Copper(I)-catalyzed one-pot synthesis of highly functionalized pyrrolidines from sulfonyl azides, alkynes, and dimethyl 2-(phenylamino)maleate

Article abstract of DOI:10.1002/ejoc.201403285

An efficient one-pot synthesis of highly functionalized pyrrolidines by using sulfonyl azides, alkynes, and dimethyl 2-(phenylamino)maleate catalyzed by copper(I)-Y zeolite under mild reaction conditions was investigated. This cascade process involves an azide-alkyne [3+2] cycloaddition/ring rearrangement/ketenimine formation/intermolecular nucleophilic addition cascade and consequent intramolecular cyclization followed by [1,3]-H shift. The important advantage of this methodology, which allows selective intramolecular nucleophilic attack of the generated ketenimine carbanion on an ester moiety for the first time, is that the starting materials can be easily prepared.

Full text of DOI:10.1002/ejoc.201403285

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403285
Copper(I)-Catalyzed One-Pot Synthesis of Highly Functionalized Pyrrolidines
from Sulfonyl Azides, Alkynes, and Dimethyl 2-(Phenylamino)maleate
Devenderan Ramanathan[a] and Kasi Pitchumani*[a,b]
Keywords: Multicomponent reactions / Rearrangement / Heterogeneous catalysis / Atom economy / Nitrogen heterocycles
An efficient one-pot synthesis of highly functionalized
pyrrolidines by using sulfonyl azides, alkynes, and dimethyl
2-(phenylamino)maleate catalyzed by copper(I)–Y zeolite
under mild reaction conditions was investigated. This
cascade process involves an azide–alkyne [3+2] cyclo-
lecular nucleophilic addition cascade and consequent intra-
molecular cyclization followed by [1,3]-H shift. The impor-
tant advantage of this methodology, which allows selective
intramolecular nucleophilic attack of the generated keten-
imine carbanion on an ester moiety for the first time, is that
addition/ring rearrangement/ketenimine formation/intermo- the starting materials can be easily prepared.
have directed intensive research activity towards the con-
Introduction
struction of these heterocycles.
The transformation of simple starting materials into
libraries of multiring heterocyclic molecules with structural
diversity constitutes a great challenge in organic synthesis.
One-pot multicomponent reactions (MCRs)[1,2] have great
potential for multibond formation to synthesize several bio-
logically active compounds simultaneously with molecular
complexity and diversity. Ketenimine chemistry, owing to
its unusual reactivity, opens a gateway for the synthesis of
diverse highly substituted heterocyclic compounds having
biological and pharmaceutical applications.[3–5] Nitrogen-
containing heterocyclic compounds have received much at-
tention as a result of their significant biological activities
and their pharmacophores.[6] Pyrrole-containing structural
moieties appear in a large number of pharmaceutical agents
and natural products, and in particular, five-membered
heterocyclic derivatives with two aryl groups in adjacent po-
sitions exhibit a variety of biological and biomedical prop-
erties;[7,8] such compounds are used as anti-HIV agents,[8a]
are used as antagonists,[8b] are used in the treatment of leu-
kemia,[8c] show antidepressant activity,[8d] show inhibitory
Figure 1. Drug molecules with pyrrolidine skeleton.
activity against various glycosidase enzymes,[8e] act as inhib-
itors of the vesicular monoamine transporter-2,[8f] and are
Various approaches are available for the synthesis of
used in the treatment of taxane-refractory cancer.[8g] The highly substituted pyrrolidines by using various transition-
pharmaceutical importance of pyrrolidines (Figure 1) and metal catalysts such as AuCl3,[9a] Rh and Grubbs cata-
their wide range of applications in organic transformations lysts,[9b] AgNO3 and Pd,[9c] Ru porphyrins,[9d] FeCl3,[9e] Cu
and Pd,[9f] RhIII catalysts,[9g] LiCl/Et3N,[9h] and phosphine
catalysts.[9i–9l] Wang et al. reported the synthesis of 2-imino-
5-arylidene-3-pyrrolines by using the copper(I)-catalyzed
multicomponent reaction of sulfonyl azides, alkynes, and
aziridines via a ketenimine intermediate.[10]
Though each of these reports has its own advantages,
they suffer from limitations, such as the high cost of the
catalyst and starting materials, harsh reaction conditions,
long reaction times, difficulty in removing the catalyst from
[a] School of Chemistry, Madurai Kamaraj University,
Madurai 625021, India
E-mail: pit12399@yahoo.com
http://mkuniversity.org/direct/schools/departments/chemistry/
pitchumani.php
[b] Centre for Green Chemistry Processes, School of Chemistry,
Madurai Kamaraj University,
Madurai 625021, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403285.
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SHORT COMMUNICATION
reaction mixture, and finally poor yield and selectivity. Re- (ESI). To enhance the yield, the reaction conditions were
cently, our group reported the cascade syntheses of pyr- optimized, and the observed results are given in Table 1.
ido[1,2-a]pyrimidin-4-imine,[11a]
imidazolidin-4-ones,[11b] The ORTEP diagram of 4m is given in Figure 2.
and bis-N-sulfonylcyclobutenes[11c] from N-sulfonylketen-
imine generated in situ from the copper(I)-catalyzed cyclo-
addition of sulfonyl azides and terminal alkynes. Encour-
aged by this simple, uncomplicated access to valuable chem-
ical motifs, we became interested in exploiting the synthetic
potential offered by this unique intermediate towards the
synthesis of other novel and pharmacologically relevant
heterocyclic systems. Though [2+2], [3+2], and [4+2] cyclo-
additions of ketenimine intermediates with suitable olefins
have been reported,[11a–11c] the selective nucleophilic attack
of the generated ketenimine carbanion at the electron-de-
ficient ester moiety in the presence of activated olefins has
not been reported. In the present study, we report the syn-
thesis of highly functionalized heterocyclic pyrrolidine skel-
etons, namely, 3-hydroxy-1,4-diphenyl-5-sulfonylamino-1H-
pyrrolidines, from sulfonyl azides, terminal alkynes, and di-
methyl 2-(phenylamino)maleate by using CuI–Y zeolite as
the catalyst.
Table 1. Optimization of the reaction conditions for the synthesis
of methyl[3-hydroxy-1,4-diphenyl-5-sulfonylamino-1H-pyrrol-2-
ylidene]acetate.[a]
Entry Catalyst
Base
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
CuI
Et3N
Et3N
Et3N
Et3N
Et3N
DIPEA
K2CO3
K3PO4
Et3N
Et3N
Et3N
Et3N
–
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
1,4-dioxane
toluene
CH2Cl2
CH2Cl2
68
65
53
72
–
49
40
34
50
48
20
–
CuCl
CuBr
Cu1Y
Cu-Al-HT
Cu1Y
Cu1Y
Cu1Y
Cu1Y
Cu1Y
Cu1Y
–
9
10
11
12[c]
13[d]
Results and Discussion
Initially, we performed the copper(I)-catalyzed four-com-
ponent reaction of an azide, an alkyne, aniline, and di-
methyl acetylenedicarboxylate (Scheme 1), in which aniline
was expected to react in situ with dimethyl acetylenedi-
carboxylate to produce dimethyl 2-(phenylamino)maleate.
Two products, that is, 3-hydroxy-1,4-diphenyl-5-sulfonyl-
amino-1H-pyrrol-2-ylidene acetate (43%) and amidine
(28%) were obtained. In this reaction, aniline reacted with
Cu1Y
–
[a] Reaction conditions: p-toluenesulfonyl azide (1.2 mmol), phen-
ylacetylene (1.0 mmol), dimethyl-2-(phenylamino)maleate
(1.0 mmol), base (1.2 mmol), solvent (3.0 mL), catalyst (12 mol-
%),[14] r.t., N2, 45 min. [b] Yield of isolated product. [c] Without
catalyst. [d] Without base.
The nature of the catalyst was found to play an impor-
the N-sulfonylketenimine to give amidine as a side prod- tant role in the above reaction. In the absence of a catalyst,
uct.[12] Because of this competitive reaction, the product the reaction failed. After screening various CuI sources, CuI
selectivity of this reaction was very low. This prompted us (68%) was found to give a better yield than CuCl (65%)
to use dimethyl 2-(phenylamino)maleate as the starting and CuBr (53%). With increasing environmental legis-
material in subsequent reactions.
lations, more environmentally friendly methodologies for
We investigated the reaction of phenylacetylene (1a), p- organic reactions that involve the use of solid and easily
toluenesulfonyl azide (2a), and dimethyl 2-(phenylamino)- recyclable catalysts are desired. In the present study, we also
maleate (3a) as starting materials by using CuI as the cata- investigated reusable copper-containing heterogeneous cata-
lyst, triethylamine as the base, and CH2Cl2 as the solvent lysts such as CuI-exchanged zeolites CuI-Y and Cu-Al-HT.
under a nitrogen atmosphere (Table 1). Desired product 4a These CuI-exchanged zeolites were prepared by following a
was successfully isolated in 68% yield, and its structure was literature procedure,[13] and they were characterized by
confirmed by X-ray diffraction (see the Supporting Infor- powder XRD, energy-dispersive X-ray (EDX) spectroscopy,
mation), NMR (1H and 13C) spectroscopy, and HRMS and ultraviolet diffuse reflectance spectroscopy (UV-DRS,
Scheme 1. Copper(I)-catalyzed azide–alkyne/aniline/dimethyl acetylenedicarboxylate intermolecular nucleophilic addition cascade to
methyl [3-hydroxy-1,4-di-R-5-sulfonylamino-1H-pyrrol-2-ylidene]acetates.
2
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CuI-Catalyzed Synthesis of Highly Functionalized Pyrrolidines
as the catalyst. The nature of the base also influenced the
efficiency of the catalytic system. It was evident that the
reaction failed in the absence of base. Among the various
bases, Et3N afforded the best results of all the bases exam-
ined, included N,N-diisopropylethylamine (DIPEA),
K2CO3, and K3PO4. Among the various solvents used, the
reaction worked well in CH2Cl2, whereas other solvents
such as MeCN, 1,4-dioxane, and toluene afforded poor
yields. Consequently, the optimized reaction conditions,
namely, CuI-Y as the catalyst, Et3N as the base, and
CH2Cl2 as the solvent under a N2 atmosphere for 45 min at
room temperature, were identified.
To explore the scope of the reaction further, the study
was extended to various azides, alkynes, and dimethyl 2-
(phenylamino)maleates containing both electron-donating
and electron-withdrawing groups; the results are given in
Table 2. All the reactions proceeded efficiently and gave
good to excellent yields. The reaction was found to be sensi-
tive to the electronic effects of the substrates. Dimethyl 2-
(phenylamino)maleates with electron-donating groups
(Table 2, entries 1–3) gave better yields than those with elec-
tron-withdrawing groups (Table 2, entries 6 and 7), whereas
halo-substituted maleates gave moderate yields (Table 2, en-
tries 4 and 5). Electron-rich azides were more active than
electron-poor azides (Table 2, entries 8–12). Electron-rich
alkynes gave better yields than electron-poor alkynes and
nonaromatic ring-functionalized alkynes (Table 2, en-
Figure 2. ORTEP diagram of compound 4m.
see the Supporting Information). The reaction failed if
Cu-Al-HT was used as the catalyst. On the other hand, to tries 12–15). To demonstrate the potential utility of this
our surprise, the yield increased to 72% upon using CuI-Y method for preparative purposes, the reaction was also per-
Table 2. CuI–Y zeolite-catalyzed cascade synthesis of methyl [3-hydroxy-1,4-substituted-5-sulfonylamino-1H-pyrrol-2-ylidene]acetates.[a]
Entry
R1
R2
R3
Yield [%][b]
1
2
3
4
5
6
7
8
H (1a)
4-CH3 (2a)
H (3a)
72 (4a)
85 (4b)
79 (4c)
66 (4d)
72 (4e)
50 (4f)
57 (4g)
73 (4h)
66 (4i)
63 (4j)
67 (4k)
55 (4l)
80 (4m)
43 (4n)
79 (4o)
54 (4p)
1a
2a
2-CH3O (3b)
1a
2a
4-CH3O (3c)
1a
2a
4-Cl (3d)
1a
2a
4-Br (3e)
1a
2a
2-O2N (3f)
1a
2a
3-O2N (3g)
1a
H (2b)
3a
3a
3a
3a
3a
3a
3a
3a
3a
9
1a
2-naphthyl (2c)
4-O2N (2d)
4-Br (2e)
2,4,5-Cl3 (2f)
2a
10
11
12
13
14
15
16
1a
1a
1a
4-CH3 (1b)
cyclopropyl (1c)
2-CH3O (1d)
1a
2a
2b
CH3 (2g)
[a] Reaction conditions: sulfonyl azide (1.2 mmol), alkyne (1.0 mmol), dimethyl 2-(phenylamino)maleate (1.0 mmol), Et3N (1.2 mmol),
CH2Cl2 (3.0 mL), CuI–Y zeolite (12 mol-%), r.t., N2, 45 min. [b] Yield of isolated product.
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D. Ramanathan, K. Pitchumani
SHORT COMMUNICATION
formed under the optimized reaction conditions with 1.2 g on highly reactive intermediate C generates carbanion D,
of dimethyl 2-(phenylamino)maleate; the product was ob- and this carbanion undergoes intramolecular nucleophilic
tained in 70% of yield, which is comparable to the yields attack on one of the COOCH3 groups in 3 to form acetate
obtained for the small-scale reaction (Table 3, reaction con- intermediate E. Finally, [1,3]-H shift in E yields acetate 4 as
ditions). We had also investigated the recovery and reusabil- the final product.
ity of CuI–Y zeolite, and the recovered catalyst was found
to exhibit good activity up to 4 consecutive cycles (Table 3).
Conclusions
Table 3. Reusability of the CuI–Y zeolite in the cascade synthesis
of highly functionalized pyrrolidines.[a]
Reuse
To conclude, we reported a CuI–Y zeolite-catalyzed one-
pot synthesis of highly functionalized pyrrolidines by using
sulfonyl azides, alkynes, and dimethyl 2-(phenylamino)ma-
leate under mild reaction conditions. This cascade process
involves a copper-catalyzed azide–alkyne [3+2] cyclo-
addition/ring rearrangement/ketenimine formation/inter-
molecular nucleophilic addition sequence and consequent
intramolecular cyclization followed by [1,3]-H shift. The im-
portant advantage of this method is that the starting mate-
rials can be easily prepared.
Yield [%][b]
1
2
3
4
70
68
66
62
[a] Reaction conditions: p-toluenesulfonyl azide (5.5 mmol, 1.1 g),
phenylacetylene (5.0 mmol, 0.6 g), dimethyl 2-(phenylamino)-
maleate (5.0 mmol, 1.175 g), Et3N (6 mmol, 0.9 mL), catalyst
(12 mol-%), solvent (10 mL), r.t., N2, 45 min. [b] Yield of isolated
product.
To the best of our knowledge, this is the first report in
which the generated ketenimine carbanion preferentially
attacks the ester group leading to cyclization, in contrast to
the normally facile cycloaddition with olefins. Other
remarkable features of this pharmacologically relevant
heterocycle synthesis include a short reaction time, mild re-
action conditions, absence of any tedious workup or purifi-
cation, excellent selectivity with good atom economy of the
desired product, and the use of an inexpensive and environ-
mentally friendly catalyst, which could be reused over four
runs without any marked change in its activity and the yield
of the desired product.
A plausible mechanism for the selective synthesis of
highly functionalized pyrrolidine 4 by way of a cascade re-
action is shown in Scheme 2. The click reaction of sulfonyl
azide 2 and terminal alkynes 1 in the presence of triethyl-
amine as the base and CuI–Y zeolite forms copper triazolyl
intermediate A; this is followed by ring opening to give B.
Intermediate B undergoes hetero-Wolff rearrangement to
release molecular nitrogen, which results in the formation
of N-sulfonylketenimine intermediate C with concomitant
protonation and regeneration of the copper catalyst. The
dipolar nature of N-sulfonylketenimine shows that it can
act as an electrophile and as a nucleophile. Intermolecular
nucleophilic attack of dimethyl 2-(phenylamino)maleate (3)
Experimental Section
General Procedure: A solution of the alkyne (1.0 mmol) was added
slowly to a mixture of CuI–Y zeolite (12 mol-%), the sulfonyl azide
(1.0 mmol), dimethyl 2-(phenylamino) maleate (1.0 mmol), and
Et3N (1.2 mmol) in CH2Cl2 (3 mL) under a N2 atmosphere at room
temperature over 45 min. Upon completion of the reaction, the
mixture was diluted with ethyl acetate (5 mL). The catalyst was
separated by filtration, which was followed by solvent evaporation
under reduced pressure. The resulting crude product was purified
by column chromatography (silica gel, 60–120 mesh; ethyl acetate/
petroleum ether, 10%). The recovered catalyst was thoroughly
washed with ethyl acetate and used in the next run.
CCDC-990744 contains the supplementary crystallographic data
for compound 4m. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
Acknowledgments
The authors thank the Department of Science and Technology
(DST), New Delhi for financial support and the instrument facility
under the FIST and IRPHA programs; special thanks to IIT-SAIF,
Madras, for single-crystal analysis.
Scheme 2. Plausible mechanistic pathway for the formation of
highly functionalized pyrrolidine.
[1] Multicomponent reactions; a) V. Estévez, M. Villacampa, J. C.
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CuI-Catalyzed Synthesis of Highly Functionalized Pyrrolidines
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Received: September 30, 2014
Published Online: ᭿
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5

Job/Unit: O43285
/KAP1
Date: 11-12-14 11:50:33
Pages: 6
D. Ramanathan, K. Pitchumani
SHORT COMMUNICATION
Nitrogen Heterocycles
D. Ramanathan, K. Pitchumani* ....... 1–6
Copper(I)-Catalyzed One-Pot Synthesis of
Highly Functionalized Pyrrolidines from
Sulfonyl Azides, Alkynes, and Dimethyl 2-
(Phenylamino)maleate
A cascade process involving a copper-cata-
lyzed azide–alkyne [3+2] cycloaddition/ring
rearrangement/ketenimine formation/inter-
molecular nucleophilic addition sequence
and consequent intramolecular cyclization
followed by [1,3]-H shift is reported.
Keywords: Multicomponent reactions / Re-
arrangement / Heterogeneous catalysis /
Atom economy / Nitrogen heterocycles
6
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