Stereoselective Synthesis of 3-Carboxy-4,5-dihydropyrroles via an Intramolecular Iminium Ion Cyclization Reaction

Article abstract of DOI:10.1021/acs.orglett.5b01787

An efficient and practical method has been developed for the synthesis of trans-4,5-disubstituted 3-carboxy-4,5-dihydropyrroles via an intramolecular iminium ion cyclization reaction of readily accessible Baylis-Hillman derivatives and aldehydes in modera

Full text of DOI:10.1021/acs.orglett.5b01787

Letter
pubs.acs.org/OrgLett
Stereoselective Synthesis of 3‑Carboxy-4,5-dihydropyrroles via an
Intramolecular Iminium Ion Cyclization Reaction
Jinbao Xiang, Hongxiang Xie, Zhuo Li, Qun Dang, and Xu Bai*
The Center for Combinatorial Chemistry and Drug Discovery of Jilin University, The School of Pharmaceutical Sciences and The
College of Chemistry, Jilin University, 1266 Fujin Road, Changchun, Jilin 130021, P. R. China
S
* Supporting Information
ABSTRACT: An efficient and practical method has been developed for the synthesis
of trans-4,5-disubstituted 3-carboxy-4,5-dihydropyrroles via an intramolecular
iminium ion cyclization reaction of readily accessible Baylis−Hillman derivatives
and aldehydes in moderate to high yield. These new dihydropyrroles could be easily
converted to pyrroles or pyrrolidines.
Scheme 1. Synthetic Strategy to 4,5-Dihydropyrrole 6
he dihydropyrrole framework is a valuable structural motif
Tfound in a number of natural products and pharmaceutical
agents.1 3-Carboxy-4,5-dihydropyrroles were not only shown to
possess interesting biological activities2 but also used as key
intermediates in the synthesis of natural products3 and
bioactive agents.4 Consequently, synthesis of 3-carboxy-
dihydropyrroles has drawn attention from both organic and
medicinal chemists.5−11 The commonly used methods include
applications of the [3 + 2] cycloaddition,6 reaction of acyclic
imides with 1-(ethoxycarbonyl)cyclopropyltriphenyl-
phosphonium tetrafluoroborate,7 nucleophilic amine ring-open-
ing cyclization of donor−acceptor cyclopropanes,8 iodocycliza-
tion of alkenyl-substituted β-enamino esters,9 and Ce(IV)-
mediated oxidative addition of allyltrimethylsilane to β-carbonyl
imines.10 Recently, continuing efforts in this area have led to
several new synthetic approaches.11 For example, Ma’s group
disclosed a versatile palladium-catalyzed domino three-
component reaction of 2-(2,3-allenyl)acylacetates with organic
halides and amines;11a Wang’s group reported the BF3·Et2O-
promoted three-component reaction of propargylic alcohols
with 2-butynedioates and benzyl-i-propylamine;11b Zhang’s
group described the DBU-catalyzed [3 + 2] cycloaddition of
electron-deficient 1,3-conjugated enynes with 2-aminomalona-
tes;11c France’s group reported Ni(ClO4)2·6H2O-catalyzed
nucleophilic amine ring-opening cyclization of donor−acceptor
cyclopropanes under milder reaction conditions.11d Despite the
numerous methods reported to date, there are few that are
efficient for the synthesis of 3-carboxy-4,5-dihydropyrroles with
a controlled 4,5-substitution pattern.5d,11a,c
reaction in situ to result in the target dihydropyrrole. Herein,
the details of these studies are presented.
As expected, the key precursors 3 were readily prepared from
the known Baylis−Hillman acetates 114 and primary amines 2
in good to excellent yields (Table 1).15 The stereochemistry of
these amines was determined as the E-configuration based on
1
the vinylic proton at 7.74−7.96 ppm (singlet) in H NMR
spectra.15a As shown in Table 1, R1 is aryl and R2 can be
aliphatic or aromatic.
Treatment of acrylate 3a with 1.2 equiv of benzaldehyde for
0.5 h in refluxing toluene with water removal via a Dean−Stark
trap gave the desired product 6a in 79% yield (entry 1, Table
2).16 Both an LC−MS and H NMR spectrum of the crude
1
product indicated that 6a is a single isomer. The trans
configuration was based on the coupling pattern at 4.16 and
4.32 ppm (J4,5 = 7.2 Hz) of 1H NMR.17 The reaction results of
precursors 3 (shown in Table 1) and various aldehydes are
summarized in Table 2. In general, the desired 3-carboxy-
dihydropyrroles 6 were obtained in good to high yields with
various functional groups (e.g., nitro, cyano, halo, and
methoxy) at the benzene ring of R1 and R3. The trans
Baylis−Hillman adducts and their derivatives have been
proven to be efficient starting materials for the synthesis of
useful carbo- and heterocycles.12 As part of our continuing
interest in the utilization of iminium ions in the synthesis of
heterocycles,13 we envisioned that 3-carboxy-4,5-dihydropyr-
role 6 could be readily prepared from key precursor 3, prepared
from simple Baylis−Hillman acetate 1 and a primary amine
(Scheme 1). The reaction of 3 and an aldehyde could form
iminium ion intermediate 5 which may undergo a cyclization
Received: June 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01787
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b
,
Table 1. Synthesis of Key Precursors 3
Table 2. Synthesis of 4,5-Dihydropyrroles 6
b
entry
R1
R2
3
yield (%)
c
entry
R1
R2
R3
time (h)
6
yield (%)
c
1
Ph
Ph
Ph
Ph
Ph
Me
3a
3b
3c
3d
3e
3f
90
79
67
78
61
67
60
73
82
73
69
64
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
0.5
3
6a
6b
6c
6d
6e
6f
79
62
68
53
67
72
78
77
75
78
67
73
0
2
3
4
n-Bu
i-Pr
2
Me
4-NO2Ph
4-CNPh
4-ClPh
3-ClPh
2-ClPh
4-MePh
3-MePh
2-MePh
4-MeOPh
2-MeOPh
2-thienyl
n-Pr
3
Me
1.5
4
Bn
4
Me
d
5
Ph
5
Me
0.5
0.5
1.5
1
6
4-NO2Ph
4-CNPh
4-ClPh
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
6
Me
7
3g
3h
3i
7
Me
6g
6h
6i
8
8
Me
9
4-MePh
2-MePh
4-MeOPh
2-MeOPh
9
Me
0.5
3
10
11
12
3j
10
11
12
Me
6j
3k
3l
Me
3.5
1
6k
6l
Me
a
Reagents and conditions (except where designated): 1 (1.0 equiv), 2
(2.0 equiv), and Et3N (1.0 equiv) in THF, 0 °C. Isolated yield.
Methylamine alcohol solution (30%) was used. 1a (1.0 equiv) and
d
13
e
Me
4
6m
6n
6o
6p
6q
6r
b
14
Me
t-Bu
4
0
c
d
15
16
17
18
19
20
21
22
23
24
25
Me
c-Hex
Ph
1
56
75
66
73
79
84
75
77
66
aniline (1.5 equiv) in H2O, 80 °C, 5 h.
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
i-Pr
Bn
1
4-NO2Ph
4-CNPh
4-ClPh
4-MePh
2-MePh
4-MeOPh
2-MeOPh
Ph
Ph
1.5
1.5
1.5
1.5
1.5
1.5
1
Ph
selectivity observed for compound 6a held true for all the
desired products, which were determined by comparison of 1H
NMR spectra with that of compound 6a.
Ph
6s
6t
Ph
Ph
6u
6v
6w
6x
6y
6z
As disclosed in Table 2, aromatic aldehydes participated in
the current reaction effectively to produce the desired products
in moderate to high yields (entries 1−12, Table 2). Both
electron-rich and -deficient aldehydes gave good yields,
suggesting that the current reaction is less sensitive to
electronic factors on the aromatic aldehydes. In contrast,
enolizable aliphatic aldehydes failed in the current reaction
(entry 13, Table 2),16,18 which could prevent the formation of
the reactive iminium ion intermediate. Pivalaldehyde also failed
to give any desired product which might be too hindered for
the cyclization (entry 14, Table 2). On the other hand,
cyclohexanecarbaldehyde was a good substrate for the current
reaction, producing the desired product 6o in 56% yield (entry
15, Table 2). When R2 = n-Bu and R3 = Ph, various R1 groups
are compatible for the current reactions to yield the expected
products 6 (entries 16−23, Table 2). Aliphatic groups were
suitable as R2 for the current cyclization reaction (entries 1, 16,
24, 25, Table 2). When R2 = i-Pr, a 50% yield of 6x and 31%
yield of cis-isomer 8x (J4,5 = 18.9 Hz) were obtained (entry 24,
Table 2). This result is consistent with the reaction mechanism
(see later section). However, when R2 = Ph, only a trace
amount with the molecular ion corresponding to product 6z
was detected by LC-MS after 36 h (entry 26, Table 2). This was
very likely due to the difficulty in forming the iminium ion
between a secondary aromatic amine and an aldehyde.
Moreover, we also attempted to expand the scope of this
reaction to ketones (e.g., cyclohexanone, acetophenone); the
reactions failed to afford the desired 3-carboxy-dihydropyrroles.
A plausible mechanism for the formation of products 6 and 8
is outlined in Scheme 2. It was proposed that the cyclization
reaction proceeded through an azomethine ylide formed from
the condensation of compound 3 with an aldehyde. When R2 =
Me, n-Bu, or Bn, the thermal 6π electrocyclization of favored
azomethine ylide 5 with a disrotatory mode gives the expected
trans-configuration products 6.19 When R2 = i-Pr, intermediate
Ph
Ph
f
Ph
6
50
Ph
Ph
2
79
g
26
Ph
Ph
Ph
36
trace
a
All reactions were performed on 0.5 mmol scale using 1.2 equiv of
aldehydes in refluxing toluene with a Dean−Stark trap under nitrogen.
Cis isomer was not obtained except for substrate 3c (entry 24).
Isolated yield. 35% of starting material 3a was recovered, and 20%
yield of byproduct (2E,2′E)-dimethyl 2,2′-(methylazanediyl)bis-
(methylene)bis(3-phenylacrylate) 7a was isolated. 32% of starting
material 3a was recovered, and 26% yield of byproduct 7a was isolated.
The trans/cis ratio is 62:38, and 31% of cis-isomer 8x was isolated.
Trace amount with molecular ion corresponding to desired product
b
c
d
e
f
g
6z was detected by LC-MS.
Scheme 2. Proposed Reaction Mechanism
5 undergoes isomerization to intermediate 9 due to the
repulsion between the methyl of i-Pr and the phenyl of
azomethine ylide; the competition of transition states 5x and 9x
leads to a mixture of isomers 6x and 8x.
The new dihydropyrrole product 6a could be readily
transformed to pyrrole 10a with DDQ oxidation in CH2Cl2
B
DOI: 10.1021/acs.orglett.5b01787
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
at room temperature (Scheme 3).20 In addition, reduction of 6a
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with the configuration as indicated (Scheme 3).21 The trans−
trans configuration was based on the coupling pattern at 3.19
and 3.58 ppm (J3,4 = 7.5 Hz) and the coupling pattern at 3.58
and 3.67 ppm (J4,5 = 8.4 Hz) of H NMR. Thus, highly
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the method.
In summary, we have developed an efficient and practical
strategy for the synthesis of trans-4,5-disubstituted 3-carboxy-
4,5-dihydropyrroles via an intramolecular iminium ion cycliza-
tion reaction of Baylis−Hillman derivatives with aldehydes in
moderate to high yield. The synthetic utility of the
dihydropyrroles obtained via this new method was further
demonstrated by oxidation to the corresponding pyrroles or
reduction to pyrrolidines with multiple substituents and a
trans−trans configuration. This new method to access
dihydropyrroles compliments the existing collection of
methods, which should allow rapid synthesis of compounds
containing the dihydropyrrole moiety.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01787.
Experimental procedures, full characterization data,
copies of LC-MS-ELSD and NMR spectra for all
products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xbai@jlu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a grant from the National Natural
Science Foundation of China (No. 81072526) and a grant from
the Sci-Tech Development Project of Jilin Province in China
(No. 20140309010YY). Additional support was provided by
Changchun Discovery Sciences, Ltd.
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DOI: 10.1021/acs.orglett.5b01787
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