Gold(I)-catalyzed domino ring-opening ring-closing hydroamination of methylenecyclopropanes (MCPs) with sulfonamides: Facile preparation of pyrrolidine derivatives

Article abstract of DOI:10.1021/ol0614830

Reaction of methylenecyclopropanes 1 with sulfonamides produces the corresponding pyrrolidine derivatives 3 in moderate to good yields under the catalysis of Au(I) via a domino ring-opening ring-closing hydroamination process.

Full text of DOI:10.1021/ol0614830

ORGANIC
LETTERS
2006
Vol. 8, No. 18
4043-4046
Gold(I)-Catalyzed Domino Ring-Opening
Ring-Closing Hydroamination of
Methylenecyclopropanes (MCPs) with
Sulfonamides: Facile Preparation of
Pyrrolidine Derivatives
Min Shi,*,† Le-Ping Liu,‡ and Jie Tang‡
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China,
and Department of Chemistry, East China Normal UniVersity, 3663 Zhongshanbei Lu,
Shanghai 200062, China
mshi@mail.sioc.ac.cn
Received June 16, 2006
ABSTRACT
Reaction of methylenecyclopropanes 1 with sulfonamides produces the corresponding pyrrolidine derivatives 3 in moderate to good yields
under the catalysis of Au(I) via a domino ring-opening ring-closing hydroamination process.
Nitrogen-containing saturated heterocyclic systems are im-
portant core structures in organic chemistry because of their
presence in many natural products.1 One of the most
appealing approaches to pyrrolidines is intramolecular hy-
droamination, which is mainly developed by Hartwig and
co-workers, under the catalysis of transition metals or
Brønsted acids.2 During our initial studies on the Lewis acids
such as Sn(OTf)2 promoted ring-opening reactions of me-
thylenecyclopropanes3 (MCPs) 1 with sulfonamides, we
found that pyrrolidine derivatives could be formed for some
substrates in moderate yields (27-51%).4 Recently, He
reported that gold(I)-mediated hydroamination of inert olefins
with p-toluenesulfonamide (TsNH2) can produce the corre-
sponding acyclic or cyclic nitrogen-containing compounds
in good to excellent yields under mild conditions.5 Therefore,
(2) (a) Beller, M.; Eichberger, M.; Trauthwein, H. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2225-2227. (b) Muller, T. E.; Beller, M. Chem. ReV.
1998, 98, 675-704. (c) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc.
2000, 122, 9546-9547. (d) Loeber, O.; Kawatsura, M.; Hartwig, J. F. J.
Am. Chem. Soc. 2001, 123, 4366-4367. (e) Kawatsura, M.; Hartwig, J. F.
Organometallics 2001, 20, 1960-1964. (f) Schlummer, B.; Hartwig, J. F.
Org. Lett. 2002, 4, 1471-1474. (g) Takaya, J.; Hartwig, J. F. J. Am. Chem.
Soc. 2005, 127, 5756-5757. (h) Takemiya, A.; Hartwig, J. F. J. Am. Chem.
Soc. 2006, 128, 6042-6043. (i) Johns, A. M.; Utsunomiya, M.; Incarvito,
C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 1828-1839. (j) Shimada,
T.; Bajracharya, G. B.; Yamamoto, Y. Eur. J. Org. Chem. 2005, 59-62.
(k) Field, L. D.; Messerle, B. A.; Vuong, K. Q.; Turner, P. Organometallics
2005, 24, 4241-4250. (l) Li, K.; Phua, P. H.; Hii, K. K. Tetrahedron 2005,
61, 6237-6242. (m) Li, X.; Chianese, A. R.; Vogel, T.; Crabtree, R. H.
Org. Lett. 2005, 7, 5437-5440.
† Chinese Academy of Sciences.
‡ East China Normal University.
(1) (a) Dewick, P. M. Medicinal Natural Products; J. Wiley & Sons:
Chichester, UK, 1997; Chapter 6. (b) Pichon, M.; Figadere, B. Tetrahedron:
Asymmetry 1996, 7, 927-964 and references therein. (c) Yus, M.; Foubelo,
F. J. Org. Chem. 2001, 66, 6207-6208. (d) Hill, K. R. Chem. Alkaloids
1970, 385-429. (e) Hagan, D. O. Nat. Prod. Rep. 2000, 17, 435-446. (f)
Laschat, S.; Dickner, T. Synthesis 2000, 1781-1813. (g) Bailey, P. D.;
Millwood, P. A.; Smith, P. D. Chem. Commun. 1998, 6, 633-640. (h)
Laschat, S. Liebigs Ann. 1997, 1, 1-11. (i) Wang, C. J. J.; Wuonola, M.
A. Org. Prep. Proced. Int. 1992, 24, 583-621. (j) Baliah, V.; Jeyaraman,
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MCPs: (a) Huang, J.-W.; Shi, M. Synlett 2004, 2343-2346. (b) Shi, M.;
Xu, B.; Huang, J.-W. Org. Lett. 2004, 6, 1175-1178. (c) Xu, B.; Shi, M.
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10.1021/ol0614830 CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/12/2006

we envisioned that pyrrolidine derivatives would be obtained
in better yields from methylenecyclopropanes and TsNH2
under the catalysis of gold(I) salt, a powerful soft Lewis
acid.6 Herein, we wish to report gold(I)-catalyzed domino
ring-opening ring-closing hydroamination of methylenecy-
clopropanes with sulfonamides, a facile synthetic route to
pyrrolidine derivatives 3 (Scheme 1).
catalyst, we investigated the hydroamination of methylenecy-
clopropane 1a with TsNH2 (1.0 equiv). As we expected, the
corresponding pyrrolidine derivative 3a was obtained in good
yield (70%) after 12 h in toluene at 85 °C (Table 1, entry
Table 1. Hydroamination of MCP 1a (0.5 mmol) with TsNH2
(0.5 mmol) in Toluene (2.0 mL)
Scheme 1. Envisioned Reaction Pathway of Au(I)-Catalyzed
Hydroamination of MCPs with TsNH2
yield (%)
entry
catalyst (mol %)
solvent
2a
3a
4a
1
2
3
Au(PPh3)Cl (5), AgOTf (5)
TfOH (10)
TfOH (2)b
toluene trace 70
toluene trace 48 trace
toluene trace 10
4
5
6
7
8
9
10
11
12
13
14
15
Sn(OTf)2 (10)
In(OTf)3 (10)
Yb(OTf)3 (10)
Sc(OTf)3 (10)
BF3‚OEt2 (10)
Au(PPh3)Cl (5)
AgOTf (5)
Au(PPh3)Cl (5), AgSbF6 (5) toluene trace 51
Au(PPh3)(NTf2 (5)
Au(PPh3)Cl (5), AgOTf (5)
Au(PPh3)Cl (5), AgOTf (5)
Au(PPh3)Cl (5), AgOTf (5)
toluene 11
toluene 24
toluene 56
toluene 34
toluene 47
toluene
36 20
22 15
6
18
8
16 trace
toluene 72
toluene
DCE
trace 61
In our initial experiment using Au(PPh3)OTf, prepared
from equal equivalents of Au(PPh3)Cl and AgOTf, as the
CH3CN
THF
a Isolated yields. b 54% of 1a was recovered.
(4) (a) Chen, Y.; Shi, M. J. Org. Chem. 2004, 69, 426-431. For other
papers on hydroamination of MCPs, see: (b) Nakamura, I.; Itakagi, H.;
Yamamoto, Y. J. Org. Chem. 1998, 63, 6458-6459. (c) Smolensky, E.;
Kapon, M.; Eisen, M. S. Organometallics 2005, 24, 5495-5498. (d) Ryu,
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Chem. 2005, 70, 5932-5937.
(5) (a) Zhang, J.; Yang, C.-G.; He, C. J. Am. Chem. Soc. 2006, 128,
1798-1799. For other papers on gold-catalyzed inter- or intramolecular
hydroamination of unsaturated compounds, see: (b) Fukuda, Y.; Utimoto,
K.; Nozake, H. Heterocycles 1987, 25, 297-300. (c) Arcadi, A.; Giuseppe,
S. D.; Marinelli, F.; Rossi, E. AdV. Synth. Catal. 2001, 343, 443-446. (d)
Mizushima, E.; Hayashi, T.; Tanaka, M. Org. Lett. 2003, 5, 3349-3352.
(e) Brouwer, C.; He, C. Angew. Chem., Int. Ed. 2006, 45, 1744-1747. (f)
Han, X.; Widenhoefer, R. A. Angew. Chem., Int. Ed. 2006, 45, 1747-
1749. (g) Nishina, N.; Yamamoto, Y. Angew. Chem., Int. Ed. 2006, 45,
3314-3317. (h) Patil, N. T.; Lutete, L. M.; Nishina, N.; Yamamoto, Y.
Tetrahedron Lett. 2006, 47, 4749-4751.
(6) For recent reviews on gold-catalyzed reactions, see: (a) Hashmi, A.
S. K. Angew. Chem., Int. Ed. 2005, 44, 6990-6993. (b) Hashmi, A. S. K.
Gold Bull. 2004, 37, 51-65. (c) Arcadi, A.; Giuseppe, S. D. Curr. Org.
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Ro¨der, A.; Krause, N. Org. Biomol. Chem. 2005, 3, 387-391. Selected
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Chem. Soc. 2004, 126, 11164-11165. (j) Zhang, L.; Kozmin, S. A. J. Am.
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1). Though a trace of ring-opening product 2a was detected
by TLC analysis, none of the dialkylated product 4a was
formed. Meanwhile, the Brønsted acid trifluoromethane-
sulfonic acid (TfOH) and various other Lewis acids including
Au(PPh3)Cl and Au(PPh3)Cl with AgSbF6 were tested in this
reaction under identical conditions. As can be seen from
Table 1, TfOH could also catalyze the reaction but led to 3a
in lower yield (Table 1, entry 2). When 2 mol % of TfOH
was used as the catalyst for a control experiment, product
3a was isolated in only 10% yield along with the recovery
of 54% of the starting materials (Table 1, entry 3). Other
Lewis acids, such as Sn(OTf)2, In(OTf)3, Yb(OTf)3, Sc-
(OTf)3, and BF3‚Et2O, could promote the ring-opening
reaction of 1a with TsNH2 to give the corresponding product
2a as the major one along with the formation of product 4a
in low yields in most cases. However, these Lewis acids were
not as efficient as gold(I) catalyst in the subsequent intramo-
lecular ring-closing hydroamination of 2a to afford pyrro-
lidine derivative 3a under identical conditions (Table 1,
entries 4-8). If Au(PPh3)Cl was used as a sole catalyst, no
reaction occurred (Table 1, entry 9). On the other hand,
AgOTf could only promote the ring-opening reaction of 1a
to give 2a in 72% yield (Table 1, entry 10). When AgSbF6
was used as the dechlorinating reagent instead of AgOTf,
3a was obtained in 51% yield under identical conditions
(Table 1, entry 11). Au(PPh3)NTf2, an air-stable gold(I)
complex,7 was also applied to the reaction as the catalyst
4044
Org. Lett., Vol. 8, No. 18, 2006

under identical conditions, but no reaction occurred (Table
1, entry 12). Solvent effects were examined with use of Au-
(PPh3)OTf as the catalyst. The results are summarized in
Table 1 as entries 13-15. Pyrrolidine derivative 3a was also
obtained in 1,2-dichloroethane (DCE) in 61% yield, but no
reaction occurred in acetonitrile (CH3CN) or tetrahydrofuran
(THF) under the standard conditions. It should be noted that
no reaction occurred at room temperature (20 °C) and product
2a was obtained in 36% yield at 50 °C after 12 h without
the formation of product 3a under the standard conditions.
Next, we carried out the gold(I)-catalyzed domino ring-
opening ring-closing hydroamination of methylenecyclopro-
panes 1b-o with TsNH2 under these optimal conditions. We
found that the corresponding pyrrolidine derivatives 3b-o
were obtained in moderate to good yields (Table 2).
subjected to the reaction and the corresponding pyrrolidine
derivative 3f was obtained in 54% yield (Table 2, entry 5).
For an aromatic group and a methyl group substituted
methylenecyclopropanes 1g-k, the reaction also proceeded
smoothly to give the expected products 3g-k in moderate
to good yields. The electron-donating groups on the aromatic
ring could accelerate the reaction and the corresponding
pyrrolidine derivatives 3h-i were obtained in higher yields
within shorter reaction time (Table 2, entries 7 and 8).
Conversely, electron-withdrawing groups on the aromatic
ring could hold back the reaction rates (Table 2, entries 9
and 10). For double aliphatic groups substituted acyclic or
cyclic methylenecyclopropanes 1l-o, the corresponding
pyrrolidine derivatives 3l-o were obtained in good yields
(Table 2, entries 11-14).
Afterward, using methylenecyclopropane 1a as substrate,
we investigated the hydroamination with other sulfonamides,
amides, and amines under these optimized conditions. We
found that when phenylsulfonamide and m- and p-nitrophe-
nylsulfonamides were used, the corresponding pyrrolidine
derivatives 3p-r were obtained in good yields (Table 3,
Table 2. Gold(I)-Catalyzed Hydroamination of MCPs 1 (0.5
mmol) with TsNH2 (0.5 mmol)
R1, R2
time (h) yield of 3 (%)a
Table 3. Gold(I)-Catalyzed Hydroamination of MCP 1a (0.5
entry
mmol) with Sulfonamides (0.5 mmol)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
o-MeC6H4, H (1b)
m-MeC6H4, H (1c)
p-MeC6H4, H (1d)
o-MeOC6H4, H (1e)
1-naphthyl, H (1f)
C6H5, Me (1g)
p-MeC6H4, Me (1h)
p-EtOC6H4, Me (1i)
p-ClC6H4, Me (1j)
m-BrC6H4, Me (1k)
n-C4H9, n-C4H9 (1l)
n-C7H15, Me (1m)
cyclohexylene (1n)
4-phenylcyclohexylene (1o)
8
8
8
3b, 68
3c,76
3d, 70
3e, 34 (46b)
3f, 54
3g, 68
3h, 72
3i, 71
3j, 43
3k, 47
3l, 70
3m, 64
3n, 63
3o, 75
4
12
12
8
entry
R
yield of 3 (%)a
8
1
2
3
4
C6H5
3p, 79
3q, 69
3r, 74
3s, 12 (2s, 36
24
24
8
8
8
m-NO2C6H4
p-NO2C6H4
o-NO2C6H4
a Isolated yields.
8
a Isolated yields. b TfOH (2 mol %) was used as the catalyst and the
reaction time was prolonged to 12 h.
entries 1-3). o-Nitrophenylsulfonamide was also employed
in the reaction but led to the corresponding product 3s in
12% yield along with the formation of 2s in 36% yield under
the standard conditions (Table 3, entry 4, also see the
Supporting Information). This may be due to that the o-nitro
group sterically retarding the hydroamination process. Nev-
ertheless, amides such as benzamide and acetamide, and
amines such as aniline and benzylamine, did not react with
MCPs at all to give the corresponding pyrrolidine derivative,
as reported by Hartwig’s group2f and He’s group.6a
For methylenecyclopropanes 1b-f substituted by a single
aromatic group, the reactions proceeded smoothly to give
the corresponding pyrrolidine derivatives 3b-f in 34-76%
yields (Table 2, entries 1-5). For methylenecyclopropanes
1b-d having a methyl group on the aromatic ring, the
corresponding pyrrolidine derivatives 3b-d were obtained
in good yields even for sterically hindered methylenecyclo-
propane 1b (Table 2, entries 1-3). For methylenecyclopro-
pane 1e having a methoxy group on the aromatic ring as
substrate, the corresponding pyrrolidine derivative 3e was
obtained in 34% yield. In addition, the yield of 3e increased
slightly to 46% when 2 mol % of TfOH was used as the
catalyst (Table 2, entry 4). This may be due to the unstability
of 1e under the reaction conditions. MCP 1f, having a
1-naphthyl group rather than a phenyl group, was also
In conclusion, we have developed a gold(I)-catalyzed
domino ring-opening ring-closing hydroamination of meth-
ylenecyclopropanes with sulfonamides to give the corre-
sponding pyrrolidine derivatives under mild conditions. In
this synthetic protocol, various pyrrolidine derivatives 3 were
easily obtained in moderate to good yields in a cascade
process, substantially enriching gold chemistry. Efforts are
underway to further explore more effective gold(I) catalyst
and to understand the scope and limitations of this process.
(7) Me´zailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133-4136.
Org. Lett., Vol. 8, No. 18, 2006
4045

Acknowledgment. We thank the State Key Project of
Basic Research (Project 973) (No. G2000048007),
Shanghai Municipal Committee of Science and Technology
(04JC14083), Chinese Academy of Sciences (KGCX2-
210-01), and the National Natural Science Foundation of
China for financial support (20472096, 203900502, and
20272069).
Supporting Information Available: The spectroscopic
data (1H, 13C spectroscopic data), MS, HRMS and analytic
data of the compounds shown in Tables 1-3 and the detailed
description of experimental procedures. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0614830
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Org. Lett., Vol. 8, No. 18, 2006