Synthesis of multisubstituted pyrroles from doubly activated cyclopropanes using an iron-mediated oxidation domino reaction

Article abstract of DOI:10.1021/jo5018487

An alternative route has been developed for the construction of multisubstituted pyrrole derivatives from readily available, doubly activated cyclopropanes and anilines using an iron-mediated oxidation domino reaction (i.e., sequential ring-opening, cyclization, and dehydrogenation reactions). This reaction uses readily available reactants and is tolerant of a broad range of substrates, with the desired products being formed in good to excellent yields.

Full text of DOI:10.1021/jo5018487

Note
pubs.acs.org/joc
Synthesis of Multisubstituted Pyrroles from Doubly Activated
Cyclopropanes Using an Iron-Mediated Oxidation Domino Reaction
Zhiguo Zhang,* Wei Zhang, Junlong Li, Qingfeng Liu, Tongxin Liu, and Guisheng Zhang*
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical
Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang,
Henan 453007, P. R. China
S
* Supporting Information
ABSTRACT: An alternative route has been developed for the
construction of multisubstituted pyrrole derivatives from readily
available, doubly activated cyclopropanes and anilines using an
iron-mediated oxidation domino reaction (i.e., sequential ring-
opening, cyclization, and dehydrogenation reactions). This
reaction uses readily available reactants and is tolerant of a
broad range of substrates, with the desired products being formed
in good to excellent yields.
yrroles1 are one of the most important types of
heterocyclic compound in organic chemistry, and com-
Scheme 1. Sequential Ring-Opening/Cyclization Reactions
of Cyclopropanes 1 with Amines 2
P
pounds belonging to this structural class are frequently used as
the core scaffold in natural products,2 pharmaceuticals,3 dyes,4
agrochemicals,5 and functional materials.6 In light of their
numerous applications, considerable research efforts have been
devoted to the development of novel synthetic methods for the
efficient construction of pyrroles.7 Traditionally, pyrroles have
been synthesized using a variety of different methods, including
the Knorr,8 Paal−Knorr,9 and Hantzsch reactions,10 which have
been used for more than a century.11 However, the synthesis of
the highly functionalized pyrroles remains challenging, with
regioselectivity being one of the biggest issues, and this
problem is invariably complicated by the poor chemical stability
of many pyrrole derivatives, which can lead to their degradation
under harsh reaction conditions.12 In this study, we have
developed an iron-mediated oxidation domino13 reaction for
the synthesis of multisubstituted pyrrole derivatives from
doubly activated cyclopropanes with a simultaneous oxida-
tive−dehydrogenation reaction (Scheme 1).
Cyclopropanes are extremely versatile building blocks in
organic syntheses because of the ease with which they can be
synthesized and their high level of reactivity.14 Several studies
on cyclopropanes have focused on the ring-opening reactions of
doubly activated donor−acceptor cyclopropanes (D−A cyclo-
propanes)14d,15 1 with nucleophilic amines 2 as a strategy for
the synthesis of 2,3-dihydropyrroles (including their conversion
to pyrroles).16 In 1987 and 1992, Lhommet et al.17 reported
two convenient methods for the synthesis of 1,2,5-trisubstituted
4,5-dihydro-3-pyrrolecarboxylates 3 in modest to good yields
by heating a mixture of doubly activated D−A cyclopropane 1
and amine 2 at 140 °C in the absence of a solvent or heating
the same compounds in a sealed tube in methanol (Scheme 1,
eq 1). In 2005, Charette et al.18 developed a stepwise procedure
for the preparation of 4-nitro- and 4-cyano-pyrroles 4. This
reaction involved the sequential ring-opening/cyclization
reaction of 1 with an amine 2 to give the corresponding 4-
cyano-2,3-dihydropyrrole 3, which was oxidized with DDQ in
refluxing toluene to give the corresponding pyrrole 4 (Scheme
1, eq 2). More recently, Nambu and Yakura et al.19 reported the
development of an efficient ring-opening reaction for the
cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes with
primary amines at room temperature. Notably, this reaction did
not require the addition of an additive, and the 2-substituted
tetrahydroindol-4-one products could be readily converted to
Received: August 10, 2014
© XXXX American Chemical Society
A
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Note
a
the corresponding 2-substituted 4-hydroxyindole derivatives in
good yields via a multistep derivatization reaction (Scheme 1,
eq 3). In 2014, France et al.20 reported their work toward the
development of a sequential ring-opening/cyclization reaction
between cyclopropanes and amines. In this particular case,
Ni(ClO4)2·6H2O was used as a mild catalyst to facilitate the
synthesis of 4-carboxy-dihydropyrroles 3 via the ring-opening/
cyclization reaction of 1 with a primary amine 2 (Scheme 1, eq
4). Despite these advances, there is still an urgent need to
develop a facile procedure for the synthesis of pyrroles via the
sequential ring-opening/cyclization/dehydrogenation reaction
of doubly activated cyclopropanes and amines.
Iron salts have been used on numerous occasions in organic
synthesis as effective, reusable, operationally simple, and
environmentally benign catalysts,21 and several studies have
been reported in the literature concerning the iron-catalyzed
ring-opening reaction of cyclopropanes.22 Iron-catalyzed
oxidation21a,23 has been applied to a wide range of synthetic
transformations, including olefin epoxidation reactions23 and
the chemistry of Fe-porphyrins.24 Iron catalysts have also been
used in various C−H oxidation reactions,25 including the Gif
reaction,26 Fenton chemistry,27 and nonheme mimicking
systems.28 Several iron-catalyzed reactions29 have been
reported by our group during the past decade, as well as
numerous ring-opening reactions involving cyclopropanes.30
Very recently, we developed two one-pot protocols for the
direct formation of structurally sophisticated α-formyl
pyrrole29e and γ-amino ketone derivatives31 from 2,3-dihydro-
1H-pyrroles 3. While preparing these substrates using
Lhommet’s method,17a it was observed that the reactions of
1-acyl-1-arylaminoformyl cyclopropane derivatives 1 generally
required several days to reach completion (Scheme 2, eq 5, 3a
Table 1. Survey of the Reaction Conditions
entry
cat. (equiv)
solvent
DCE
time/h
yield/%
b
1
FeCl3·6H2O (0)
FeCl3·6H2O (0.2)
FeCl3·6H2O (0.5)
FeCl3·6H2O (1.2)
FeCl3·6H2O (0.5)
FeCl3·6H2O (0.5)
FeCl3·6H2O (0.5)
FeCl3·6H2O (0.5)
FeCl3·6H2O (0.5)
FeCl3·6H2O (0.5)
FeCl3·6H2O (0.5)
Fe2(SO4)3·xH2O (0.5)
Fe2O3 (0.5)
24
9
30
c
2
DCE
50
3
DCE
21
21
21
48
48
48
48
48
48
48
48
30
48
20
68
b
4
DCE
35
d
5
DCE
63
e
6
EtOH
CH3CN
THF
16
b
7
0
b
8
trace
f
9
DMSO
1,4-dioxane
toluene
DCE
trace
b
10
11
12
13
14
15
16
20
g
38
h
45
i
DCE
15
b
Fe(OTf)2 (0.5)
DCE
55
Fe(acac)3 (0.5)
DCE
NR
70
FeCl3 (0.5)
DCE
a
Unless otherwise indicated, all of the reactions were carried out with
1a (217 mg, 1.0 mmol) and 2a (1.2 mmol) in solvent (4.0 mL) at
reflux in air. Along with a complex mixture. 30% 1a was recovered.
Reaction was performed under an atmosphere of O2. 72% ethyl 1-
(4-chlorophenyl)-2-methyl-1H-pyrrole-3-carboxylate was obtained.
Reaction was performed at 100 °C, and 90% 1a was recovered.
Reaction was performed at 100 °C, and 29% 1a was recovered. 15%
b
c
d
e
f
g
h
i
1a was recovered. 50% 1a was recovered.
were selected as model substrates to explore the optimal
conditions for the ring-opening/cyclization/oxidation se-
quence. Some of the key results of these optimization
experiments are summarized in Table 1. Pleasingly, the results
of these screening reactions not only indicated that the reaction
time could be dramatically reduced but also showed that the
Lhommet product 3a could be oxidized in situ to give 1-(4-
chlorophenyl)-2-methyl-N-(p-tolyl)-1H-pyrrole-3-carboxamide
(4a) in 68% yield when a mixture of 1a and 2a in 1,2-
dichloroethane (DCE) was heated at reflux in the presence of
FeCl3·6H2O (0.5 equiv) for 21 h in air (Table 1, entry 3).
When the reaction was conducted in the presence of 0.2 equiv
of FeCl3·6H2O, compound 4a was obtained in 50% yield after
9.0 h, together with recovered 1a (30%), and the yield of 4a
could not be further increased by prolonging the reaction times
(Table 1, entry 2). When the reaction was conducted in the
absence of or with increasing amounts of FeCl3·6H2O, the yield
of 4a decreased dramatically (Table 1, entries 1 and 4).
Furthermore, the use of a pure oxygen atmosphere was not
necessary to achieve a high conversion (Table 1, entry 5).
Several other solvents were also screened against the reaction,
including EtOH, CH3CN, THF, DMSO, 1,4-dioxane, and
toluene,18 and all six of these solvents were found to be much
less efficient than DCE for the desired conversion process
(Table 1, entries 6−11). Several other iron salts were also
screened against this intermolecular domino reaction, including
Fe2(SO4)3·xH2O, Fe2O3, Fe(OTf)2, Fe(acac)3, and anhydrous
FeCl3, and Fe2(SO4)3·xH2O, Fe2O3, Fe(OTf)2, and Fe(acac)3
showed much lower levels of catalytic activity than FeCl3·6H2O
(Table 1, entries 12−15). In contrast, the use of anhydrous
FeCl3 afforded 4a in 70% yield (Table 1, entry 16), but its
Scheme 2. Our Initial Attempts
as an example). It was later envisaged that the addition of an
appropriate green catalyst such as an iron salt would accelerate
the reaction and provide the desired product over a much
shorter reaction time. Subsequent experimental work revealed
that cyclopropane 1a reacted with 4-chloroaniline in EtOH in
the presence of FeCl3·6H2O to give pyrrole 4a and its
transesterification derivative ethyl 1-(4-chlorophenyl)-2-meth-
yl-1H-pyrrole-3-carboxylate in yields of 16% and 72%,
respectively, where the desired product 3a was simultaneously
oxidized (Table 1, entry 6). These findings indicated that it
could be possible to develop a new approach for the direct
synthesis of multisubstituted pyrroles 4 from doubly activated
cyclopropanes 1 (Scheme 2, eq 6).
Based on these preliminary results, 1-acetyl-1-N-(4-methyl-
phenyl) carbamyl cyclopropane (1a) and 4-chloroaniline (2a)
B
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a
Table 2. Extension of the Reaction Scope
C
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Table 2. continued
a
Unless otherwise indicated, all of the reactions were carried out with 1 (1.0 mmol), 2 (1.2 mmol), and FeCl3·6H2O (0.5 equiv) in DCE (4.0 mL) at
b
c
d
100 °C in air. 3.0 equiv of amine were used. 2.0 equiv of amine were used. 91% 1a was recovered, and 86% starting material was recovered after
48 h when the reaction was performed in the absence of FeCl3·6H2O. 42% starting material was recovered, and the yield of 4n could not be
increased by prolonging the reaction times. 26% 1-butyl-3-(p-tolyl)urea was also obtained. 23% starting material was recovered together with 21%
1-(prop-2-yn-1-yl)-3-(p-tolyl)urea. 33% N,1-bis(4-chlorophenyl)-2-methyl-5-vinyl-4,5-dihydro-1H-pyrrole-3-carboxamide (3s) was obtained
together with some unidentified complex mixture. 29% N,1-bis(4-chlorophenyl)-2-methyl-5-phenyl-4,5-dihydro-1H-pyrrole-3-carboxamide (3t)
was obtained together with some unidentified complex mixture. 51% starting material was recovered together with some unidentified complex
mixture. 40% starting material was recovered together with some unidentified complex mixture. 35% starting material was recovered together with
some unidentified complex mixture.
e
f
g
h
i
j
k
l
Table 3. Radical Trapping Experiments
FeCl3·6H2O (0.5 equiv)
3a ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→ 4a
DCE, Air, 100°C
Radical scavengers
TEMPO
10 equiv, 2 h
diphenylethylene
duroquinone
radical scavengers
no scavenger
1 equiv, 8 h
1 equiv, 21 h
10 equiv, 8 h
1 equiv, 21 h
10 equiv, 6 h
recovered 3a
0
trace
25
0
23
32
22
28
32
20
27
19
4a
68
21
hygroscopic properties and higher price precluded its use over
FeCl3·6H2O.
electronic nature of the substituent pattern of 1. Starting
materials 1i′−k′ with a −CN, −COPh, and −COMe group at
their 1-position did not give the desired compounds 4i′−k′,
and some of the starting materials were recovered along with
some unidentified complex mixture.
Several radical trapping experiments were conducted using
three different kinds of radical scavenger, including 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO), diphenylethylene, and
2,3,5,6-tetramethylbenzo-1,4-quinone (duroquinone), to deter-
mine whether a radical process was involved in the trans-
formation of 3 to 4. The results of these experiments revealed
that the reactions were significantly inhibited by the radical
scavengers, which resulted in the formation of complex
mixtures containing unidentified materials (Table 3). These
results suggested that a radical process could be involved in this
transformation.34
With the optimized conditions in hand (Table 1, entry 3), we
proceeded to investigate the scope of this new domino reaction
using a series of different doubly activated cyclopropanes 1 and
amines 2. As shown in Table 2, doubly activated arylamino-
formyl cyclopropane substrates 1b−i bearing electron-with-
drawing groups (EWG) or electron-donating groups (EDG) on
the phenyl ring of their R2 groups reacted with arylamines 2
with EWG or EDG on their phenyl ring to afford the
corresponding multisubstituted pyrroles 4b−i in 61−86%
yields. Interestingly, the use of benzylamines instead of anilines
was well tolerated with the desired annulation products 4j−l
being formed in 61−81% yields. It is noteworthy, however, that
these reactions required more than 2 equiv of the benzylamine,
which could be readily oxidized under the reaction conditions.
Starting materials bearing an acetyl group at their 1-position
(i.e., R1 = Me) gave lower yields than those bearing an aryl
formyl group at their 1-position (i.e., R1 = Ar) (e.g., 4g vs 4b
and 4d, 4i vs 4c, 4k vs 4j). Unfortunately, the aliphatic amine
tert-butylamine did not perform well in the reaction and
afforded none of the desired compound 4m. To determine
whether the failure of this reaction was caused by the steric
hindrance of the tert-butyl group, several less sterically hindered
amines were investigated, including cyclohexylamine, n-butyl-
amine, and propargylamine. Notably, 4n and 4o were obtained
in yields of 21% and 31%, respectively, whereas the
propargylamine only afforded the 1-(prop-2-yn-1-yl)-3-(p-
tolyl)urea in 21% yield together with recovered 1a (23%)
instead of the desired compound 4p.32 Interestingly, com-
pounds 1q and 1r (R4 = −Me) reacted with 4-chloroaniline to
form the corresponding highly substituted pyrroles 4q and 4r in
yields of 78% and 70%, respectively, without any of the 3-
methyl isomers being formed.33 However, compounds 1s and
1t (R4 = −CHCH2 or −Ph) only afforded 2,3-dihydro-1H-
pyrroles 3s and 3t in 33% and 29% yields, respectively. Several
1-acyl-1-ethoxylcarbonyl cyclopropanes 1u−h′ were also
reacted under the optimized conditions and gave the
corresponding 3-ester substituted pyrroles 4u−h′ in 51−78%
yields. In these cases, the yields roughly decreased according to
the position of the substituent on the phenyl ring of 2 (i.e.,
para- > meta- > ortho-substituted anilines), regardless of the
A mechanism was proposed for the current reaction, which is
shown in Scheme 3. Briefly, the aniline 2 would initially attack
Scheme 3. Proposed Mechanism
the more electrophilic carbon of the doubly activated
cyclopropane 1 in an SN2-like reaction to afford the
corresponding 2,3-dihydro-1H-pyrrole 3 via the γ-amino ketone
intermediate A.17a,19,30a,c The subsequent single electron-
transfer (SET) oxidation of 3 by Fe3+ and O2 would generate
the radical species B,35 which would give the 1H-pyrrole 4
through sequential radical dehydrogenation and deprotonation
reactions.36 It is also possible, however, that amine 2 could
react with the carbonyl to form an imine, which could undergo
a Cloke-type rearrangement to give the five-membered 2,3-
dihydro-1H-pyrrole 3.19,37
D
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The Journal of Organic Chemistry
Note
HRMS (ESI), m/z calcd for C25H22N2O3 ([M + H]+) 399.1703;
found, 399.1708.
In conclusion, we have developed a straightforward and
efficient domino reaction for the synthesis of multisubstituted
pyrrole derivatives 4 in moderate to good yields (51−86%) via
the reaction of readily available doubly activated cyclopropanes
1 with anilines 2 in the presence of air and Fe(III). This
method offers a complementary approach to highly substituted
pyrrole compounds with advantages that include a variety of
cheap and readily available reactants and a wide range of
substrates with dense or flexible substitution patterns.
N,1-Bis(4-chlorophenyl)-2-(4-methoxyphenyl)-1H-pyrrole-3-
carboxamide (4d). The product was isolated by flash chromatog-
raphy (eluent: petroleum ether/ethyl acetate = 15/2) as a white solid
(376 mg, 86%). Mp 150−152 °C; 1H NMR (400 MHz, CDCl3) δ 7.33
(s, 1H), 7.24−7.13 (m, 8H), 6.99 (d, J = 8.4 Hz, 2H), 6.92−6.90 (m,
3H), 6.87 (d, J = 2.8 Hz, 1H), 3.82 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 162.7, 160.2, 137.8, 137.0, 133.5, 133.2, 132.7, 129.2, 128.8,
128.2, 127.2, 122.8, 122.3, 120.5, 119.2, 114.5, 110.8, 55.4. HRMS
(ESI), m/z calcd for C24H18Cl2N2O2 ([M + H]+) 437.0818; found,
437.0818.
N,1-Bis(2-chlorophenyl)-2-methyl-1H-pyrrole-3-carbox-
amide (4e). The product was isolated by flash chromatography
(eluent: petroleum ether/ethyl acetate = 10/2) as a white solid (210
mg, 61%). Mp 128−130 °C; 1H NMR (400 MHz, CDCl3) δ 8.57 (dd,
J = 8.4 Hz, 1.6 Hz, 1H), 8.19 (s, 1H), 7.57−7.55 (m, 1H), 7.43−7.37
(m, 3H), 7.34−7.29 (m, 2H), 7.04−6.99 (m, 1H), 6.66 (d, J = 3.2 Hz,
1H), 6.59 (d, J = 3.2 Hz, 1H), 2.40 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 163.6, 136.6, 136.4, 135.5, 132.8, 130.5, 130.4, 129.7, 129.0,
127.8, 127.8, 123.8, 122.5, 121.5, 121.3, 115.7, 107.0, 11.7. HRMS
(ESI), m/z calcd for C18H14Cl2N2O ([M + Na]+) 367.0375; found,
367.0385.
EXPERIMENTAL SECTION
■
General Information. All reagents were purchased from
commercial sources and used without further treatment. All reactions
were carried out under an air atmosphere. H NMR and 13C{1H}
1
NMR spectra were recorded on a 400 MHz NMR spectrometer (1H:
400 MHz, 13C{1H}: 100 MHz at 25 °C), and TMS was the internal
standard. Data are represented as follows: chemical shift, integration,
multiplicity (br = broad, s = singlet, d = doublet, dd = double doublet,
t = triplet, q = quartet, m = multiplet), coupling constants in hertz
(Hz). All high-resolution mass spectra (HRMS) were measured on a
mass spectrometer by using electrospray ionization (ESI-oa-TOF), and
the purity of all samples used for HRMS (>95%) were confirmed by
1H and 13C{1H} NMR spectroscopic analysis. Melting points were
N,1-Bis(3-chlorophenyl)-2-phenyl-1H-pyrrole-3-carbox-
amide (4f). The product was isolated by flash chromatography
(eluent: petroleum ether/ethyl acetate = 10/2) as a white solid (228
measured on a melting point apparatus equipped with a thermometer
and were uncorrected. All reactions were monitored by TLC with
GF254 silica gel coated plates. Flash chromatography was carried out
on SiO2 (silica gel 200−300 mesh).
1
mg, 66%). Mp 175−178 °C; H NMR (400 MHz, CDCl3) δ 7.77 (s,
1H), 8.19 (s, 1H), 7.65 (s, 1H), 7.43−7.40 (m, 3H), 7.30 (s, 1H),
7.25−7.21 (m, 1H), 7.19−7.17 (m, 1H), 7.05 (d, J = 3.2 Hz, 1H), 6.71
(d, J = 3.2 Hz, 1H), 6.50 (d, J = 3.2 Hz, 1H), 2.49 (s, 3H) . 13C{1H}
NMR (100 MHz, CDCl3) δ 163.9, 130.5, 130.0, 128.5, 126.6, 124.6,
123.8, 121.5, 120.1, 118.0, 107.2, 12.3. HRMS (ESI), m/z calcd for
C18H14Cl2N2O ([M + H]+) 345.0556; found, 345.0567.
Typical Experimental Procedure for the Synthesis of 4 (4a as
an Example). To a round-bottom flask (25 mL) equipped with a
spherical condenser (20 cm length) were added 1-acetyl-N-(p-
tolyl)cyclopropane-1-carboxamide 1a (217 mg, 1.0 mmol), 4-
chloroaniline 2a (154 mg, 1.2 mmol), FeCl3·6H2O (135 mg, 0.5
mmol), and DCE (4.0 mL). Then the mixture was well stirred at 100
°C in air until 1a was completely consumed (TLC monitor). After
cooling off, the mixture was filtered through a pad of Celite, eluting
with CH2Cl2 (6 mL × 3). The volatiles were removed under reduced
pressure, and the residue was purified by short flash silica gel column
chromatography to give compound 4a (221 mg, 68%) (eluent:
petroleum ether/ethyl acetate = 10/1).
1-(4-Chlorophenyl)-2-methyl-N-(p-tolyl)-1H-pyrrole-3-car-
boxamide (4a). The product was isolated by flash chromatography
(eluent: petroleum ether/ethyl acetate = 10/2) as a white solid (221
mg, 68%). Mp 180−182 °C; 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J
= 8.4 Hz, 3H), 7.47−7.44 (m, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.15 (d, J
= 8.4 Hz, 2H), 6.70 (d, J = 3.2 Hz, 1H), 6.48 (d, J = 3.2 Hz, 1H), 2.48
(s, 3H), 2.33 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 163.9,
137.7, 136.0, 134.8, 134.1, 133.5, 129.7, 129.6, 127.6, 121.3, 120.2,
116.7, 107.1, 22.0, 12.2. HRMS (ESI), m/z calcd for C19H17ClN2O
([M + H]+) 325.1102; found, 325.1131.
N,1-Bis(4-chlorophenyl)-2-methyl-1H-pyrrole-3-carbox-
amide (4g). The product was isolated by flash chromatography
(eluent: petroleum ether/ethyl acetate = 10/2) as a white solid (235
mg, 68%). Mp 184−186 °C; 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J
= 8.4 Hz, 3H), 7.46 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H), 7.23
(d, J = 8.4 Hz, 2H), 6.70 (s, 1H), 6.48 (s, 1H), 2.48 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 163.9, 137.6, 137.2, 135.3, 134.2, 129.7,
129.1, 128.8, 127.6, 121.5, 121.3, 116.2, 107.1, 12.2. HRMS (ESI), m/z
calcd for C18H14Cl2N2O ([M + Na]+) 367.0375; found, 367.0399.
2-Methyl-N,1-di-p-tolyl-1H-pyrrole-3-carboxamide (4h). The
product was isolated by flash chromatography (eluent: petroleum
ether/ethyl acetate = 10/2) as a white solid (192 mg, 63%). Mp 158−
160 °C; 1H NMR (400 MHz, CDCl3) δ 7.56−7.51 (m, 3H), 7.29 (d, J
= 8.8 Hz, 2H), 7.17 (t, J = 8.0 Hz, 4H), 6.72 (d, J = 3.2 Hz, 1H), 6.48
(d, J = 3.2 Hz, 1H), 2.50 (s, 3H), 2.44 (s, 3H), 2.35 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 164.1, 138.1, 136.7, 136.1, 135.1, 130.0,
129.6, 126.2, 121.5, 120.2, 116.1, 106.6, 21.2, 21.0, 12.2. HRMS (ESI),
m/z calcd for C20H20N2O ([M + Na]+) 327.1468; found, 327.1466.
N,1-Bis(4-methoxyphenyl)-2-methyl-1H-pyrrole-3-carbox-
amide (4i). The product was isolated by flash chromatography
(eluent: petroleum ether/ethyl acetate = 10/2) as a white solid (218
N,1-Bis(4-chlorophenyl)-2-phenyl-1H-pyrrole-3-carboxa-
mide (4b). The product was isolated by flash chromatography
(eluent: petroleum ether/ethyl acetate = 15/2) as a white solid (346
1
mg, 85%). Mp 190−192 °C; H NMR (400 MHz, CDCl3) δ 7.44−
1
mg, 65%). Mp 161−163 °C; H NMR (400 MHz, CDCl3) δ 7.62 (s,
7.39 (m, 3H), 7.32−7.30 (m, 2H), 7.24 (d, J = 8.8 Hz, 2H), 7.18−7.10
(m, 5H), 7.01 (d, J = 8.4 Hz, 2H), 6.93 (dd, J = 9.6, 3.2 Hz, 2H).
13C{1H} NMR (100 MHz, CDCl3) δ 162.6, 137.8, 137.0, 133.5, 133.4,
1H), 7.51 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 9.2
Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 6.66 (d, J = 3.2 Hz, 1H), 6.47 (d, J
= 2.8 Hz, 1H), 3.84 (s, 3H), 3.78 (s, 3H), 2.45 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 164.1, 159.1, 156.0, 135.0, 132.0, 131.7, 127.5,
122.0, 121.5, 115.8, 114.4, 114.1, 106.5, 55.6, 55.5, 12.1. HRMS (ESI),
m/z calcd for C20H20N2O3 ([M + H]+) 337.1547; found, 337.1553.
1-Benzyl-N-(4-chlorophenyl)-2-phenyl-1H-pyrrole-3-carbox-
amide (4j). The product was isolated by flash chromatography
(eluent: petroleum ether/ethyl acetate = 15/2) as a white solid (313
131.5, 130.7, 129.5, 129.3, 129.2, 128.9, 128.4, 127.3, 123.2, 120.4,
119.7, 111.1. HRMS (ESI), m/z calcd for C23H16Cl2N2O ([M + Na]+)
429.0532; found, 429.0544.
N,1-Bis(4-methoxyphenyl)-2-phenyl-1H-pyrrole-3-carboxa-
mide (4c). The product was isolated by flash chromatography (eluent:
petroleum ether/ethyl acetate =15/2) as a white solid (318 mg, 80%).
Mp 155−158 °C; 1H NMR (400 MHz, CDCl3) δ 7.38−7.36 (m, 3H),
7.33−7.31 (m, 2H), 7.13 (d, J = 8.8 Hz, 2H), 7.06 (s, 1H), 7.00 (d, J =
8.8 Hz, 2H), 6.91 (d, J = 3.2 Hz, 1H), 6.88 (d, J = 3.2 Hz, 1H), 6.78−
6.74 (m, 4H), 3.76 (s, 3H), 3.73 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 162.8, 158.7, 155.9, 133.4, 132.4, 131.8, 131.6, 131.2, 129.0,
128.9, 127.4, 123.3, 121.0, 119.3, 114.2, 114.1, 110.4, 55.53, 55.50.
1
mg, 81%). Mp 137−139 °C; H NMR (400 MHz, CDCl3) δ 7.55−
7.48 (m, 3H), 7.39−7.36 (m, 2H), 7.29−7.26 (m, 2H),7.15−7.06 (m,
5H), 6.94−6.92 (m, 2H), 6.88 (d, J = 2.8 Hz, 1H), 6.77 (d, J = 3.2 Hz,
1H), 4.92 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 162.6, 137.4,
137.2, 134.1, 131.2, 131.0, 129.9, 129.4, 128.8, 128.1, 127.8, 126.8,
E
dx.doi.org/10.1021/jo5018487 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
122.1, 120.2, 118.4, 110.3, 51.0. HRMS (ESI), m/z calcd for
C24H19ClN2O ([M + H]+) 387.1259; found, 387.1267.
114.9, 113.2, 111.5, 59.7, 55.2, 14.4. HRMS (ESI), m/z calcd for
C20H18ClNO3 ([M + H]+) 356.1048; found, 356.1042.
Ethyl 1-(3-Chlorophenyl)-2-(4-methoxyphenyl)-1H-pyrrole-
3-carboxylate (4v). The product was isolated by flash chromatog-
raphy (eluent: petroleum ether/ethyl acetate = 15/1) as a white solid
(241 mg, 68%). Mp 140−142 °C; 1H NMR (400 MHz, CDCl3) δ 7.27
(s, 1H), 7.24−7.14 (m, 5H), 6.89−6.80 (m, 4H), 4.22−4.17 (m, 2H),
3.80 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 164.8, 159.5, 140.8, 138.0, 134.7, 132.6, 130.0, 127.5, 126.3,
124.6, 123.2, 122.4, 115.1, 113.3, 111.6, 59.8, 55.3, 14.4. HRMS (ESI),
m/z calcd for C20H18ClNO3 ([M + H]+) 356.1048; found, 356.1048.
Ethyl 1-(2-Chlorophenyl)-2-(4-methoxyphenyl)-1H-pyrrole-
3-carboxylate (4w). The product was isolated by flash chromatog-
raphy (eluent: petroleum ether/ethyl acetate = 15/1) as a white solid
(181 mg, 51%). Mp 112−114 °C; 1H NMR (400 MHz, CDCl3) δ 7.38
(dd, J = 8.0, 1.6 Hz, 1H), 7.25−7.21 (m, 1H), 7.19−7.11 (m, 4H),
6.84 (d, J = 2.8 Hz, 1H), 3.80 (s, 3H), 6.74−6.72(m, 3H), 1.22 (t, J =
7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.8, 159.3, 139.1,
137.3, 132.4, 132.2, 130.3, 130.2, 129.6, 127.3, 123.2, 122.8, 114.0,
112.9, 111.0, 59.6, 55.2, 14.4. HRMS (ESI), m/z calcd for
C20H18ClNO3 ([M + H]+) 356.1048; found, 356.1046.
1-Benzyl-N-(4-chlorophenyl)-2-methyl-1H-pyrrole-3-carbox-
amide (4k). The product was isolated by flash chromatography
(eluent: petroleum ether/ethyl acetate = 10/2) as a white solid (198
mg, 61%). Mp 120−122 °C; 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J
= 7.6 Hz, 3H), 7.35−7.28 (m, 5H), 7.01 (d, J = 7.2 Hz, 2H), 6.61 (s,
1H), 6.39 (s, 1H), 5.06 (s, 2H), 2.50 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3) δ 164.1, 137.3, 136.9, 135.3, 129.0, 129.0, 128.6, 127.9,
126.5, 121.3, 121.0, 115.4, 106.2, 100.1, 50.6, 11.1. HRMS (ESI), m/z
calcd for C19H17ClN2O ([M + H]+) 325.1102; found, 325.1124.
2-Methyl-1-(4-methylbenzyl)-N-(p-tolyl)-1H-pyrrole-3-
carboxamide (4l). The product was isolated by flash chromatography
(eluent: petroleum ether/ethyl acetate = 10/2) as a white solid (204
mg, 64%). Mp 122−124 °C; 1H NMR (400 MHz, CDCl3) δ 7.48 (d, J
= 8.0 Hz, 3H), 7.14 (d, J = 8.0 Hz, 4H), 6.92 (d, J = 7.6 Hz, 2H), 6.59
(d, J = 2.8 Hz, 1H), 6.39 (d, J = 3.2 Hz, 1H), 5.02 (s, 2H), 2.52 (s,
3H), 2.34 (s, 3H), 2.32 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
164.1, 137.6, 136.1, 134.8, 134.0, 133.2, 129.6, 129.5, 126.5, 120.7,
120.1, 115.7, 106.1, 50.3, 21.2, 21.0, 11.0. HRMS (ESI), m/z calcd for
C21H22N2O ([M + Na]+) 341.1624; found, 341.1624.
Ethyl 2-(4-Methoxyphenyl)-1-(p-tolyl)-1H-pyrrole-3-carbox-
ylate (4x). The product was isolated by flash chromatography (eluent:
petroleum ether/ethyl acetate = 10/1) as a white solid (261 mg, 78%).
Mp 103−105 °C; 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 8.8 Hz,
2H), 7.05 (d, J = 8.4 Hz, 2H), 6.94 (d, J = 8.4 Hz, 2H), 6.82 6 (d, J =
1.6 Hz, 2H), 6.78 (d, J = 8.8 Hz, 2H), 4.23−4.17 (m, 2H), 3.77 (s,
3H), 2.31 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 164.9, 159.2, 137.9, 137.2, 137.0, 132.5, 129.5, 125.9, 123.6,
122.6, 114.3, 113.0, 110.9, 59.5, 55.1, 21.0, 14.4. HRMS (ESI), m/z
calcd for C21H21NO3 ([M + H]+) 336.1594; found, 336.1593.
Ethyl 2-(4-Methoxyphenyl)-1-(m-tolyl)-1H-pyrrole-3-carbox-
ylate (4y). The product was isolated by flash chromatography (eluent:
petroleum ether/ethyl acetate = 10/2) as a white solid (224 mg, 67%).
Mp 138−140 °C; 1H NMR (400 MHz, CDCl3) δ7.16−7.13 (m, 2H),
7.10 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 7.6 Hz, 1H), 6.93 (s, 1H), 6.84(d,
J = 3.2 Hz, 2H), 6.82−6.77 (m, 4H), 4.22−4.17 (m, 2H), 3.77 (s, 3H),
2.28 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 164.9, 159.2, 139.6, 139.0, 137.9, 132.5, 128.7, 127.9, 126.7,
123.6, 123.3, 122.6, 114.4, 113.0, 111.0, 59.6, 55.2, 21.3, 14.4. HRMS
(ESI), m/z calcd for C21H21NO3 ([M + H]+) 336.1594; found,
336.1594.
1-Cyclohexyl-2-methyl-N-(p-tolyl)-1H-pyrrole-3-carbox-
amide (4n). The product was isolated by flash chromatography
(eluent: petroleum ether/ethyl acetate = 10/2) as a white solid (62
mg, 21%). Mp 121−123 °C; 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J
= 8.0 Hz, 2H), 7.41 (s, 1H), 7.12 (d, J = 8.0 Hz, 2H), 6.66 (d, J = 3.2
Hz, 1H), 6.34 (d, J = 3.2 Hz, 1H), 3.90−3.84 (m, 1H), 2.59 (s, 3H),
2.31 (s, 3H), 1.99−1.89 (m, 4H), 1.76 (d, J = 12.8 Hz, 1H), 1.64−1.54
(m, 2H), 1.47−1.37 (m, 2H), 1.29−1.21 (m, 1H).13C{1H} NMR (100
MHz, CDCl3) δ 164.2, 136.0, 133.7, 133.0, 129.3, 119.9, 115.9, 114.7,
105.6, 55.0, 33.9, 25.8, 25.3, 20.8, 10.7. HRMS (ESI), m/z calcd for
C19H24N2O ([M + H]+) 297.1961; found, 297.1964.
1-Butyl-2-methyl-N-(p-tolyl)-1H-pyrrole-3-carboxamide
(4o). The product was isolated by flash chromatography (eluent:
petroleum ether/ethyl acetate = 10/2) as a white solid (83.7 mg,
1
31%). Mp 115−117 °C; H NMR (400 MHz, CDCl3) δ 7.46 (d, J =
8.0 Hz, 2H), 7.41 (s, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.54 (d, J = 2.8 Hz,
1H), 6.31 (d, J = 2.8 Hz, 1H), 3.82 (t, J = 7.2 Hz, 2H), 2.57 (s, 3H),
2.31 (s, 3H), 1.73−1.65 (m, 2H), 1.39−1.29 (m, 2H), 0.95 (t, J = 7.2
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.0, 136.0, 134.1,
133.0, 129.3, 119.8, 114.9, 105.4, 46.4, 32.9, 20.8, 19.8, 13.6, 10.8.
HRMS (ESI), m/z calcd for C17H22N2O ([M + H]+) 271.1805; found,
271.1809.
Ethyl 2-(4-Methoxyphenyl)-1-(o-tolyl)-1H-pyrrole-3-carbox-
ylate (4z). The product was isolated by flash chromatography (eluent:
petroleum ether/ethyl acetate = 10/2) as a white solid (194 mg, 58%).
Mp 100−102 °C; 1H NMR (400 MHz, CDCl3) δ 7.21−7.20 (m, 1H),
7.14−7.12 (m, 5H), 6.84 (d, J = 2.8 Hz, 1H), 6.71 (d, J = 8.8 Hz, 2H),
6.68 (d, J = 2.8 Hz, 1H), 4.23−4.18 (m, 2H), 3.73 (s, 3H), 1.93 (s,
3H), 1.24 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
165.0, 159.1, 138.9, 138.7, 135.5, 132.1, 130.8, 128.5, 128.5, 126.4,
123.4, 122.6, 113.5, 112.9, 110.9, 59.6, 55.1, 17.6, 14.4. HRMS (ESI),
m/z calcd for C21H21NO3 ([M + H]+) 336.1594; found, 336.1593.
Ethyl 1-(4-Chlorophenyl)-2-methyl-1H-pyrrole-3-carbox-
ylate (4a′). The product was isolated by flash chromatography
(eluent: petroleum ether/ethyl acetate = 15/1) as a white solid (189
N,1-Bis(4-chlorophenyl)-5-methyl-2-phenyl-1H-pyrrole-3-
carboxamide (4q). The product was isolated by flash chromatog-
raphy (eluent: petroleum ether/ethyl acetate = 10/2) as a white solid
1
(328 mg, 78%). Mp 254−256 °C; H NMR (400 MHz, CDCl3) δ
7.36−7.34 (m, 2H), 7.29−7.24 (m, 5H), 7.16−7.13 (m, 4H), 7.05−
7.00 (m, 3H), 6.64 (s, 1H), 2.10 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 162.8, 134.2, 131.6, 129.8, 129.4, 129.2, 129.0, 128.9, 120.4,
108.9, 13.0. HRMS (ESI), m/z calcd for C24H18Cl2N2O ([M + H]+)
421.0869; found, 421.0868.
N,1-Bis(4-chlorophenyl)-2,5-dimethyl-1H-pyrrole-3-carbox-
amide (4r). The product was isolated by flash chromatography
(eluent: petroleum ether/ethyl acetate = 10/2) as a white solid (251
mg, 70%). Mp 175−178 °C; 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J
= 8.8 Hz, 2H), 7.51−7.47 (m, 3H), 7.28 (d, J = 8.8 Hz, 2H), 7.14 (d, J
= 8.8 Hz, 2H), 6.18 (s, 1H), 2.33 (s, 3H), 2.00 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 164.0, 137.3, 136.1, 135.4, 134.8, 129.9, 129.6,
129.1, 129.0, 128.5, 121.1, 114.4, 104.6, 12.9, 12.4. HRMS (ESI), m/z
calcd for C19H16Cl2N2O ([M + H]+) 359.0712; found, 359.0712.
Ethyl 1-(4-Chlorophenyl)-2-(4-methoxyphenyl)-1H-pyrrole-
3-carboxylate (4u). The product was isolated by flash chromatog-
raphy (eluent: petroleum ether/ethyl acetate = 15/1) as a white solid
(252 mg, 71%). Mp 152−154 °C; 1H NMR (400 MHz, CDCl3) δ 7.23
(d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 8.8 Hz, 2H),
6.82 (s, 2H), 6.79 (d, J = 8.8 Hz, 2H), 4.21−4.16 (m, 2H), 3.79 (s,
3H), 1.22 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
164.8, 159.4, 138.2, 137.9, 133.0, 132.5, 129.2, 127.3, 123.2, 122.4,
1
mg, 72%). Mp 58−60 °C; H NMR (400 MHz, CDCl3) δ 7.45−7.43
(m, 2H), 7.23−7.19 (m, 2H), 6.65 (dd, J = 12.0, 3.2 Hz, 2H), 4.29 (q,
J = 7.2 Hz, 2H), 2.43 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 165.5, 137.7, 136.0, 133.9, 129.6, 127.6, 121.2,
113.7, 110.5, 59.6, 14.6, 12.3. HRMS (ESI), m/z calcd for
C14H14ClNO2 ([M + Na]+) 286.0605; found, 286.0584.
Ethyl 1-(3-Chlorophenyl)-2-methyl-1H-pyrrole-3-carbox-
ylate (4b′). The product was isolated by flash chromatography
(eluent: petroleum ether/ethyl acetate =15/1) as a yellow oil liquid
1
(179 mg, 68%). H NMR (400 MHz, CDCl3) δ 7.41−7.40 (m, 2H),
7.30−7.29 (m, 1H), 7.19−7.17 (m, 1H), 6.67−6.65 (m, 2H), 4.33−
4.27 (m, 2H), 2.45 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 165.6, 140.4, 136.0, 135.1, 130.4, 128.4, 126.7,
124.7, 121.3, 114.0, 110.8, 59.7, 29.9, 14.7, 12.3. HRMS (ESI), m/z
calcd for C14H14ClNO2 ([M + Na]+) 286.0605; found, 286.0592.
F
dx.doi.org/10.1021/jo5018487 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
Ethyl 1-(2-Chlorophenyl)-2-methyl-1H-pyrrole-3-carbox-
ylate (4c′). The product was isolated by flash chromatography
(eluent: petroleum ether/ethyl acetate = 15/1) as a yellow oil liquid
yellow oil (123 mg, 29%). H NMR (400 MHz, DMSO) δ 8.63 (s,
1H), 7.70 (d, J = 8.8 Hz, 2H), 7.33 (s, 2H), 7.30 (d, J = 2.8 Hz, 2H),
7.28 (s, 1H), 7.13 (d, J = 8.8 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.54
(d, J = 8.8 Hz, 2H), 5.44 (t, J = 9.2 Hz, 1H), 3.47 (t, J = 12.8 Hz, 1H),
2.89−2.73 (m, 1H), 2.28 (s, 3H). 13C{1H} NMR (101 MHz, DMSO)
δ 165.1, 156.4, 148.1, 143.1, 140.5, 139.5, 129.3, 129.1, 128.9, 128.6,
127.1, 126.9, 121.8, 115.6, 102.1, 67.5, 38.8, 14.3. HRMS (ESI), m/z
calcd for C24H20Cl2N2O ([M + H]+) 423.1025; found, 423.1014.
1
(147 mg, 56%). H NMR (400 MHz, CDCl3) δ 7.54 (dd, J = 8.0, 1.6
Hz, 1H), 7.44−7.36 (m, 2H), 7.30 (dd, J = 7.6, 1.6 Hz, 1H), 6.70 (d, J
= 3.2 Hz, 1H), 2.43 (d, J = 3.2 Hz, 1H), 4.33−4.28 (m, 2H), 2.31 (s,
3H), 1.36 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ
165.7, 137.1, 137.0, 132.9, 130.5, 130.2, 129.8, 127.8, 121.2, 113.1,
110.4, 59.6, 29.8, 14.7, 11.7. HRMS (ESI), m/z calcd for
C14H14ClNO2 ([M + H]+) 264.0786; found, 264.0783.
Ethyl 2-Methyl-1-(p-tolyl)-1H-pyrrole-3-carboxylate (4d′).
The product was isolated by flash chromatography (eluent: petroleum
ether/ethyl acetate = 15/2) as a white solid (175 mg, 72%). Mp 43−
45 °C; 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 8.4 Hz, 2H), 7.14
(d, J = 8.0 Hz, 2H), 6.66−6.64 (m, 2H), 4.33−4.27 (m, 2H), 2.43 (s,
3H), 4.42 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 165.8, 138.1, 136.8, 136.2, 129.9, 126.2, 121.5, 113.2, 110.1,
59.5, 21.2, 14.7, 12.3. HRMS (ESI), m/z calcd for C15H17NO2 ([M +
H]+) 244.1332; found, 244.1321.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C{1H} NMR spectra of compound 4. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: zhangzg@htu.edu.cn.
*E-mail: zgs6668@yahoo.com.
■
Ethyl 2-Methyl-1-(m-tolyl)-1H-pyrrole-3-carboxylate (4e′).
The product was isolated by flash chromatography (eluent: petroleum
1
Notes
ether/ethyl acetate =15/2) as a yellow oil liquid (187 mg, 77%). H
NMR (400 MHz, CDCl3) δ 7.34 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 7.6
Hz, 1H), 6.65 (s, 2H), 4.33−4.27 (m, 2H), 2.44 (s, 3H), 4.41 (s, 3H),
1.36 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 165.8,
139.5, 139.3, 136.2, 129.1, 128.8, 127.0, 123.4, 121.4, 113.3, 110.1,
59.5, 21.4, 14.7, 12.3. HRMS (ESI), m/z calcd for C15H17NO2 ([M +
H]+) 244.1322; found, 244.1332.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSFC (21172056, 21272057, and 21372065),
PCSIRT (IRT1061), China Postdoctoral Science Foundation
funded project (2012M521397, 2013T60701, and
2013M530339), the Program of Foundation and Frontier
Technology Research of Henan Province (122300410296), and
Innovation Scientists and Technicians Troop Construction
Projects of Henan Province (134200510016).
Ethyl 2-Methyl-1-(o-tolyl)-1H-pyrrole-3-carboxylate (4f′).
The product was isolated by flash chromatography (eluent: petroleum
1
ether/ethyl acetate = 15/2) as a yellow oil liquid (151 mg, 62%). H
NMR (400 MHz, CDCl3) δ 7.36−7.28 (m, 3H), 7.15 (d, J = 8.0 Hz,
1H), 6.68 (d, J = 2.8 Hz, 1H), 6.52 (d, J = 3.2 Hz, 1H), 4.33−4.27 (m,
2H), 2.25 (s, 3H), 2.01 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3) δ 165.8, 138.3, 136.6, 136.1, 131.0, 129.0,
128.0, 126.8, 121.0, 112.6, 110.0, 59.5, 17.3, 14.7, 11.7. HRMS (ESI),
m/z calcd for C15H17NO2 ([M + H]+) 244.1332; found, 244.1312.
Ethyl 2-Methyl-1-phenyl-1H-pyrrole-3-carboxylate (4g′).
The product was isolated by flash chromatography (eluent: petroleum
REFERENCES
■
(1) Sadimenko, A. P. Adv. Heterocycl. Chem. 2001, 79, 116.
(2) (a) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem. Rev. 2008,
108, 264. (b) Gupton, J.; Lee, M. Heterocyclic Antitumor Antibiotics;
Springer: Berlin, Heidelberg, 2006; Vol. 2, p 53. (c) O’Hagan, D. Nat.
Prod. Rep. 1997, 14, 637.
1
ether/ethyl acetate = 15/2) as a yellow oil liquid (167 mg, 73%). H
NMR (400 MHz, CDCl3) δ 7.46 (d, J = 7.6 Hz, 2H), 7.41 (d, J = 7.2
Hz, 1H), 7.27 (d, J = 7.6 Hz, 2H), 6.67 (s, 2H), 4.33−4.28 (m, 2H),
2.45 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3) δ 165.7, 139.3, 136.1, 129.4, 128.1, 126.4, 121.4, 113.4, 110.3,
59.5, 14.7, 12.3. HRMS (ESI), m/z calcd for C14H15NO2 ([M + H]+)
230.1176; found, 230.1150.
(3) (a) Bando, T.; Sugiyama, H. Acc. Chem. Res. 2006, 39, 935. (b) Di
Santo, R.; Costi, R.; Artico, M.; Massa, S.; Ragno, R.; Marshall, G. R.;
La Colla, P. Bioorg. Med. Chem. 2002, 10, 2511.
(4) Wu, D.; Descalzo, A. B.; Weik, F.; Emmerling, F.; Shen, Z.; You,
X. Z.; Rurack, K. Angew. Chem., Int. Ed. 2008, 47, 193.
(5) Speck-Planche, A.; Guilarte-Montero, L.; Yera-Bueno, R.; Rojas-
Ethyl 2-(4-Methoxyphenyl)-1-phenyl-1H-pyrrole-3-carbox-
ylate (4h′). The product was isolated by flash chromatography
(eluent: petroleum ether/ethyl acetate = 10/1) as a white solid (238
Vargas, J. A.; García-Lop
Manag. Sci. 2011, 67, 438.
́ ́
ez, A.; Uriarte, E.; Molina-Perez, E. Pest
1
(6) Novak, P.; Muller, K.; Santhanam, K. S.; Haas, O. Chem. Rev.
1997, 97, 207.
mg, 74%). Mp 95−97 °C; H NMR (400 MHz, CDCl3) δ 7.28−7.23
(m, 3H), 7.15 (d, J = 8.8 Hz, 2H), 7.07−7.05 (m, 2H), 6.87−6.83 (m,
2H), 4.78 (d, J = 8.8 Hz, 2H), 4.02 (m, 2H), 3.77 (s, 3H),1.23 (t, J =
7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 164.9, 159.2, 139.6,
137.9, 132.5, 129.0, 127.2, 126.1, 123.5, 122.5, 114.5, 113.0, 111.1,
59.6, 55.2, 14.4. HRMS (ESI), m/z calcd for C20H19NO3 ([M + H]+)
322.1438; found, 322.1439.
(7) (a) Jiang, Y.; Chan, W. C.; Park, C.-M. J. Am. Chem. Soc. 2012,
134, 4104. (b) Geng, W.; Zhang, W.-X.; Hao, W.; Xi, Z. J. Am. Chem.
Soc. 2012, 134, 20230. (c) Li, Y.; Xu, X.; Tan, J.; Xia, C.; Zhang, D.;
Liu, Q. J. Am. Chem. Soc. 2011, 133, 1775. (d) Joule, J. A.; Mills, K.
Heterocyclic Chemistry; John Wiley & Sons Ltd.: 2010. (e) Rakshit, S.;
Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9585.
(f) Jones, R. A. Chemistry of Heterocyclic Compounds: Pyrroles, Part 2:
The Synthesis, Reactivity, and Physical Properties of Substituted Pyrroles,
Vol. 48; John Wiley & Sons, 2008.
(8) Knorr, L. Ber. Dtsch. Chem. Ges. 1884, 17, 1635.
(9) (a) Paal, C. Ber. Dtsch. Chem. Ges. 1884, 17, 2756. (b) Knorr, L.
Ber. Dtsch. Chem. Ges. 1884, 17, 2863.
(10) Hantzsch, A. Ber. Dtsch. Chem. Ges. 1890, 23, 1474.
(11) Jones, R. A. Pyrroles: The synthesis, reactivity, and physical
properties of substituted pyrroles; John Wiley & Sons Ltd.: 1992.
(12) Schmuck, C.; Rupprecht, D. Synthesis 2007, 2007, 3095.
(13) Tietze, L. F. Chem. Rev. 1996, 96, 115.
N,1-Bis(4-chlorophenyl)-2-methyl-5-vinyl-4,5-dihydro-1H-
pyrrole-3-carboxamide (3s). The product was isolated by flash
chromatography (eluent: petroleum ether/ethyl acetate = 10/2) as a
1
white solid (123 mg, 33%). Mp 171−173 °C; H NMR (400 MHz,
CDCl3) δ 7.55 (s, 1H), 7.49 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.0 Hz,
2H), 7.24 (s, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.78 (s, 1H), 5.84 (dt,
1H), 5.13−5.06 (q, 2H), 4.56−4.50 (t, J = 8.4 Hz, 1H), 3.15 (t, J =
11.2 Hz, 1H), 2.71 (t, J = 9.6 Hz, 1H), 2.22 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3) δ 164.9, 158.0, 139.6, 137.6, 137.5, 131.4, 129.3,
128.8, 128.1, 127.6, 121.0, 118.2, 100.9, 68.3, 35.3, 14.3. HRMS (ESI),
m/z calcd for C20H18Cl2N2O ([M + H]+) 373.0869; found, 373.0848.
N,1-Bis(4-chlorophenyl)-2-methyl-5-phenyl-4,5-dihydro-1H-
pyrrole-3-carboxamide (3t). The product was isolated by flash
chromatography (eluent: petroleum ether/ethyl acetate = 10/2) as a
(14) (a) Reichelt, A.; Martin, S. F. Acc. Chem. Res. 2006, 39, 433.
(b) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321. (c) Sydnes, L.
G
dx.doi.org/10.1021/jo5018487 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
K. Chem. Rev. 2003, 103, 1133. (d) Reissig, H.-U.; Zimmer, R. Chem.
Rev. 2003, 103, 1151. (e) Lebel, H.; Marcoux, J.-F.; Molinaro, C.;
Charette, A. B. Chem. Rev. 2003, 103, 977. (f) Gnad, F.; Reiser, O.
Chem. Rev. 2003, 103, 1603. (g) Wong, H. N. C.; Hon, M. Y.; Tse, C.
W.; Yip, Y. C.; Tanko, J.; Hudlicky, T. Chem. Rev. 1989, 89, 165.
(15) (a) Schneider, T. F.; Kaschel, J.; Werz, D. B. Angew. Chem., Int.
Ed. 2014, 53, 5504. (b) Cavitt, M. A.; Phun, L. H.; France, S. Chem.
Soc. Rev. 2014, 43, 804. (c) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005,
61, 321. (d) Reißig, H.-U. In Small ring compounds in organic synthesis
III; Springer: Berlin, Heidelberg, 1988; Vol. 144. (e) Danishefsky, S.
Acc. Chem. Res. 1979, 12, 66.
(16) (a) Wang, P.; Song, S.; Miao, Z.; Yang, G.; Zhang, A. Org. Lett.
2013, 15, 3852. (b) Kaschel, J.; Schneider, T. F.; Kratzert, D.; Stalke,
D.; Werz, D. B. Org. Biomol. Chem. 2013, 11, 3494. (c) Zhou, Y.-Y.;
Wang, L.-J.; Li, J.; Sun, X.-L.; Tang, Y. J. Am. Chem. Soc. 2012, 134,
9066. (d) Kaschel, J.; Schneider, T. F.; Kratzert, D.; Stalke, D.; Werz,
D. B. Angew. Chem., Int. Ed. 2012, 51, 11153. (e) Lifchits, O.; Charette,
A. B. Org. Lett. 2008, 10, 2809. (f) Maruoka, H.; Okabe, F.; Yamagata,
K. J. Heterocycl. Chem. 2007, 44, 201. (g) Lu, L.; Chen, G.; Ma, S. Org.
Lett. 2006, 8, 835. (h) Ni, S.; Zhu, C.; Chen, J.; Ma, S. Org. Synth.
2013, 90, 327.
(34) Join, B.; Moller, K.; Ziebart, C.; Schroder, K.; Gordes, D.;
̈ ̈ ̈
Thurow, K.; Spannenberg, A.; Junge, K.; Beller, M. Adv. Synth. Catal.
2011, 353, 3023.
(35) (a) Choudhary, M.; Islam, R. U.; Witcomb, M. J.; Mallick, K. J.
Chem. Soc., Dalton Trans. 2014, 43, 6396. (b) Wiener, J.; Ramadan, M.
A.; Gomaa, R.; Abbassi, R.; Hebeish, A. Materials Sci. Appl. 2013, 04,
649. (c) Liu, W.; Liu, J.; Ogawa, D.; Nishihara, Y.; Guo, X.; Li, Z. Org.
Lett. 2011, 13, 6272.
(36) (a) Liu, P.; Liu, J.; Wang, H.; Pan, Y.; Liang, H.; Chen, Z. Chem.
Commun. 2014, 50, 4795. (b) Hu, J.; Wang, J.; Nguyen, T. H.; Zheng,
N. Beilstein J. Org. Chem. 2013, 9, 1977.
(37) (a) Jabin, I.; Monnier-Benoit, N.; Le Gac, S.; Netchitaïlo, P.
Tetrahedron Lett. 2003, 44, 611. (b) Cloke, J. B. J. Am. Chem. Soc.
1929, 51, 1174. (c) Liu, J.; Ma, S. Org. Lett. 2013, 15, 5150. (d) Wang,
N.; Liu, R.; Chen, J.; Liang, X. Chem. Commun. 2005, 5322.
(17) (a) Celerier, J. P.; Haddad, M.; Jacoby, D.; Lhommet, G.
Tetrahedron Lett. 1987, 28, 6597. (b) Jacoby, D.; Celerier, J. P.;
Haviari, G.; Petit, H.; Lhommet, G. Synthesis 1992, 1992, 884.
(18) Wurz, R. P.; Charette, A. B. Org. Lett. 2005, 7, 2313.
(19) Nambu, H.; Fukumoto, M.; Hirota, W.; Yakura, T. Org. Lett.
2014, 16, 4012.
(20) Martin, M. C.; Patil, D. V.; France, S. J. Org. Chem. 2014, 79,
3030.
(21) (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004,
104, 6217. (b) Sarhan, A. A. O.; Bolm, C. Chem. Soc. Rev. 2009, 38,
2730. (c) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2010, 111, 1293.
(d) Riener, K.; Haslinger, S.; Raba, A.; Hogerl, M. P.; Cokoja, M.;
̈
Herrmann, W. A.; Kuhn, F. E. Chem. Rev. 2014, 114, 5215.
̈
(e) Gopalaiah, K. Chem. Rev. 2013, 113, 3248.
(22) (a) Highton, A. J.; Majid, T. N.; Simpkins, N. S. Synlett 1999,
1999, 237. (b) Benfatti, F.; Nanteuil, F. D.; Waser, J. Org. Lett. 2011,
14, 386. (c) Taber, D. F.; Sheth, R. B. J. Org. Chem. 2008, 73, 8030.
(d) Dieskau, A. P.; Holzwarth, M. S.; Plietker, B. J. Am. Chem. Soc.
2012, 134, 5048. (e) Sherry, B. D.; Furstner, A. Chem. Commun. 2009,
7116. (f) Wang, Y.; Fordyce, E. A. F.; Chen, F. Y.; Lam, H. W. Angew.
Chem., Int. Ed. 2008, 47, 7350.
(23) Iron Catalysis: Fundamentals and Applications; Plietker, B., Ed.;
Topics in Organometallic Chemistry; Springer: Heidelberg, 2011; Vol.
33.
(24) The Porphyrin Handbook; Kadish, K. M., Smith, K. M., Guilard,
R., Eds.; Academic Press: San Diego, CA, 2000.
(25) Jia, F.; Li, Z. Org. Chem. Frontiers 2014, 1, 194.
(26) Barton, D. H. R. Chem. Soc. Rev. 1996, 25, 237.
(27) Pereira, M. C.; Oliveira, L. C. A.; Murad, E. Clay Miner. 2012,
47, 285.
(28) Tshuva, E. Y.; Lippard, S. J. Chem. Rev. 2004, 104, 987.
(29) (a) Zhang, X.; Li, L.; Zhang, G. Green Chem. 2003, 5, 646.
(b) Zhang, G.; Liu, Q.; Shi, L.; Wang, J. Tetrahedron 2008, 64, 339.
(c) Shi, L.; Zhang, G.; Pan, F. Tetrahedron 2008, 64, 2572. (d) Zhang,
L.; Zhang, Z.; Liu, Q.; Liu, T.; Zhang, G. J. Org. Chem. 2014, 79, 2281.
(e) Zhang, Z.; Tian, Q.; Qian, J.; Liu, Q.; Liu, T.; Shi, L.; Zhang, G. J.
Org. Chem. 2014, 79, 8182.
(30) (a) Zhang, Z.; Zhang, Q.; Sun, S.; Xiong, T.; Liu, Q. Angew.
Chem., Int. Ed. 2007, 46, 1726. (b) Zhang, Z.; Xue, C.; Liu, X.; Zhang,
Q.; Liu, Q. Tetrahedron 2011, 67, 7081. (c) Xiong, T.; Zhang, Q.;
Zhang, Z.; Liu, Q. J. Org. Chem. 2007, 72, 8005.
(31) Zhang, Z.; Wang, D.; Wang, B.; Liu, Q.; Liu, T.; Zhang, W.;
Yuan, B.; Zhao, Z.; Han, D.; Zhang, G. Tetrahedron 2013, 69, 9063.
(32) Wei, Y.; Liu, J.; Lin, S.; Ding, H.; Liang, F.; Zhao, B. Org. Lett.
2010, 12, 4220.
(33) Nambu, H.; Fukumoto, M.; Hirota, W.; Yakura, T. Org. Lett.
2014, 16, 4012.
H
dx.doi.org/10.1021/jo5018487 | J. Org. Chem. XXXX, XXX, XXX−XXX