A general method for the synthesis of N-unsubstituted 3,4-diarylpyrrole-2, 5-dicarboxylates

Article abstract of DOI:10.3987/COM-08-S(F)89

A general method for the synthesis of N-unsubstituted 3,4-diarylpyrrole-2, 5-dicarboxylates (3) has been developed. The key reactions involved are the Hinsberg-type synthesis of dimethyl N-benzyl-3,4-dihydroxypyrrole-2,5- dicarboxylate (6) followed by palladium-catalyzed Suzuki-Miyaura coupling of its bis-triflate derivative (7). The N-benzyl protecting group of the resulting 3,4-diaryl pyrrole-2,5-dicarboxyl ates (8) is cleanly removed under hydrogenolytic or solvolytic conditions.

Full text of DOI:10.3987/COM-08-S(F)89

HETEROCYCLES, Vol. 77, No. 2, 2009
1105
HETEROCYCLES, Vol. 77, No. 2, 2009, pp. 1105 - 1122. © The Japan Institute of Heterocyclic Chemistry
Received, 31st July, 2008, Accepted, 3rd October, 2008, Published online, 6th October, 2008
DOI: 10.3987/COM-08-S(F)89
A GENERAL METHOD FOR THE SYNTHESIS OF
N-UNSUBSTITUTED 3,4-DIARYLPYRROLE-2,5-DICARBOXYLATES
Tsutomu Fukuda,a Yukie Hayashida,a and Masatomo Iwaob*
b
aGraduate School of Science and Technology, and Department of Applied
Chemistry, Faculty of Engineering, Nagasaki University, 1-14 Bunkyo-machi,
Nagasaki 852-8521, Japan, e-mail: iwao@nagasaki-u.ac.jp
Abstract – A general method for the synthesis of N-unsubstituted
3,4-diarylpyrrole-2,5-dicarboxylates (3) has been developed. The key reactions
involved are the Hinsberg-type synthesis of dimethyl N-benzyl-3,4-
dihydroxypyrrole-2,5-dicarboxylate (6) followed by palladium-catalyzed
Suzuki-Miyaura coupling of its bis-triflate derivative (7). The N-benzyl
protecting group of the resulting 3,4-diarylpyrrole-2,5-dicarboxylates (8) is
cleanly removed under hydrogenolytic or solvolytic conditions.
INTRODUCTION
Pyrrole moieties possessing two aryl groups at the 3- and 4-positions appear frequently in marine natural
products, such as lamellarins,1 lukianols,2 ningalins,3 storniamides,4 polycitones,5 purpurone,6 halitulin,7
and dictyodendrins.8 These natural products have attracted considerable attention due to their unique
structures and highly useful biological activities. As the result, a number of synthetic approaches have
been developed so far.1b,9 These syntheses can be divided into two classes depending on the construction
method of 3,4-diarylpyrrole scaffold. The first employed de novo ring construction of the pyrrole ring
via titanium-mediated reaction,10 biomimetic synthesis,11 N-ylide-mediated cyclization,12 intra- or
intermolecular [3+2] cycloaddition,13,14 Diels-Alder cyclization of azadiene,15 vinylogous iminium
ion-mediated ring formation,16,17 and aminoquinone-mediated cyclization.18 The second utilized
regioselective arylation of preexisting pyrrole core by palladium-catalyzed cross-coupling and related
reactions.19
In 2003, we reported a short and flexible route to 3,4-diarylpyrrole marine alkaloids.20 The key reactions
involved are the synthesis of N-substituted dimethyl 3,4-dihydroxypyrrole-2,5-dicarboxylates via
This paper is dedicated to Professor Emeritus, Tohoku University, Keiichiro Fukumoto on the occasion of
his 75th birthday.

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HETEROCYCLES, Vol. 77, No. 2, 2009
Hinsberg-type reaction followed by palladium-catalyzed Suzuki-Miyaura coupling of their bis-triflate
derivatives. This strategy has been successfully applied to the total synthesis of biologically significant
lamellarins D, L, N and α 20-sulfate.21 In this paper, we report further application of this strategy for the
synthesis of N-unsubstituted dimethyl 3,4-diarylpyrrole-2,5-dicarboxylates.
RESULTS AND DISCUSSION
Initially, we examined Suzuki-Miyaura coupling of dimethyl 3,4-bis(trifluoromethanesulfonyloxy)-
pyrrole-2,5-dicarboxylate (1) with 4-methoxyphenylboronic acid (2a). Under the previously established
conditions,20 bis-triflate (1) was treated with 2a (3.0 equiv.) and aqueous Na2CO3 in the presence of a
catalytic amount of Pd(PPh3)4 in refluxing THF for 20 h, however, only trace amount (3%) of the desired
3,4-bis(4-methoxyphenyl)pyrrole (3a) was obtained and unreacted 1 was recovered in 68% yield
(Scheme 1).
MeO
OMe
MeO
B(OH)2
TfO
MeO2C
OTf
CO2Me
2a (3 equiv.)
Pd(PPh3)4 (4 mol%), aq. Na2CO3
THF, reflux, 20 h
MeO2C
CO2Me
N
H
N
H
1
3a
(3%) (+ 68% 1)
Scheme 1
This result suggested N-protection of bis-triflate (1) may be indispensable for the smooth
cross-coupling.22 Thus, we decided to test the cross-coupling of N-benzyl protected bis-triflate (7).
The synthesis of 7 is shown in Scheme 2. Benzylamine (4) was alkylated with methyl bromoacetate to
give N-benzyliminodiacetate (5) in 90% yield. Hinsberg reaction of 5 with dimethyl oxalate using NaH
as a base afforded 3,4-dihydroxypyrrole (6) in 88% yield. The conventional conditions using NaOMe in
MeOH afforded 6 in much lower yield (58%).23 Triflation of 6 with trifluoromethanesulfonic anhydride
in pyridine gave the bis-triflate (7) in 96% yield.
HO
MeO2C
OH
CO2Me
TfO
MeO2C
OTf
CO2Me
(a)
(b)
(c)
MeO2C
N
CO2Me
Bn-NH2
Bn
N
N
Bn
Bn
4
5
6
7
Scheme 2. Reagents and conditions: (a) BrCH2CO2Me (2.1 equiv.), NaHCO3, MeCN, reflux, 2 h (90%). (b)
(CO2Me)2, NaH, THF, reflux, 3 h (88%). (c) Tf2O (2.2 equiv.), pyridine, 0 °C, 1 h (96%).
The results of the cross-coupling of 7 with a variety of arylboronic acids (2a-i) are summarized in Table 1.

HETEROCYCLES, Vol. 77, No. 2, 2009
1107
In contrast to the reaction of 1, 7 reacted with 2a-i quite smoothly to give 3,4-diarylated products 8a-i in
excellent yields. The reactions were not affected by electronic or steric effects of the substituents on the
aryl ring of the boronic acids.
Table 1. Palladium-catalyzed cross-coupling of bis-triflate (7) with arylboronic acids (2)
R2
R1
R4 R4
R3
R3
R3
B(OH)2
R2
R2
TfO
MeO2C
OTf
CO2Me
2 (3 equiv.)
R4
R1
R1
MeO2C
CO2Me
Pd(PPh3)4 (4 mol%), aq. Na2CO3
THF, reflux, 20 h
N
N
Bn
Bn
7
8
entry
2
R1
H
H
H
H
H
R2
H
R3
OMe
H
R4
H
8
yield (%)a
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
8a
8b
8c
8d
8e
8f
99
98
H
H
H
Oi-Pr
F
H
quant.
99
H
H
H
Cl
H
98
OMe
H
H
H
H
97
2g
2h
2i
OMe
OMe
H
OMe
OMe
OMe
H
8g
8h
8i
99
H
OMe
OMe
96
9
OMOM
99
a Isolated yield.
Having established the cross-coupling reactions of 7, we next carried out debenzylation of 8 to produce
N-unsubstituted 3,4-diarylpyrroles (3). The results are summarized in Table 2. 3,4-Diarylpyrroles
(8a-i) were treated with Pearlman’s catalyst24 and ammonium formate in refluxing EtOH to give the
debenzylated compounds (3) in excellent yields, except for compound (8e). In this case, hydrogenolysis
of C-Cl bonds on the aryl groups also proceeded and 3,4-diphenylpyrrole (3b) was isolated (entry 5).
Fortunately, however, deprotection of 8e was cleanly effected under solvolytic conditions25 (Scheme 3).
Since an efficient synthesis of 3,4-symmetrically arylated pyrroles (3a-i) was established, we next
examined the stepwise cross-coupling with different arylboronic acids to produce 3,4-unsymmetrically
arylated pyrrole (11) (Scheme 4). Thus, the bis-triflate (7) was treated with 1.0 equiv. of
3,4-dimethoxyphenylboronic acid (2g) to give the mono-arylated pyrrole (9) in 75% yield accompanied
by 8% of 8g. The second cross-coupling of 9 with 4-methoxyphenylboronic acid (2a) gave the
3,4-differentially arylated pyrrole (10) in excellent yield. Hydrogenolysis of 10 gave the deprotected 11
in 69% yield.

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HETEROCYCLES, Vol. 77, No. 2, 2009
Table 2. Debenzylation of 3,4-diarylpyrrole (8)
R4 R4
R4 R4
R3
R3
R3
R3
R2
R2
R2
R2
HCO2NH4 (30 equiv.), Pd(OH)2-C
EtOH, reflux, time
R1
R1
R1
MeO2C
R1
MeO2C
CO2Me
CO2Me
N
N
H
Bn
8
3
entry
8
R1
R2
H
R3
OMe
H
R4
H
time (h)
3
yield (%)a
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
H
H
H
H
H
1
1
3a
3b
3c
3d
3e
3f
97
quant.
95
H
H
H
Oi-Pr
F
H
3
H
H
3
89
H
Cl
H
2
0b
OMe
H
H
H
H
1
88
8g
8h
8i
OMe
OMe
H
OMe
OMe
OMe
H
1.5
2
3g
3h
3i
95
H
OMe
OMe
96
9
OMOM
1
94
a Isolated yield.
b Dimethyl 3,4-diphenylpyrrole-2,5-dicarboxylate (3b) was obtained (85%).
Finally, we briefly describe the utility of our procedure for the synthesis of natural products. Recently,
Cl
Cl
Cl
Cl
conc. H2SO4, anisole, TFA
reflux, 0.5 h
(80%)
MeO2C
CO2Me
MeO2C
CO2Me
N
N
H
Bn
8e
3e
Scheme 3
MeO
MeO
MeO
MeO
OMe
MeO
MeO
OMe
TfO
MeO2C
OTf
CO2Me
OTf
(a)
(b)
(c)
MeO2C
CO2Me
MeO2C
CO2Me
MeO2C
CO2Me
N
N
N
N
H
Bn
Bn
Bn
7
9
10
11
Scheme 4. Reagents and conditions: (a) 2g (1 equiv.), Pd(PPh3)4 (2 mol%), aq. Na2CO3, THF, reflux, 4 h
(9: 75%, 8g: 8%). (b) 2a (1.5 equiv.), Pd(PPh3)4 (4 mol%), aq. Na2CO3, THF, reflux, 20 h
(96%). (c) HCO2NH4 (30 equiv.), Pd(OH)2-C, EtOH, reflux, 3 h (69%).

HETEROCYCLES, Vol. 77, No. 2, 2009
1109
we reported the short-step synthesis of lamellarins O, P, Q, and R using 13 as a common intermediate.26
This key intermediate was prepared in two steps from 3c by partial hydrolysis and decarboxylation
(Scheme 5).
i-PrO
Oi-Pr
i-PrO
Oi-Pr
i-PrO
Oi-Pr
LiOH•H2O (0.5 equiv.)
THF-MeOH-H2O=3:1:1
Cu2O
quinoline
rt, 44 h
(47%) (+51% 3c)
220 °C, 7 min
(80%)
MeO2C
CO2Me
HO2C
CO2Me
CO2Me
N
H
N
H
N
H
3c
12
13
ref. 26
OH
HO
HO
OH
MeO
CO2Me
CO2Me
N
N
R
lamellarin O (R=H)
lamellarin P (R=OH)
lamellarin Q (R=H)
lamellarin R (R=C6H4-p-OH)
R
O
Scheme 5
It is also noteworthy, that the 3,4-diarylpyrroles (3h) and (3i) were utilized as the key intermediates in the
synthesis of permethyl storniamide A and ningalin A, respectively, by Boger et al.15a (Scheme 6).
In conclusion, we have developed an efficient procedure to produce N-unsubstituted
MeO
OMe
MeO
MeO
OMe
OMe
MeO
OMe
MeO
MeO
OMe
OMe
H
N
H
N
ref. 15a
MeO
OMe
N
O
O
MeO2C
CO2Me
N
H
3h
OMe
permethyl storniamide A
MeO
OMe
OMe
HO
OH
MeO
HO
OH
ref. 15a
MOMO
OMOM
O
O
MeO2C
CO2Me
N
H
N
O
O
H
3i
ningalin A
Scheme 6

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HETEROCYCLES, Vol. 77, No. 2, 2009
3,4-diarylpyrrole-2,5-dicarboxylates. This method can be utilized for the synthesis of 3,4-diarylpyrrole
marine natural products and their analogues.
EXPERIMENTAL
Melting points were determined with a Yanagimoto micro melting points apparatus and are uncorrected.
IR spectra were obtained with a Perkin-Elmer System 2000 instrument. NMR spectra were recorded on
1
13
a JEOL JNM-AL400 instrument (400 MHz for H and 100 MHz for C) using tetramethylsilane as an
internal standard. High resolution mass spectra were recorded on a JEOL JMS-700N spectrometer.
Flash chromatography was conducted on Silica Gel 60N, 40-50 µm (Kanto Chemical Co., Inc.).
Column chromatography was conducted on Silica Gel 60N, 63-210 µm (Kanto Chemical Co., Inc.) or
Chromatorex NH-DM1020 silica gel (Fuji Silysia Chemical Ltd.). Dry THF were distilled from
Na-benzophenone ketyl under argon immediately before use.
Dimethyl 3,4-bis(trifluoromethanesulfonyloxy)pyrrole-2,5-dicarboxylate (1)
Under an argon atmosphere, a suspension of dimethyl oxalate (2.36 g, 20.0 mmol) and NaH (60%
dispersion in mineral oil, 1.63 g, ca. 40.8 mmol, prewashed with hexane) in THF (10 mL) was heated to
reflux. To this suspension was added dropwise a solution of dimethyl iminodiacetate (1.61 g, 10.0
mmol) in THF (30 mL) under reflux. After being refluxed for additional 3 h, the reaction mixture was
cooled to rt, quenched with acetic acid (3 mL) and evaporated under reduced pressure. The residue was
poured into ice-cold water and the suspension was acidified with 2 M aqueous HCl to pH 3. The
precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give
dimethyl 3,4-dihydroxypyrrole-2,5-dicarboxylate as pale yellow powder (1.50 g, 70%).
Recrystallization from MeOH gave pale yellow powder. Mp 180-210 °C (decomp) (sealed capillary);
IR (KBr): 3399, 3302, 1701, 1565, 1500, 1438, 1311, 1194, 1157 cm–1; 1H NMR (400 MHz, acetone-d6):
13
δ 3.84 (s, 6H), 7.53 (s, 2H), 9.89 (s, 1H); C NMR (100 MHz, acetone-d6): δ 51.7, 109.9, 138.5, 162.4.
Anal. Calcd for C8H9NO6: C, 44.66; H, 4.22; N, 6.51. Found: C, 44.90; H, 4.33; N, 6.30.
Under an argon atmosphere, trifluoromethanesulfonic anhydride (3.70 mL, 22.6 mmol) was added as a
neat liquid to a solution of dimethyl 3,4-dihydroxypyrrole-2,5-dicarboxylate (2.19 g, 10.2 mmol) in
pyridine (20 mL) at 0 °C. After being stirred for 3 h, the reaction mixture was quenched with water at
the same temperature and allowed to warm to rt. The product was extracted with Et2O and the extract
was washed successively with 3 M aqueous HCl, water, and brine, and dried over Na2SO4. The solvent
was removed by evaporation and the residue was purified by column chromatography over Silica Gel
60N (hexane-EtOAc=2:1) to give 1 as colorless solid (4.27 g, 87%). Recrystallization from
Et2O-hexane gave colorless needles. Mp 122-122.5 °C; IR (KBr): 3307, 3273, 1738, 1714, 1439, 1297,

HETEROCYCLES, Vol. 77, No. 2, 2009
1111
1
13
1228, 1135 cm-1; H NMR (400 MHz, CDCl3): δ 4.00 (s, 6H), 10.42 (br s, 1H); C NMR (100 MHz,
CDCl3): 52.9, 115.9, 118.4 (q, J= 320 Hz), 127.4, 158.0. Anal. Calcd for C10H7F6NO10S2: C, 25.06; H,
1.47; N, 2.92. Found: C, 24.99; H, 1.22; N, 2.87.
Suzuki-Miyaura coupling of bis-triflate (1) with arylboronic acids (2a).
Under an argon atmosphere, a degassed solution of Na2CO3 (700 mg, 6.60 mmol) in water (2.0 mL) was
added to a solution of 1 (479 mg, 1.00 mmol), 2a (456 mg, 3.00 mmol) and Pd(PPh3)4 (46.2 mg, 40.0
µmol) in THF (20 mL) at rt and the mixture was refluxed for 20 h. The mixture was cooled to rt and
evaporated under reduced pressure. The residue was diluted with water, adjusted to pH 3 with 1 M
aqueous HCl, and saturated with NaCl. The products were extracted with CH2Cl2 and the extract was
washed successively with water and brine, dried over Na2SO4, and evaporated under reduced pressure.
The residue was purified successively by flash chromatography over Silica Gel 60N
(toluene-EtOAc=5:1~EtOAc) and column chromatography over Chromatorex NH-DM1020 silica gel
(hexane-EtOAc=3:1) to give 3a as colorless solid (12.0 mg, 3%) and unreacted 1 (326 mg, 68%).
Dimethyl N-benzyliminodiacetate (5)
Methyl bromoacetate (90 mL, 0.951 mol) was added as a neat liquid to a suspension of benzylamine (4)
(49 mL, 0.449 mol) and NaHCO3 (159 g, 1.89 mol) in MeCN (700 mL) at rt. The mixture was refluxed
for 2 h and then cooled to rt. After removal of inorganic salts by filtration, the filtrate was evaporated
under reduced pressure. The residue was purified by distillation (112 °C/ 0.2 mmHg) to give 5 as pale
yellow oil (101 g, 90%). IR (neat): 1746, 1454, 1436, 1202, 1010 cm-1; 1H NMR (400 MHz, CDCl3): δ
13
3.56 (s, 4H), 3.70 (s, 6H), 3.91 (s, 2H), 7.23-7.29 (m, 1H), 7.29-7.35 (m, 2H), 7.35-7.40 (m, 2H); C
NMR (100 MHz, CDCl3): δ 51.5, 54.0, 58.0, 127.4, 128.4, 129.0, 138.1, 171.6. HREIMS m/z. Calcd for
C13H17NO4 (M+): 251.1158. Found: 251.1155.
Dimethyl N-benzyl-3,4-dihydroxypyrrole-2,5-dicarboxylate (6)
Under an argon atmosphere, a suspension of dimethyl oxalate (14.9 g, 126 mmol) and NaH (60%
dispersion in mineral oil, 10.0 g, ca. 250 mmol, prewashed with hexane) in THF (80 mL) was heated to
reflux. To this suspension was added dropwise a solution of 5 (15.7 g, 62.5 mmol) in THF (150 mL)
under reflux. After being refluxed for additional 3 h, the reaction mixture was cooled to rt, quenched
with acetic acid (16 mL) and evaporated under reduced pressure. The residue was poured into ice-cold
water and the suspension was acidified with 2 M aqueous HCl to pH 3. The precipitated solid was
collected by filtration, washed with water, and dried under reduced pressure to give 6 as pale brown
powder (16.8 g, 88%). Recrystallization from MeOH gave pale brown powder. Mp 166.5-167 °C; IR

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HETEROCYCLES, Vol. 77, No. 2, 2009
(KBr): 3365, 1692, 1658, 1509, 1461, 1296, 1195, 1160 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.85 (s, 6H),
5.75 (s, 2H), 6.90-6.94 (m, 2H), 7.16-7.20 (m, 3H), 7.65 (br s, 2H); 13C NMR (100 MHz, CDCl3): δ 49.3,
51.8, 111.0, 125.6, 126.9, 128.4, 138.9, 139.4, 162.5. Anal. Calcd for C15H15NO6: C, 59.01; H, 4.95; N,
4.59. Found: C, 59.07; H, 4.85; N, 4.55.
Dimethyl N-benzyl-3,4-bis(trifluoromethanesulfonyloxy)pyrrole-2,5-dicarboxylate (7)
Under an argon atmosphere, trifluoromethanesulfonic anhydride (18.2 mL, 108 mmol) was added as a
neat liquid to a solution of 6 (15.0 g, 49.1 mmol) in pyridine (75 mL) at 0 °C. After being stirred for 1 h,
the reaction mixture was quenched with water at the same temperature and allowed to warm to rt. The
product was extracted with Et2O and the extract was washed successively with 3 M aqueous HCl, water,
and brine, and dried over Na2SO4. The solvent was removed by evaporation and the residue was
purified by column chromatography over Silica Gel 60N (hexane-EtOAc=5:1) to give 7 as colorless solid
(26.9 g, 96%). Recrystallization from Et2O-hexane gave colorless granules. Mp 70.5-71 °C; IR (KBr):
1
1745, 1438, 1289, 1248, 1211, 1134 cm-1; H NMR (400 MHz, CDCl3): δ 3.88 (s, 6H), 6.19 (s, 2H),
6.95-7.02 (m, 2H), 7.21-7.34 (m, 3H); 13C NMR (100 MHz, CDCl3): δ 49.8, 52.4, 117.6, 118.4 (q, J= 320
Hz), 126.0, 127.6, 128.3, 128.7, 136.2, 158.0. Anal. Calcd for C17H13F6NO10S2: C, 35.86; H, 2.30; N,
2.46. Found: C, 35.64; H, 2.12; N, 2.42.
Suzuki-Miyaura coupling of bis-triflate (7) with arylboronic acids (2). General procedure
Under an argon atmosphere, a degassed solution of Na2CO3 (2.10 g, 19.8 mmol) in water (6.0 mL) was
added to a solution of 7 (3.02 mmol), 2 (9.02 mmol) and Pd(PPh3)4 (140 mg, 0.121 mmol) in THF (60
mL) at rt and the mixture was refluxed for 20 h. The mixture was cooled to rt and evaporated under
reduced pressure. The product was extracted with CH2Cl2 and the extract was washed successively with
water and brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified
by column chromatography to give 8.
Dimethyl N-benzyl-3,4-bis(4-methoxyphenyl)pyrrole-2,5-dicarboxylate (8a)
According to the general procedure, 7 (1.72 g, 3.02 mmol) and 2a (1.37 g, 9.02 mmol) were reacted.
After chromatographic purification over Silica Gel 60N (toluene~toluene-EtOAc=10:1), 8a was obtained
as colorless solid (1.45 g, 99%). Recrystallization from CH2Cl2-hexane gave colorless granules. Mp
1
142-143 °C; IR (KBr): 1717, 1694, 1534, 1431, 1293, 1246, 1203, 1032 cm-1; H NMR (400 MHz,
CDCl3): δ 3.52 (s, 6H), 3.75 (s, 6H), 6.01 (s, 2H), 6.69-6.73 (m, 4H), 6.93-6.96 (m, 4H), 7.07-7.11 (m,
2H), 7.18-7.24 (m, 1H), 7.26-7.32 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 49.7, 51.4, 55.1, 112.7, 124.4,
126.2, 126.4, 126.9, 128.4, 130.9, 131.4, 138.6, 158.1, 162.0. Anal. Calcd for C29H27NO6: C, 71.74; H,

HETEROCYCLES, Vol. 77, No. 2, 2009
1113
5.61; N, 2.88. Found: C, 71.52; H, 5.62; N, 2.84.
Dimethyl N-benzyl-3,4-diphenylpyrrole-2,5-dicarboxylate (8b)
According to the general procedure, 7 (1.71 g, 3.00 mmol) and 2b (1.10 g, 9.00 mmol) were reacted.
After chromatographic purification over Silica Gel 60N (toluene), 8b was obtained as colorless solid
(1.25 g, 98%). Recrystallization from Et2O-pentane gave colorless needles. Mp 138-139 °C; IR (KBr):
1
1716, 1435, 1296, 1228, 1201, 1173 cm-1; H NMR (400 MHz, CDCl3): δ 3.49 (s, 6H), 6.05 (s, 2H),
13
7.01-7.06 (m, 4H), 7.09-7.25 (m, 9H), 7.27-7.33 (m, 2H); C NMR (100 MHz, CDCl3): δ 49.6, 51.4,
124.4, 126.2, 126.4, 126.9, 127.1, 128.3, 130.2, 131.1, 134.0, 138.4, 161.8. Anal. Calcd for C27H23NO4:
C, 76.22; H, 5.45; N, 3.29. Found: C, 76.05; H, 5.38; N, 3.22.
Dimethyl N-benzyl-3,4-bis(4-isopropoxyphenyl)pyrrole-2,5-dicarboxylate (8c)
According to the general procedure, 7 (5.29 g, 9.29 mmol) and 2c (5.02 g, 27.9 mmol) were reacted.
After chromatographic purification over Silica Gel 60N (toluene~toluene-EtOAc=10:1), 8c was obtained
as colorless solid (5.02 g, quant.). Recrystallization from Et2O-pentane gave colorless. Mp
1
140-141 °C; IR (KBr): 1713, 1531, 1435, 1298, 1244, 1201, 1182 cm-1; H NMR (400 MHz, CDCl3): δ
1.30 (d, J= 6.1 Hz, 12H), 3.52 (s, 6H), 4.43-4.53 (m, 2H), 6.00 (s, 2H), 6.68-6.72 (m, 4H), 6.90-6.94 (m,
4H), 7.07-7.10 (m, 2H), 7.18-7.23 (m, 1H), 7.26-7.31 (m, 2H);13C NMR (100 MHz, CDCl3): δ 22.0, 49.6,
51.3, 69.7, 114.7, 124.3, 126.2, 126.2, 126.9, 128.3, 130.8, 131.4, 138.6, 156.3, 162.0. Anal. Calcd for
C33H35NO6: C, 73.18; H, 6.51; N, 2.59. Found: C, 73.31; H, 6.63; N, 2.47.
Dimethyl N-benzyl-3,4-bis(4-fluorophenyl)pyrrole-2,5-dicarboxylate (8d)
According to the general procedure, 7 (1.71 g, 3.00 mmol) and 2d (1.26 g, 9.01 mmol) were reacted.
After chromatographic purification over Silica Gel 60N (toluene), 8d was obtained as colorless solid
(1.37 g, 99%). Recrystallization from CH2Cl2-hexane gave colorless granules. Mp 126.5-127.5 °C; IR
(KBr): 1714, 1534, 1436, 1299, 1225, 1201, 1176 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.52 (s, 6H), 6.05
(s, 2H), 6.84-6.91 (m, 4H), 6.95-7.01 (m, 4H), 7.08-7.11 (m, 2H), 7.20-7.26 (m, 1H), 7.27-7.33 (m, 2H);
13C NMR (100 MHz, CDCl3): δ 49.8, 51.5, 114.3 (d, J= 21 Hz), 124.5, 126.3, 127.1, 128.5, 129.9 (d, J=
3.3 Hz), 130.3, 131.9 (d, J= 8.3 Hz), 138.4, 161.6 (d, J= 245 Hz), 161.6. Anal. Calcd for C27H21F2NO4:
C, 70.28; H, 4.59; N, 3.04. Found: C, 70.56; H, 4.61; N, 2.98.
Dimethyl N-benzyl-3,4-bis(4-chlorophenyl)pyrrole-2,5-dicarboxylate (8e)
According to the general procedure, 7 (1.71 g, 3.00 mmol) and 2e (1.41 g, 9.02 mmol) were reacted.
After chromatographic purification over Silica Gel 60N (toluene), 8e was obtained as colorless solid (1.45

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HETEROCYCLES, Vol. 77, No. 2, 2009
g, 98%). Recrystallization from CH2Cl2-hexane gave colorless prisms. Mp 128-129 °C; IR (KBr):
1
1707, 1455, 1434, 1292, 1196, 1171, 1102, 1020 cm-1; H NMR (400 MHz, CDCl3): δ 3.52 (s, 6H), 6.05
(s, 2H), 6.93-6.96 (m, 4H), 7.07-7.11 (m, 2H), 7.14-7.18 (m, 4H), 7.20-7.25 (m, 1H), 7.27-7.33 (m, 2H);
13C NMR (100 MHz, CDCl3): δ 49.8, 51.6, 124.5, 126.3, 127.1, 127.6, 128.5, 129.9, 131.6, 132.4, 132.7,
138.2, 161.5. Anal. Calcd for C27H21Cl2NO4: C, 65.60; H, 4.28; N, 2.83. Found: C, 65.54; H, 4.27; N,
2.72.
Dimethyl N-benzyl-3,4-bis(2-methoxyphenyl)pyrrole-2,5-dicarboxylate (8f)
According to the general procedure, 7 (564 mg, 0.990 mmol) and 2f (453 mg, 2.98 mmol) were reacted.
After
successive
purification
by
column
chromatography
over
Silica
Gel
60N
(toluene-EtOAc=20:1~10:1) and column chromatography over Silica Gel 60N (hexane-CH2Cl2=1:5), 8f
was obtained as colorless solid (466 mg, 97%). Recrystallization from CH2Cl2-Et2O gave colorless
1
granules. Mp 168.5-169.5 °C; IR (KBr): 1721, 1698, 1438, 1291, 1248, 1201, 1176, 1029 cm-1; H
NMR (400 MHz, CDCl3): δ 3.47 (s, 6H), 3.57 (s, 6H), 6.10 (s, 2H), 6.69-6.77 (m, 4H), 6.86-6.90 (m, 2H),
7.09-7.15 (m, 4H), 7.16-7.22 (m, 1H), 7.25-7.31 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 49.6, 51.2, 55.3,
110.0, 119.6, 124.0, 125.1, 126.2, 126.7, 127.2, 127.9, 128.3, 131.3, 138.9, 156.8, 161.9. Anal. Calcd
for C29H27NO6: C, 71.74; H, 5.61; N, 2.88. Found: C, 71.62; H, 5.71; N, 2.72.
Dimethyl N-benzyl-3,4-bis(3,4-dimethoxyphenyl)pyrrole-2,5-dicarboxylate (8g)
According to the general procedure, 7 (1.71 g, 3.00 mmol) and 2g (1.64 g, 9.01 mmol) were reacted.
After chromatographic purification over Silica Gel 60N (toluene-EtOAc=5:1), 8g was obtained as
colorless solid (1.62 g, 99%). Recrystallization from CH2Cl2-hexane gave colorless needles. Mp
1
154.5-155.5 °C; IR (KBr): 1718, 1532, 1439, 1318, 1235, 1206, 1178, 1028 cm-1; H NMR (400 MHz,
CDCl3): δ 3.56 (s, 6H), 3.65 (s, 6H), 3.84 (s, 6H), 6.00 (s, 2H), 6.55 (d, J= 1.7 Hz, 2H), 6.61 (dd, J= 1.7
13
and 8.1 Hz, 2H), 6.71 (d, J= 8.1 Hz, 2H), 7.11-7.14 (m, 2H), 7.20-7.26 (m, 1H), 7.28-7.34 (m, 2H); C
NMR (100 MHz, CDCl3): δ 49.6, 51.5, 55.7, 110.1, 113.8, 122.7, 124.3, 126.3, 126.6, 127.0, 128.4, 130.6,
138.4, 147.5, 147.7, 162.0. Anal. Calcd for C31H31NO8: C, 68.25; H, 5.73; N, 2.57. Found: C, 68.09; H,
5.86; N, 2.51.
Dimethyl N-benzyl-3,4-bis(3,4,5-trimethoxyphenyl)pyrrole-2,5-dicarboxylate (8h)
According to the general procedure, 7 (410 mg, 0.720 mmol) and 2h (455 mg, 2.15 mmol) were reacted.
After successive purification by column chromatography over Silica Gel 60N (toluene-EtOAc=10:1~5:1)
and column chromatography over Chromatorex NH-DM1020 silica gel (toluene-EtOAc=10:1), 8h was
obtained as colorless solid (418 mg, 96%). Recrystallization from CH2Cl2-Et2O gave colorless granules.

HETEROCYCLES, Vol. 77, No. 2, 2009
1115
1
Mp 159.5-160.5 °C; IR (KBr): 1717, 1582, 1434, 1341, 1279, 1239, 1196, 1128, 1099, 1001 cm-1; H
NMR (400 MHz, CDCl3): δ 3.59 (s, 6H), 3.64 (s, 12H), 3.81 (s, 6H), 5.99 (s, 2H), 6.28 (s, 4H), 7.13-7.18
13
(m, 2H), 7.22-7.24 (m, 1H), 7.27-7.35 (m, 2H); C NMR (100 MHz, CDCl3): δ 49.7, 51.7, 56.1, 60.9,
107.9, 124.2, 126.4, 127.1, 128.4, 129.4, 130.4, 136.8, 138.2, 152.2, 161.9. Anal. Calcd for C33H35NO10:
C, 65.44; H, 5.82; N, 2.31. Found: C, 65.73; H, 5.87; N, 2.19.
Dimethyl N-benzyl-3,4-bis(4,5-dimethoxy-2-methoxymethoxyphenyl)pyrrole-2,5-dicarboxylate (8i)
According to the general procedure, 7 (2.29 g, 4.02 mmol) and 2i (2.90 g, 12.0 mmol) were reacted.
After successive purification by column chromatography over Silica Gel 60N (hexane-EtOAc=1:1) and
column chromatography over Chromatorex NH-DM1020 silica gel (hexane-EtOAc=2:1), 8i was obtained
as colorless solid (2.65 g, 99%). Recrystallization from CH2Cl2-Et2O gave colorless granules. Mp
1
139.5-140.5 °C; IR (KBr): 1722, 1703, 1533, 1439, 1288, 1214, 1078, 1031, 1005 cm-1; H NMR (400
MHz, CDCl3): δ 3.28 (s, 6H), 3.55 (s, 6H), 3.56 (s, 6H), 3.83 (s, 6H), 4.83 (br s, 4H), 6.06 (s, 2H), 6.47
13
(br s, 2H), 6.68 (s, 2H), 7.12-7.16 (m, 2H), 7.19-7.24 (m, 1H), 7.26-7.33 (m, 2H); C NMR (100 MHz,
CDCl3): δ 49.5, 51.5, 55.8, 55.9, 56.0, 96.6, 101.7, 114.4, 117.1, 125.3, 126.5, 126.8, 127.0, 128.4, 138.9,
143.7, 148.5, 149.2, 162.2. Anal. Calcd for C35H39NO12: C, 63.15; H, 5.91; N, 2.10. Found: C, 63.12;
H, 5.97; N, 1.99.
Synthesis of dimethyl 3,4-diarylpyrrole-2,5-dicarboxylates (3). General procedure
Under an argon atmosphere, ammonium formate (1.53 g, 24.3 mmol) was added portionwise to a mixture
of 8 (0.801 mmol), Pearlman’s catalyst (129 mg), and EtOH (16 mL) at rt. After being refluxed for an
appropriate reaction time shown in Table 2, the mixture was cooled to rt and passed through a pad of
Celite. The filtrate was evaporated under reduced pressure. The residue was purified by column
chromatography to give 3.
Dimethyl 3,4-bis(4-methoxyphenyl)pyrrole-2,5-dicarboxylate (3a)
According to the general procedure, 8a (389 mg, 0.801 mmol) and Pearlman’s catalyst (129 mg) were
reacted. After chromatographic purification over Silica Gel 60N (CH2Cl2), 3a was obtained as colorless
solid (308 mg, 97%).
Recrystallization from CH2Cl2-hexane gave colorless needles.
Mp
1
195.5-196 °C; IR (KBr): 3351, 1710, 1537, 1469, 1438, 1311, 1249, 1181 cm-1; H NMR (400 MHz,
13
CDCl3): δ 3.77 (s, 12H), 6.73-6.77 (m, 4H), 7.01-7.05 (m, 4H), 9.80 (br s, 1H); C NMR (100 MHz,
CDCl3): δ 51.7, 55.0, 112.8, 121.0, 125.0, 131.1, 131.8, 158.3, 160.6. Anal. Calcd for C22H21NO6: C,
66.83; H, 5.35; N, 3.54. Found: C, 66.75; H, 5.44; N, 3.45.

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HETEROCYCLES, Vol. 77, No. 2, 2009
Dimethyl 3,4-diphenylpyrrole-2,5-dicarboxylate (3b)
According to the general procedure, 8b (3.68 g, 8.64 mmol) and Pearlman’s catalyst (368 mg) were
reacted. After chromatographic purification over Silica Gel 60N (CH2Cl2), 3b was obtained as colorless
solid (2.89 g, quant.). Recrystallization from CH2Cl2-Et2O gave colorless cube. Mp 195-196 °C; IR
1
(KBr): 3310, 1710, 1462, 1429, 1297, 1242, 1157 cm-1; H NMR (400 MHz, CDCl3): δ 3.75 (s, 6H),
7.08-7.13 (m, 4H), 7.17-7.21 (m, 6H), 9.89 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 51.7, 121.1, 126.8,
127.2, 130.6, 131.4, 132.7, 160.5. Anal. Calcd for C20H17NO4: C, 71.63; H, 5.11; N, 4.18. Found: C,
71.62; H, 5.19; N, 4.12.
Dimethyl 3,4-bis(4-isopropoxyphenyl)pyrrole-2,5-dicarboxylate (3c)
According to the general procedure, 8c (7.02 g, 13.0 mmol) and Pearlman’s catalyst (751 mg) were
reacted. After chromatographic purification over Silica Gel 60N (CH2Cl2), 3c was obtained as colorless
solid (5.56 g, 95%). Recrystallization from CH2Cl2-pentane gave colorless granules. Mp 148-149 °C;
IR (KBr): 3290, 1703, 1534, 1464, 1297, 1246, 1185, 1120, 1106, 955 cm-1; 1H NMR (400 MHz, CDCl3):
δ 1.31 (d, J= 6.1 Hz, 12H), 3.77 (s, 6H), 4.44-4.55 (m, 2H), 6.70-6.74 (m, 4H), 6.98-7.02 (m, 4H), 9.80
13
(br s, 1H); C NMR (100 MHz, CDCl3): δ 22.1, 51.7, 69.6, 114.6, 120.9, 124.7, 131.2, 131.8, 156.7,
160.6. Anal. Calcd for C26H29NO6: C, 69.16; H, 6.47; N, 3.10. Found: C, 69.16; H, 6.36; N, 3.01.
Dimethyl 3,4-bis(4-fluorophenyl)pyrrole-2,5-dicarboxylate (3d)
According to the general procedure, 8d (462 mg, 1.00 mmol) and Pearlman’s catalyst (49 mg) were
reacted. After chromatographic purification over Silica Gel 60N (hexane-CH2Cl2=1:5), 3d was obtained
as colorless solid (329 mg, 89%). Recrystallization from CH2Cl2-hexane gave colorless needles. Mp
174-175 °C; IR (KBr): 3319, 1725, 1691, 1475, 1463, 1294, 1255, 1223, 1160 cm-1; 1H NMR (400 MHz,
CDCl3): δ 3.77 (s, 6H), 6.84-6.94 (m, 4H), 7.03-7.09 (m, 4H), 9.90 (br s, 1H); 13C NMR (100 MHz,
CDCl3): δ 51.8, 114.4 (d, J= 22 Hz), 121.2, 128.4 (d, J= 3.3 Hz), 130.3, 132.2 (d, J= 8.3 Hz), 160.4, 161.8
(d, J= 246 Hz). Anal. Calcd for C20H15F2NO4: C, 64.69; H, 4.07; N, 3.77. Found: C, 64.58; H, 3.95; N,
3.68.
Dimethyl 3,4-bis(2-methoxyphenyl)pyrrole-2,5-dicarboxylate (3f)
According to the general procedure, 8f (195 mg, 0.402 mmol) and Pearlman’s catalyst (100 mg) were
reacted. After chromatographic purification over Silica Gel 60N (CH2Cl2~CH2Cl2-EtOAc=10:1), 3f was
obtained as colorless solid (140 mg, 88%). Recrystallization from CH2Cl2-pentane gave colorless
1
granules. Mp 203-205 °C; IR (KBr): 3290, 1713, 1694, 1470, 1434, 1300, 1270, 1248, 1157 cm-1; H
NMR (400 MHz, CDCl3): δ 3.53 (br s, 6H), 3.72 (s, 6H), 6.76 (dd, J= 1.0 and 7.5 Hz, 2H), 6.78 (dt, J=

HETEROCYCLES, Vol. 77, No. 2, 2009
1117
1.0 and 7.5 Hz, 2H), 6.98 (dd, J= 1.8 and 7.5 Hz, 2H), 7.16 (dt, J= 1.8 and 7.5 Hz, 2H), 9.86 (br s, 1H);
13C NMR (100 MHz, CDCl3): δ 51.5, 55.1, 110.2, 119.5, 122.0, 122.7, 127.8, 128.4, 131.6, 157.0, 160.6.
Anal. Calcd for C22H21NO6: C, 66.83; H, 5.35; N, 3.54. Found: C, 66.76; H, 5.41; N, 3.37.
Dimethyl 3,4-bis(3,4-dimethoxyphenyl)pyrrole-2,5-dicarboxylate (3g)
According to the general procedure, 8g (546 mg, 1.00 mmol) and Pearlman’s catalyst (55 mg) were
reacted. After chromatographic purification over Silica Gel 60N (CH2Cl2), 3g was obtained as colorless
solid (432 mg, 95%).
Recrystallization from CH2Cl2-hexane gave colorless needles.
Mp
1
168.5-169.5 °C; IR (KBr): 3313, 1719, 1683, 1531, 1469, 1438, 1319, 1279, 1245, 1138, 1024 cm-1; H
NMR (400 MHz, CDCl3): δ 3.64 (s, 6H), 3.79 (s, 6H), 3.85 (s, 6H), 6.61-6.63 (m, 2H), 6.71-6.77 (m, 4H),
9.83 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 51.8, 55.7, 55.7, 110.2, 114.2, 120.9, 123.2, 125.2, 131.1,
147.7, 147.9, 160.6. Anal. Calcd for C24H25NO8: C, 63.29; H, 5.53; N, 3.08. Found: C, 63.33; H, 5.47;
N, 2.98.
Dimethyl 3,4-bis(3,4,5-trimethoxyphenyl)pyrrole-2,5-dicarboxylate (3h)
According to the general procedure, 8h (612 mg, 1.01 mmol) and Pearlman’s catalyst (67 mg) were
reacted. After chromatographic purification over Silica Gel 60N (CH2Cl2), 3h was obtained as colorless
solid (502 mg, 96%). Recrystallization from CH2Cl2-hexane gave colorless needles. Mp 166-167 °C;
1
IR (KBr): 3273, 1730, 1702, 1586, 1480, 1460, 1412, 1344, 1239, 1124 cm-1; H NMR (400 MHz,
CDCl3): δ 3.65 (s, 12H), 3.83 (s, 12H), 6.38 (s, 4H), 9.90 (br s, 1H); 13C NMR (100 MHz, CDCl3): δ 51.9,
56.0, 60.8, 108.4, 120.9, 128.0, 131.0, 137.1, 152.2, 160.4. Anal. Calcd for C26H29NO10: C, 60.58; H,
5.67; N, 2.72. Found: C, 60.57; H, 5.68; N, 2.60.
Dimethyl 3,4-bis(4,5-dimethoxy-2-methoxymethoxyphenyl)pyrrole-2,5-dicarboxylate (3i)
According to the general procedure, 8i (1.22 g, 1.83 mmol) and Pearlman’s catalyst (128 mg) were
reacted. After chromatographic purification over Silica Gel 60N (hexane-EtOAc=1:2), 3i was obtained
as colorless solid (993 mg, 94%). Recrystallization from CH2Cl2-Et2O gave colorless granules. Mp
150.5-151.5 °C; IR (KBr): 3277, 1713, 1494, 1233, 1152, 1099, 1011 cm-1; 1H NMR (400 MHz, CDCl3):
δ 3.31 (br s, 6H), 3.58 (br s, 6H), 3.77 (s, 6H), 3.84 (s, 6H), 4.61 (br s, 1H), 4.85 (br s, 2H), 5.02 (br s,
13
1H), 6.50 (br s, 2H), 6.77 (br s, 2H), 9.84 (br s, 1H); C NMR (100 MHz, CDCl3): δ 51.7, 55.7, 55.9,
56.1, 96.8, 101.4, 114.5, 122.2, 127.6, 143.6, 149.0, 150.0, 160.8. Anal. Calcd for C28H33NO12: C, 58.43;
H, 5.78; N, 2.43. Found: C, 58.48; H, 5.82; N, 2.26.
Dimethyl 3,4-bis(4-chlorophenyl)pyrrole-2,5-dicarboxylate (3e)

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HETEROCYCLES, Vol. 77, No. 2, 2009
Under an argon atmosphere, a mixture of 8e (509 mg, 1.03 mmol), anisole (140 µL, 1.29 mmol), and 98%
H2SO4 (36 µL, 0.68 mmol) in trifluoroacetic acid (1.2 mL) was refluxed for 0.5 h. After being cooled to
rt, the mixture was evaporated under reduced pressure. The residue was basified with saturated aqueous
NaHCO3 and the mixture was extracted with CH2Cl2. The extract was washed successively with water
and brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was purified by
column chromatography over Silica Gel 60N (hexane-CH2Cl2=1:5~CH2Cl2) to give 3e as colorless solid
(333 mg, 80%). Recrystallization from Et2O-pentane gave colorless granules. Mp 191.5-193 °C; IR
1
(KBr): 3281, 1713, 1462, 1436, 1298, 1248, 1163, 1091, 1027 cm-1; H NMR (400 MHz, CDCl3): δ 3.77
13
(s, 6H), 7.00-7.04 (m, 4H), 7.17-7.21 (m, 4H), 9.92 (br s, 1H); C NMR (100 MHz, CDCl3): δ 51.9,
121.3, 127.7, 129.9, 130.9, 131.9, 133.1, 160.2. HREIMS m/z. Calcd for C20H15Cl2NO4 (M+): 403.0378.
Found: 403.0379.
Dimethyl
N-benzyl-3-(3,4-dimethoxyphenyl)-4-(trifluoromethanesulfonyloxy)pyrrole-2,5-
dicarboxylate (9)
Under an argon atmosphere, a degassed solution of Na2CO3 (4.23 g, 39.9 mmol) in water (12 mL) was
added to a solution of 7 (3.46 g, 6.08 mmol), 2g (1.10 g, 6.05 mmol) and Pd(PPh3)4 (140 mg, 0.121
mmol) in THF (120 mL) at rt and the mixture was refluxed for 4 h. The mixture was cooled to rt and
evaporated under reduced pressure. The products were extracted with CH2Cl2 and the extract was
washed successively with water and brine, dried over Na2SO4, and evaporated under reduced pressure.
The residue was purified successively by column chromatography over Silica Gel 60N
(toluene~toluene-EtOAc=5:1) and over Silica Gel 60N (CH2Cl2) to give 9 as colorless solid (2.54 g, 75%),
3,4-diarylated 8g (258 mg, 8%), and unreacted 7 (461 mg, 13%). Recrystallization from CH2Cl2-hexane
gave colorless granules. Mp 131-132 °C; IR (KBr): 1728, 1442, 1425, 1294, 1265, 1212, 1139 cm-1; 1H
NMR (400 MHz, CDCl3): δ 3.58 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 6.09 (s, 2H), 6.82-6.90
13
(m, 3H), 7.01-7.05 (m, 2H), 7.21-7.27 (m, 1H), 7.27-7.33 (m, 2H); C NMR (100 MHz, CDCl3): 49.6,
51.9, 51.9, 55.8, 55.9, 110.5, 113.2, 117.8, 117.9 (q, J= 320 Hz), 121.9, 122.7, 123.2, 123.2, 126.1, 127.3,
128.5, 136.0, 137.3, 148.3, 148.8, 159.1, 160.8. Anal. Calcd for C24H22F3NO9S: C, 51.71; H, 3.98; N,
2.51. Found: C, 51.90; H, 3.93; N, 2.40.
Dimethyl N-benzyl-3-(3,4-dimethoxyphenyl)-4-(4-methoxyphenyl)pyrrole-2,5-dicarboxylate (10)
Under an argon atmosphere, a degassed solution of Na2CO3 (2.10 g, 19.8 mmol) in water (6.0 mL) was
added to a solution of 9 (1.67 g, 3.00 mmol), 2a (685 mg, 4.51 mmol) and Pd(PPh3)4 (145 mg, 0.125
mmol) in THF (60 mL) at rt and the mixture was refluxed for 20 h. The mixture was cooled to rt and
evaporated under reduced pressure. The products were extracted with CH2Cl2 and the extract was

HETEROCYCLES, Vol. 77, No. 2, 2009
1119
washed successively with water and brine, dried over Na2SO4, and evaporated under reduced pressure.
The residue was purified successively by column chromatography over Silica Gel 60N
(toluene-EtOAc=10:1) and over Chromatorex NH-DM1020 silica gel (EtOAc) to give 10 as colorless
solid (1.48 g, 96%). Recrystallization from CH2Cl2-hexane gave colorless granules. Mp 110.5-112 °C;
IR (KBr): 1715, 1535, 1435, 1299, 1245, 1202, 1173, 1025 cm-1; 1H NMR (400 MHz, CDCl3): δ 3.53 (s,
3H), 3.55 (s, 3H), 3.62 (s, 3H), 3.75 (s, 3H), 3.83 (s, 3H), 6.01 (s, 2H), 6.51 (d, J= 2.0 Hz, 1H), 6.62 (dd,
J= 2.0 and 8.3 Hz, 1H), 6.70 (d, J= 8.3 Hz, 1H), 6.70-6.75 (m, 2H), 6.94-6.98 (m, 2H), 7.09-7.13 (m, 2H),
13
7.19-7.25 (m, 1H), 7.27-7.32 (m, 2H); C NMR (100 MHz, CDCl3): 49.6, 51.4, 51.5, 55.0, 55.6, 55.6,
110.0, 112.7, 113.8, 122.7, 124.2, 124.4, 126.2, 126.5, 126.9, 128.3, 130.6, 130.8, 131.3, 138.5, 147.4,
147.6, 158.1, 161.9, 162.1. Anal. Calcd for C30H29NO7: C, 69.89; H, 5.67; N, 2.72. Found: C, 69.73; H,
5.64; N, 2.63.
Dimethyl 3-(3,4-dimethoxyphenyl)-4-(4-methoxyphenyl)pyrrole-2,5-dicarboxylate (11)
Under an argon atmosphere, ammonium formate (1.93 g, 30.6 mmol) was added portionwise to a mixture
of 10 (523 mg, 1.01 mmol), Pearlman’s catalyst (51 mg), and EtOH (20 mL) at rt. After being refluxed
for 3 h, the mixture was cooled to rt and passed through a pad of Celite. The filtrate was evaporated
under reduced pressure. The residue was purified by column chromatography over Silica Gel 60N
(CH2Cl2) to give 11 as colorless solid (298 mg, 69%). Recrystallization from CH2Cl2-pentane gave
colorless granules. Mp 181-182 °C; IR (KBr): 3282, 1721, 1702, 1463, 1299, 1249, 1190, 1024 cm-1; 1H
NMR (400 MHz, CDCl3): δ 3.61 (s, 3H), 3.77 (s, 3H), 3.77 (s, 3H), 3.79 (s, 3H), 3.85 (s, 3H), 6.56-6.58
(m, 1H), 6.72-6.79 (m, 4H), 7.01-7.06 (m, 2H), 9.82 (br s, 1H); 13C NMR (100 MHz, CDCl3): 51.7, 55.1,
55.6, 55.6, 110.0, 112.8, 114.2, 120.9, 121.0, 123.3, 125.1, 125.1, 131.1, 131.1, 131.7, 147.6, 147.7, 158.4,
160.6. HREIMS m/z. Calcd for C23H23NO7 (M+): 425.1475. Found: 425.1469.
3,4-Bis(4-isopropoxyphenyl)-5-methoxycarbonylpyrrole-2-carboxylic acid (12)
Under an argon atmosphere, 3c (2.71 g, 6.00 mmol) and LiOH·H2O (126 mg, 3.00 mmol) were dissolved
in a degassed mixture of THF (36 mL), MeOH (12 mL), and water (12 mL). After being stirred for 44 h
at rt, the mixture was acidified with 3 M aqueous HCl to pH 1 and evaporated under reduced pressure.
The product was extracted with EtOAc and the extract was washed with brine, dried over Na2SO4, and
evaporated under reduced pressure. The residue was purified by column chromatography over Silica
Gel 60N [hexane-EtOAc=1:1~EtOAc-water (upper phase)] to give 12 as colorless solid (1.23 g, 47%) and
unreacted 3c (1.38 g, 51%). Recrystallization from CH2Cl2-pentane gave colorless powder. Mp
219-220 °C; IR (KBr): 3308, 1700, 1466, 1298, 1242, 1119, 952 cm-1; 1H NMR (400 MHz, DMSO-d6): δ
1.22 (d, J= 6.0 Hz, 12H), 3.64 (s, 3H), 4.47-4.58 (m, 2H), 6.67-6.72 (m, 4H), 6.89-6.95 (m, 4H), 11.94 (br

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HETEROCYCLES, Vol. 77, No. 2, 2009
s, 1H); 13C NMR (100 MHz, DMSO-d6): δ 21.7, 21.8, 51.1, 68.7, 68.7, 113.9, 114.0, 120.6, 122.5, 125.1,
125.3, 129.4, 130.0, 131.5, 131.6, 155.7, 155.8, 160.1, 161.2. Anal. Calcd for C25H27NO6: C, 68.63; H,
6.22; N, 3.20. Found: C, 68.63; H, 6.11; N, 3.14.
Methyl 3,4-bis(4-isopropoxyphenyl)pyrrole-2-carboxylate (13)
Under an argon atmosphere, a mixture of 12 (500 mg, 1.14 mmol) and copper(I) oxide (164 mg, 1.14
mmol) in quinoline (10 mL) was heated at 220 °C for 7 min. The mixture was cooled to rt and passed
through a pad of Celite. The filtrate was diluted with CH2Cl2, washed successively with 6 M aqueous
HCl, water and brine, dried over Na2SO4, and evaporated under reduced pressure. The residue was
purified by flash chromatography over Silica Gel 60N (hexane-EtOAc=3:1) to give 13 as yellow solid
(361 mg, 80%). Recrystallization from EtOAc-hexane gave yellow needles. The spectroscopic data
are identical with those reported in ref. 26.
ACKNOWLEDGEMENTS
The authors acknowledge the Ministry of Education, Culture, Sports, Science and Technology of Japan
for financial support; Grant-in-Aid for Scientific Research (B) (No. 20310135).
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