MgI2-mediated ring expansions of secondary methylenecyclopropyl amides

Article abstract of DOI:10.1021/ja028967l

Ring expansion of secondary methylenecyclopropyl amides in the presence of MgI₂ was investigated. Various isomeric five-membered unsaturated lactams were obtained, depending on the character of the substituent Q. The amide group served as a nuc

Full text of DOI:10.1021/ja028967l

Published on Web 03/15/2003
MgI2-Mediated Ring Expansions of Secondary Methylenecyclopropyl Amides
Mark Lautens,* Wooseok Han, and Jack Hung-Chang Liu
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto, 80 St. George St.,
Toronto, Ontario, Canada M5S 3H6
Received October 15, 2002; E-mail: mlautens@chem.utoronto.ca
Scheme 1
The generation of a bifunctional intermediate via ring opening
of a highly strained and activated three-membered carbocycle is a
synthetically useful tool for the construction of expanded ring
systems.1 Recently, we reported the MgI2-mediated ring expansion
of monoactivated methylenecyclopropanes (MCPs) whereby two
Scheme 2
different types of heterocycles, 2 and 3, were obtained, depending
on the substituent Z of the MCPs 1 (Scheme 1).1a
As we expanded our study to other “Z” groups, we observed a
completely different process for secondary MCP amides 1 (Z )
NHQ, Scheme 2). In the absence of an electrophile, the secondary
MCP amides 1 (Q ) aryl and heteroaryl group) underwent ring
expansion to the isomeric five-membered unsaturated lactam 7.2
In the presence of a wide range of aryl aldimines or aldehydes, 1
afforded the γ′-amino- or -hydroxy-alkylated products 8 when the
substituent Q bearing an o-nitrogen atom was present. The net
transformation gave the difficult-to-access â-(or 4-)alkylated pyrrol-
2-one skeleton via a single step under mild and neutral conditions.
In addition, we showed that isomeric γ-hydroxy-alkylated products
12 could be obtained via a direct vinylogous aldol reaction of the
product 7a.
Table 1. Ring Expansiona of Secondary MCP Amides
Initial experiments with amide 1a (Q ) pyrid-2-yl) and an
aldimine 4 (X ) NTs, Ar ) aryl) using stoichiometric MgI2 in
refluxing THF (0.05 M) provided neither the five- or six-membered
heterocycle 2 or 3 (Scheme 1). Instead, a mixture of five-membered
unsaturated lactam 7a and the γ′-amino-alkylated product3 8a was
obtained (Scheme 2). Both have a 4-methyl-1,5-dihydropyrrol-2-
one as a common structural motif and may arise from a common
intermediate. Either vinylogous enolate 54 resulting from ring
opening of 1 or cyclic enolate 6 from ring closing of 5 (dotted
arrow, Scheme 2) could be intermediates which would react
subsequently with a proton and/or an aldimine at the γ′-position to
give a mixture of 7 and 8.
The scope of MgI2-mediated ring expansion for various second-
ary MCP amides5 was then examined in order to determine the
structural requirements of Z. The isomeric 2-, 3-, and 4-pyridyl
and phenyl amides 1a-d furnished 4-methylpyrrol-2-ones in good
to excellent yields (entries 1-4, Table 1). However, the amides 1e
and 1f having alkyl groups such as benzyl and 2-pyridylmethyl
and the benzoyl imide 1g failed to give the expected products and
provided either complex mixtures (entries 5 and 7) or recovery of
the starting material 1f (entry 6). The primary amide 1h underwent
only the ring opening reaction, resulting in the iodo-substituted open
chain amide 10 which was best isolated as the alkyl azide 11 (entry
8). It appears that an aryl group acidifies the N-H bond that
participates in the cyclization. As a result, secondary MCP amides
1 bearing an N-aryl or hetero-aryl group gave rise to ring expansion,
leading to the corresponding isomeric lactam 7.
entry
1
product
yield (%)
entry
1
product
yield (%)
1
2
3
4
a
b
c
7a
7b
7c
7d
89b
95
5
6
7
8
e
f
g
h
7e
7f
7g
11
d
d
d
87
d
80c
67
a All reactions were carried out using stoichiometric MgI2. b,c In each
case, the regioisomer 9 was obtained in 9% and 10% yields, respectively.
d No yields; see text.
nately, the desired alkylated product 8a was obtained in better yield
at 0.1 M in THF (entries 1-4, Table 2).
Several aryl aldimines6 as well as aryl aldehydes furnished the
amino- or hydroxy-alkylated pyrrol-2-ones in good yields (entries
5-10, Table 2). However, it was quite surprising that when the
phenyl amide 1d reacted with 4d under the standard conditions
(0.1 M THF), no desired product was obtained.7 Even in the
reactions with isomeric pyridyl amides 1b and 1c, only complex
mixtures were produced. On the basis of these results, the o-nitrogen
atom of the 2-pyridyl group appeared to play a crucial role in the
alkylative ring expansion process.
Thus, we prepared additional hetero-aryl amides 1i, 1j, and 1k
(Table 1) to examine the effect of the o-atom for alkylative ring
expansion. The pyrimid-2-yl and isoxazol-5-yl amides 1i and 1j
did not give the desired products despite bearing two o-nitrogen
atoms and one o-oxygen atom, respectively. The isoxazol-3-yl
amide 1k having one o-nitrogen atom reacted with aryl aldehydes,
but aryl aldimines failed to react under these conditions (Table 3).
Better yields were obtained at higher concentration (entries 3-4
and 6-7) or with excess MgI2 (entries 4-5 and 9-11). The change
With a clearer understanding of the ring expansion process, we
turned our attention to optimizing the yield of the γ-alkylative
product 8. Reaction of the pyrid-2-yl amide 1a at 0.05 M in THF
led to significant amounts of the unalkylated product 7a. Fortu-
9
4028
J. AM. CHEM. SOC. 2003, 125, 4028-4029
10.1021/ja028967l CCC: $25.00 © 2003 American Chemical Society

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
of charge via the Internet at http://pubs.acs.org.
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