Synthesis of highly functionalized pyrrolidines via a selective iodide-mediated ring expansion of methylenecyclopropyl amides

Article abstract of DOI:10.1021/jo802049u

(Chemical Equation Presented) This manuscript describes a highly selective iodide-mediated, tandem Mannich/cyclization to afford trans-2,3-disubstituted pyrrolidines from methylenecyclopropyl amides in good to excellent yields and selectivities. The reaction scope has been drastically expanded to include a wide array of aromatic, heteroaromatic and α,β-unsaturated imines, as well as a variety of methylenecyclopropyl amides. Additionally, mechanistic studies were carried out to ascertain the nature of the ring-opening/ring- closing mechanism using deuterated substrates. Results from these studies indicate that the primary mechanism is an S_N2/S_N2 ring opening/ring closing and that iodine- or iodide-mediated isomerization of the iodo enolate is likely occurring.

Full text of DOI:10.1021/jo802049u

Synthesis of Highly Functionalized Pyrrolidines via a Selective
Iodide-Mediated Ring Expansion of Methylenecyclopropyl Amides
Mark E. Scott and Mark Lautens*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto, 80 St. George Street,
Toronto, Ontario, Canada M5S 3H6
mlautens@chem.utoronto.ca
ReceiVed September 16, 2008
This manuscript describes a highly selective iodide-mediated, tandem Mannich/cyclization to afford trans-
2,3-disubstituted pyrrolidines from methylenecyclopropyl amides in good to excellent yields and
selectivities. The reaction scope has been drastically expanded to include a wide array of aromatic,
heteroaromatic and R,ꢀ-unsaturated imines, as well as a variety of methylenecyclopropyl amides.
Additionally, mechanistic studies were carried out to ascertain the nature of the ring-opening/ring-closing
mechanism using deuterated substrates. Results from these studies indicate that the primary mechanism
is an SN2/SN2 ring opening/ring closing and that iodine- or iodide-mediated isomerization of the iodo
enolate is likely occurring.
Introduction
carbon dipole equivalents in a variety of [3 + 3] and [3 + 2]
cycloaddition processes.5,6
The development of all-carbon 1,3-dipole synthons represents
an important facet of organic chemistry, primarily due to their
ability to quickly construct a broad range of complex carbo-
and heterocyclic scaffolds. While transition-metal-catalyzed
cycloaddition strategies1 involving trimethylmethylene (TMM)
complexes are a valuable method for generating these types of
1,3-dipoles, new and complementary approaches to their
synthesis and preparation are of value. Recently, cyclopropanes2
and their more highly strained methylenecyclopropane (MCP)
derivatives3,4 have garnered significant interest in the synthetic
community due to their ease of preparation and diverse range
of reactivity. In particular, the ability to selectively tune the
reactivity pattern of these systems based on their substitution
pattern and reaction conditions has ultimately led to the use of
these three-membered ring systems as highly versatile 1,3-
Our own interest in this area has focused on the halide-
mediated ring expansion of monoactivated MCP systems for
the construction of a variety of heterocyclic motifs.7 In this
system, a Lewis acid and halide act in concert to facilitate halide
addition to the activated cyclopropane, affording a bifunctional
(2) For a review of the synthetic use of cyclopropanes, see: (a) de Meijere,
A. In Houben-Weyl Methods of Organic Chemistry; Thieme: Stuttgart, 1997E17c.
(b) Wong, H. N. C.; Hon, M.-Y.; Tse, C.-W.; Yip, Y.-C. Chem. ReV. 1989, 89,
165. (c) Salau¨n, J. Top. Curr. Chem. 2000, 207, 1. (d) Reissig, H.-U.; Zimmer,
R. Chem. ReV. 2003, 103, 1151. (e) The Chemistry of the Cyclopropyl Group;
Rappoport, Z., Ed.; John Wiley & Sons: New York, 1987; Vols. 1-2, Chapters
9-13. For some recent select articles on the synthetic use of cyclopropanes,
see: (f) Yang, Y.-H.; Shi, M. Org. Lett. 2006, 8, 1709. (g) Shi, M.; Tang, X.-Y.;
Yang, Y.-H. Org. Lett. 2007, 9, 4017. (h) Tanaka, M.; Ubukata, M.; Matsuo,
T.; Yasue, K.; Matsumoto, K.; Kajimoto, Y.; Ogo, T.; Inaba, T. Org. Lett. 2007,
9, 3331. (i) Zhang, J.; Schmalz, H.-G. Angew. Chem., Int. Ed. 2006, 45, 6704.
(j) Ganton, M. D.; Kerr, M. A. J. Org. Chem. 2004, 69, 8554. (k) Young, I. S.;
Kerr, M. A. Angew. Chem., Int. Ed. 2003, 26, 3023. (l) Young, I. S.; Kerr, M. A.
Org. Lett. 2004, 6, 139. (m) Carson, C. A.; Kerr, M. A. J. Org. Chem. 2005, 70,
8242. (n) Lebold, T. P.; Carson, C. A.; Kerr, M. A. Synlett 2006, 3, 364. (o)
England, D. B.; Kuss, T. D. O.; Keddy, R. G.; Kerr, M. A. J. Org. Chem. 2001,
66, 4704. (p) Sibi, M. P.; Ma, Z.; Jasperse, C. P. J. Am. Chem. Soc. 2005, 127,
5764. (q) Young, I. S.; Williams, J. L.; Kerr, M. A. Org. Lett. 2005, 7, 953. (r)
Pohlhaus, P. D.; Johnson, J. S. J. Am. Chem. Soc. 2005, 127, 16014. (s) Pohlhaus,
P. D.; Sanders, S. D.; Parsons, A. T.; Li, W.; Johnson, J. S. J. Am. Chem. Soc.
2008, 130, 8642.
(1) For reviews of transition-metal-catalyzed cycloadditions, see: (a) Lautens,
M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. (b) Varela, J. A.; Saa, C.
Chem. ReV. 2003, 103, 3787. (c) Saito, S.; Yamamoto, Y. Chem. ReV. 2000,
100, 2901. (d) Yet, L. Chem. ReV. 2000, 100, 2963. (e) Gevorgyan, V.;
Yamamoto, Y. J. Organomet. Chem. 1999, 576, 232.
8154 J. Org. Chem. 2008, 73, 8154–8162
10.1021/jo802049u CCC: $40.75 2008 American Chemical Society
Published on Web 10/08/2008

Synthesis of Highly Functionalized Pyrrolidines
SCHEME 1. Halide-Mediated Ring Expansion of
Monoactivated Methylenecyclopropanes
vated methylenecyclopropane system to afford trans 2,3-
disubstituted pyrrolidines (Scheme 2, eq 2).
In addition to providing access to a variety of stereochemi-
cally defined pyrrolidine building blocks, this versatile and
highly selective methodology has subsequently been used by
our group to synthesize (-)-kainic acid,7d showcasing the
potential utility of this methodology. Herein we report a full
account of our studies toward the development of the first highly
stereoselective halide-mediated tandem Mannich/cyclization of
monoactivated methylenecyclopropanes, including extensive
studies of reaction scope as well as new mechanistic studies.
Reaction Optimization. Initial studies found that addition
of MgI2 followed by immediate heating of the reaction mixture
led to generally irreproducible yields of the desired trans
pyrrolidine product 1 (Table 1, entry 1). Instead, extensive
decomposition was observed along with significant formation
of the allylic iodide 2. Additional attempts to improve the yield
of the pyrrolidine product using longer reaction times also failed,
owing to the instability of the allylic iodide intermediate.
Surprisingly, significant improvement in reaction yields could
be achieved by ensuring the dissolution of MgI2 by prestirring
the reaction mixture for a period of 20 min prior to heating
(entry 2). In doing so, the desired pyrrolidine 1 was obtained
in a highly reproducible 82% yield. More importantly, the crude
1H NMR showed no evidence of the unreacted allylic iodide 2.
Using this protocol, the amount of MgI2 employed in the
reaction could also be reduced to 1 equivalent without any
detrimental effect on the yield (entry 4). These conditions were
effective using catalytic amounts of MgI2, although in this case
the desired pyrrolidine product was obtained in somewhat lower
yields (entry 5). Further improvement in reaction efficiency
could be realized by increasing the concentration of the reaction
mixture (entry 6), affording a single pyrrolidine product in 90%
isolated yield. Finally, we examined the use Ellman’s chiral
tert-butyl sulfinimine derivative, since it has been shown to have
improved reactivity over the Davis sulfoxide derivative in some
instances.9 Unfortunately, use of the corresponding chiral tert-
butyl sulfinimine under our reaction conditions resulted in lower
yields along with some detectable amounts of the unreacted
allylic iodide (entry 7).
halo enolate that is equivalent to a functionalized 1,3-carbon
dipole (Scheme 1). The resulting intermediate can subsequently
undergo a formal [3 + 2] cycloaddition process in the presence
of a suitable electrophile to afford a variety of pharmaceutically
relevant heterocyclic scaffolds. Inspired by the work of Carreira
and others,5,6 we sought to develop highly stereoselective
variants of this halide-mediated cycloaddition transformation.
Recently, we reported a tandem Lewis acid iodide-mediated
ring expansion of methylenecyclopropanes (Scheme 2, eq 1).7a
Although yields for this process were good, selectivities were
found to be highly dependent on the substitution on the aryl
imine. Notably, the application of this methodology toward aryl
imines lacking an ortho substituent led to low diastereoselec-
tivities between the cis and trans 2,3-disubstituted pyrrolidine
products. Subsequent efforts by our group7c led to the discovery
that readily available chiral sulfinimines8 could be used with
magnesium iodide to achieve the first highly stereoselective
iodide-mediated, tandem Mannich/cyclization of a monoacti-
(3) For some recent select articles on the Lewis and Brønsted acid ring
opening of methylenecyclopropane derivatives, see: (a) Shao, L.-X.; Shi, M Curr.
Org. Chem 2007, 11, 1135. (b) Yao, L.-F.; Shi, M. Org. Lett. 2007, 9, 5187. (c)
Tian, G.-Q.; Shi, M. Org. Lett. 2007, 9, 4917. (d) Li, W.; Shi, M. Tetrahedron
2007, 63, 11016. (e) Lu, J.-M.; Shi, M. Tetrahedron 2007, 7545. (f) Zhang,
Y.-P.; Lu, J.-M.; Xu, G.-C.; Shi, M. J. Org. Chem. 2007, 72, 509. (g) Tian,
G.-Q.; Shi, M. Org. Lett. 2007, 9, 2405. (h) Liu, L.-P.; Shi, M. Tetrahedron
2007, 63, 4535. (i) Lu, J.-M.; Shi, M. Org. Lett. 2007, 9, 1805. (j) Zhu, Z.-B.;
Liu, L.-P.; Shao, L.-X.; Shi, M. Synlett 2007, 1, 115. (k) Shi, M.; Liu, L.-P.;
Tang, J. J. Am. Chem. Soc. 2006, 128, 7430. (l) Wang, B.-Y.; Jiang, R.-S.; Li,
J.; Shi, M. Eur. J. Org. Chem. 2005, 18, 4002. (m) Xu, G.-C.; Ma, M.; Liu,
L.-P.; Shi, M. Synlett 2005, 12, 1869. (n) Xu, G.-C.; Liu, L.-P.; Lu, J.-M.; Shi,
M. J. Am. Chem. Soc. 2005, 127, 14552. (o) Huang, J.-W.; Shi, M. Synlett 2004,
13, 2343. (p) Huang, J.-W.; Shi, M. Tetrahedron Lett. 2003, 44, 9343. (q) Shi,
M.; Xu, B. Org. Lett. 2002, 4, 2145. (r) Shao, L.-X.; Xu, B.; Huang, J.-W.; Shi,
M. Chem.-Eur. J. 2006, 12, 510. (s) Lu, L.; Chen, G.; Ma, S. Org. Lett. 2006,
8, 835.
(4) For some reviews on transition metal-mediated reactions of methylenecy-
clopropanes, see: (a) Nakamura, I.; Yamamoto, Y. AdV. Synth. Catal. 2002, 344,
111. (b) Binger, P.; Schmidt, T. Metal-Catalyzed Cycloadditions of Methyl-
enecyclopropanes. In Carbocyclic three- and four-membered ring compounds;
de Meijere, A., Ed.; Houben-Weyl Thieme: Stuttgart, Germany, 1997; Vol. E
17b, p 2217. (c) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. ReV. 2007, 107,
3117. For some recent select articles on transition metal-mediated reactions of
methylenecyclopropanes, see: (d) Saito, S.; Komagawa, S.; Azumaya, I.; Masuda,
M. J. Org. Chem. 2007, 72, 9114. (e) Saito, S.; Takeuchi, K. Tetrahedron Lett.
2007, 48, 595. (f) Maeda, K.; Saito, S. Tetrahedron Lett. 2007, 48, 3173. (g)
Gul´ıas, M.; Dura´n, J.; Lo´pez, F.; Castedo, L.; Mascaren˜as, J. L. J. Am. Chem.
Soc. 2007, 129, 11026.
Results and Discussion
The substrate scope for this reaction was found to be broad
for a variety of aromatic and heteroaromatic sulfinimines (Table
2). For nonheteroaromatic imines, only the trans isomer was
observed by 1H NMR, the absolute configuration for which was
(5) (a) Alper, P. B.; Meyers, C.; Lerchner, A.; Siegel, D. R.; Carreira, E. M.
Angew. Chem., Int. Ed. 1999, 38, 3186. (b) Fischer, C.; Meyers, C.; Carreira,
E. M. HelV. Chim. Acta 2000, 83, 1175. (c) Meyers, C.; Carreira, E. M. Angew.
Chem., Int. Ed. 2003, 42, 694. (d) Marti, C.; Carreira, E. M. J. Am. Chem. Soc.
2005, 127, 11505. (e) Lerchner, A.; Carreira, E. M. Chem.sEur. J. 2006, 12,
8208. (f) Bertozzi, F.; Gustafsson, M.; Olsson, R. Org. Lett. 2002, 4, 3147. (g)
Huang, W.; Chin, J.; Karpinski, L; Gustafson, G.; Baldino, C. M.; Yu, L.
Tetrahedron Lett. 2006, 47, 4911. (h) Bertozzi, F.; Gustafsson, M.; Olsson, R.
Org. Lett. 2002, 4, 4333.
(6) Several two-step procedures involving halide-mediated ring opening of
activated cyclopropane systems followed by treatment with base have been
reported as a route to cyclic frameworks: (a) Wiedemann, S. H.; Noda, H.;
Harada, S.; Matsunaga, S.; Shibasaki, M Org. Lett. 2008, 10, 1661. (b) Xiong,
T.; Zhang, Q.; Zhang, Z.; Liu, Q. J. Org. Chem. 2007, 72, 8005. (c) Timmons,
C.; Guo, L.; Liu, J.; Cannon, J. F.; Li, G. J. Org. Chem. 2005, 70, 7634. (d)
Brown, S. P.; Bal, B. S.; Pinnick, H. W. Tetrahedron Lett. 1981, 22, 4891. (e)
Fleming, A.; Sinai-Zingde, G.; Natchus, M.; Hudlicky, T. Tetrahedron Lett. 1987,
28, 167. (f) Han, Z.; Uehira, S.; Tsuritani, T.; Shinokubo, H.; Oshima, K.
Tetrahedron 2001, 57, 987. (g) Timmons, C.; Chen, D.; Cannon, J. F.; Headley,
A. D.; Li, G. Org. Lett. 2004, 6, 2075.
(7) (a) Lautens, M.; Han, W. J. Am. Chem. Soc. 2002, 124, 6312. (b) Lautens,
M.; Han, W.; Liu, J. H.-C. J. Am. Chem. Soc. 2003, 125, 4028. (c) Scott, M. E.;
Han, W.; Lautens, M. Org. Lett. 2004, 6, 3309. (d) Scott, M. E.; Lautens, M.
Org. Lett. 2005, 7, 3045. (e) Scott, M. E.; Schwarz, C. A.; Lautens, M. Org.
Lett. 2006, 8, 5521. (f) Taillier, C.; Lautens, M. Org. Lett. 2007, 9, 591. (g)
Taillier, C.; Bethuel, Y.; Lautens, M. Tetrahedron 2007, 63, 8469. (h) Scott,
M. E.; Bethuel, Y.; Lautens, M. J. Am. Chem. Soc. 2007, 129, 1482.
(8) Chiral p-tolyl sulfinimines can easily be prepared from the starting
aldehyde and chiral sulfinamide on large scale according to the procedure by
Davis and co-workers: Fanelli, D.; Szewczyk, J M.; Zhang, Y.; Reddy, G. V.;
Burns, D. M.; Davis, F. A Org. Synth. 2000, 77, 50. For the synthesis of the
requisite menthol ester, see: Hulce, M.; Mallomo, J. P.; Frye, L. L.; Kogan,
T. P.; Posner, G. H. Org. Syn. 1986, 64, 196. Alternatively, the starting chiral
sulfinamide is commercially available from Aldrich in either antipode.
(9) For example, see: (a) Han, Z.; Krishnamurthy, D.; Pflum, D. A.; Grover,
P.; Wald, S. A.; Senanayake, C. H. Org. Lett. 2002, 4, 4025. (b) Han, Z.;
Krishnamurthy, D.; Grover, P.; Fang, Q. K.; Pflum, D. A.; Senanayake, C. H
Tetrahedron Lett. 2003, 44, 4195. (c) For the synthesis of enantiomerically
enriched tert-butanesulfinamide, see: Weix, D. J.; Ellman, J. A Org. Lett. 2003,
5, 1317.
J. Org. Chem. Vol. 73, No. 21, 2008 8155

Scott and Lautens
SCHEME 2. Development of a Stereoselective Iodide-Mediated Ring Expansion of Monoactivated Methylenecyclopropanes
TABLE 1. Select Optimization Studies
entry
R
MgI2 (equiv)
protocola
% yieldb
trans/cisc
1
2
3
4
5
6
7
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
t-Bu
3.0
3.0
1.5
1.0
0.5
1.0
1.0
THF added to mixture and immediately heated to reflux
prestirred with THF prior to reflux
prestirred with THF prior to reflux
prestirred with THF prior to reflux
prestirred with THF prior to reflux
prestirred with THF prior to refluxd
prestirred with THF prior to refluxe
30-60
82
82
84
72
20:1
20:1
20:1
20:1
20:1
20:1
20:1
90
79
a Reactions carried out using 0.05 M MCP (0.1 mmol) and 1.2 equiv of sulfinimine in THF for 3.25 h. See the Supporting Information for full details.
c
b Isolated yields. Determined by H NMR of the crude reaction mixture. d Reaction carried out at 0.1 M. e Reaction carried out at 0.1 M for 4 h.
1
determined by X-ray crystallography (for Table 2, entry 8).10
In general, reaction yields and diastereoselectivities were
excellent for aromatic imines, regardless of the electronic nature
and substitution pattern on the aryl moiety. In particular, the
reaction was found to afford good to excellent yields for the
desired trans pyrrolidine for a variety of electron-rich (entries
5 and 7 and 8) and electron-poor (entries 6 and 9) imines. The
reaction was also tolerant of sterically-demanding substrates
(entries 2, 5 and 10), furnishing the pyrrolidine product in good
yield and in >20:1 selectivity over the other three possible
isomers. In particular, we were pleased to see that our conditions
allowed for a highly selective route to trans pyrrolidines bearing
meta- and para-substituted aromatic groups (entries 3, 4, 6-9,
and 11), since our previous studies using the corresponding tosyl
imines7a resulted in lower trans selectivities for these imine
classes.
This methodology could also be extended to a variety of
heteroaromatic systems (Table 2). In general, yields were good
for all heteroatom-containing aromatic sulfinimines, while the
diastereoselectivity was dependent on the location of the
heteroatom in the aromatic ring. For pyridine and quinoline-
derived sulfinimines (entries 12-14), the desired pyrrolidines
were obtained in good yields and in excellent levels of
diastereocontrol. In the furyl series however, the diastereose-
lectivity decreased in favor of the cis isomer when the oxygen
was adjacent to the imine substituent (entry 15 versus 16).11 In
contrast, use of the corresponding 3-thienyl analogue (entry 17)
was found to give the desired trans-pyrrolidine in excellent yield
and selectivity, with no evidence of the cis isomer.12 Finally,
this methodology was found to be compatible with pyrrole-based
systems (entry 18), affording the desired pyrrolidine in good
yield, albeit in a modest, yet synthetically useful diastereose-
lectivity.
Given the success of aromatic-based sulfinimines in this
transformation, we wished to extend the scope of the reaction
to include nonaromatic imines. While simple aliphatic systems
were found to give complex mixtures (Table 3, entry 1),
nonenolizable R,ꢀ-unsaturated sulfinimines gave the desired
trans pyrrolidines in modest yields and in good to excellent
diastereoselectivities. In particular, use of E-substituted sulfin-
imines (Table 3, entries 2 and 3, Table 3) could also be
employed in the reaction, although in these examples the trans
pyrrolidine product was obtained in somewhat reduced selectiv-
ity.13 Gratifyingly, use of R-substituted R,ꢀ-unsaturated sulfin-
imine derivatives (entries 4-8) were found to drastically
improve selectivity in favor of the expected trans-pyrrolidine
product for a variety of trisubstituted olefinic imines.
(11) In these cases, unequivocal proof of the minor cis isomer was determined
by TFA/MeOH cleavage of the auxiliary for both the major and minor isomers
followed by comparison of their corresponding 1H NMR. In addition, the trans
geometry for the major isomer was proven by NOE experiments.
(12) Confirmation of the trans geometry for the 3-thiophenyl example was
also proven by NOE experiments.
(13) Confirmation of the stereochemistry of the major trans isomer was made
on the basis of comparison with coupling and chemical shifts of other compounds
previously reported. In the case of entries 2 and 3 (Table 3), the stereochemistry
for the cis and other trans isomer was determined by removal of the chiral
auxiliary and comparing the resulting 1H NMR spectra of the corresponding
free amines to that obtained by auxiliary removal for the major trans isomer.
(10) See the Supporting Information for X-ray structures. Full crystallographic
details have been deposited in the Cambridge Crystallographic database.
8156 J. Org. Chem. Vol. 73, No. 21, 2008

Synthesis of Highly Functionalized Pyrrolidines
TABLE 2. Reaction Scope Using Aromatic and Heteroaromatic Iminesa
a Reactions carried out using 0.1 M MCP (0.2 mmol), 1.2 equiv of sulfinimine, and 1.0 equiv of MgI2 in THF at reflux. b Combined isolated yield of
diastereomers. c In this instance, the diastereomeric ratio refers to the ratio of (2R,3R):(2S,3S) products. d Determined by crude 1H NMR. >20:1
indicates only one isomer was observed. e Diastereoselectivities are based on the ratio of isolated yields.
J. Org. Chem. Vol. 73, No. 21, 2008 8157

Scott and Lautens
TABLE 3. Reaction Scope Using r,ꢀ-Unsaturated Iminesa
a Reactions carried out using 0.1 M MCP (0.2 mmol), 1.2 equiv of sulfinimine, and 1.0 equiv of MgI2 in THF at reflux unless otherwise noted in the
Supporting Information. b Combined isolated yield of diastereomers. c In this instance the diastereomeric ratio refers to the ratio of (2R,3R):(2S,3S)
products. d Determined by crude 1H NMR. >20:1 indicates only one isomer was observed. e Complex mixtures were obtained. f The major trans isomer
for the structure indicated in the general scheme is actually (2S,3S) for this example. g Diastereoselectivities are based on the ratio of isolated yields.
Our methodology could also be extended to a variety of other
activated methylenecyclopropyl derivatives (Table 4). While less
activating esters did not undergo ring opening under our standard
conditions (entry 1), the use of a more electron-withdrawing
tert-butyl thioester group (entry 2) was found to afford the
desired pyrrolidine product in a modest yield. In this example,
the low yields obtained for the desired pyrrolidine product are
attributed to the low reactivity of the intermediate iodo enolate,
since the intermediate allylic iodide was observed by TLC and
addition, our system is further complicated by the possibility
that ring closing may occur by either an SN2 or a Baldwin-
disfavored SN2′ process.16 Accordingly, there are three possible
pathways by which the overall iodide-mediated ring expansion
may occur. The first, but highly unlikely, pathway (Scheme 3,
pathway A) is one that involves initial ring opening by imine
addition to the MCP amide (through either an SN2 or SN2′
mechanism) to afford an iminium enolate which could then
undergo cyclization to generate the requisite pyrrolidine product.
The poor nucleophilicity of the imine nitrogen disfavors this
pathway, as does the observation of the allylic iodide 2 during
our optimization and scope investigations. The second, and more
likely pathway (Scheme 3, pathway B) is Lewis acid activation
of the MCP followed by iodide-mediated ring opening by either
an SN2 or SN2′ mechanism. Subsequent enolate attack of the
sulfinimine would then generate the intermediate sulfinamide
1
also by crude H NMR even after prolonged heating. Interest-
ingly, we note that a small amount of the isomerized R,ꢀ-
unsaturated pyrrolidine product was observed in this case
(<10%), presumably due to the decreased 1,3-allylic strain
compared with the corresponding amide-substituted derivatives.
Our conditions could also be used with a variety of aromatic
and aliphatic tertiary amide MCPs. For all of these examples
(entries 3-7), the desired pyrrolidines were obtained in generally
good yields and in excellent selectivities over all other diaster-
eomers for this reaction. For the N-methyl-N-phenyl amide
example (entry 4), the absolute stereochemistry was confirmed
to be identical to that of the 4-methoxyphenyl-N,N-diphenyl
amide adduct (Table 2, entry 8).10
Stereochemical Analysis and Mechanistic Studies. We next
investigated the ring-opening and ring-closing mechanism for
this process, since it has been proposed by both Liu14 and Ma15
that ring opening of activated methylenecyclopropanes may
occur either via an SN2 or SN2′ ring-opening pathway. In
(14) (a) Li, D.; Guo, Z.; Liu, H.-W. J. Am. Chem. Soc. 1996, 118, 275. (b)
Li, D.; Agnihotri, G.; Dakoji, S.; Oh, E.; Lantz, M.; Liu, H.-W. J. Am. Chem.
Soc. 1999, 121, 9034.
(15) Ma, S.; Lu, L.; Zhang, J. J. Am. Chem. Soc. 2004, 126, 9645.
(16) Although an SN2′ ring closing pathway is disfavored by Baldwin’s rules,
similar 5-endo-trig ring-closing reactions have been reported for the synthesis
of pyrrolidines. See, for example: (a) Padwa, A.; Norman, B. H. J. Org. Chem.
1990, 55, 4801. (b) Craig, D.; Jones, P. S.; Rowlands, G. J. Synlett 1997, 1423.
(c) Auvray, P.; Knochel, P.; Normant, J. F. Tetrahedron Lett. 1985, 26, 4455.
(d) Berry, M. B.; Craig, D.; Jones, P. S.; Rowlands, G. J. Chem. Commun. 1997,
22, 2141. (e) Jones, A. D.; Knight, D. W. Chem. Commun. 1996, 915. (f)
Dell’Erba, C.; Mugnoli, A.; Novi, M.; Pani, M.; Petrillo, G.; Tavani, C. Eur. J.
Org. Chem. 2000, 903. (g) Chang, K. T.; Jang, H. Y.; Kim, Y. K.; Park, K. H.;
Lee, W. S. Heterocycles 2001, 55, 1173.
8158 J. Org. Chem. Vol. 73, No. 21, 2008

Synthesis of Highly Functionalized Pyrrolidines
TABLE 4. Reaction Scope Using Other Activated
Methylenecyclopropanesa
nucleophilic displacement of the allylic iodide moiety by imine
to generate an iminium intermediate. Intramolecular cyclization
of the enolate would then produce the pyrrolidine product.
Again, this pathway is unlikely given the poor nucleophilicity
of this nitrogen and the fact that 1H NMR experiments showed
no evidence of such an intermediate.
In order to examine the exact nature of the ring-opening/
ring-closing mechanism, we carried out the reaction using a
deuterium-labeled tertiary MCP amide (Scheme 4). Initial ring-
opening studies in the presence of a chiral sulfinimine found
86% of the deuterium were incorporated at the 5-position of
the pyrrolidine ring, indicating that the major mechanism by
which ring opening/ring closing was occurring was via either
an SN2/SN2 or SN2′/SN2′ process. Interestingly, a small amount
of deuterium scrambling at the exo-methylene position (14%)
was also observed, presumably by a nonselective ring-opening/
ring-closing process or alternatively, by iodide-17 or iodine-
mediated18 scrambling of the allylic iodide. Additional ring-
opening studies using DMSO in place of the sulfinimine afforded
the intermediate allylic iodide with 74% of the deuterium
incorporated at the allylic position (Scheme 5). These experi-
ments indicate that the major pathway for ring opening and ring
closing occurs by an SN2/SN2 process, while suggesting that an
iodine or iodide-mediated interconversion between the enolates
is likely operative under the reaction conditions. Although we
note that these results do not completely rule out the possibility
of a minor SN2′ ring opening process, orbital arguments would
prevent such a possibility since a coplanar alignment of the
alkene π* and the σ* of the C-leaving group is required for
SN2′ processes to occur.19 However, in our system the π* of
the alkene and the σ* of the C-C cyclopropane system are
almost orthogonal, thereby disfavoring such a ring-opening
process (Scheme 6).
a Reactions carried out using 0.1 M MCP (0.2 mmol), 1.2 equiv of
sulfinimine, and 1.0 equiv of MgI2 in THF at reflux. b Combined yield
of diastereomers. c In this instance, the diastereomeric ratio refers to the
ratio of (2R,3R):(2S,3S) products. d Determined by crude 1H NMR.
>20:1 indicates only one isomer was observed. e No ring opening
observed.
Initial ring opening of the activated MCP should afford the
expected Z(O) enolate intermediate. Support for this enolate
geometry is provided from our early optimization studies in
which we observed the formation of the highly air-sensitive
2-aminofuran byproduct (Scheme 7). The formation of this
2-aminofuran presumably arises via cyclization of the Z(O) iodo
enolate followed by isomerization. In fact, concurrent with our
studies, Ma and co-workers reported the synthesis of substituted
which would undergo cyclization by an SN2 or SN2′ mechanism
to afford the desired pyrrolidine product. The final possible
pathway (Scheme 3, pathway C) involves initial ring opening
by MgI2 by either an SN2 or SN2′ mechanism followed by
SCHEME 3. Proposed Mechanisms for the Iodide-Mediated Ring-Opening/Ring-Closing of Monoactivated
Methylenecyclopropyl Amides
J. Org. Chem. Vol. 73, No. 21, 2008 8159

Scott and Lautens
SCHEME 4. Pyrrolidine Formation Using a Deuterium-Labeled Tertiary Methylenecyclopropyl Amide
SCHEME 5. Ring-Opening Studies Using a Deuterium-Labeled Tertiary Methylenecyclopropyl Amide
Given this enolate geometry and based on the absolute
stereochemistry of the pyrrolidine products, the sulfinimine must
approach the intermediate Z(O) enolate from the Si face via
either a boat or twist-boat transition state (Scheme 8). This
conformation prevents any unfavorable 1,3-diaxial interactions
between the diphenylamide and imine aromatic moieties, while
still allowing for possible stabilization of the transition state
via coordination of the sulfoxide oxygen to the nearby magne-
sium.21 Alternatively, the cis pyrrolidine product arises via a
less favored chair transition state. Based on X-ray crystal-
lographic analysis of the minor cis isomer for the 2-phenyl
substituted pyrrolidine (Table 2, entry 1),22 we propose that
SCHEME 6. Orbital Argument for SN2 Addition of Iodide
furan derivatives by a similar NaI-mediated ring expansion of
substituted MCP ketones.15,20 Furthermore, Oshima and co-
workers have also reported a similar iodo enolate intermediate
in their TiCl4/TBAI-mediated ring opening of cyclopropyl
ketones.6f
SCHEME 7. Synthesis of 2-Aminofuran Byproduct
SCHEME 8. Proposed Transition States for Both the trans- and cis-Pyrrolidine Diastereomers
8160 J. Org. Chem. Vol. 73, No. 21, 2008

Synthesis of Highly Functionalized Pyrrolidines
TABLE 5. Pyrrolidine Deprotection
sulfinimines. In general, yields and diastereoselectivities for
this transformation were good to excellent, allowing for the
use of a range of aromatic, heteroaromatic, and R,ꢀ-
unsaturated sulfinimines. Mechanistic studies indicate that
ring opening/ring closing occurs primarily by an SN2/SN2
route, and that iodine- or iodide-mediated isomerization of
the iodo enolate is likely occurring under the reactions
conditions. Subsequent auxiliary removal could also be
carried out under mild reaction conditions to efficiently afford
a variety of valuable enantioenriched pyrrolidine building
blocks.
Experimental Section
General Procedure for the MgI2-Mediated Ring Expansion
of Tertiary Methylenecyclopropyl Amides. To a flame dried flask
was added MCP (1 equiv), MgI2 (1 equiv), and sulfinimine (1.2
equiv). THF was added (0.1 M), and the solution was stirred for
20 min at room temperature before heating to reflux. Reaction
completion was monitored by TLC. The reaction was then cooled
to room temperature, diluted with ethyl acetate (2.0 mL), and
quenched with saturated aqueous sodium sulfite (2.0 mL). The
aqueous layer was separated and a 0.5 M tetrasodium ethylenedi-
aminetetraacetic acid salt (EDTA) solution was added (50 mL).
The aqueous phase was then extracted with ethyl acetate (4 × 50
mL), and the combined organic layers were dried with Na2SO4,
filtered and concentrated in vacuo.
(2R,3R,SS)-4-Methylene-2-naphthalen-1-yl-1-(toluene-4-sulf-
inyl)pyrrolidine-3-carboxylic Acid Diphenylamide (Table 2,
Entry 5). Following the general procedure outlined above (heat at
reflux for 3.25 h) for the MgI2-mediated ring expansion of
2-methylenecyclopropane carboxylic acid diphenylamide in the
presence of (S)-(+)-N-(naphthalen-1-ylmethylene)-p-toluenesulfi-
namide. Following workup, chromatography on silica gel using 1:2
ethyl acetate/hexanes (Rf ) 0.26) gave the title compound (0.0796
g, 73%) as an amorphous white foam: [R]20 ) +20.8 (c ) 0.9,
D
CHCl3); IR (neat, cm-1) 3008, 1674, 1595, 1490, 1373, 1091, 1068,
804, 777, 755, 702; δH (400 MHz, CDCl3) 8.29 (bs, 2H), 7.94 (t,
2H, J ) 8.8 Hz), 7.70 (bs, 1H), 7.55-7.47 (m, 5H), 7.26-7.17
(m, 5H), 7.10-6.96 (m, 5H), 6.27 (bs, 1H), 5.15 (bs, 1H), 5.06
(bs, 1H), 4.30 (d, 1H, J ) 14.0 Hz), 3.20 (d, 1H, J ) 14.0 Hz),
2.36 (s, 3H); δC (125 MHz, CDCl3) 170.5, 144.7, 142.3, 141.9,
141.3, 140.7, 134.4, 131.7, 129.6, 129.5, 129.2, 128.9, 128.2, 127.7,
126.3, 126.2, 125.6, 125.4, 108.4, 45.7, 21.5 (remaining carbons
not observed); C35H31N2O2S (MH+) (EI) requires 543.2106, found
543.2114.
a Isolated yield.
attack of the imine in this case occurs from the Re face of the
enolate as shown in Scheme 8.
Pyrrolidine Deprotection. The utility of this highly stereo-
selective methodology for the synthesis of enantioenriched
pyrrolidines is highlighted in Table 5. Facile deprotection of
the chiral sulfoxide protecting group could be achieved under
mild conditions, affording enantioenriched free pyrrolidines in
high yields for a wide range of aromatic, heteroaromatic, as
well as aliphatic-based pyrrolidines (Table 5).23
Acknowledgment. We thank Dr. Wooseok Han for initial
experimental contributions and helpful suggestions at the outset
of this work. We also thank Merck-Frosst Canada, the Natural
Sciences and Engineering Research Council (NSERC) of
Canada and the University of Toronto for supporting this
research. M.E.S. thanks NSERC and the Walter C. Sumner
Foundation for providing postgraduate funding.
Conclusions
The broad synthetic utility of MCPs has made these three
carbon synthons attractive building blocks for a variety of
carbo- and heterocyclic motifs. Recent studies by our group
have focused on an iodide-mediated ring expansion of
monoactivated MCPs as an in situ route to an all-carbon 1,3-
dipole. These studies report for the first time a one-step,
highly stereoselective halide-mediated Mannich/cyclization
to afford a wide range of trans-2,3-pyrrolidines using chiral
(18) (a) Sibbett, D. J.; Noyes, R. M. J. Am. Chem. Soc. 1953, 75, 761. (b)
Sibbett, D. J.; Noyes, R. M. J. Am. Chem. Soc. 1953, 75, 763. (c) Cain, W. P.;
Noyes, R. M. J. Am. Chem. Soc. 1959, 81, 2031.
(19) Whitehead, A.; McParland, J. P.; Hanson, P. R. Org. Lett. 2006, 8, 5025.
(20) Ma, S.; Zhang, J. Angew. Chem., Int. Ed. 2003, 42, 184.
(21) For reviews highlighting the importance of metal chelation with chiral
sulfoxides, see: (a) Morton, D.; Stockman, R. A. Tetrahedron 2006, 62, 8869.
(b) Zhou, P.; Chen, B.-C.; Davis, F. A. Tetrahedron 2004, 60, 8003.
(22) Full crystallographic details for this minor cis isomer have been deposited
in the Cambridge Crystallographic database.
(17) For an example of an iodide-mediated SN2′ reactions of allylic iodides,
see: McDowell, C. A.; Lossing, F. P.; Henderson, I. H. S.; Farmer, J. B Can.
J. Chem. 1956, 34, 345.
(23) Davis, F. A.; Reddy, R. E.; Szewczyk, J. M.; Reddy, G. V.; Portonovo,
P. S.; Zhang, H.; Fanelli, D.; Reddy, R. T.; Zhou, P.; Carroll, P. J. J. Org. Chem.
1997, 62, 2555.
J. Org. Chem. Vol. 73, No. 21, 2008 8161

Scott and Lautens
Supporting Information Available: X-ray data for Table
2, entry 8, and Table 4 entry 4, as well as the minor cis isomer
of Table 2, entry 1, experimental procedures, and characteriza-
tion data (1H and 13C NMR, HRMS, IR) of all new pyrrolidine
compounds listed in Tables 2-5 as well as starting materials.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO802049U
8162 J. Org. Chem. Vol. 73, No. 21, 2008