Enantioselective catalytic ring expansion of methylenecyclopropane carboxamides promoted by a chiral magnesium lewis acid

Article abstract of DOI:10.1021/ol0628614

A catalytic enantioselective ring expansion of monoactivated methylenecyclopropanes (MCP) in the presence of N-tosyl aldimines was developed using a chiral bis(oxazoline) ligand-MgI₂ complex. After evaluation of ligands and optimization of the

Full text of DOI:10.1021/ol0628614

ORGANIC
LETTERS
2007
Vol. 9, No. 4
591-593
Enantioselective Catalytic Ring
Expansion of Methylenecyclopropane
Carboxamides Promoted by a Chiral
Magnesium Lewis Acid
Catherine Taillier and Mark Lautens*
Department of Chemistry, DaVenport Chemical Laboratories, 80 St. George Street,
UniVersity of Toronto, Toronto, Ontario M5S 3H6, Canada
mlautens@chem.utoronto.ca
Received November 24, 2006
ABSTRACT
A catalytic enantioselective ring expansion of monoactivated methylenecyclopropanes (MCP) in the presence of N-tosyl aldimines was developed
using a chiral bis(oxazoline) ligand MgI2 complex. After evaluation of ligands and optimization of the reaction conditions, the reaction has
−
been applied to a variety of aromatic and heteroaromatic aldimines providing the corresponding trans-C2,C3-disubstituted methylenepyrrolidines
in generally good yields (greater than 52%) and up to 86% ee.
We previously reported the preparation of methylene pyr-
rolidines via a cascade ring opening/cyclization of mono-
activated methylenecyclopropanes (MCPs) with aldimines
and chiral sulfinimines in the presence of MgI2.1 A key step
of this transformation is the ring opening of MCPs with MgI2,
generating a vinylogous enolate intermediate, which incor-
porates both nucleophilic and electrophilic sites within the
same molecule. Subsequent reaction of the enolate with
electrophiles at the R-site, followed by cyclization, then led
to the formation of the corresponding five-membered het-
erocyclic compounds (Scheme 1).
magnesium complexes, the advantage being the availability
of either enantiomer of the ligand, which should enable the
synthesis of either enantiomer of the target molecule.
In our initial studies, the enantioselectivity was assessed
in the ring expansion of N,N-diphenyl MCP amide 1 with
aldimine 2 (Table 1). In recent years, C2-symmetric chiral
bis(oxazoline) ligand-metal complexes have received a great
deal of attention through their use in various catalytic
processes.2 Our optimization thus began with an evaluation
Scheme 1. MgI2-Mediated Ring Expansion of MCP Tertiary
We now report the first enantioselective catalytic variant
of the ring expansion of MCP amides allowing direct access
to enantioenriched methylenepyrrolidines. The strategy used
to induce stereoselection was based on the use of chiral
Amides
(1) (a) Lautens, M.; Han, W. J. Am. Chem. Soc. 2002, 124, 6312-6316.
(b) Scott, M. E.; Han, W.; Lautens, M. Org. Lett. 2004, 6, 3309-3312. (c)
For an early report on the use of MgI2 for ring opening of cyclopropyl
derivatives, see: Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.;
Carreira, M. E. Angew. Chem., Int. Ed. 1999, 38, 3186-3189.
10.1021/ol0628614 CCC: $37.00
© 2007 American Chemical Society
Published on Web 01/25/2007

Table 1. Evaluation of Ligands and Reaction Conditions
Table 2. Optimization of the Reaction Conditions
MgI2
ratio
yielda
(%)
eeb
(%)
entry equiv L*/MgI2
L*
product
MgI2
ratio
temp reaction yieldb eec
1
2
3
4
5
6
1.0
1.0
1.0
0.3
0.3
0.3
1:1
1:1
1:1
1:1
1:1
1:1
(S)-4
(S)-5
(R,S)-6a
R,S)-6a
R,S)-6b
(R,S)-6c
ent-3
ent-3
3
3
3
3
56
74
60
43
62
65
16
39
52
40
18
56
entry equiv L*/MgI2 solvent
(°C)
timea
(%)
(%)
1
2
3
4
5
6
7
8
9
0.3
0.3
0.3
0.3
0.6
0.15
0.3
0.3
0.3
0.3
1.1:1 THF
1.25:1 THF
1.5:1 THF
2.0:1 THF
1.5:1 THF
1.5:1 THF
1.5:1 DCM
1.5:1 DCE
1.5:1 benzene
1.5:1 toluene
60
60
60
60
60
60
40
60
60
80
16 h
12 h
12 h
12 h
12 h
24 h
24 h
24 h
12 h
6 h
62
60
64
56
56
51
0d
0d
0e
80
81
86
84
84
79
83
-
a
Isolated yields. b Determined by HPLC on the chiral stationary phase.
-
86
10
46
a
Time needed to get complete conversion of the starting MCP. b Isolated
yields. c Determined by HPLC on the chiral stationary phase. d No reaction.
Decomposition.
e
of magnesium complexes prepared in situ by mixing MgI2
and bis(oxazoline) ligands 4-6 containing two and three
coordination sites.3
selectivity could be significantly increased (Table 2, entries
1-4). Use of CP-Indabox 6c (45 mol %) and MgI2 (30
mol %) was found to be the optimal conditions providing
the ring-expanded product 8 in 64% yield and 86% ee.6 When
the reaction was carried out in the presence of ligand 6c with
twice as much MgI2 (60 mol %), no significant improvement
was observed in terms of reactivity or selectivity (entry 5).
On the other hand, use of only 15 mol % of MgI2 was found
to slow the rate of the reaction, giving the product in only
21% yield after a prolonged reaction time but with compa-
rable selectivity (entry 6).
Our next set of experiments focused on solvent screening.
When the ring expansion was run in dichloromethane at
reflux, good selectivity but low reactivity were observed
(entry 7). Surprisingly, no reaction occurred in dichloroethane
and only decomposition of the starting materials was
observed in benzene (entries 8 and 9). Finally, a fast and
selective reaction was observed in toluene at 80 °C, but
pyrrolidine 8 was isolated in only 46% yield (entry 10).
To further demonstrate the efficiency of the MgI2-bis-
(oxazoline) 6c complex in ring expansion reactions of MCP
1, a series of aromatic N-tosyl aldimines were subjected to
the optimal reaction conditions described above [MgI2 (30
mol %), CP-Indabox 6c (45 mol %), THF, 60 °C]. In all
cases, the reactions proceeded smoothly giving the trans-
methylene pyrrolidine derivatives as the major product in
yields greater than 50% with ee’s up to 86% (Table 3).
Use of (R,S)-CP-Indabox 6c produced methylene pyrro-
lidine 8a with 86% ee (entry 1), whereas (S,R)-6c delivered
the opposite enantiomer of 8a with 84% ee (entry 2).7,8 When
Reactions were first performed using stoichiometric amounts
of bis(oxazoline) ligands (4-6)/MgI2 complexes. In all cases,
ring expansion proceeded smoothly and the trans-pyrrolidine
3 was obtained in good yields (entries 1-3). It is noteworthy
that the analogous reaction in the absence of the ligand gave
a mixture of cis and trans adducts.4 Whereas the use of
ligands 4 and 5 provided low enantioselectivities, ring
expansion with the MgI2-Indabox 6a complex proceeded
with a higher level of asymmetric induction. Interestingly,
when a substoichiometric amount (30 mol %) of the chiral
Lewis acid was used, the ring-expanded product 3 was
formed in 53% yield but with lower ee (40%) (entry 4).
Subsequent optimization experiments demonstrated that use
of DiMe-Indabox 6b resulted in low enantioselectivity
(entry 5), whereas CP-Indabox 6c was effective in affording
3 in 65% yield and with the best ee (entry 6).5
To avoid background reactions arising from noncomplexed
MgI2 that could diminish the ee, the use of an excess of
ligand compared to MgI2 was tested. As anticipated, by
increasing the ratio L*/Mg, both reactivity and enantio-
(2) For reviews on the use of oxazoline-containing ligands in asymmetric
catalysis, see: (a) Ghosh, A. K.; Mathivanan, P.; Cappiello, J. Tetrahe-
dron: Asymmetry 1998, 9, 1-45. (b) McManus, H.; Guiry, P. J. Chem.
ReV. 2004, 104, 4151-4202.
(3) For an early report of the use of a bis(oxazoline)-Mg complex, see:
Corey, E. J.; Ishihara, K. Tetrahedron Lett. 1992, 33, 6807-6810.
(4) Indeed, MgI2-mediated ring expansion usually affords mixtures of
diastereomers depending on the substitution pattern of the aldimines.
However, when the reaction was performed in the presence of bis(oxazoline)
ligand 6c, only traces of the cis diastereomer were observed.
(5) (a) Davies, I. E.; Gerena, L.; Castonguay, L.; Senanayake, C. H.;
Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. Synth. Commun. 1996, 1753-
1754. (b) Davies, I. E.; Deeth, R. J.; Larsen, R. D.; Reider, P. J. Tetrahedron
Lett. 1999, 40, 1233-1236.
(6) Other conditions, such as solvent, temperature, concentration, and
quantity of the chiral complex, were also tested, but these reaction conditions
were found to give the optimal balance of reaction yields and enantio-
selectivity.
592
Org. Lett., Vol. 9, No. 4, 2007

selectivity. Indeed, ortho-substituted substrates 7g and 7h
exhibited higher enantioselectivities compared to meta- and
para-substituted imines 7i, j (entries 11-14).
Table 3. Enantioselective Ring Expansion of MCP 1 with
Various Aromatic Aldimines
This methodology was further extended to heteroaromatic
systems (Table 4). When 2-furyl and 3-furyl N-tosyl aldi-
Table 4. Reaction with Heteroaromatic Substrates
yielda eeb
entry imine
R
L*
product
(%)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
7a
7a
7a
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
2-CF3
(R,S)-6c
(R,S)-6c
(R,S)-6cc
8a
ent-8a
8a
64
61
55
59
52
52
54
55
60
71
55
70
61
59
86
84
70
47
83
76
76
78
78
71
76
57
69
71
yielda eeb
entry MCP
Ar1
imine
Ar2
product (%) (%)
2-CF3
2-CF3
2-CF3
4-CF3
2-Br
1
2
3
4
1
1
1
9
Ph
Ph
Ph
10a 2-furyl
10b 2-furyl
11a
11b
55
66
67
92
72
72
49
78
(R,S)-6cd 8a
10c 2-(N-Me-pyrrole) 11c
Ph 11d
(R,S)-6c
(R,S)-6c
(R,S)-6c
(R,S)-6c
(R,S)-6c
8b
8c
8d
8e
8f
8g
8h
8i
2-pyridine
2
Isolated yields. b Determined by HPLC on the chiral stationary phase.
a
3-Br
4-Br
2,4-dichloro
2,4-dimethyl (R,S)-6c
2-OMe
4-OMe
3,4-O-CH2-O (R,S)-6c
4-OAc (R,S)-6c
mines 10a and 10b were employed, reactions appeared to
be equally selective and the corresponding trans-pyrrolidines
were isolated in 55% (72% ee) and 66% yield (72% ee),
respectively (entries 1 and 2). On the other hand, ring
expansion with N-Me-pyrrole imine 10c also gave the trans
product in good yield but with lower enantioselectivity (entry
3). Finally, it was tested whether the introduction of a second
site for Lewis acid coordination on the MCP moiety would
influence the enantioselectivity. N-Phenyl-N-(2-pyridyl) MCP
amide 9 was then subjected to the optimized reaction
conditions in the presence of aldimine 2. The reaction was
found to be particularly efficient, but no improvement was
observed on the enantioselectivity (entry 4).
In conclusion, we have developed the first catalytic
enantioselective ring expansion of monoactivated MCPs
using a chiral magnesium Lewis acid. The reaction has been
shown to proceed in good yields and with good enantio-
selectivities in a number of cases, yielding trans-methyl-
enepyrrolidines. Elucidation of the factors responsible for
the enantioselectivity, improvements in the ee, the search
for more efficient catalysts, and expansion of the scope to
less reactive substrates are currently being investigated in
our laboratory.
(R,S)-6c
(R,S)-6c
8j
8k
a
Isolated yields. b Determined by HPLC on the chiral stationary phase.
c
d
Ligand 6c of 80% ee was used. Ligand 6c of 50% ee was used.
the reaction was performed with ligand (R,S)-6c of 80% ee
and 50% ee, the trans-methylenepyrrolidine 8a could be
obtained in 70% ee and 47% ee, respectively, suggesting
that monomeric species are involved in the catalytic process
(entries 3 and 4).9
Surprisingly, the electronic nature and the position of the
substituents seemed to have little or no influence on the
success of the ring expansion process or on the diastereo-
selectivity.10 It was also found that higher ee’s were obtained
in the case of substrates bearing electron-withdrawing groups
on the aromatic ring (entries 1-10). In contrast, the position
of electron-donating substituents on the aromatic ring of the
imine seemed to have a greater influence on the enantio-
(7) The absolute configuration assignment was based upon the published1b
X-ray structure of the methylenepyrrolidine resulting from MgI2-mediated
ring expansion of MCP 1 with the chiral p-methoxy-substituted aromatic
sulfinime. After oxidation with m-CPBA, it was possible to assign the
absolute configuration of the ring-expanded product 8i to be (2R,3R) by
comparison of both optical rotations and chiral HPLC retention times (see
Supporting Information).
(8) The absolute configuration of the other products was assigned in
analogy to 8i.
(9) The plot eeprod ) f(eeL*) was found to be linear showing that
diastereomeric dimeric species are not involved in the catalytic process.
Kagan, H. B. Synlett 2001, 888-899.
(10) Only traces of cis-pyrrolidines were occasionally detected in reaction
mixtures.
Acknowledgment. This work is supported by NSERC
(Canada), Merck Frosst (IRC), and the University of Toronto.
We also thank Dr. Yann Be´thuel and Mark Scott (University
of Toronto) for helpful discussions.
Supporting Information Available: Experimental pro-
cedures and characterization for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL0628614
Org. Lett., Vol. 9, No. 4, 2007
593