Base and copper(i) catalyzed Mannich, alkyne hydroamination cascades for the direct synthesis of 2-methylenepyrrolidines

Article abstract of DOI:10.1039/b905629g

An efficient, simple-to-perform, one-pot reaction cascade to 2-methylenepyrrolidines from p-toluenesulfonyl protected imines and propargylated malonates under a combination of base and copper(i) catalysis is reported.

Full text of DOI:10.1039/b905629g

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Base and copper(I) catalyzed Mannich, alkyne hydroamination cascades
for the direct synthesis of 2-methylenepyrrolidinesw
Hai-Fei Wang,a Ting Yang,b Peng-Fei Xu*a and Darren J. Dixon*c
Received (in Cambridge, UK) 20th March 2009, Accepted 11th May 2009
First published as an Advance Article on the web 1st June 2009
DOI: 10.1039/b905629g
An efficient, simple-to-perform, one-pot reaction cascade to
2-methylenepyrrolidines from p-toluenesulfonyl protected imines
and propargylated malonates under a combination of base and
copper(I) catalysis is reported.
As a new development of this research herein we report
our studies leading to a two component Mannich, alkyne
hydroamination cascade6 for the direct synthesis of 2-methylene-
pyrrolidines. The outline design of the cascade is shown in
Scheme 1. Initially, under base catalysis it was envisaged
that a propargylated carbon acid should undergo addition
(a Mannich reaction) to a suitably protected and activated
imine resulting in the formation of a protected b-amino ester
product. This adduct would then be poised to react with the
pendent alkyne group when suitably activated by a ‘soft’
alkynophilic metal ion complex. Protodemetallation should
then afford the product and release the catalysts back into the
cycle. In part, this proposed cascade is supported by the work
of Balme7c and co-workers who have described domino aza
Michael, metal-catalyzed cycloisomerization reactions leading
to 3-methylenepyrrolidines.7
The desire for practically simple and synthetically efficient
organic transformations has led to the development of many
innovative strategies, concepts and methodologies. One attractive
approach is to employ reaction cascades. These multi-step
reaction sequences significantly improve the overall yield
and resource efficiency compared to one-reaction, one-pot
approaches.1 A myriad of elegant cascade sequences catalyzed
either by single chemical entities2 or by multiple, mutually
compatible catalysts have facilitated some elegant transforma-
tions of relatively simple starting materials to more complex
molecular architectures. One area in particular within the
cascade field that has witnessed significant interest over the
past decade is that of additions to alkyne functionality,3 more
specifically, cascade reactions involving alkyne functionality,
wherein ‘soft’ transition metal ions are employed to provide
the necessary activation to trigger the process.4 To this end
our group recently reported a one-pot, multi-step reaction
cascade to cyclopentenes from a,b-unsaturated ketones
and propargylated carbon acids using a combination of
pyrrolidine and copper ion catalysts.5
Ours would bring together new components at different
stages and thus result in the production of isomeric
2-methylenepyrrolidines through initial carbon–carbon bond
Table 1 Proof of principle, catalyst identification and reaction
optimization studies
Time/ Yielda
Entry Base
Metal/ligand
h
(%)
1
2
3
4
5
6
7
8
BEMP
—
Au(PPh3)Cl, AgOTf
AgOTf
CuOTf/PPh3
Cu(OTf)2/PPh3
Cu(OTf)2
CuOTf
CuI
Yb(OTf)3
RuCl2(PPh3)3
(PPh3)2NiCl2
Zn(OTf)2
48
16
18
16
16
24
24
24
24
24
24
24
24
24
31
36
24
27
27
16
0
27
24
69
68
0
0
0
0
0
BEMP
BEMP
BEMP
BEMP
BEMP
BEMP
BEMP
BEMP
BEMP
BEMP
BEMP
BEMP
Scheme 1 Concept of the Mannich, alkyne hydroamination cascade
for the direct synthesis of 2-methylenepyrrolidines.
9
10
11
12
13
14
15
16
17
18
19
20
21
22b
a State Key Laboratory of Applied Organic Chemistry,
College of Chemistry and Chemical Engineering,
Lanzhou University, Lanzhou 730000, P.R. China.
E-mail: xupf@lzu.edu.cn; Fax: +86 931 8915557;
Tel: +86 931 8912281
0
0
0
PdCl2(PPh3)2
PS-BEMP Cu(OTf)2/PPh3(20 mol%)
65
34
Trace
Trace
0
49
73
74
94
DBU
DABCO
Et3N
NaOAc
NaOMe
KOtBu
KOtBu
KOtBu
Cu(OTf)2/PPh3 (20 mol%)
Cu(OTf)2/PPh3 (20 mol%)
Cu(OTf)2/PPh3 (20 mol%)
Cu(OTf)2/PPh3 (20 mol%)
Cu(OTf)2/PPh3 (20 mol%)
b School of Chemistry, The University of Manchester, Oxford Road,
Manchester, UK M13 9PL
c Department of Chemistry, Chemistry Research Laboratory,
University of Oxford, Mansfield Road, Oxford, UK OX1 3TA.
E-mail: Darren.Dixon@chem.ox.ac.uk; Fax: +44 (0)1865 285002;
Tel: +44 (0)1865 275648
Cu(OTf)2/PPh3 (20 mol%)
1
CuOTfÁ C6H6/PPh3 (15 mol%) 16
2
1
CuOTfÁ C6H6/PPh3 (15 mol%) 16
w Electronic supplementary information (ESI) available: Experimental
procedures and spectral data for compounds 3–5. See DOI:
10.1039/b905629g
2
a
b
Isolated yield after flash column chromatography. [1a] 0.4 mM.
ꢀc
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3916 | Chem. Commun., 2009, 3916–3918

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formation followed by hydroamination. Having direct experience
of Mannich reactions using malonate pro-nucleophiles8 we
were confident of the reactivity match between the malonate
functionality and the imine, however finding a catalyst
combination that would allow this and the concomitant
hydroamination remained the challenge.
Preliminary catalyst screening studies were performed using
p-toluenesulfonyl imine 1a and malonate 2 in methanol at
room temperature. A range of base and metal ion catalyst
combinations were screened for overall performance (reaction
efficiency and rate) and the results are presented in Table 1.
Various combinations of strong bases (organic or inorganic)
and copper complexes were soon identified as effective for
the process and additional screening revealed potassium
tert-butoxide (10 mol%) and Cu(I)OTf benzene complex
(5 mol%) in the presence of triphenylphosphine (15 mol%)
in methanol at room temperature to be optimal for the
cascade. With optimal conditions identified the scope of the
reaction with respect to the imine substrate was then probed.
The results are presented in Table 2.
Scheme 2 Proposed mechanistic pathway.
adduct under (alkoxide) base catalysis. This adduct with its
acidic sulfonamide N–H and the tethered terminal alkyne
group cyclizes under base and copper(I) catalysis to give a
vinyl copper species which then undergoes protodemetallation
in the methanolic solvent to give the observed 2-methylene-
pyrrolidine product.
Support for this proposed pathway comes from a number of
experiments performed to probe the mechanism (Scheme 3). In
the reaction of 1a and 2, omission of any added copper
complex from the optimized reaction conditions resulted in
the formation of neither Mannich product 4 nor 2-methylene-
pyrrolidine 3a, and the propargyl malonate 2 was returned
unreacted. However, in THF at À40 1C for 8 hours with
1.5 eq. of KOtBu the Mannich product 4 was the major
reaction product. Subsequent treatment of 4 with KOtBu in
methanol at room temperature resulted in degradation to
the propargyl malonate 2, presumably via retro-Mannich
reaction. Treatment of 4 with Cu(I)OTf benzene complex
and triphenylphosphine in the absence of any base resulted
in no reaction. However, subjection of 4 to the standard
cascade led to the production of the 2-methylenepyrrolidine
product 3a. This result supports the intermediacy of 4 in the
reaction sequence and the need for both base and copper
catalysts in the second stage of the cascade. The suggested anti
addition of nitrogen and copper to the alkyne is in agreement
with the results of Urabe and co-workers who isolated a
single Z-stereoisomer in their CuI catalyzed intramolecular
hydroamination study of a non-terminal alkyne.10
A range of electron rich and electron poor aromatic and
heteroaromatic toluenesulfonyl imines were good components
in the cascade and yielded the desired 2-methylenepyrrolidine
products in high yields in between 10 and 48 hours. A
representative aliphatic imine (derived from butyraldehyde)
also underwent the reaction albeit in lower yield (entry 17).9
Interestingly, analogous N-Boc, N-phenyl, N-p-methoxyphenyl
and N-tert-butyl sulfoxide imines did not afford the 2-methylene-
pyrrolidine cascade products under the same reaction
conditions, and either unreacted starting materials or the
Mannich addition product was isolated from the reaction
mixture.
The proposed course of the reaction cascade (Scheme 2)
begins with a rapid and reversible formation of the Mannich
Table 2 Scope of the Mannich, alkyne hydroamination cascade
The 2-methylenepyrrolidines are the kinetic products in
the reaction. This was readily demonstrated when 3g was
Time/
h
Yielda
(%)
Entry
R
3
1
2
3
4
5
6
7
8
Ph
14
34
34
34
48
48
14
14
14
14
14
10
14
14
14
18
24
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
94
85
86
81
75
69
79
91
96
89
87
92
85
81
88
82
32
p-CH3Ph
m-CH3Ph
o-CH3Ph
p-CH3OPh
o-CH3OPh
o-FPh
p-CNPh
p-ClPh
m-ClPh
o-ClPh
p-NO2Ph
p-BrPh
o-BrPh
2-Furyl
3-Pyridyl
n-Propyl
9
10
11
12
13
14
15
16
17
a
Isolated yield after flash column chromatography.
Scheme 3 Probing the mechanism.
ꢀc
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Chem. Commun., 2009, 3916–3918 | 3917

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Adv. Synth. Catal., 2007, 349, 1897; (e) I. Ibrahem and A. Cordova,
´
Angew. Chem., Int. Ed., 2006, 45, 1952; (f) B. G. Jellerichs,
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Scheme 4 Product isomerization studies.
dissolved in deuterochloroform and the sample left for 3 days.
Essentially complete conversion to the endo-isomer 5 was
observed (Scheme 4).
In summary,
a mutually compatible combination of
6 For selected examples describing alkyne hydroamination:
(a) L. Ackermann, R. Sandmann, A. Villar and L. T. Kaspar,
Tetrahedron, 2008, 64, 769; (b) Y. Fukumoto, H. Asai, M. Shimizu
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potassium tert-butoxide and CuOTf/PPh3 catalysts have been
identified that promote a two stage cascade to 2-methylene-
pyrrolidine products from N-p-toluenesulfonyl protected
imines and propargylated malonates. Initiated through a base
catalyzed Mannich reaction, the b-amino ester product
is poised to undergo aminocupration with the copper(I)
activated alkyne. Subsequent protodemetallation afforded
the 2-methylenepyrrolidine products in good yields for a wide
range of aryl and heteroaryl N-p-toluenesulfonyl imines.
Further work to uncover and develop new catalysis cascades
is under investigation and the results will be reported in due
course.
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´
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7 For selected synthetic approaches to 3-methylenepyrrolidines, see:
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thereinSee also: (b) B. H. Oh, I. Nakamura, S. Saito and
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We thank the Universities UK, the University of Manchester,
and AstraZeneca (studentship to TY) for support. We are
grateful for the financial support of the National Natural
Science Foundation of China (NSFC No. 20772051).
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ꢀc
This journal is The Royal Society of Chemistry 2009
3918 | Chem. Commun., 2009, 3916–3918