int.
Ed. Engl. 1979, 18, 248 and ref 1l.
Scheme 3
(3) The structure of 8ad was identified by X-ray crystallography.
(4) The E-enolate should be a prerequisite for the product formation. Otherwise
isomerization of double bond would be necessary.
(5) For a review of synthesis of MCP derivatives, see: Brandi, A.; Goti, A.
Chem. ReV. 1998, 98, 589.
(6) For a review of synthesis of N-sulfonyl imines, see: Weinreb, S. M. Top.
Curr. Chem. 1997, 190, 131.
(7) Interestingly, only trans-methylenepyrrolidine 2dd was isolated in 31%.
(8) For recent examples of chelation effect of pyrid-2-yl group, see: (a)
Lautens, M.; Roy, A.; Fukuoka, K.; Fagnou, K.; Mart´ın-Matute, B. J.
Am. Chem. Soc. 2001, 123, 5358. (b) Ko, S.; Na, Y.; Chang, S. J. Am.
Chem. Soc. 2002, 124, 750. (c) Jun, C.-H.; Lee, H.; Moon, C. W.; Hong,
H.-S. J. Am. Chem. Soc. 2001, 123, 8600. (d) Tobisu, M.; Chatani, N.;
Asaumi, T.; Amako, K.; Ie, Y.; Fukumoto, Y.; Murai, S. J. Am. Chem.
Soc. 2000, 122, 12663. (e) Itami, K.; Mitsudo, K.; Kamei, T.; Koike, T.;
Nokami, T.; Yoshida, J.-i. J. Am. Chem. Soc. 2000, 122, 12013. (f)
Paquette, L. A.; Rothhaar, R. R. J. Org. Chem. 1999, 64, 217.
(9) (a) Dieter, R. K.; Lu, K. J. Org. Chem. 2002, 67, 847. (b) Clark, A. J.;
Battle, G. M.; Bridge, A. Tetrahedron Lett. 2001, 42, 1999. (c) Kobayashi,
Y.; Fujimoto, T.; Fukuyama, T. J. Am. Chem. Soc. 1999, 121, 6501. (d)
Reginato, G.; Capperucci, A.; Degl’Innocenti, A.; Mordini, A.; Pecchi,
S. Tetrahedron 1995, 51, 2129. (e) Ojima, I.; Korda, A.; Shay, W. R. J.
Org. Chem. 1991, 56, 2024. (f) Barluenga, J.; Fan˜ana´s, F. J.; Foubelo, F.;
Yus, M. Tetrahedron Lett. 1988, 29, 4859. (g) Klemm, L. H.; Hwang, Y.
N.; McGuire, T. M. J. Org. Chem. 1976, 41, 3813.
(10) (a) Bella, M.; Piancatelli, G.; Squarcia, A.; Trolli, C. Tetrahedron Lett.
2000, 41, 3669 and references therein. (b) Jones, R. C. F.; Patience, J. M.
J. Chem. Soc., Perkin Trans. 1 1990, 2350. For recent reviews of the
corresponding silyloxy derivatives, see: (c) Bur, S. K.; Martin, S. F.
Tetrahedron 2001, 57, 3221. (d) Casiraghi, G.; Zanardi, F.; Appendino,
G.; Rassu, G. Chem. ReV. 2000, 100, 1929. (e) Rassu, G.; Zanardi, F.;
Battistini, L.; Casiraghi, G. Chem. Soc. ReV. 2000, 29, 109.
(11) The relative stereochemistry for the major diastereomer was proven to be
anti by X-ray crystallography.
(12) de Meijere, A.; Kozhushkov, S. I.; Khlebnikov, A. F. Top. Curr. Chem.
2000, 207, 89.
in reactivity in the presence of a Q with one o-nitrogen atom may
be due to coordination effects.8
Using this method, highly functionalized γ′-amino- or -hydroxy-
alkylated five-membered lactams 8 can be produced in a single
step under mild and neutral conditions. Regioselective alkylation
took place at the γ-position of either a vinylogous intermediate 5
or 6 (Scheme 2). The resulting â-(or 4-)alkylated pyrrol-2-one
scaffolds9 are not easily prepared by other methods. In fact, aldol
or alkylation of a pyrrol-2-one always yields isomeric products.10
For example, a modified direct vinylogous aldol process10a for the
4-methylpyrrol-2-one 7a yielded a mixture of the γ-substituted
pyrrol-2-ones 1211 in 77% yield (anti:syn ) 2.3:1) (Scheme 3).
Finally, we compared the analogous cyclopropane (CP) com-
pounds of 1a and 1k. Under the same conditions the CP amides
were found to be completely inert leading to recovery of the starting
materials. It appears that the driving force for preferential reaction
of the MCP is the release of strain energy (a MCP is 13.6 kcal/
mol12 more strained than the CP ring).
In summary, we have observed a novel ring expansion of the
secondary MCP amide 1 in the presence of MgI2. A key feature in
this rearrangement was the dual effect of the activating group Q.
JA028967L
9
J. AM. CHEM. SOC. VOL. 125, NO. 14, 2003 4029