Iodine-Promoted Construction of Polysubstituted 2,3-Dihydropyrroles from Chalcones and β-Enamine Ketones (Esters)

Article abstract of DOI:10.1021/acs.orglett.5b01652

A novel approach for the synthesis of a variety of polysubstituted trans-2,3-dihydropyrroles from a wide range of chalcones and β-enamine ketones (esters) via iodine-promoted tandem Michael/cyclization sequence has been developed, affording the desired products in moderate to excellent yields. This methodology is a highly efficient, convenient way to access functionalized 2,3-dihydropyrroles from readily accessible substrates under mild reaction conditions.

Full text of DOI:10.1021/acs.orglett.5b01652

Letter
pubs.acs.org/OrgLett
Iodine-Promoted Construction of Polysubstituted 2,3-
Dihydropyrroles from Chalcones and β‑Enamine Ketones (Esters)
Yujin Li,*,† Hui Xu,† Mengming Xing,† Fang Huang,‡ Jianhong Jia,† and Jianrong Gao*,†
†College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, P. R. China
‡Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, P. R. China
S
* Supporting Information
ABSTRACT: A novel approach for the synthesis of a variety
of polysubstituted trans-2,3-dihydropyrroles from a wide range
of chalcones and β-enamine ketones (esters) via iodine-
promoted tandem Michael/cyclization sequence has been
developed, affording the desired products in moderate to
excellent yields. This methodology is a highly efficient,
convenient way to access functionalized 2,3-dihydropyrroles
from readily accessible substrates under mild reaction conditions.
ubstituted 2,3-dihydropyrroles represent one of the most
a one-component intramolecular C−C bond-forming reaction
which generated cyclopropane rings through iodine-promoted
C−H bond functionalization.12 Recently, a direct method for
the synthesis of indolizines by means of iodine-mediated C−N
bond formation was developed by Yan.13
S
important classes of five-membered heterocycles. They are
found in numerous natural and biologically active compounds1
such as sibiromycin and anthramycin (Figure 1),2 which exhibit
As part of our continued interest in developing methods for
the preparation of nitrogen-containing heterocyclic scaffolds,14
we herein report a simple, efficient approach for the synthesis
of polysubstituted trans-2,3-dihydropyrrole derivatives from
chalcones and β-enamines promoted by molecular iodine
(Scheme 1). To the best of our knowledge, this report
Figure 1. Representative examples of biologically active products.
Scheme 1. Tandem Michael/Cyclization Reaction of
Chalcones and β-Enamine Ketones (Esters)
significant antitumor properties. In addition, 2,3-dihydropyr-
roles can be used as versatile synthetic intermediates in the
preparation of highly functionalized pyrrolidines,3 pyrroles,4
and other more complex systems.5 As a consequence,
considerable effort has been devoted to the synthesis of these
heterocyclic motifs. Metal-mediated reactions6 and cyclo-
additions7 are some of the commonly used approaches for
the synthesis of these systems. However, the development of an
efficient and practical strategy for the synthesis of substituted
2,3-dihydropyrroles from readily accessible starting materials is
still highly sought after.
Over the past decade, organic reactions promoted by
molecular iodine have attracted considerable attention because
of their low toxicity, low cost in comparison with transition-
metal catalysts, and high tolerance to air and moisture and the
abundant availability of iodine.8,9 Iodine-promoted direct
oxidative C−H functionalization is an efficient method for
constructing C−C and C−heteroatom bonds, and much
attention has been focused on the construction of highly
functionalized cyclic rings using this methodology.10 For
example, Wang reported a useful iodine-mediated C−C and
C−O bond formation reaction to construct dihydrofurans and
cyclopropanes.11 Subsequently, Yang and co-workers exploited
represents the first thorough investigation of the tandem
cyclization reaction of chalcones with β-enamines for the direct
construction of 2,3-dihydropyrroles.
An initial experiment was carried out using 1,3-diphenyl-2-
propen-1-one (1a, 0.5 mmol), ethyl 3-(phenylamino)but-2-
enoate (2a, 0.6 mmol), and molecular iodine (0.6 mmol) in dry
1,2-dichloroethane (DCE, 3 mL) at 80 °C for 8 h (Table 1). To
our delight, the expected product, ethyl trans-5-benzoyl-2-
methyl-1,4-diphenyl-4,5-dihydro-1H-pyrrole-3-carboxylate
(3a), was isolated in 59% yield (Table 1, entry 1). The
1
structure of 3a was confirmed by H and 2D-ROESY NMR
spectra.7c,15 Further experiments indicated that iodine was an
important promoter in this transformation, as none of the
Received: June 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01652
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
With the optimized reaction conditions in hand, we then
examined the scope of the reaction for the construction of
various trans-2,3-dihydropyrroles (Schemes 2 and 3). First,
Table 1. Optimization of the Reaction Conditions
Scheme 2. Synthesis of Substituted 2,3-Dihydropyrroles
a,b
from Substituted Chalcones and β-Enamines
b
entry
ratio (1a/2a/I2)
additive (1 equiv)
solvent
yield (%)
1
1:1.2:1
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
EtOH
THF
toluene
MeCN
DMF
DMSO
59
d
2
1:1.2:0
ND
3
1:1.2:0.5
1:1.2:1.2
1:1.2:1.5
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
1:1.2:1.2
45
80
81
4
5
c
6
70
7
K2CO3
Na2CO3
NaOH
KF
86
72
78
77
51
60
56
63
32
26
70
8
9
10
11
12
13
14
15
16
17
18
19
20
DBU
DMAP
Et3N
piperidine
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
d
ND
d
ND
d
ND
a
Reaction conditions: a mixture of 1a (0.5 mmol), 2a, I2, and additive
b
in dry solvent (3 mL) was stirred for 8 h at 80 °C. Isolated yield
based on 1a. Reacted at 50 °C for 8 h. ND = not detected.
c
d
desired product was detected in the absence of iodine (Table 1,
entry 2). This result prompted us to explore and optimize the
reaction conditions for this transformation. The aim was to
develop a new general method to synthesize a variety of
polysubstituted 2,3-dihydropyrrole derivatives, potentially
providing rapid access to these interesting products in a simple
and economical way. The yield of 3a decreased to 45% when
the amount of iodine was lowered to 0.5 equiv (Table 1, entry
3). Conversely, the yield of the target product 3a significantly
improved to 80% when 1.2 equiv of iodine was used (Table 1,
entry 4). Interestingly, the yield of 3a improved to 86% when 1
equiv of K2CO3 was added to the reaction mixture (Table 1,
entry 7). Encouraged by this result, other bases such as
Na2CO3, NaOH, KF, 1,8-diazabicycloundec-7-ene (DBU),
DMAP, Et3N, and piperidine were investigated, but none
were effective for the formation of the dihydropyrrole (Table 1,
entries 8−14). Thus, we chose K2CO3 as the additive for this
reaction. When the reaction temperature was lowered to 50 °C,
the yield of 2,3-dihydropyrrole 3a decreased to 70% (Table 1,
entry 6). Solvent screening then revealed that the use of DCE
as the reaction solvent is very important for the reactivity and
selectivity of the transformation. Other solvents were inferior
with regard to the yield of the desired dihydropyrrole 3a, for
example, toluene (70%), EtOH (32%), and THF (26%) (Table
1, entries 15−17). In addition, none of the desired product 3a
was detected when strongly polar solvents such as MeCN,
DMF, and DMSO were used (Table 1, entries 18−20). The
optimal reaction conditions were therefore found to be 1 equiv
of K2CO3 and 1.2 equiv of molecular iodine in dry DCE at 80
°C for 8 h.
a
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), K2CO3 (0.5
mmol) and I2 (0.6 mmol) in dry DCE (3 mL) at 80 °C for 8 h.
b
Isolated yields based on 1.
various substituted chalcones were reacted with β-enamino
ester 2a under the optimal conditions. Pleasingly, the results
indicated that a range of chalcones with different substituents
on the aryl ring reacted smoothly with the β-enamino ester to
generate the desired products in moderate to good yields
(Scheme 2, 3a−k). For some substituted chalcones, the yield of
product 3 slightly decreased when the R1 group of chalcone 1
was p-CH3 or the R2 group was p-OCH3 or p-Cl (Scheme 2,
3b, 3h, 3j). The yield of the product 3 was reduced further
when the R1 and R2 substituents of the chalcone were nitro
groups (Scheme 2, 3g, 3i). In addition, we investigated the
steric effects of the substituents on the benzene ring on the
B
DOI: 10.1021/acs.orglett.5b01652
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Scheme 3. Synthesis of Substituted 2,3-Dihydropyrroles
Scheme 4. Proposed Mechanism
from Fused Heterocyclic Chalcones/Benzalacetone and β-
a,b
Enamines
with iodine. Finally, intermediate B undergoes intramolecular
nucleophilic substitution to give the target product 3a.
In summary, we have developed a novel protocol for the
synthesis of polysubstituted trans-2,3-dihydropyrroles via a one-
pot, I2-promoted direct cyclization reaction between chalcones
and β-enamines in dry DCE at 80 °C. This reaction provides a
novel, rapid, and efficient route for the preparation of a variety
of trans-2,3-dihydropyrrole derivatives in moderate to excellent
yields from readily accessible starting materials. These results
will be important for developing new reactions for synthesis of
2,3-dihydropyrroles, which have potential application in
construction of building blocks for natural products.
a
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), K2CO3 (0.5
mmol) and I2 (0.6 mmol) in dry DCE (3 mL) at 80 °C for 8 h.
Isolated yields based on 1.
b
ASSOCIATED CONTENT
* Supporting Information
■
S
chalcone by varying the position of the R1 methyl substituent.
Reaction with β-enamino ester 2a indicated that steric
hindrance of the substituent on benzene ring does not
significantly affect the reaction (Scheme 2, 3d, 3e).
Complete experimental procedure and characterization data for
the prepared compounds. The Supporting Information is
available free of charge on the ACS Publications website at
DOI: 10.1021/acs.orglett.5b01652.
To explore the substrate scope further, different β-enamino
esters were investigated (Scheme 2, 3l−q). When the
derivatives of N-aryl β-enamino esters with substituents on
the aryl ring were examined, the product dihydropyrroles 3
were obtained in good yields (Scheme 2, 3p, 3q). N-Alkyl-
substituted β-enamino esters were reacted with chalcone 1a to
give good yields of the desired products (Scheme 2, 3l−o).
Notably, when β-enaminone 4-(phenylamino)-3-penten-2-one
was used in this transformation, the corresponding dihydro-
pyrrole 3r was obtained in low yield (26%) due to the
formation of some unidentified byproducts.
Further experiments involved the evaluation of heteroaryl
chalcones and benzalacetone under the optimal reaction
conditions (Scheme 3). It was shown that 2-furyl-, 2-thienyl-,
and 2-naphthyl-substituted chalcones reacted smoothly with N-
phenyl-substituted β-enamino esters, and the corresponding
dihydropyrroles were obtained in good yields (Scheme 3, 3s−
u). In particular, the product 3t from the reaction of 3-phenyl-
1-(2-thienyl)-2-propen-1-one was obtained in excellent yield
(93%). When benzalacetone was used in this reaction, the
expected products 3v and 3w were afforded in lower yields (45
and 47%, respectively) together with a significant amount of
unreacted starting material. In the same manner as discussed
above, dihydropyrrole 3x was only obtained in a low yield
(23%) when N-phenyl β-enaminone was used, due to the
formation of unidentified byproducts.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: lyjzjut@zjut.edu.cn.
*E-mail: gdgjr@zjut.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the Natural
Science Foundation of China (21176223), the National Natural
Science Foundation of Zhejiang (Grant no. LY13B020016),
and the Key Innovation Team of Science and Technology in
Zhejiang Province (2010R50018).
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