Br?nsted Acid-Catalyzed Three-Component 1,3-Dipolar Cycloadditions of 1,2-Disubstituted Alkynes with Aldehyde-Generated Azomethine Ylides

Article abstract of DOI:10.1002/jhet.2111

The first 1,3-dipolar cycloadditions (1,3-DCs) of 1,2-disubstituted alkynes with aldehyde-generated azomethine ylides have been established, leading to the efficient synthesis of poly-substituted 2,5-dihydropyrroles.The Br?nsted acid-catalyzed three-compo

Full text of DOI:10.1002/jhet.2111

Month 2014 Brønsted Acid-Catalyzed Three-Component 1,3-Dipolar Cycloadditions of
1,2-Disubstituted Alkynes with Aldehyde-Generated Azomethine Ylides
a
a
a
a
Wei Tan,a† Bai-Xiang Du,a† Lu Guo, Mei Li, Gui-Juan Xing, and Feng Shi
*
School of Chemistry & Chemical Engineering, and Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional
Materials, Jiangsu Normal University, Xuzhou, 221116, China
*
E-mail: fshi@jsnu.edu.cn
Additional Supporting Information may be found in the online version of this article.
Received June 14, 2013
DOI 10.1002/jhet.2111
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
The first 1,3-dipolar cycloadditions (1,3-DCs) of 1,2-disubstituted alkynes with aldehyde-generated azomethine
ylides have been established, leading to the efficient synthesis of poly-substituted 2,5-dihydropyrroles.The
Brønsted acid-catalyzed three-component 1,3-DCs of but-2-ynedioates, aldehydes, and diethyl 2-aminomalonate
tolerate a wide range of substrates, offering structurally diverse poly-substituted 2,5-dihydropyrroles in high yields.
This protocol not only provides an easy and efficient approach to poly-substituted 2,5-dihydropyrroles but also
greatly enriches the chemistry of 1,3-DCs, especially alkyne-involved 1,3-DCs.
J. Heterocyclic Chem., 00, 00 (2014).
anti-tumor [9], and anti-inflammatory [10] properties
(Fig. 1). The significance of 2,5-dihydropyrrole motifs
relevant to synthetic and medicinal applications has led to a
demand for efficient synthesis of related compounds.
INTRODUCTION
1,3-Dipolar cycloadditions (1,3-DCs) have achieved great
success and exhibited great importance in organic chemistry
[1]. Especially, the 1,3-DCs of azomethine ylides with olefins
have offered a robust method to access pyrrolidine structural
motifs, which frequently existed in natural alkaloids and
artificial molecules with vital bioactivities [2]. As a result,
elegant developments have been described in the field of
1,3-DCs of azomethine ylides to electron-deficient olefins
by using either metal-based catalysts [3] or organocatalysts
(eq. 1) [4]. However, in contrast to well-developed 1,3-DCs
using olefins as dipolarophiles, 1,3-DCs of azomethine ylides
with alkynes are rather limited, which have sporadically been
described in last decades (eq. 2) [2b-2e,5]. Therefore, this
transformation has remained a formidable challenge.
We have recently established a series of enantioselective
1,3-DCs between terminal alkynes and azomethine ylides
using chiral phosphoric acids [11] as catalysts (eq. 3) [12],
but the 1,3-DCs of 1,2-disubstituted alkynes with azomethine
ylides are not available yet, which may be ascribed to the ste-
ric hindrance of 1,2-disubstituted alkynes. But-2-ynedioates
represent an important and typical 1,2-disubstituted alkynes,
which will introduce two ester groups to the products, thus
facilitating the subsequent derivations or transformations.
Initiated by the great challenge of developing alkyne-
involved 1,3-DCs with azomethine ylides and the importance
of 2,5-dihydropyrrole skeleton, we decided to use
but-2-ynedioates as dipolarophile to react with azomethine
ylides under the catalysis of Brønsted acid (B-H). Herein,
we report the Brønsted acid-catalyzed three-component 1,
3-DCs of but-2-ynedioates, aldehydes, and diethyl
2-aminomalonate, which represents the first 1,3-DCs of 1,
2-disubstituted alkynes with aldehyde-generated azomethine
ylides, leading to the efficient synthesis of poly-substituted
2,5-dihydropyrroles (eq. 4).
On the other hand, the 2,5-dihydropyrrole skeleton, which
can be constructed by 1,3-DC of azomethine ylides with
alkynes, not only exists in a number of natural alkaloids
(Fig. 1) [6] but also serves as an important building block in
organic synthesis by the functionalization of its carbon–
carbon double bond [7]. Besides, this structural motif is
featured in a large family of medicinally relevant compounds
exhibiting important bioactivities such as antibiotic [8],
© 2014 HeteroCorporation

W. Tan, B.-X. Du, L. Guo, M. Li, G.-J. Xing, and F. Shi
Vol 000
Figure 1. Natural alkaloids and bioactive compounds containing 2,5-dihydropyrrole core.
(B-H) could catalyze the desired reaction (entries 2–5).
Among different Brønsted acids, trifluoroacetic acid exhibited
the highest catalytic activity, affording product 4a in an excel-
lent yield of 93% (entry 5). Then, various solvents were
screened to find the best suitable reaction media under the
catalysis of trifluoroacetic acid (entries 5–9), which revealed
that no other tested solvents were better than toluene in terms
of yields. In order to evaluate the role of 3Å molecular sieves
(MS), we also performed the model reaction in the absence of
RESULTS AND DISCUSSION
Our study on the 1,3-DCs of 1,2-disubstituted alkynes with
aldehyde-generated azomethine ylides commenced with a
three-component reaction of p-nitrobenzaldehyde 1a, diethyl
2-aminomalonate 2a, and dimethyl but-2-ynedioate 3a, which
was performed in toluene at 25°C (Table 1). The control
experiment without any catalysts failed to deliver the desired
cycloaddition products (entry 1), whereas Brønsted acids
Table 1
The optimization of reaction conditions.a
Entry
B-H
Solvent
Yield (%)b
c
1
2
3
-
PhCH3
PhCH3
PhCH3
Trace
62
38
PhCO2H
AcOH
4
TsOH
PhCH3
70
5
6
7
8
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
CF3CO2H
PhCH3
93
90
58
68
81
52
1,4-Dioxane
CH3CN
EtOH
ClCH2CH2Cl
PhCH3
9
10d
aUnless indicated otherwise, the reaction was carried out in 0.1-mmol scale in solvent (1 mL) with molecular sieves (100 mg) at 25°C for 24 h, and the
mole ratio of 1a:2a:3a was 1.2:1:2.
bIsolated yield.
cIn the absence of catalyst.
dIn the absence of 3Å molecular sieves.
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Month 2014
Brønsted Acid-Catalyzed Three-Component 1,3-Dipolar Cycloadditions of 1,2-
Disubstituted Alkynes with Aldehyde-Generated Azomethine Ylides
MS (entry 10). Although the desired 1,3-DC could occur, the
reaction was very sluggish, and the yield was decreased from
93 to 52% (entry 5 vs 10). So, 3Å MS played an important role
in accelerating the reaction, which may be attributed to the
action of 3Å MS in efficiently scavenging water molecules
generated by the condensation of 1a with 2a, thus facilitating
the production of aldehyde-derived azomethine ylide.
With the optimal conditions in hand, the substrate scope
of the 1,2-disubstituted alkyne-involved 1,3-DCs was
investigated by the three-component reactions of various alde-
hydes 1, diethyl 2-aminomalonate 2a, and but-2-ynedioate 3.
As shown in Table 2, this protocol was amenable to a wide
range of aldehydes including aromatic, hetero-aromatic,
and aliphatic ones (1a–1j), providing poly-substituted 2,5-
dihydropyrroles in good to excellent yields in most cases.
Besides, this approach was also applicable to different but-2-
ynedioates (3a and 3b), which acted as dipolarophiles to react
with a variety of aldehyde-derived azomethine ylides, thus
offering the products with structural diversity. In detail,
aromatic aldehydes including electronically poor and rich
ones (1a–1f) smoothly participated in the reaction in high
yields of 57–95% (entries 1–6 and 10–15). The position of
the substituents of benzaldehydes appeared to exert some
impact on the reactivity (entries 1–3 and 10–12), and p-
nitrobenzaldehydes 4a exhibited remarkably distinct reactivity
when using different but-2-ynedioates (entry 1 vs 10). More-
over, when disubstituted benzaldehyde 1g was employed
to the reaction, different reactivity with but-2-ynedioates
3a and 3b was still observed (entry 7 vs 16). Notably, het-
ero-aromatic aldehydes (1h and 1i) and aliphatic aldehyde
(1j) could also be applied to this reaction in acceptable to
high yields (entries 8, 9, and 17–18).
The structures of all these new poly-substituted 2,5-
dihydropyrroles 4 were unambiguously determined by IR,
1H-NMR, 13C-NMR and HRMS (ESI) [13]. Besides,
the structure of compound 4a was further confirmed by an
X-ray crystallographic analysis (Fig. 2) [14].
On the basis of the experimental results and previous
studies on the reaction mechanism [12a], we proposed the
possible reaction mechanism and transition state (Scheme 1).
First, the condensation of aldehydes 1 with diethyl 2-
aminomalonate 2a in the presence of trifluoroacetic acid
generated the corresponding azomethine ylides, which then
took part in the 1,3-DCs with but-2-ynedioates 3 to give
Table 2
The substrate scope of the 1,2-disubstituted alkyne-involved 1,3-dipolar cycloadditions.a
Entry
4
R
R1
Yield (%)b
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4-NO2C6H4 (1a)
3-NO2C6H4 (1b)
2-NO2C6H4 (1c)
4-CF3C6H4 (1d)
4-OMeC6H4 (1e)
3-MeC6H4 (1f)
3,4-Cl2C6H3 (1g)
2-Thiophenyl (1h)
3-Thiophenyl (1i)
4-NO2C6H4 (1a)
3-NO2C6H4 (1b)
2-NO2C6H4 (1c)
4-CF3C6H4 (1d)
4-OMeC6H4 (1e)
3-MeC6H4 (1f)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Et (3b)
Et (3b)
Et (3b)
Et (3b)
Et (3b)
Et (3b)
Et (3b)
Et (3b)
Et (3b)
93
79
61
71
95
57
47
39
56
58
90
83
62
83
63
73
74
59
9
10
11
12
13
14
15
16
17
18
3,4-Cl2C6H3 (1g)
2-Thiophenyl (1h)
Cyclohexyl (1j)
aUnless indicated otherwise, the reaction was carried out in 0.1-mmol scale in toluene (1 mL) with 3Å molecular sieves (100 mg) at 25°C for 24 h, and the
mole ratio of 1:2a:3 was 1.2:1:2.
bIsolated yield.
Journal of Heterocyclic Chemistry
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W. Tan, B.-X. Du, L. Guo, M. Li, G.-J. Xing, and F. Shi
Vol 000
EXPERIMENTAL
General information.
NMR spectra were measured
respectively at 400 and 100 MHz on a Brucker (Brucker Biospin
Company, Switzerland) 400-MHz spectrometer. The solvent used
for NMR spectroscopy was CDCl3, using tetramethylsilane as the
internal reference. HRMS (Bio TOF Q) spectra were recorded with
an ESI resource on P-SIMS-Gly of Bruker Daltonics Inc. Infrared
spectra were recorded on a Nicolet MX-1E FT-IR spectrometer.
Analytical grade solvents for the column chromatography and
commercially available reagents were used as received. All
starting materials commercially available were used directly.
General procedure for the 1,3-dipolar cycloadditions
of 1,2-disubstituted alkynes with aldehyde-generated
azomethine ylides.
The solution of aldehydes 1 (0.12 mmol),
2-aminomalonate 2a (0.1 mmol), trifluoroacetic acid (0.02 mmol),
and 3Å MS (100 mg) in toluene (0.5 mL) was stirred at RT for
20 min. Then, this resultant mixture was added with but-2-
ynedioate 3 (0.2 mmol) and another 0.5 mL of toluene. The reaction
mixture was stirred at 25°C for 24 h. Then the reaction mixture was
filtered to remove MS, and the solid powder was washed with ethyl
acetate. The resultant solution was evaporated under the reduced
pressure, and the residue was purified through flash column
Figure 2. The molecular structure of compound 4a.
Scheme 1. Proposed reaction pathway and transition state.
chromatography on silica gel to yield pure products 4.
Characterization of products 4. 2,2-Diethyl 3,4-dimethyl 5-
(4-nitrophenyl)-1H-pyrrole-2,2,3,4(5H)-tetracarboxylate(4a).
(Flash column chromatography eluent, petroleum ether/ethyl
acetate = 6/1); Reaction time = 24 h; yield: 93%; white solid;
1H-NMR (CDCl3, 400 MHz) δ (ppm): 8.20 (d, J = 8.3 Hz, 2H),
7.67 (d, J = 8.4 Hz, 2H), 5.63 (s, 1H), 4.41–4.25 (m, 4H), 3.83
(s, 3H), 3.63 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H), 1.31 (t, J = 7.1 Hz,
3H); 13C-NMR (CDCl3, 100 MHz) δ (ppm): 168.8, 168.4,
162.5, 162.4, 147.9, 147.4, 142.6, 135.3, 130.9, 128.9, 123.8,
79.7, 68.6, 63.0, 62.8, 52.6, 14.0, 13.9; IR (KBr): γ 3352,
3046, 2988, 2960, 2866, 1737, 1717, 1654, 1597, 1525, 1436,
1353, 1307, 1244, 1139, 1107, 1042, 1014, 918, 861, 746, 709,
646; ESI Fourier transform mass spectrometry (FTMS) exact
mass calcd for (C20H22N2O10-H)À requires m/z 449.1196,
found m/z 449.1208.
products 4 via a sequential Michael addition and Mannich-
type cyclization [12a]. Trifluoroacetic acid served as a
Brønsted acid/Lewis base bifunctional catalyst to activate both
the azomethine ylides and but-2-ynedioates by H-bonding in-
teractions at the same time, thus accelerating the desired
reaction to afford poly-substituted 2,5-dihydropyrroles.
2,2-Diethyl 3,4-dimethyl 5-(3-nitrophenyl)-1H-pyrrole-2,2,3,4
(5H)-tetracarboxylate (4b).
(Flash column chromatography
eluent, petroleum ether/ethyl acetate = 6/1); reaction time= 24h;
1
yield: 79%; colorless oil; H-NMR (CDCl3, 400 MHz) δ (ppm):
8.43 (s, 1H), 8.16 (d, J = 8.2 Hz, 1H), 7.80 (d, J = 7.6 Hz, 1H),
7.51 (t, J = 7.9 Hz, 1H), 5.66 (d, J = 6.4 Hz, 1H), 4.47–4.24
(m, 4H), 3.83 (d, J = 1.1 Hz, 3H), 3.78 (d, J = 6.6Hz, 1H), 3.63
(s, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H);
13C-NMR (CDCl3, 100 MHz) δ (ppm): 168.8, 168.4, 162.5,
162.4, 148.5, 142.7, 142.6, 135.1, 134.0, 129.4, 123.3, 123.1,
79.7, 68.5, 63.1, 63.0, 52.6, 52.5, 29.7, 14.0, 13.9; IR(KBr): γ
3649, 3352, 2985, 1735, 1656, 1524, 1437, 1368, 1251, 1167,
1136, 1106, 1039, 926, 861, 739; ESI FTMS exact mass calcd for
(C20H22N2O10-H)À requires m/z 449.1196, found m/z 449.1208.
2,2-Diethyl 3,4-dimethyl 5-(2-nitrophenyl)-1H-pyrrole-2,2,3,4
CONCLUSIONS
In summary, we have established the first 1,3-DCs of 1,2-
disubstituted alkynes with aldehyde-generated azomethine
ylides, leading to the efficient synthesis of poly-substituted
2,5-dihydropyrroles. The Brønsted acid-catalyzed three-com-
ponent 1,3-DCs of but-2-ynedioates, aldehydes, and diethyl
2-aminomalonate tolerate a wide range of substrates, offering
structurally diverse poly-substituted 2,5-dihydropyrroles in
high yields. This protocol not only provides an easy and
efficient approach to poly-substituted 2,5-dihydropyrroles
but also greatly enriches the chemistry of 1,3-DCs, especially
alkyne-involved 1,3-DCs.
(5H)-tetracarboxylate (4c).
(Flash column chromatography
eluent, petroleum ether/ethyl acetate = 6/1); reaction time= 24h;
yield: 61%; yellow oil; 1H-NMR (CDCl3, 400 MHz) δ (ppm):
7.91–7.84 (m, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.8 Hz,
1H), 6.22 (d, J = 5.7 Hz, 1H), 4.36–4.24 (m, 4H), 3.94 (d,
J = 5.9Hz, 1H), 3.83 (s, 3H), 3.62 (s, 3H), 1.32 (t, J = 7.1 Hz, 6H);
13C-NMR (CDCl3, 100 MHz) δ (ppm): 188.6, 174.9, 168.5,
167.1, 143.1, 142.4, 138.9, 136.3, 132.4, 132.1, 132.0, 131.8,
Journal of Heterocyclic Chemistry
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Brønsted Acid-Catalyzed Three-Component 1,3-Dipolar Cycloadditions of 1,2-
Disubstituted Alkynes with Aldehyde-Generated Azomethine Ylides
128.7, 128.7, 128.2, 127.5, 126.9, 126.6, 125.1, 125.1, 124.8,
124.3, 122.8, 122.1, 108.7, 78.7, 74.3, 61.9, 61.9, 43.7, 13.1,
13.0; IR (KBr): γ 3447, 1734, 1718, 1699, 1684, 1670, 1653,
1637, 1617, 1576, 1570, 1558, 1542, 1508, 1474, 1434, 1419,
1397, 1363, 1275, 1175, 1133, 1035, 764, 750; ESI FTMS exact
mass calcd for (C20H22N2O10-H)À requires m/z 449.1196, found
m/z 449.1208.
2,2-Diethyl 3,4-dimethyl 5-(4-(trifluoromethyl)phenyl)-
1H-pyrrole-2,2,3,4(5H)-tetracarboxylate (4d). (Flash column
chromatography eluent, petroleum ether/ethyl acetate = 6/1);
reaction time = 24 h; yield: 71%; colorless oil; 1H-NMR (CDCl3,
400 MHz) δ (ppm): 7.61–7.56 (m, 4H), 5.57 (d, J= 6.1 Hz, 1H),
4.41–4.25 (m, 4H), 3.83 (s, 3H), 3.65 (s, 1H), 3.62 (s, 3H),
1.37–1.29 (m, 6H); 13C-NMR (CDCl3, 100 MHz) δ (ppm):
168.9, 168.5, 162.7, 162.6, 144.0, 143.3, 135.0, 130.5 (J= 32.1 Hz),
125.5(J= 3.8 Hz), 125.4, 122.7, 79.7, 69.0, 62.9, 62.8, 53.5, 52.5,
52.5, 14.0, 13.9; IR (KBr): γ 3362, 2996, 2951, 1729, 1655, 1619,
1541, 1439, 1421, 1392, 1329, 1242, 1163, 1120, 1069, 1041,
1017, 980, 923, 866, 811, 781, 759, 704, 681, 654; ESI FTMS
exact mass calcd for (C21H22F3NO8-H)À requires m/z 472.122,
found m/z 472.122.
2,2-Diethyl 3,4-dimethyl 5-(thiophen-2-yl)-1H-pyrrole-2,2,3,4
(5H)-tetracarboxylate (4h). (Flash column chromatography
eluent, petroleum ether/ethyl acetate = 6/1); reaction time= 24h;
1
yield: 39%; colorless oil; H-NMR (CDCl3, 400 MHz) δ (ppm):
7.26 (s, 1H), 7.04 (d, J = 3.4 Hz, 1H), 6.97–6.92 (m, 1H), 5.81
(s, 1H), 4.34–4.26 (m, 4H), 3.82 (s, 3H), 3.69 (s, 3H), 1.35–1.27
(m, 6H); 13C-NMR (CDCl3, 100 MHz) δ (ppm): 168.7, 168.3,
162.8, 162.7, 143.9, 143.3, 134.3, 131.7, 128.1, 126.9, 126.0,
125.6, 79.3, 64.7, 63.2, 62.9, 62.7, 52.8, 52.5, 52.4, 14.0, 14.0; IR
(KBr): γ 3567, 3447, 1733,1717, 1699, 1684, 1670, 1636, 1634,
1576, 1558, 1541, 1508, 1474, 1457, 1436, 1363, 1339, 1259,
1032, 857, 750, 669; ESI FTMS exact mass calcd for
(C18H21NO8S-H)À requires m/z 410.0910, found m/z 410.0939.
2,2-Diethyl 3,4-dimethyl 5-(thiophen-3-yl)-1H-pyrrole-2,2,3,4
(5H)-tetracarboxylate (4i).
(Flash column chromatography
eluent, petroleum ether/ethyl acetate = 6/1); reaction time= 24h;
1
yield: 56%; colorless oil; H-NMR (CDCl3, 400 MHz) δ (ppm):
7.23 (s, 1H), 7.20–7.19 (m, 1H), 7.06 (d, J = 4.9 Hz, 1H), 5.54
(s, 1H), 4.23 (dd, J = 8.7, 6.8 Hz, 4H), 3.74 (s, 3H), 3.59 (s, 3H),
2.86 (s, 1H), 1.27–1.24 (m, 3H), 1.27–1.21 (m, 3H). 13C-NMR
(CDCl3, 100MHz) δ (ppm): 168.0, 167.7, 162.1, 162.0, 161.8,
142.8, 139.8, 133.2, 128.5, 126.6, 125.6, 125.4, 125.3, 122.4,
78.5, 64.0, 62.2, 61.7, 52.2, 51.7, 51.4, 12.9, 12.9; IR(KBr): γ
3357, 3108, 2960, 2853, 1734, 1717, 1699, 1670, 1653, 1637,
1558, 1542, 1508, 1489, 1473, 1457, 1396, 1364, 1339, 1260,
1096, 926, 861, 797, 750, 669; ESI FTMS exact mass calcd for
(C19H23NO8S-H)À requires m/z 410.0910, found m/z 410.0939.
Tetraethyl 5-(4-nitrophenyl)-1H-pyrrole-2,2,3,4(5H)-tetra-
2,2-Diethyl 3,4-dimethyl 5-(4-methoxyphenyl)-1H-pyrrole-2,2,3,4
(5H)-tetracarboxylate (4e). (Flash column chromatography eluent,
petroleum ether/ethyl acetate = 6/1); reaction time = 24 h; yield:
1
95%; yellow oil; H-NMR (CDCl3, 400 MHz) δ (ppm): 7.36–
7.30 (m, 2H), 6.90–6.83 (m, 2H), 5.44 (s, 1H), 4.37–4.27
(m, 4H), 3.82 (s, 3H), 3.80 (s, 3H), 3.62 (s, 3H), 3.46 (s, 1H),
1.36–1.39 (m, 6H); 13C-NMR (CDCl3, 100 MHz) δ (ppm):
169.2, 168.8, 163.2, 162.8, 159.6, 144.7, 134.0, 131.7, 130.2,
129.0, 114.0, 79.5, 69.3, 62.7, 62.7, 55.2, 52.4, 52.4, 14.0, 13.9;
IR (KBr): γ 3447, 1734, 1718, 1699, 1684, 1670, 1653, 1637,
1617, 1576, 1570, 1558, 1542, 1508, 1474, 1434, 1419, 1397,
1363, 1275, 1260, 1175, 1133, 1035, 764, 750; ESI FTMS exact
mass calcd for (C21H25NO9-H)À requires m/z 434.1451, found
m/z 434.1483.
carboxylate (4j).
(Flash column chromatography eluent,
petroleum ether/ethyl acetate= 6/1); reaction time = 24 h; yield:
58%; colorless oil; 1H-NMR (CDCl3, 400MHz) δ (ppm): 8.19 (d,
J = 8.3Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 5.63 (s, 1H, CH), 4.42–
4.24 (m, 6H), 4.12–4.02 (m, 2H), 3.73 (s, 1H, NH), 1.37 (t,
J = 7.1Hz, 3H), 1.32 (t, J = 7.1 Hz, 6H), 1.09 (t, J = 7.1Hz, 3H);
13C-NMR (CDCl3, 100 MHz) δ (ppm): 168.9, 168. 6, 162.0,
161.9, 147.8, 147.5, 142.8, 134.9, 129.0, 123.7, 79.7, 68.7, 63.0,
62.8, 61.8, 61.7, 14.0, 13.9, 13.9, 13.8; IR(KBr): γ 3447, 2985,
2361, 1734, 1654, 1577, 1541, 1523, 1473, 1447, 1419, 1396,
1369, 1349, 1276, 1258, 1135, 1102, 1037, 858, 750, 699; ESI
FTMS exact mass calcd for (C22N26N2O10-H)À requires m/z
477.1509, found m/z 477.1511.
2,2-Diethyl 3,4-dimethyl 5-m-tolyl-1H-pyrrole-2,2,3,4(5H)-tetra-
carboxylate (4f).
(Flash column chromatography eluent,
petroleum ether/ethyl acetate = 6/1); reaction time = 24 h; yield:
57%; colorless oil; 1H-NMR (CDCl3, 400 MHz) δ (ppm): 7.26–
7.16 (m, 2H), 7.10 (d, J= 7.2 Hz, 1H), 5.44 (d, J= 4.5 Hz, 1H),
5.32–5.28 (m, 1H), 4.39–4.25 (m, 4H), 3.82 (s, 3H), 3.62 (s, 3H),
3.50 (d, J= 4.3 Hz, 1H), 2.34 (s, 3H), 1.35 (t, J=7.2Hz, 3H), 1.31
(d, J=7.2Hz, 3H); 13C-NMR (CDCl3, 100 MHz) δ (ppm): 169.2,
168.7, 163.1, 162.8, 144.5, 139.6, 138.3, 134.3, 129.2, 128.5,
128.5, 124.9, 113.2, 79.6, 69.8, 62.7, 62.7, 52.4, 52.3, 21.5, 14.0,
13.9; IR (KBr): γ 3447, 2921, 2851, 1734, 1699, 1685, 1671, 1654,
1637, 1624, 1559, 1542, 1522, 1508, 1489, 1474, 1458, 1437,
1397, 1363, 1339, 1248, 1039, 861, 750, 669; ESI FTMS exact
mass calcd for (C21H25NO8-H)À requires m/z 418.1502, found m/z
418.1516.
Tetraethyl 5-(3-nitrophenyl)-1H-pyrrole-2,2,3,4(5H)-tetra-
carboxylate (4k).
(Flash column chromatography eluent,
petroleum ether/ethyl acetate = 6/1); reaction time = 24 h; yield:
90%; colorless oil; 1H-NMR (CDCl3, 400 MHz) δ (ppm): 8.44
(s, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.51
(t, J = 7.9 Hz, 1H), 5.66 (s, 1H), 4.46–4.23 (m, 6H), 4.14–4.02
(m, 2H), 3.80 (s, 1H), 1.40 (t, J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz,
6H), 1.10 (t, J = 7.1 Hz, 3H); 13C-NMR (CDCl3, 100 MHz) δ
(ppm): 169.0, 168.6, 162.1, 161. 9, 148.4, 142.9, 142.7, 134.7,
134.2, 129.3, 123.2, 123.2, 79.7, 68.6, 63.0, 62.9, 61.8, 61.7,
14.0, 13.9, 13.9, 13.8; IR (KBr): γ 3358, 2985, 2939, 1734,
1684, 1554, 1658, 1533, 1473, 1457, 1395, 1351, 1259,
1136, 1099, 1038, 861, 809, 750, 689; ESI FTMS exact mass
calcd for (C22H26N2O10-H)À requires m/z 477.1509, found m/z
477.1500.
2,2-Diethyl 3,4-dimethyl 5-(3,4-dichlorophenyl)-1H-pyrrole-2,2,3,4
(5H)-tetracarboxylate (4g).
(Flash column chromatography
eluent, petroleum ether/ethyl acetate= 6/1); reaction time= 24h;
yield: 47%; white solid; m.p. 69–70°C;1H-NMR (CDCl3,
400 MHz) δ (ppm): 7.62 (s, 1H), 7.40 (d, J = 8.3 Hz, 1H), 7.30–
7.27 (m, 1H), 5.48 (s, 1H), 4.33 (m, 4H), 3.82 (s, 3H), 3.65
(s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H); IR (KBr):
γ 3356, 2986, 2959, 2925, 2853, 1727, 1653, 1615, 1467, 1437,
1396, 1370, 1346, 1302, 1251, 1196, 1171, 1140, 1106, 1059,
1045, 926, 863, 837, 811, 781, 730, 711, 696, 670; ESI FTMS
exact mass calcd for (C20H21Cl2NO8-H)À requires m/z 472.0566,
found m/z 472.0605.
Tetraethyl 5-(2-nitrophenyl)-1H-pyrrole-2,2,3,4(5H)-tetra-
carboxylate (4l).
(Flash column chromatography eluent,
petroleum ether/ethyl acetate = 6/1); reaction time = 24 h;
1
yield: 83%; yellow oil; H-NMR (CDCl3, 400 MHz) δ (ppm):
7.89–7.87 (m, 2H), 7.62 (t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.8 Hz,
1H), 6.20 (s, 1H), 4.39–4.24 (m, 6H), 4.06 (q, J = 7.1 Hz, 2H),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

W. Tan, B.-X. Du, L. Guo, M. Li, G.-J. Xing, and F. Shi
Vol 000
3.96 (s, 1H), 1.34–1.30 (m, 9H), 1.07 (t, J = 7.1 Hz, 3H); 13C-
NMR (CDCl3, 100 MHz) δ (ppm): 168.8, 168.7, 162.0, 161.9,
149.0, 143.0, 135.7, 135.7, 133.4, 130.5, 128.8, 124.1, 79.3,
63.6, 63.0, 62.5, 61.7, 61.7, 13.9, 13.9, 13.9, 13.7; IR (KBr):
γ 3650, 2985, 1735, 1654, 1637, 1577, 1559, 1541, 1526,
1508, 1499, 1474, 1458, 1420, 1364, 1249, 1098, 1037, 860, 788,
745, 669; ESI FTMS exact mass calcd for (C22H26N2O10-H)À
requires m/z 477.1509, found m/z 477.1509.
1717, 1699, 1685, 1670, 1654, 1648, 1624, 1542, 1522,
1508, 1458, 1459, 1419, 1397, 1364, 1276, 1260, 1131,
1098, 1031, 750, 669; ESI FTMS exact mass calcd for
(C22H25Cl2NO8-H)À requires m/z 500.0879, found m/z
500.0879.
Tetraethyl 5-(thiophen-2-yl)-1H-pyrrole-2,2,3,4(5H)-tetra-
carboxylate (4q).
(Flash column chromatography eluent,
petroleum ether/ethyl acetate = 6/1); reaction time = 24 h; yield:
1
Tetraethyl 5-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,2,3,4
74%; colorless oil; H-NMR (CDCl3, 400 MHz) δ (ppm): 7.27
(5H)-tetracarboxylate (4m).
(Flash column chromatography
(dd, J = 5.1, 1.2 Hz, 1H), 7.07–7.04 (m, 1H), 6.95 (dd, J = 5.1,
3.5 Hz, 1H), 5.82 (s, 1H), 4.36–4.26 (m, 6H), 4.15 (q,
J = 7.1 Hz, 2H), 3.71 (s, 1H), 1.37–1.29 (m, 9H), 1.16 (t,
J = 7.1 Hz, 3H); 13C-NMR (CDCl3, 100 MHz) δ (ppm): 169.0,
168.5, 162.5, 162.1, 144.0, 143.6, 133.7, 126.8, 125.9, 125.6,
79.3, 64.8, 62.8, 62.6, 61.6, 61.6, 14.0, 13.9, 13.8; IR(KBr): γ
3356, 2984, 2939, 2906, 1734, 1685, 1655, 1558, 1542,
1508, 1489, 1458, 1446, 1419, 1394, 1370, 1246, 1187,
1135, 1098, 1037, 943, 859, 706, 669; ESI FTMS exact mass
calcd for (C20H25NO8S-H)À requires m/z 438.1223, found m/z
438.1243.
eluent, petroleum ether/ethyl acetate = 6/1); reaction time = 24 h;
1
yield: 62%; colorless oil; H-NMR (CDCl3, 400 MHz) δ (ppm):
7.61 (s, 3H), 5.58 (d, J = 5.9 Hz, 1H), 4.45–4.23 (m, 6H), 4.08
(q, J = 7.1 Hz, 2H), 3.68 (s, 1H), 1.37 (t, J = 7.1 Hz, 3H), 1.33
(t, J = 7.1 Hz, 6H), 1.08 (t, J = 7.1 Hz, 3H); 13C-NMR (CDCl3,
100 MHz) δ (ppm): 169.1, 168.7, 162.3, 162.0, 144.1, 143.6,
134.4, 130.6, 130.3, 128.4, 128.2, 125.5(J = 3.8 Hz), 122.7,
113.2, 79.6, 69.1, 62.9, 62.7, 61.7, 61.6, 31.5, 29.7, 22.7, 14.0,
13.9, 13.9, 13.7; IR (KBr): γ 3357, 2986, 2926, 1733, 1654,
1618, 1542, 1508, 1466, 1437, 1396, 1370, 1326, 1300, 1252,
1166, 1127, 1043, 927, 862, 750, 670; ESI FTMS exact mass
calcd for (C23H26F3NO8-H)À requires m/z 500.1533, found m/z
500.1532.
Tetraethyl 5-cyclohexyl-1H-pyrrole-2,2,3,4(5H)-tetracarboxylate
(4r).
(Flash column chromatography eluent, petroleum
ether/ethyl acetate = 6/1); reaction time = 24 h; yield: 59%;
colorless oil; 1H-NMR (CDCl3, 400 MHz) δ (ppm): 5.44 (d,
J = 2.9 Hz, 1H), 4.33–4.21 (m, 8H), 2.83 (s, 1H), 1.38–1.16
(m, 22H); 13C-NMR (CDCl3, 100 MHz) δ (ppm): 169.8,
169.1, 164.2, 163.3, 162.1, 146.1, 132.6, 79.0, 71.0, 63.0,
62.6, 62.1, 62.0, 61.9, 61.6, 61.2, 41.4, 40.1, 30.2, 30.1, 26.6,
26.4, 26.2, 26.1, 25.9, 25.8, 14.0, 14.0, 13.9, 13.9, 13.9; IR
(KBr): γ 3503, 2982, 2929, 2853, 1734, 1718, 1699, 1671,
1653, 1637, 1624, 1559, 1542, 1508, 1474, 1457, 1396,
1364, 1339, 1244, 1037, 861, 750, 669; ESI FTMS exact
mass calcd for (C22H33NO8-H)À requires m/z 438.2128,
found m/z 418.2128.
Tetraethyl 5-(4-methoxyphenyl)-1H-pyrrole-2,2,3,4(5H)-tetra-
carboxylate (4n).
(Flash column chromatography eluent,
petroleum ether/ethyl acetate = 6/1); reaction time= 24h; yield:
83%; colorless oil; 1H-NMR (CDCl3, 400 MHz) δ (ppm): 7.34
(d, J = 8.3 Hz, 2H), 6.85 (d, J = 8.2 Hz, 2H), 5.43 (s, 1H), 4.39–
4.21 (m, 6H), 4.11–4.02 (m, 2H), 3.79 (s, 3H), 3.47 (s, 1H),
1.36–1.29 (m, 9H), 1.07 (t, J = 7.1 Hz, 3H); 13C-NMR (CDCl3,
100 MHz) δ (ppm): 169.4, 168.9, 162.8, 162.3, 159.6, 145.0,
133.5, 131.9, 129.1, 113.9, 79.4, 69.4, 62.6, 62.6, 61.5, 61.4,
55.3, 14.0, 13.9, 13.8; IR (KBr): γ 3447, 1734, 1717, 1699,
1684, 1670, 1653, 1637, 1616, 1576, 1558, 1542,1508, 1489,
1474, 1458, 1437, 1419, 1364, 1243, 1175, 1032, 838, 749, 669;
ESI FTMS exact mass calcd for (C23H29NO9-H)À requires m/z
462.1764, found m/z 462.1763.
Tetraethyl 5-m-tolyl-1H-pyrrole-2,2,3,4(5H)-tetracarboxylate
(4o). (Flash column chromatography eluent, petroleum ether/
ethyl acetate = 6/1); reaction time = 24 h; yield: 63%; colorless
oil; 1H-NMR (CDCl3, 400 MHz) δ (ppm): 7.25 (s, 1H), 7.23–
7.22 (m, 2H), 7.12–7.10 (m, 1H), 5.45 (s, 1H), 4.37–4.24 (m,
6H), 4.08 (q, J = 7.1 Hz, 2H), 3.54 (s, 1H), 2.35 (s, 3H), 1.37 (t,
J = 7.2 Hz, 3H), 1.33 (t, J = 7.2 Hz, 6H), 1.07 (t, J = 7.1 Hz, 3H);
13C-NMR (CDCl3, 100 MHz) δ (ppm): 169.4, 168.9, 162.8,
162.3, 145.0, 139.6, 138.2, 133.7, 129.1, 128.6, 128.4, 125.0,
79.5, 69.9, 62.7, 62.6, 61.5, 61.3, 21.4, 14.0, 13.9, 13.7; IR
(KBr): γ 3447, 2923, 1734, 1717, 1699, 1684, 1670, 1653,
1637, 1624, 1558, 1542, 1508, 1489, 1474, 1419, 1363, 1339,
1260, 1035, 750, 669; ESI FTMS exact mass calcd for
(C23H29N08-H)À requires m/z 446.1815, found m/z 446.1828.
Tetraethyl 5-(3,4-dichlorophenyl)-1H-pyrrole-2,2,3,4(5H)-tetra-
Acknowledgments. We are grateful for the financial support from
the project on Cultivating Innovative Graduate Students of Jiangsu
Province (CXLX13_973), National Natural Science Foundation of
China (21002083 and 21232007) and PAPD of Jiangsu Higher
Education Institutions.
REFERENCES AND NOTES
† Wei Tan and Bai-Xiang Du are contributed equally to the work.
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(Flash column chromatography eluent,
petroleum ether/ethyl acetate = 6/1); reaction time= 24h; yield:
73%; colorless oil; 1H-NMR (CDCl3, 400 MHz) δ (ppm): 7.64
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See supporting information for original NMR spectra of
products 4 and crystal data of product 4a.
[14] CCDC 937234. See supporting information for details.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet