Synthesis of Polysubstituted Pyrroles through Electro-Oxidative Annulation of 1,3-Dicarbonyl Compounds and Primary Amines

Article abstract of DOI:10.1021/acs.joc.0c02911

Reported herein is a synthetic method of polysubstituted pyrroles from easily available materials, 1,3-dicarbonyl compounds and primary amines, via electro-oxidative intermolecular annulation. Under similar conditions, enamines are also converted smoothly into desired products, indicating that in situ formed enamines are crucial intermediates for the first transformation. Neither transition-metal salts nor harsh conditions are required to facilitate the dehydrocyclization process.

Full text of DOI:10.1021/acs.joc.0c02911

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Article
Synthesis of Polysubstituted Pyrroles through Electro-Oxidative
Annulation of 1,3-Dicarbonyl Compounds and Primary Amines
Mingteng Xiong, Xiao Liang, Yifeng Zhou,* and Yuanjiang Pan*
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ABSTRACT: Reported herein is a synthetic method of poly-
substituted pyrroles from easily available materials, 1,3-dicarbonyl
compounds and primary amines, via electro-oxidative intermolec-
ular annulation. Under similar conditions, enamines are also
converted smoothly into desired products, indicating that in situ
formed enamines are crucial intermediates for the first trans-
formation. Neither transition-metal salts nor harsh conditions are
required to facilitate the dehydrocyclization process.
dicarbonyl compounds and amines for the synthesis of pyrrole
derivatives.
INTRODUCTION
■
The polysubstituted pyrroles, an important class of molecular
frameworks which widely existed in numerous known
compounds, had attracted chemists’ attention in the past few
decades because of the satisfactory pharmaceutical activities of
the skeleton-containing drugs or the efficient practicability of the
relevant materials.1 As is well known, the Paal−Knorr reaction,
in which pyrrole derivatives are formed via the condensation of
1,4-dicarbonyl compounds with primary amines under the
anhydrous and acidic conditions, is a well-documented classic
approach.2 Of course, other common methods,3 such as Knorr,4
Hantzsch,5 Barton−Zard,6 and Piloty−Robinson reactions,7 are
also of great utility to synthesize pyrroles. Recently, transition-
metal-catalyzed synthesis of pyrroles has gradually become the
predominant avenue and has been continually disclosed from all
over the world.8 However, transition metals and strong oxidants,
which are sometimes destructive to the biomedical field, are
usually indispensable in these dehydrogenation processes.
Therefore, it is of great urgency to establish a green and mild
method for the synthesis of pyrrole compounds from the simple
and readily available materials.
Recent years have witnessed the renaissance of organic
electrosynthesis, which is widely believed as a mild and eco-
friendly pathway because chemical oxidants or reductants could
be replaced with electrons, thereby reducing the undesirable side
reactions.9 Although in 2019, Lei’s group had successfully
achieved the electrochemical condensation/cyclization between
aldehydes and amines to construct the pyrrole skeletons via one
step,10 experimental results show that 1,3-dicarbonyl com-
pounds are invalid substrates for this transformation, perhaps
because of the inferior reactivity of ketone (see the Supporting
Information for detailed information). Based on our interest in
electro-oxidative cyclodehydrogenation to synthesize hetero-
cyclic compounds,11 herein, we tried to achieve the electro-
chemical strategy to realize the intermolecular annulation of 1,3-
RESULTS AND DISCUSSION
■
At the outset, we chose benzylamine 1a and methyl acetoacetate
2a as the model substrates to screen the reaction conditions
(Table 1). After a series of trials, we finally determined the
optimal reaction conditions under which the target product 3a
was formed in 69% gas chromatography (GC) yield (Table 1,
entry 1). Obviously, both increasing and decreasing the
electricity have the negative effect on the transformation
(Table 1, entries 2−3). Notably, the reaction yields decreased
sharply to 21 and 10% when tetrabutylammonium tetrafluor-
oborate (nBuN4BF4) was replaced with tetrabutylammonium
hexafluorophosphate (nBuN4PF6) and tetrabutylammonium
acetate (nBuN4OAc), respectively (Table 1, entries 4−5).
After screening a lot of additives, we found that other acids
such as acetic acid (HOAc) or trifluoroacetic acid (CF3COOH)
went against the reaction, and no target product was detected
when using bases such as potassium carbonate (K2CO3) instead
of trifluoromethanesulfonic acid (CF3SO3H) (Table 1, entries
6−8). Thereafter, the solvent effect was investigated, and the
declining yields were obtained when other common solvents,
such as methanol, acetonitrile, and 1,2-dichloroethane, were
used instead of isopropanol (Table 1, entry 9). Moreover, using
the same amount of the single solvent also led to the
unsatisfactory results (Table 1, entries 10−11). Also, inferior
yields were observed when using higher or lower reaction
Received: December 9, 2020
Published: March 16, 2021
https://doi.org/10.1021/acs.joc.0c02911
© 2021 American Chemical Society
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a
Table 1. Optimization of Reaction Conditions
b
entry
variation from the standard conditions
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
none
69
43
58
21
10
13
51
N.D.
15
48
42, 38, 11
59
54
52
trace
15 or 35
51
4 mA instead of 6 mA, 6.5 h
8 mA instead of 6 mA, 3.75 h
nBu4NPF6 instead of nBu4NBF4
nBu4NOAc instead of nBu4NBF4
HOAc instead of CF3SO3H
CF3COOH instead of CF3SO3H
K2CO3 instead of CF3SO3H
MeOH, CH3CN, and DCE instead of iPrOH
without EtOH
without iPrOH
45 °C instead of 55 °C
65 °C instead of 55 °C
C (+) I Ni (−) instead of C (+) I Pt (−)
Pt (−) I Pt (−) instead of C (+) I Pt (−)
adding a 4 Å molecular sieve or Na2SO4 as the drying agent
under air
c
c
f
d
d
d
e
without electricity
N.D.
a
Reaction conditions: graphite rod anode (Φ 6 mm), Pt plate cathode (1 mm × 1 mm × 0.1 mm), constant current = 6 mA, 1a (0.6 mmol), 2a
b
c
n
i
(0.3 mmol), Bu4NBF4 (0.9 mmol), CF3SO3H (0.3 mmol), PrOH/EtOH (10 mL, 4:1), 55 °C, 5 h, undivided cell, Ar. Isolated yield. The
electrolyte cannot be dissolved fully, or the voltage is out of range (>20 V). The reaction volume is kept constant (10 mL). 100 mg of the drying
agents. Not detected.
d
e
f
temperatures (Table 1, entries 12−13). In addition, the reaction
efficiency declined slightly to 52% when a nickel plate cathode
was used; however, the use of a platinum plate as an anode nearly
prevented the transformation (Table 1, entries 14−15).
Disappointingly, subjecting some drying reagents such as a 4
Å molecular sieve or sodium sulfate to the reaction to facilitate
the dehydration process did not work well, instead giving worse
yields (Table 1, entry 16).
When the reaction was conducted under air, the yield fell to
51% (Table 1, entry 17). Expectedly, the reaction did not take
place when no electric current passed through the system (Table
1, entry 18).
With the optimized conditions in hand, the scope of reaction
substrates in regard to amines 1 and 1,3-dicarbonyl compounds
2 is explored in Scheme 1. First, several alkyl-substituted
benzylamines, including methyl, isopropyl, and tert-butyl, were
suitable substrates for this transformation and could afford the
desired products 3b−3f in moderate yields. In addition, 3,4-
dimethylbenzylamine was also converted smoothly into the
corresponding pyrrole 3g in 53% isolated yield. Moreover, other
electron-donating substitutions like the methoxy group were
tolerated in this transformation, leading to final products 3h and
3i in acceptable yields. Thereafter, some benzylamines bearing
electron-withdrawing substitutions including trifluoromethyl
and cyano groups were also subjected into the reaction, and the
target products 3j−3m were obtained in moderate yields.
Similarly, ortho- and para-substituted halo-benzylamines also
showed better reaction activities under the standard conditions,
leading to the corresponding halogenated pyrrole derivatives
3n−3s, which could subsequently undergo the functionalization
via transition-metal-catalyzed reactions. Unfortunately, no
target products were observed when some heterocyclic aromatic
amines, such as 2-furfurylamine, 2-thiophenemethylamine, and
4-(aminomethyl)pyridine, were selected as substrates. Besides,
other alkylamines like 2-phenylethylamine could also participate
in the reaction, and product 3t was isolated in 28% yield. Finally,
we investigated the scope of 1,3-dicarbonyl compounds, and
expectedly, pyrrole 3u was formed in satisfactory yield when
using ethyl acetoacetate as the starting material.
In order to explore the mechanism, confirmatory cyclic
voltammetry (CV) experiments were conducted, and the results
are shown in Figure 1. Notably, the CV experiments are
performed in CH3CN because the oxidation peaks are
disordered and complex in the standard solvents. As can be
seen from Figure 1, the oxidant potential of benzylamine 1a is
1.40 V, where no obvious oxidation peak of 2a was observed. In
addition, when we stirred the mixture of benzylamine 1a and
methyl acetoacetate 2a at 60 °C for an hour, apparent oxidation
peaks were detected at 1.48 V, which, we speculated, might be
attributed to the formation of enamine 4a via the condensation
of the materials. Obviously, enamine 4a has a similar oxidant
potential at 1.32 V. Therefore, it is reasonable to believe that
enamine derivatives might be the intermediates in this
transformation.
According to the aforementioned speculation, several
enamines were synthesized and then subjected to the reactions
under similar conditions. Also, the results are shown in Scheme
2. In short, a series of desired pyrrole products 3a, 3i−3j, and
3v−3z were generated in moderate to high yields when the
corresponding enamines were used as the substrates. It was
worth mentioning that this reaction could achieve the synthesis
of some pyrrole derivatives which could not be formed through
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a
Scheme 1. Synthesis of Pyrroles
a
Reaction conditions: graphite rod anode (Φ 6 mm), Pt plate cathode (10 mm × 10 mm × 0.1 mm), constant current = 6 mA, 1a (0.6 mmol), 2a
(0.3 mmol), nBu4NBF4 (0.9 mmol), CF3SO3H (0.3 mmol), iPrOH/EtOH (10 mL, 4:1), 55 °C, 5 h, undivided cell, Ar. bUsing MeOH instead of
c
EtOH. See the Supporting Information for failed substrates.
Figure 1. CV experiments.
the first transformation. Also, to some extent, we could make the
conclusion that the yield of the first transformation is mainly
determined by the formation rate of the enamine intermediate.
Based on the aforementioned experimental results and the
published literature,10,12 a proposed mechanism is depicted in
Scheme 3. Initially, enamine 4a, tautomerized from Schiff base
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a
Scheme 2. Synthesis of Pyrroles
a
Reaction conditions: graphite rod anode (Φ 6 mm), Pt plate cathode (10 mm × 10 mm × 0.1 mm), constant current = 8 mA, 4a (0.3 mmol),
nBu4NBF4 (0.9 mmol), PrOH/EtOH (10 mL, 4:1), 60 °C, 3.75 h, undivided cell, Ar. See the Supporting Information for failed substrates.
i
b
Scheme 3. Proposed Mechanism
complex I, which was formed from the condensation of methyl
acetoacetate 2a with benzylamine 1a under acidic conditions by
heating, was oxidized at the anode to release the nitrogen-
centered radical species II, which underwent tautomerism to
generate the more stable radical intermediate III. Also,
subsequent homo-coupling to give dimer IV and final
intramolecular cyclization took place to deliver the target
product 3a by removal of benzylamine. In the meantime, alkoxyl
anions were generated at the cathode to maintain the electronic
conservation.
To further clarify the potentially synthetic application of the
protocols, the scale-up experiments were carried out with 6
mmol (Scheme 4). To our delight, the considerable isolated
yields of 66 and 45% were obtained.
CONCLUSIONS
■
In summary, we have disclosed an electro-oxidative approach to
form pyrrole derivatives from 1,3-dicarbonyl compounds and
primary amines via the intermolecular cyclization. Moreover, the
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Scheme 4. Scale-Up Reactions
Methyl 3-((4-(Trifluoromethyl)benzyl)amino)but-2-enoate (4j).
Yellow solid (995 mg, 73%). mp 72−74 °C. PE/EA = 5:1. H NMR
synthesis of pyrroles from enamines by using the electrosyn-
thesis strategy has also been reported in the paper, indicating the
rationality of the proposed mechanism. Based on the reported
methods, a lot of polysubstituted pyrroles could by obtained in
moderate yields. What is more, the further research studies on
electro-oxidative annulation are underway in our laboratory.
1
(400 MHz, CDCl3): δ 9.01 (br, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.38 (d, J
= 8.0 Hz, 2H), 4.59 (s, 1H), 4.48 (d, J = 6.5 Hz, 2H), 3.63 (s, 3H), 1.88
(s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 170.9, 161.6, 143.1,
129.6 (q, 2JC−F = 32.3 Hz), 126.9, 125.7 (q, 3JC−F = 4.0 Hz), 124.1 (q,
1JC−F = 272.7 Hz), 83.6, 50.0, 46.2, 19.1. HRMS (GC-TOF, EI) m/z:
[M]+ calcd for C13H14F3NO2, 273.0977; found, 273.0978.
Ethyl 3-(Benzylamino)but-2-enoate (4v).13 Yellow oil (986.3 mg,
90%). PE/EA = 10:1. 1H NMR (400 MHz, CDCl3): δ 8.95 (br, 1H),
7.37−7.30 (m, 2H), 7.27−7.21 (m, 3H), 4.53 (s, 1H), 4.41 (d, J = 6.3
Hz, 2H), 4.09 (q, J = 7.1 Hz, 2H), 1.90 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 170.6, 161.8, 138.8, 128.8, 127.4,
126.7, 83.2, 58.4, 46.8, 19.4, 14.7.
EXPERIMENTAL SECTION
■
General Information. All glassware was oven-dried at 110 °C for
hours and cooled down under air. Unless otherwise noted, benzyl-
amines and 1,3-dicarbonyl compounds were obtained from commercial
suppliers and used without further purification. Enamines were
prepared according to the literature procedures; enamines 4a, 4i, 4v,
4x, and 4z are the known compounds, and the corresponding NMR
data are in accord with the previous literature. The instrument for
electrolysis was a dual display potentiostat (DJS-292B) (made in
China). The anode electrode comprises carbon rod electrodes (Φ 6
mm), and the cathode electrode comprises platinum plate electrodes
(10 mm × 10 mm × 0.1 mm). Thin-layer chromatography employed
glass 0.25 mm silica gel plates. Flash chromatography columns were
used with 300−400 silica gel. 1H and 13C NMR data were recorded in
CDCl3 on a Bruker Ascend-400 spectrometer (400 MHz) with
tetramethylsilane as an internal standard. All chemical shifts are
reported relative to tetramethylsilane (0 ppm for 1H) and d-solvent
peaks (77.16 ppm for 13C), respectively. GC analyses were performed
on a SHIMADZU GC-2014 GC instrument with a flame-ionization
detector, and benzophenone was added as internal standard. Cyclic
voltammograms were obtained on a CHI 660E 413713 potentiostat.
High-resolution mass spectra were recorded on a Waters GCT premier
of EI.
Isopropyl 3-(Benzylamino)but-2-enoate (4w). Yellow oil (1.03 g,
88%). PE/EA = 10:1. 1H NMR (400 MHz, CDCl3): δ 8.96 (br, 1H),
7.37−7.29 (m, 2H), 7.30−7.21 (m, 3H), 5.00 (hept, J = 6.2 Hz, 1H),
4.51 (s, 1H), 4.41 (d, J = 6.4 Hz, 2H), 1.90 (s, 3H), 1.23 (d, J = 6.3 Hz,
6H). 13C{1H} NMR (101 MHz, CDCl3): δ 170.25, 161.68, 138.85,
128.83, 127.39, 126.80, 83.75, 65.21, 46.86, 22.32, 19.44. HRMS (GC-
TOF, EI) m/z: [M]+ calcd for C14H19NO2, 233.1416; found, 233.1416.
Methyl 3-(Benzylamino)pent-2-enoate (4x).15 Yellow oil (930.9
1
mg, 85%). PE/EA = 10:1. H NMR (400 MHz, CDCl3): δ 8.95 (br,
1H), 7.37−7.31 (m, 2H), 7.29−7.25 (m, 3H), 4.56 (s, 1H), 4.43 (d, J =
6.3 Hz, 2H), 3.64 (s, 3H), 2.23 (q, J = 7.5 Hz, 2H), 1.12 (t, J = 7.5 Hz,
3H). 13C{1H} NMR (101 MHz, CDCl3): δ 171.4, 167.2, 138.9, 128.9,
127.5, 126.8, 80.9, 50.2, 46.5, 25.3, 12.3.
Methyl 4-(((4-Methoxy-4-oxobut-2-en-2-yl)amino)methyl)-
benzoate (4y). Yellow solid (1.06 g, 81%). mp 52−54 °C. PE/EA =
10:1. 1H NMR (400 MHz, CDCl3): δ 9.00 (br, 1H), 8.01 (d, J = 8.3 Hz,
2H), 7.33 (d, J = 8.3 Hz, 2H), 4.57 (s, 1H), 4.49 (d, J = 6.5 Hz, 2H),
3.91 (s, 3H), 3.64 (s, 3H), 1.89 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 171.0, 166.8, 161.7, 144.2, 130.2, 129.4, 126.6, 83.5, 52.2,
50.2, 46.6, 19.4. HRMS (GC-TOF, EI) m/z: [M]+ calcd for
C14H17NO4, 263.1158; found, 263.1157.
General Procedure for the Synthesis of Enamines 4. To a 25
mL round-bottom flask with a magnetic bar were added benzylamines 1
(5 mmol), 1,3-dicarbonyl compound 2 (6 mmol), ZnCl2 (0.5 mmol),
and CH3CN (10 mL). The reaction mixture was stirred at room
temperature for 24 h. After completion of the reaction, the solvent was
removed under reduced pressure to afford the residue, which was
purified by flash column chromatography on silica gel using a mixture of
petroleum ether (PE) and ethyl acetate (EA) to give products 4.
Methyl 3-(Benzylamino)but-2-enoate (4a).13 Yellow oil (931 mg,
91%). PE/EA = 10:1. 1H NMR (400 MHz, CDCl3): δ 8.94 (br, 1H),
7.37−7.30 (m, 2H), 7.29−7.23 (m, 3H), 4.54 (s, 1H), 4.42 (d, J = 6.4
Hz, 2H), 3.63 (s, 3H), 1.91 (s, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 171.0, 162.0, 138.8, 128.9, 127.4, 126.8, 82.9, 50.1, 46.9,
19.5.
Methyl 3-(Propylamino)but-2-enoate (4z).13 Colorless oil (720
1
mg, 92%). PE/EA = 10:1. H NMR (400 MHz, CDCl3): δ 8.58 (br,
1H), 4.44 (s, 1H), 3.62 (s, 3H), 3.17 (q, J = 6.9 Hz, 2H), 1.92 (s, 3H),
1.66−1.53 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (101 MHz,
CDCl3): δ 171.0, 162.1, 81.4, 49.9, 44.8, 23.7, 19.4, 11.4.
General Procedure A for the Synthesis of 3 from 1 and 2. To
an oven-dried undivided three-necked bottle (10 mL) with a magnetic
bar were added benzylamine 1 (0.6 mmol), 1,3-dicarbonyl compound 2
(0.3 mmol), CF3SO3H (0.3 mmol), nBu4NBF4 (0.9 mmol), and
iPrOH/EtOH (8 mL/2 mL). The bottle was equipped with a carbon
rod (Φ 6 mm) anode and a platinum plate (10 mm × 10 mm × 0.1 mm)
cathode and was then flushed with nitrogen. The reaction mixture was
stirred and electrolyzed at a constant current of 6 mA at 55 °C for 5 h.
After completion of the reaction, the solvent was removed under
reduced pressure to afford the residue, which was purified by flash
Methyl 3-((4-Methoxybenzyl)amino)but-2-enoate (4i).14 Yellow
oil (1.05 g, 89%). PE/EA = 10:1. 1H NMR (400 MHz, CDCl3): δ 8.87
(br, 1H), 7.18 (d, J = 8.6 Hz, 2H), 6.87 (d, J = 8.6 Hz, 2H), 4.52 (s, 1H),
4.36 (d, J = 6.2 Hz, 2H), 3.79 (s, 3H), 3.62 (s, 3H), 1.92 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3): δ 171.0, 162.0, 159.0, 130.7, 128.2,
114.3, 82.7, 55.4, 50.1, 46.4, 19.6.
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column chromatography on silica gel using a mixture of PE and EA to
give products 3.
Dimethyl 1-(3,4-Dimethylbenzyl)-2,5-dimethyl-1H-pyrrole-3,4-
1
dicarboxylate (3g). Yellow oil (26.3 mg, 53%). PE/EA = 20:1. H
NMR (400 MHz, CDCl3): δ 7.06 (d, J = 7.7 Hz, 1H), 6.71 (s, 1H), 6.60
(d, J = 7.6 Hz, 1H), 4.98 (s, 2H), 3.82 (s, 6H), 2.31 (s, 6H), 2.22 (s,
3H), 2.22 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ 166.3, 137.5,
136.2, 134.0, 133.4, 130.3, 126.8, 123.1, 112.4, 51.5, 46.9, 20.0, 19.5,
11.1. HRMS (GC-TOF, EI) m/z: [M]+ calcd for C19H23NO4,
329.1627; found, 329.1628.
General Procedure B for the Synthesis of 3 from 4. To an oven-
dried undivided three-necked bottle (10 mL) with a magnetic bar were
n
i
added enamine 4 (0.3 mmol), Bu4NBF4 (0.9 mmol), and PrOH/
EtOH (8 mL/2 mL). The bottle was equipped with a carbon rod (Φ 6
mm) anode and a platinum plate (10 mm × 10 mm × 0.1 mm) cathode
and was then flushed with nitrogen. The reaction mixture was stirred
and electrolyzed at a constant current of 8 mA at 60 °C for 3.75 h. After
completion of the reaction, the solvent was removed under reduced
pressure to afford the residue, which was purified by flash column
chromatography on silica gel using a mixture of PE and EA to give
products 3.
Dimethyl 1-(2-Methoxybenzyl)-2,5-dimethyl-1H-pyrrole-3,4-di-
1
carboxylate (3h). Yellow oil (20.1 mg, 40%). PE/EA = 15:1. H
NMR (400 MHz, CDCl3): δ 7.24 (t, J = 7.2 Hz, 1H), 6.89 (d, J = 7.9 Hz,
1H), 6.83 (t, J = 7.5 Hz, 1H), 6.30 (d, J = 7.5 Hz, 1H), 5.00 (s, 2H), 3.89
(s, 3H), 3.82 (s, 6H), 2.29 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3):
δ 166.2, 156.1, 134.2, 128.7, 125.8, 124.3, 121.0, 112.4, 109.9, 55.4,
51.5, 42.7, 10.9. HRMS (GC-TOF, EI) m/z: [M]+ calcd for
C18H21NO5, 331.1420; found, 331.1422.
Dimethyl 1-(4-Methoxybenzyl)-2,5-dimethyl-1H-pyrrole-3,4-di-
carboxylate (3i). Yellow oil (24.6 mg, 50%). PE/EA = 15:1. 1H
NMR (400 MHz, CDCl3): δ 6.83 (s, 4H), 4.98 (s, 2H), 3.81 (s, 6H),
3.78 (s, 3H), 2.32 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ 133.8,
128.0, 126.9, 114.5, 112.5, 55.4, 51.5, 46.6, 11.1. HRMS (GC-TOF, EI)
m/z: [M]+ calcd for C18H21NO5, 331.1420; found, 331.1419.
Dimethyl 2,5-Dimethyl-1-(4-(trifluoromethyl)benzyl)-1H-pyrrole-
3,4-dicarboxylate (3j). Yellow oil (25.0 mg, 45%). PE/EA = 10:1. 1H
NMR (400 MHz, CDCl3): δ 7.59 (d, J = 8.1 Hz, 2H), 7.02 (d, J = 8.0
Hz, 2H), 5.11 (s, 2H), 3.83 (s, 6H), 2.30 (s, 6H). 13C{1H} NMR (101
MHz, CDCl3): δ 166.0, 140.2, 133.6, 130.3 (q, 2JC−F = 32.4 Hz), 126.2
(q, 3JC−F = 3.8 Hz), 126.0, 124.0 (q, 1JC−F = 270.5 Hz), 113.0, 51.6, 46.7,
11.0. HRMS (GC-TOF, EI) m/z: [M]+ calcd for C18H18F3NO4,
369.1188; found, 369.1188.
General Procedure for the Scale-Up Reactions. To a 250 mL
three-necked flask with a magnetic bar were added materials, iPrOH/
EtOH (120 mL/30 mL). Other processes are in accord with procedures
A and B.
General Procedure for Cyclic Voltammetry. CV was performed
in a three-electrode cell connected to a Schlenk line under nitrogen at
room temperature. The working electrode was a glassy carbon electrode
(Φ 3 mm), and the counter electrode was a platinum wire. The
reference electrode was a Ag/AgCl electrode submerged in saturated
aqueous KCl solution. 10 mL of CH3CN containing 1.0 M nBu4NBF4
was poured into the electrochemical cell in all experiments. CV of
substrates was performed at the concentration of 0.05 M. The scan rate
is 0.1 V/s, ranging from 0 to 2 V.
Dimethyl 1-Benzyl-2,5-dimethyl-1H-pyrrole-3,4-dicarboxylate
(3a).16 Yellow oil (31.0 mg, 69%). PE/EA = 15:1. H NMR (400
1
MHz, CDCl3): δ 7.37−7.22 (m, 3H), 6.90 (d, J = 7.3 Hz, 2H), 5.05 (s,
2H), 3.82 (s, 6H), 2.31 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ
166.2, 136.0, 133.9, 129.1, 127.8, 125.6, 112.5, 51.5, 47.1, 11.0. HRMS
(GC-TOF, EI) m/z: [M]+ calcd for C17H19NO4, 301.1314; found,
301.1313.
Dimethyl 2,5-Dimethyl-1-(2-methylbenzyl)-1H-pyrrole-3,4-dicar-
boxylate (3b). Yellow oil (26 mg, 55%). PE/EA = 15:1. 1H NMR (400
MHz, CDCl3): δ 7.23−7.14 (m, 2H), 7.12−7.04 (m, 1H), 6.25 (d, J =
7.6 Hz, 1H), 4.95 (s, 2H), 3.83 (s, 6H), 2.38 (s, 3H), 2.27 (s, 6H).
13C{1H} NMR (101 MHz, CDCl3): δ 166.2, 134.3, 134.0, 134.0, 130.3,
Dimethyl 2,5-Dimethyl-1-(3-(trifluoromethyl)benzyl)-1H-pyrrole-
3,4-dicarboxylate (3k). Yellow oil (24.6 mg, 45%). PE/EA = 10 : 1. 1H
NMR (400 MHz, CDCl3): δ 7.55 (d, J = 7.8 Hz, 1H), 7.44 (t, J = 7.8 Hz,
1H), 7.34 (s, 1H), 6.94 (d, J = 7.7 Hz, 1H), 5.11 (s, 2H), 3.83 (s, 6H),
2.31 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ 166.1, 137. 2, 133.6,
2
1
131.6 (q, JC−F = 32.0 Hz), 130.0, 128.8, 123.9 (q, JC−F = 270 Hz),
124.9 (q, 3JC−F = 4.0 Hz), 122.6 (q, 4JC−F = 4.0 Hz), 113.0, 51.6, 46.7,
11.1. HRMS (GC-TOF, EI) m/z: [M]+ calcd for C18H18F3NO4,
369.1188; found, 369.1189.
Dimethyl 1-(3-Cyanobenzyl)-2,5-dimethyl-1H-pyrrole-3,4-dicar-
127.6, 126.9, 124.4, 112.5, 51.5, 45.1, 19.1, 10.9. HRMS (GC-TOF, EI)
m/z: [M]+ calcd for C18H21NO4, 315.1471; found, 315.1471.
Dimethyl 2,5-Dimethyl-1-(3-methylbenzyl)-1H-pyrrole-3,4-dicar-
1
boxylate (3l). Yellow oil (25.0 mg, 51%). PE/EA = 10:1. H NMR
(400 MHz, CDCl3): δ 7.59 (d, J = 7.7 Hz, 1H), 7.46 (t, J = 7.8 Hz, 1H),
7.27 (d, J = 5.6 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 5.09 (s, 2H), 3.83 (s,
6H), 2.30 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ 165.9, 137.8,
133.4, 131.7, 130.2, 130.0, 130.0, 118.3, 113.5, 113.1, 51.6, 46.4, 11.1.
HRMS (GC-TOF, EI) m/z: [M]+ calcd for C18H18N2O4, 326.1267;
found, 326.1268.
1
boxylate (3c). Yellow oil (29.4 mg, 63%). PE/EA = 15:1. H NMR
(400 MHz, CDCl3): δ 7.20 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 7.5 Hz, 1H),
6.74 (s, 1H), 6.68 (d, J = 7.6 Hz, 1H), 5.01 (s, 2H), 3.82 (s, 6H), 2.32 (s,
9H). 13C{1H} NMR (101 MHz, CDCl3): δ 166.3, 139.0, 136.0, 134.0,
129.0, 128.6, 126.2, 122.7, 112.5, 51.5, 47.1, 21.6, 11.1. HRMS (GC-
TOF, EI) m/z: [M]+ calcd for C18H21NO4, 315.1471; found, 315.1472.
Dimethyl 2,5-Dimethyl-1-(4-methylbenzyl)-1H-pyrrole-3,4-dicar-
Dimethyl 1-(4-Cyanobenzyl)-2,5-dimethyl-1H-pyrrole-3,4-dicar-
1
boxylate (3m). Yellow oil (25.2 mg, 52%). PE/EA = 10:1. H NMR
(400 MHz, CDCl3): δ 7.63 (d, J = 8.3 Hz, 2H), 7.01 (d, J = 8.2 Hz, 2H),
5.11 (s, 2H), 3.83 (s, 6H), 2.29 (s, 6H). 13C{1H} NMR (101 MHz,
CDCl3): δ 165.9, 141.5, 133.4, 133.0, 126.4, 118.4, 113.1, 112.0, 51.6,
46.7, 11.0. HRMS (GC-TOF, EI) m/z: [M]+ calcd for C18H18N2O4,
326.1267; found, 326.1267.
1
boxylate (3d). Yellow oil (33.0 mg, 70%). PE/EA = 10:1. H NMR
(400 MHz, CDCl3): δ 7.11 (d, J = 7.9 Hz, 2H), 6.79 (d, J = 7.9 Hz, 2H),
5.00 (s, 2H), 3.81 (s, 6H), 2.32 (s, 3H), 2.31 (s, 6H). 13C{1H} NMR
(101 MHz, CDCl3): δ 166.2, 137.5, 133.9, 133.0, 130.0, 125.6, 112.5,
51.5, 46.9, 21.1, 11.1. HRMS (GC-TOF, EI) m/z: [M]+ calcd for
C18H21NO4, 315.1471; found, 315.1469.
Dimethyl 1-(4-Fluorobenzyl)-2,5-dimethyl-1H-pyrrole-3,4-dicar-
1
boxylate (3n). Yellow oil (17.5 mg, 39%). PE/EA = 15:1. H NMR
Dimethyl 1-(4-Isopropylbenzyl)-2,5-dimethyl-1H-pyrrole-3,4-di-
carboxylate (3e). Yellow oil (28.8 mg, 56%). PE/EA = 15:1. 1H
NMR (400 MHz, CDCl3): δ 7.16 (d, J = 8.1 Hz, 2H), 6.83 (d, J = 8.1
Hz, 2H), 5.01 (s, 2H), 3.81 (s, 6H), 2.93−2.82 (m, 1H), 2.32 (s, 6H),
1.22 (d, J = 8.0 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ 166.3,
148.6, 134.0, 133.4, 127.2, 125.7, 112.5, 51.5, 47.0, 33.9, 24.1, 11.1.
HRMS (GC-TOF, EI) m/z: [M]+ calcd for C20H25NO4, 343.1784;
found, 343.1786.
Dimethyl 1-(4-(tert-Butyl)benzyl)-2,5-dimethyl-1H-pyrrole-3,4-di-
carboxylate (3f). Yellow oil (27.0 mg, 50%). PE/EA = 15:1. 1H NMR
(400 MHz, CDCl3): δ 7.32 (d, J = 8.3 Hz, 2H), 6.84 (d, J = 8.3 Hz, 2H),
5.01 (s, 2H), 3.81 (s, 6H), 2.32 (s, 6H), 1.29 (s, 9H). 13C{1H} NMR
(101 MHz, CDCl3): δ 166.2, 150.8, 134.0, 133.0, 126.0, 125.4, 112.5,
77.5, 77.2, 76.8, 51.5, 46.9, 34.6, 31.4, 11.1. HRMS (GC-TOF, EI) m/z:
[M]+ calcd for C21H27NO4, 357.1940; found, 357.1939.
(400 MHz, CDCl3): δ 7.32−7.22 (m, 1H), 7.12−7.03 (m, 2H), 6.47 (t,
J = 7.3 Hz, 1H), 5.08 (s, 2H), 3.82 (s, 6H), 2.31 (s, 6H). 13C{1H} NMR
(101 MHz, CDCl3): δ 166.1, 159.8 (d, 1JC−F = 247.5 Hz), 133.9, 129.5
(d, 4JC−F = 8.1 Hz), 127.0 (d, 5JC−F = 4.0 Hz), 125.0 (d, 6JC−F = 3.0 Hz),
123.4 (d, 3JC−F = 14.1 Hz), 115.5 (d, 2JC−F = 20.2 Hz), 112.8, 51.6, 41.3,
11.0. HRMS (GC-TOF, EI) m/z: [M]+ calcd for C17H18FNO4,
319.1220; found, 319.1220.
Dimethyl 1-(2-Chlorobenzyl)-2,5-dimethyl-1H-pyrrole-3,4-dicar-
1
boxylate (3o). Yellow oil (35.5 mg, 71%). PE/EA = 15:1. H NMR
(400 MHz, CDCl3): δ 7.40 (d, J = 7.8 Hz, 1H), 7.25−7.20 (m, 1H),
7.19−7.13 (m, 1H), 6.31 (d, J = 7.6 Hz, 1H), 5.07 (s, 2H), 3.82 (s, 6H),
2.28 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ 166.1, 133.9, 133.6,
131.9, 129.6, 129.1, 127.8, 126.4, 112.8, 77.5, 77.2, 76.8, 51.6, 45.1,
10.9. HRMS (GC-TOF, EI) m/z: [M]+ calcd for C17H18ClNO4,
335.0924; found, 335.0924.
4991
https://doi.org/10.1021/acs.joc.0c02911
J. Org. Chem. 2021, 86, 4986−4993

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Dimethyl 1-(2-Bromobenzyl)-2,5-dimethyl-1H-pyrrole-3,4-dicar-
129.9, 125.6, 112.8, 52.3, 51.6, 46.9, 11.0. HRMS (GC-TOF, EI) m/z:
[M]+ calcd for C19H21NO6, 359.1369; found, 359.1372.
1
boxylate (3p). Yellow oil (26.1 mg, 48%). PE/EA = 15:1. H NMR
(400 MHz, CDCl3): δ 7.61−7.57 (m, 1H), 7.24−7.14 (m, 2H), 6.29 (d,
J = 6.7 Hz, 1H), 5.03 (s, 2H), 3.83 (s, 6H), 2.28 (s, 6H). 13C{1H} NMR
(101 MHz, CDCl3): δ 166.1, 135.2, 133.8, 133.0, 129.4, 128.4, 126.5,
121.6, 112.9, 77.5, 77.2, 76.8, 51.6, 47.6, 10.9. HRMS (GC-TOF, EI)
m/z: [M]+ calcd for C17H18BrNO4, 379.0419; found, 379.0417.
Dimethyl 1-(4-Fluorobenzyl)-2,5-dimethyl-1H-pyrrole-3,4-dicar-
Dimethyl 2,5-Dimethyl-1-propyl-1H-pyrrole-3,4-dicarboxylate
(3z). Yellow oil (19.8 mg, 52%). PE/EA = 15:1. 1H NMR (400 MHz,
CDCl3): δ 3.80 (s, 6H), 3.72 (m, 2H), 2.38 (s, 6H), 1.70−1.59 (m,
2H), 0.96 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3): δ
166.3, 133.3, 112.1, 51.5, 45.5, 23.7, 11.3, 11.1. HRMS (GC-TOF, EI)
m/z: [M]+ calcd for C13H19NO4, 253.1314; found, 253.1313.
1
boxylate (3q). Yellow oil (20.0 mg, 42%). PE/EA = 15:1. H NMR
(400 MHz, CDCl3): δ 7.09−6.95 (m, 2H), 6.96−6.78 (m, 2H), 5.02 (s,
2H), 3.82 (s, 6H), 2.31 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ
166.1, 162.3 (d, 1JC−F = 245 Hz), 133.7, 131.8 (d, 4JC−F = 3.1 Hz), 127.3
(d, 3JC−F = 8.1 Hz), 116.1 (d, 2JC−F = 21.6 Hz), 112.8, 51.6, 46.5, 11.1.
HRMS (GC-TOF, EI) m/z: [M]+ calcd for C17H18FNO4, 319.1220;
found, 319.1222.
Dimethyl 1-(4-Chlorobenzyl)-2,5-dimethyl-1H-pyrrole-3,4-dicar-
boxylate (3r). Yellow oil (25.3 mg, 51%). PE/EA = 15:1. 1H NMR (400
MHz, CDCl3): δ 7.29 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.4 Hz, 2H), 5.01
(s, 2H), 3.82 (s, 6H), 2.30 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3):
δ 166.1, 134.6, 133.7, 133.7, 129.4, 127.0, 112.8, 51.6, 46.5, 11.1.
HRMS (GC-TOF, EI) m/z: [M]+ calcd for C17H18ClNO4, 335.0924;
found, 335.0926.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c02911.
■
sı
Experimental procedures, characterization data, and
copies of 1H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Yifeng Zhou − College of Life Sciences, China Jiliang University,
Hangzhou 310027, China; Email: zhouyifeng@cjlu.edu.cn
Yuanjiang Pan − Department of Chemistry, Zhejiang
University, Hangzhou 310027, China; orcid.org/0000-
0003-2900-2600; Email: panyuanjiang@zju.edu.cn
Dimethyl 1-(4-Bromobenzyl)-2,5-dimethyl-1H-pyrrole-3,4-dicar-
1
boxylate (3s). Yellow oil (25.3 mg, 48%). PE/EA = 15:1. H NMR
(400 MHz, CDCl3): δ 7.44 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H),
5.00 (s, 2H), 3.82 (s, 6H), 2.29 (s, 6H). 13C{1H} NMR (101 MHz,
CDCl3): δ 166.0, 135.1, 133.6, 132.2, 127.3, 121.7, 112.7, 51.5, 46.5,
11.1. HRMS (GC-TOF, EI) m/z: [M]+ calcd for C17H18BrNO4,
379.0419; found: 379.0418.
Authors
Mingteng Xiong − Department of Chemistry, Zhejiang
University, Hangzhou 310027, China
Xiao Liang − Department of Chemistry, Zhejiang University,
Hangzhou 310027, China
Dimethyl 2,5-Dimethyl-1-phenethyl-1H-pyrrole-3,4-dicarboxy-
1
late (3t). Yellow solid (14.2 mg, 28%). PE/EA = 15:1. H NMR
(400 MHz, CDCl3): δ 7.32−7.23 (m, 3H), 7.11−7.03 (m, 2H), 3.98 (t,
2H), 3.80 (s, 6H), 2.88 (t, J = 7.5 Hz, 2H), 2.27 (s, 6H). 13C{1H} NMR
(101 MHz, CDCl3): δ 166.2, 137.4, 133.3, 129.0, 128.8, 127.2, 112.3,
51.5, 45.5, 36.4, 10.9. HRMS (GC-TOF, EI) m/z: [M]+ calcd for
C18H21NO4, 315.1471; found, 315.1472.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c02911
Author Contributions
All authors have given approval to the final version of the
Diethyl 2,5-Dimethyl-1-(4-methylbenzyl)-1H-pyrrole-3,4-dicar-
1
boxylate (3u). Yellow oil (28.9 mg, 57%). PE/EA = 15:1. H NMR
(400 MHz, CDCl3): δ 7.11 (d, J = 7.9 Hz, 2H), 6.81 (d, J = 8.0 Hz, 2H),
5.00 (s, 2H), 4.28 (q, J = 7.1 Hz, 4H), 2.32 (s, 3H), 2.31 (s, 6H), 1.33 (t,
J = 7.1 Hz, 6H). 13C{1H} NMR (101 MHz, CDCl3): δ 165.9, 137.5,
133.6, 133.1, 129.8, 125.7, 112.7, 60.2, 46.9, 21.2, 14.4, 11.0. HRMS
(GC-TOF, EI) m/z: [M]+ calcd for C20H25NO4, 343.1784; found,
343.1786.
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Diethyl 1-Benzyl-2,5-dimethyl-1H-pyrrole-3,4-dicarboxylate
This work was supported by the China State Key Research, grant
no. 2016YEF0200503, and the National Natural Science
Foundation of China (no. 21532005).
(3v).17 Yellow oil (29.5 mg, 60%). PE/EA = 15:1. H NMR (400
1
MHz, CDCl3): δ 7.36−7.23 (m, 3H), 6.92 (d, J = 6.9 Hz, 2H), 5.04 (s,
2H), 4.28 (q, J = 7.1 Hz, 4H), 2.32 (s, 6H), 1.33 (t, J = 7.1 Hz, 6H).
13C{1H} NMR (101 MHz, CDCl3): δ 165.8, 136.1, 133.6, 129.2, 127.8,
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■
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Yellow oil (31.1 mg, 58%). PE/EA = 10:1. H NMR (400 MHz,
CDCl3): δ 7.35−7.21 (m, 3H), 6.89 (d, J = 7.1 Hz, 2H), 5.09 (s, 2H),
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J. Org. Chem. 2021, 86, 4986−4993