One-pot three-component tandem reaction of diazo compounds with anilines and unsaturated ketoesters: A novel synthesis of 2,3-dihydropyrrole derivatives

Article abstract of DOI:10.1039/b822626a

A facile synthesis of 2,3-dihydropyrrole derivatives has been achieved through the one-pot, three-component tandem reaction of diazo compounds with anilines and β,γ-unsaturated α-ketoesters in moderate to good yields.

Full text of DOI:10.1039/b822626a

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One-pot three-component tandem reaction of diazo compounds
with anilines and unsaturated ketoesters: a novel synthesis of
2,3-dihydropyrrole derivativesw
Yingguang Zhu, Changwei Zhai, Yongli Yue, Liping Yang and Wenhao Hu*
Received (in College Park, MD, USA) 17th December 2008, Accepted 15th January 2009
First published as an Advance Article on the web 9th February 2009
DOI: 10.1039/b822626a
A facile synthesis of 2,3-dihydropyrrole derivatives has been
achieved through the one-pot, three-component tandem reaction
of diazo compounds with anilines and b,c-unsaturated a-ketoesters
in moderate to good yields.
Scheme 1 Trapping of ammonium ylides with aldehydes and imines.
Pyrrolidine or dihydropyrrole derivatives are common
structural motifs found in many naturally occurring alkaloids
and pharmaceutically active substances, such as hygrine,
nicotine, tropine and cocaine, which show a wide range of
biological activities.1,2 In addition, these derivatives serve as
building blocks commonly used in the synthesis of natural
products.3 In particular, 2,3-dihydropyrroles bearing two
adjacent aryl groups have been reported to be important
precursors for the synthesis of a variety of biologically active
molecules.4 Although many synthetic methods have been
reported for the preparation of pyrrolidine or dihydropyrrole
derivatives,5,6 methods for the synthesis of 2,3-dihydro-
pyrroles with two aryl groups on adjacent positions are
scarce.7 There is a clear demand for efficient synthetic proto-
cols to construct the 2,3-dihydropyrrole derivatives.
tandem Michael addition/cyclization reaction proceeded
smoothly to afford a mixture of four diastereomers 4a, 4b,
4c and 4d in 41% total yield (Table 1, entry 1). To improve the
yield, additional catalysts and reaction conditions were
surveyed, and the results were summarized in Table 1. It was
found that CuOTf, Cu(OTf)2 and Cu(MeCN)4PF6 were also
effective catalysts to produce the desired products, though
with lower yields (Table 1, entries 2–4). The screening of
various solvents revealed that toluene was the best solvent,
as it gave the highest yield of 55% at room temperature
(Table 1, entries 5–7). Having established the choice of catalyst
and solvent, we moved on to screen the reaction temperatures.
When the reaction temperature increased from room
Multicomponent reactions (MCRs) offer significant advan-
tages over traditional chemical syntheses.8 Recently, we reported
a novel three-component reaction based on the trapping of
Table 1 Catalyst screening and optimization of reaction conditionsa
protonated oxonium yields with aldehydes and imines.9
A
similar trapping process also occurred with ammonium ylides
generated in situ from an aryl diazoacetate with an arylamine
in the presence of dirhodium acetate, leading to b-hydroxyl/
amino-a-amino acid derivatives (Scheme 1).10 Herein, we
first report that such an ammonium ylide can also be trapped
by b,g-unsaturated a-ketoesters via a 1,4-addition followed
by a subsequent ring closure. Thus, the three-component
tandem reaction of an aryl diazoacetate, an aryl amine, and
a b,g-unsaturated a-ketoester proceeds via sequential 1,4-addition,
cyclization and dehydration, leading to functionalized
2,3-dihydropyrrole derivatives bearing two adjacent aryl groups
in just one operation.
Total
yieldb (%)
Entry
Catalyst
Solvent
T/oC
1
2c
3c
4c
5
Rh2(OAc)4
CuOTf
Cu(OTf)2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
ClCH2CH2Cl
Toluene
Toluene
Toluene
Toluene
Toluene
rt
rt
rt
rt
rt
rt
rt
45
85
0
41
25
28
30
35
30
55
69
27
23
10e
Cu(MeCN)4PF6
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
Rh2(OAc)4
6
We began with the reaction of methyl phenyl diazoacetate
(1a) with aniline (2a) and (3E)-2-oxo-4-phenylbut-3-enoic acid
methyl ester (3a) in CH2Cl2 at room temperature, in the
presence of 1 mol% dirhodium acetate. The three-component
7
8d
9
10
11
ꢀ20
a
Unless otherwise noted, all reactions were carried out with 1a
b
(0.6 mmol), 2a (0.6 mmol) and 3a (0.5 mmol). Isolated yields
Advanced Research Center of Drug Discovery and Development, and
Department of Chemistry, East China Normal University, 3663
Zhongshan Bei Road, Shanghai, 200062, China.
c
after column chromatography purification. 10 mol% of catalyst
d
loading. The ratio of 4a/4b/4c/4d is 37 : 34 : 11 : 18, determined by
E-mail: whu@chem.ecnu.edu.cn
1H NMR of the crude reaction mixture. Significant amount of N–H
insertion product was observed.
e
w Electronic supplementary information (ESI) available: Experimental
section. CCDC 714098 and 714099. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/b822626a
ꢁc
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1362 | Chem. Commun., 2009, 1362–1364

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temperature to 45 1C, the yield was increased to 69% (Table 1,
entry 8). Further increasing the reaction temperature to
85 1C resulted in a lower yield (Table 1, entry 9). Also, a
much lower yield was observed when the reaction temperature
was decreased below room temperature (Table 1, entries
10 and 11).
Table
2
One-pot, three-component tandem reaction of diazo
compounds with anilines and b, g-unsaturated a-ketoestersa
The diastereoselectivity of the reaction was found to be poor, as
one reaction gave a diastereomeric ratio of 4a : 4b : 4c : 4d =
37 : 34 : 11 : 18 (Table 1, entry 8). Products 4a, 4b and 4c were
isolated as single diastereomers in a pure form. The relative
stereochemistry of 4a and 4c was established by single-crystal
X-ray analyses.z In compound 4a, the two phenyl groups are
placed trans each other, while in compound 4c, a cis relation-
ship holds for the adjacent phenyl substitutions. In both
compounds, the 5-OH functionality is placed trans to the
3-Ph group (Fig. 1).
Entry
1
2
3
Product
Yieldb (%)
Drc (cis : trans)
To confirm the stereochemistry of the other two diastereomers
4b and 4d, we investigated the dehydration reaction, hoping
to find correlation of the stereochemistry in the four isomers.
We found that when the diastereomers 4a or 4d were treated
with 20 mol% of citric acid monohydrate in toluene, the
identical 2,3-dihydropyrrole product cis-5a was obtained in
greater than 90% yield. Accordingly, the dehydration of 4b or
4c under the same reaction conditions afforded trans-5a
(Scheme 2). It thus appears that 4d and 4b have opposite
relative configurations only at the 5-position compared to 4a
and 4c, respectively. Thus, the stereochemistries of all four
diastereomers were established.
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2a
2a
2a
3a
3b
3c
3d
3e
3f
3g
3h
3a
3a
3a
3a
3a
3a
3a
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
61
75
74
70
84
51
57
65
74
52
53
41
73
52
57
67 : 33
71 : 29
50 : 50
65 : 35
63 : 37
43 : 57
43 : 57
41 : 59
12 : 88
55 : 45
23 : 77
62 : 38
17 : 83
37 : 63
43 : 57
9
10
11
12
13
14
15
In order to improve the synthetic efficiency of the dihydro-
pyrrole derivatives, and to simplify the product analysis of
4, we combined the three-component reaction and the
subsequential dehydration reaction in one pot. The three-
component reactions of a variety of diazo compounds, anilines
a
All reactions were first carried out with 1 (1.2 mmol), 2 (1.2 mmol)
and 3 (1 mmol) in the presence of Rh2(OAc)4 (1 mol%) in toluene at
45 1C for 1 h; citric acid monohydrate (20 mol%) was then added,
and the reaction mixture was refluxed for 3–4 h under azeotropic
distillation conditions. Isolated yield. Determined by 1H NMR of
b
c
the crude reaction mixtures.
and b,g-unsaturated a-ketoesters were investigated in the
one-pot reaction set-up under optimized conditions
(Table 2). The g-aryl-b,g-unsaturated a-ketoesters, including
different electronic and steric substituents on the aryl ring,
were first investigated. The product yield was found to be
roughly dependent on the electronic features of the substituents.
Due to higher electrophilicity, more electron-deficient sub-
strates gave higher yields of the product (Table 2, entries
2–7). For example, nitro-substituted ketoester 3e afforded
the desired product in 84% isolated yield (Table 2, entry 5).
The substrate was extended to b,g-unsaturated a-ketoesters
bearing a heterocyclic functionality, as thienyl substituted
ketoester 3h gave the desired product with a 65% yield
(Table 2, entry 8). However, the trend for ketoester substrate
effects on the stereochemistry is not clear yet. This transforma-
tion was further extended to other anilines and diazo com-
pounds (Table 2, entries 9–15). A more electron-rich aryl
amine, such as p-methoxy aniline, gave a higher product
yield (74%) with a relatively higher d.r. favoring trans-5
(cis : trans = 12 : 88) (Table 2, entry 9 vs. entries 10–12).
Similar effects can be found in diazo compound substrates.
The reaction of the electron-rich methyl p-methoxyphenyl
diazoacetate with phenylamine and 3a afforded product 5m
Fig. 1 X-Ray crystal structures of 4a and 4c.
Scheme 2 Synthesis of cis-5a and trans-5a from diastereomers 4a/4d
and 4b/4c.
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Scheme 3 Proposed reaction mechanism for the formation of 5.
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in good yield (73%), and with better diastereoselectivity
(cis : trans = 17 : 83) (Table 2, entry 13 vs. entries 14 and 15).
The reaction was proposed to proceed through the ammonium
ylide intermediates IIa or IIb (Scheme 3). The ylide intermediates
were generated in situ from 1 and anilines 2 in the presence of
Rh2(OAc)4. Trapping of the intermediates II with b,g-unsaturated
a-ketoesters 3 via a 1,4-addition resulted in intermediates
IIIa/IIIb. Intramolecular cyclization of III occurred subsequently
to generate pyrrolidine derivatives 4. Dehydration of 4 under
acidic conditions gave 2,3-dihydropyrrole derivatives 5.
In summary, our studies show that the ammonium ylide was
trapped by conjugated ketoesters through a 1,4-addition. This
is the first successful example of the ammonium ylide trapping
process by a CQC bond. The one-pot three-component
tandem reaction provides an easy and efficient access to
polyfunctional 2,3-dihydropyrrole derivatives bearing two
adjacent aryl groups in moderate to good yields. Further
investigations on its asymmetric variant are in progress in
our laboratory.
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We are grateful for financial support from the National
Science Foundation of China (Grant No. 20872036) and
Shanghai Pujiang program for the support. We thank Lab
of Organic Functional Molecules, the Sino–French Institute of
ECNU for supports.
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Notes and references
z Crystal data for 4a (296(2) K): C26H25NO5, M = 431.47, triclinic,
ꢀ
space group P1, 0.628 ꢂ 0.624 ꢂ 0.516 mm, a = 9.0431(2), b =
A. Orru and M. de Greef, Synthesis, 2003, 1471; (g) A. Domling
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¨
9.1987(2), c = 14.3311(2) A, a = 104.7420(10), b = 98.0810(10), g =
101.1600(10)1, V = 1108.22(4) A3, Dc = 1.293 Mg mꢀ3, Z = 2, 15 997
reflections collected, 3889 unique (Rint = 0.0181). Final R indices
R1 = 0.0375 with I 4 2s(I), wR2 = 0.1062 for all data.
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Crystal data for 4c (296(2) K): C26H25NO5, M = 431.47, monoclinic,
space group P21/n, 0.354 ꢂ 0.340 ꢂ 0.255 mm, a = 13.6991(6), b =
9.8616(5), c = 17.5991(8) A, b = 105.5260(10), V = 2290.79(19) A3,
Dc = 1.251 Mg mꢀ3, Z = 4, 26067 reflections collected, 4025 unique
(Rint = 0.0213). Final R indices R1 = 0.0426 with I 4 2s(I),
wR2 = 0.1257 for all data.
1 (a) S. Castellano, H. D. G. Fiji, S. S. Kinderman, M. Watanabe,
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This journal is The Royal Society of Chemistry 2009
1364 | Chem. Commun., 2009, 1362–1364