One-pot synthesis of pentasubstituted pyrroles from propargylic alcohols, amines, and dialkyl acetylenedicarboxylates; Tandem amination, propargylation and cycloisomerization catalyzed by molecular iodine

Article abstract of DOI:10.1055/s-0032-1318485

A multicomponent one-pot synthesis of fully substituted pyrroles has been developed by the tandem reaction of amines, dialkyl acetylenedicarboxylates, and propargylic alcohols using iodine as a catalyst. The reaction was complete in three hours and afforded the products in high yields (75-88%). The method is simple, efficient, cost-effective, and metal-free. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0032-1318485

PAPER
▌1045
pOapnere-Pot Synthesis of Pentasubstituted Pyrroles from Propargylic Alcohols,
Amines, and Dialkyl Acetylenedicarboxylates; Tandem Amination, Propar-
gylation and Cycloisomerization Catalyzed by Molecular Iodine1
One-Pot Synthesis of Pentasubstituted Pyrroles
Nisith Bhunia, Biswanath Das*
Organic Chemistry Division-1, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Fax +91(40)27193198; E-mail: biswanathdas@yahoo.com
Received: 18.01.2013; Accepted after revision: 25.02.2013
three-component coupling of propargylic alcohols,
Abstract: A multicomponent one-pot synthesis of fully substituted
amines, and dialkyl acetylenedicarboxylates in the pres-
pyrroles has been developed by the tandem reaction of amines, di-
ence of molecular iodine as a catalyst in toluene afforded
the corresponding pentasubstituted pyrroles under reflux
alkyl acetylenedicarboxylates, and propargylic alcohols using io-
dine as a catalyst. The reaction was complete in three hours and
afforded the products in high yields (75–88%). The method is sim- condition (Scheme 1).
ple, efficient, cost-effective, and metal-free.
CO2R1
+
Key words: pentasubstituted pyrrole, tandem reaction, iodine,
metal-free synthesis
R3
R1O2C
R1O2C
OH
R4
I2 (10 mol%)
R2NH2
+
R3
toluene
reflux, 3 h
N
R2
CO2R1
R4
Pyrrole derivatives are a class of important heterocyclics
representing structural elements of various bioactive nat-
ural products such as chlorophyll, bile pigments, heme,
and vitamin B12.2,3 The pyrrole ring is also the structural
unit of different drugs having anticancer,4a antitumor,3a
antibacterial,3b and immune suppression activities.3c Sev-
eral pyrrole derivatives are cholesterol lowering agents
(atorvastatin or lipitor)4b and HIV fusion inhibitors. In ad-
dition, they are flexible intermediates for transformation
into valuable bioactive heterocyclic systems.5 Pyrrole de-
rivatives are also applied for the preparation of semicon-
ducting and fluorescence materials.6 Consequently, a
wide range of methods have been discovered for the syn-
thesis of pyrroles7 using various metal salts (Pd, Ni, Fe,
Cu, Zn, Mg, etc.). However, these methods suffer from
several drawbacks such as, use of toxic metals, tedious ex-
perimental procedure, and unsatisfactory yield. Recently,
synthesis of pyrroles applying multi-component reaction
(MCR) strategy has attracted much attention of chemists.
The MCR strategy combining three or more starting ma-
terials in a single synthetic operation provides high atom
economy and bond forming efficiency without isolation
and purification of any intermediate, which in turn mini-
mize the waste, labor, and cost.8 Recently, we reported a
simple and efficient metal-free synthesis of tetrasubstitut-
ed pyrroles by applying iodine-catalyzed four-component
coupling reactions of aldehydes, amines, dialkyl acetyl-
enedicarboxylates, and nitromethane in one pot.9 Herein
we wish to report a three-component metal-free synthesis
of pentasubstituted pyrroles.
1
2
3
4
75–88%
R
R
R
R
1 = Me, Et
2 = aryl, alkyl
3 = aryl, heteroaryl
4 = alkyl, aryl
Scheme 1 Synthesis of pentasubstituted pyrroles from propargylic
alcohols, amines, and dialkyl acetylenedicarboxylates
Initially, the reaction of secondary propargylic alcohol
(derived from the benzaldehyde and phenylacetylene) and
aniline was conducted directly with dimethyl acetylenedi-
carboxylates in the presence of 10 mol% of Cu(OTf)2 as a
single catalyst in 1,2-dichloroethane (DCE) under reflux
(Scheme 2). After 12 hours, complete consumption of
propargylic alcohol was observed and the corresponding
pentasubstituted pyrrole was obtained in 61% yield (Table
1, entry 1). To extend the scope of the amination, propar-
gylation, and cycloisomerization tandem reaction for the
synthesis of pyrroles, the present reaction was screened
with other different catalysts and solvent systems. When
the reaction was performed in toluene in the presence of 5
mol% of AgOAc along with 10 mol% of Cu(OTf)2 the
yield increased to 70% (entry 3). By using 10 mol% of the
copper-free catalyst InCl3 the reaction furnished the ex-
pected pyrrole in 77% yield under similar conditions (en-
try 4). However, with the catalysts like FeCl3, YbCl3,
BiCl3, or AgOTf, the tandem reaction led not to the ex-
pected pyrrole but to the intermediate γ-alkynylamine B
(Scheme 2, vide infra) (entries 5–8). Further to extend the
scope for better catalytic system, the reaction mixture was
treated with 10 mol% of molecular iodine in DCE; after
refluxing for six hours, the expected pyrrole was obtained
in 72% yield (entry 9). To get better yield the mixture was
again treated with 5 mol% of AgOAc along with 10 mol%
of molecular iodine affording the pyrrole in 83% yield.
Use of CuOAc instead of AgOAc did not lead to better re-
In continuation of our work10 on the development of use-
ful synthetic methodologies, we have discovered that the
SYNTHESIS 2013, 45, 1045–1050
Advanced online publication: 13.03.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1318485; Art ID: SS-2013-Z0046-OP
© Georg Thieme Verlag Stuttgart · New York

1046
N. Bhunia, B. Das
PAPER
sult. Finally, when the reaction mixture was treated with ethyl acetylenedicarboxylates. The conversion was
10 mol% of iodine in toluene under reflux for three hours completed only in three hours and the products were
the expected pyrrole was formed in 88% yield. This is the formed in high yields (75–88%). The structures of the
best result in comparison to other catalysts investigated in products were established from their spectral (IR, 1H and
the present reaction (Table 2).
13C NMR, and MS) and analytical data.
Table 1 Optimization of Reaction Parameters for the Synthesis of
Table 2 Pentasubstituted Pyrroles 4 Prepareda,b
Pentasubstituted Pyrrolesa,b
CO2R1
R3
Ph
R1O2C
R1O2C
OH
CO2Me
+
R4
catalyst
I
2 (10 mol%)
MeO2C
MeO2C
R2NH2
OH
+
+
(10 mol%)
Ph
PhNH2
R3
toluene
reflux, 3 h
+
Ph
N
R2
CO2R1
solvent
reflux
R4
N
CO2Me
Ph
Ph
Entry R1
R2
R3
R4
Product Yield
(%)c
Entry Catalyst
Solvent
Time (h) Yield (%)c
1
Cu(OTf)2
Cu(OTf)2
DCE
12
12
12
6
61
68
70
77
0
1
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a
4b
4c
4d
4e
4f
88
83
85
78
81
80
82
77
75
82
85
86
82
87
82
86
79
76
53d
0e
2
toluene
2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
4-ClC6H4
4-FC6H4
4-FC6H4
3
Cu(OTf)2/AgOAc toluene
3
4
InCl3
FeCl3
YbCl3
BiCl3
AgOTf
I2
toluene
toluene
toluene
toluene
toluene
DCE
4
4-MeC6H4
5
12
12
12
12
6
5
4-MeOC6H4 4-FC6H4
4-MeC6H4 4-ClC6H4
4-MeOC6H4 4-ClC6H4
6
0
6
7
0
7
4g
4h
4i
8
0
8
4-MeC6H4
4-MeC6H4
4-MeOC6H4 Ph
4-MeC6H4 Ph
9
72
65
83d
80
85
88
9
10
11
12
13
14
I2
MeCN
toluene
toluene
toluene
toluene
6
10
11
12
13
14
15
16
17
18
19
4-MeOC6H4 4-MeC6H4 Ph
4j
I2/AgOAc
I2/CuOAc
I2
6
4-MeC6H4
4-ClC6H4
4-FC6H4
PhCH2
Ph
Ph
Ph
Ph
Ph
Ph
4k
4l
6
6
4m
4n
I2
3
4-MeC6H4 Ph
Ph
a Reaction conditions: aniline (0.5 mmol), dimethyl acetylenedicar-
boxylate (0.56 mmol), 1,3-diphenylprop-2-yn-1-ol (0.5 mmol), sol-
vent (3 mL), and catalyst (10 mol%) under reflux.
b The structure of the product was established from their spectral (IR,
1H and 13C NMR, and ESI-MS) data.
Ph
C6H13 4o
4-MeOC6H4 Ph
4-MeC6H4 Ph
4-MeOC6H4 Ph
C6H13 4p
C6H13 4q
c Isolated yields after purification.
Ph
Ph
Ph
Ph
4r
4s
4t
d AgOAc (5 mol%) along with I2 (10 mol%) were used.
Me
Me
Me
Ph
furfuryl
With the optimized reaction conditions, a series of penta- 20
substituted pyrroles were subsequently synthesized from
4-MeOC6H4 c-C6H11
21
Ph
c-C6H11
4u
0e
various secondary propargylic alcohols containing both
terminal alkyne as well as internal alkyne having aryl and a Reaction conditions: amine (0.5 mmol), dialkyl acetylenedicarbox-
ylate (0.56 mmol), propargylic alcohol (0.5 mmol), toluene (3 mL),
alkyl substituents in excellent yields (Table 2). Both aro-
matics and heteroaromatics containing electron-donating
and I2 (10 mol%) under reflux.
b The structures of the products were established from their spectral
and -withdrawing groups underwent the conversion
smoothly. Secondary propargylic alcohols furnished the
corresponding pyrroles in good yields. However, when
R2 = alkyl (Table 2, entries 19, 20) the reaction did not
yield the required product probably due to less electron
density at the carbon atom attached to the alcohol. On the
other hand, amines containing both aromatic and aliphatic
substituents underwent the conversion smoothly. The pyr-
roles were efficiently prepared by using dimethyl and di-
(IR,1H and 13C NMR, and ESI-MS) data.
c Isolated yields after purification.
d Product characterized by GCMS.
e Reaction carried out for 12 h.
Iodine, used as a catalyst here, is less expensive and easily
available. It acts as a Lewis acid in the tandem reaction of
amines, dialkyl acetylenedicarboxylates, and propargylic
alcohols. The plausible mechanism of the present conver-
Synthesis 2013, 45, 1045–1050
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of Pentasubstituted Pyrroles
1047
I2
CO2R1
+
R1O2C
R1O2C
OH
I2
+
R2NH2
R3
amination
R3
R1O2C
R1O2C
NH
R2
R4
CO2R1
R4
A
N
R2
propargylation
R1O2C
R1O2C
cycloisomerization
R4
3
H
R3
R1O2C
R1O2C
R
I2
R4
N
R2
NH
R2
B
C
Scheme 2 Proposed mechanism for the iodine-catalyzed tandem reaction involving amination, propargylation, and cycloisomerization for the
synthesis of pyrroles
IR (neat): 1731, 1692, 1590, 1452 cm–1.
sion involves the initial formation of the intermediate, al-
1H NMR (200 MHz, CDCl3): δ = 7.41–7.29 (m, 5 H), 7.29–7.21 (m,
4 H), 7.05 (d, J = 7.0 Hz, 2 H), 6.98 (m, 2 H), 6.66–6.59 (m, 2 H),
3.75 (s, 2 H), 3.70 (s, 3 H), 3.61 (s, 3 H).
kenylamine A catalyzed by iodine (Scheme 2).
Subsequent nucleophilic attack of intermediate A to the
propargylic alcohol gives the γ-alkynylamine B. Coordi-
nation of iodine to the alkyne enhances the electrophilicity 13C NMR (50 MHz, CDCl3): δ = 167.0, 160.2, 138.5, 138.0, 135.3,
133.5, 129.7, 129.1, 129.0, 129.9, 128.8, 127.0, 126.1, 123.7, 122.5,
of the alkyne and nuclophilic attack of the amino group to
the alkyne led to the intermediate C, which undergoes cy-
cloisomerization to furnish the pyrrole derivative
122.0, 114.2, 52.1, 51.8, 30.8.
MS (ESI): m/z = 426 [M + H]+, 448 [M + Na]+.
(Scheme 2).
HRMS: m/z calcd for C27H23NO4 + Na: 448.149; found: 448.151.
Anal. Calcd for C27H23NO4: C, 64.96; H, 4.36; N, 3.79. Found: C,
64.89; H, 4.39; N, 3.82.
In conclusion, we have developed a simple and efficient
iodine-catalyzed method for the synthesis of fully substi-
tuted pyrroles directly from amines, dialkyl acetylenedi-
carboxylates, and propargylic alcohols in excellent yields.
High functional-group tolerance, operational simplicity,
minimal waste generation (only water was generated as
by-product), and use of cheap catalyst are the main advan-
tages of this method.
Dimethyl 5-Benzyl-4-(4-chlorophenyl)-1-phenyl-1H-pyrrole-
2,3-dicarboxylate (4b)
Following the general procedure, the crude residue was subjected to
column chromatography (hexane–EtOAc, 10:1) to give 4b (190 mg,
83%) as a yellowish oil.
IR (neat): 1731, 1699, 1592, 1451 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.40–7.35 (m, 4 H), 7.23 (d,
J = 8.30 Hz, 1 H), 7.12–7.05 (m, 6 H), 6.90 (d, J = 9.06 Hz, 1 H),
6.68–6.63 (m, 2 H), 3.80 (s, 3 H), 3.75 (s, 5 H), 3.65 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 166.5, 160.0, 138.1, 136.2, 135.5,
134.5, 133.1, 129.5, 129.3, 128.7, 128.3, 128.2, 129.9, 127.3, 126.2,
123.9, 122.2, 122.0, 114.1, 52.1, 51.6, 29.9.
Silica gel F254 plates were used for TLC; the spots were examined
under UV light and then developed by I2 vapor. Column chromatog-
raphy was performed with silica gel (BDH 100–200 mesh). Sol-
vents were purified according to standard procedures. The spectra
were recorded with the following instruments; IR: PerkinElmer RX
FT-IR spectrophotometer; NMR: Varian Gemini 200 MHz (1H) and
50 MHz (13C) spectrometer; MS (ESI): VG-Autospec micromass.
MS (ESI): m/z = 460 [M + H]+, 482 [M + Na]+.
Anal. Calcd for C27H22ClNO4: C, 70.51; H, 4.82; N, 3.05. Found: C,
70.55; H, 4.79; N, 3.09.
Pentasubstituted Pyrroles 4; General Procedure
To a stirred solution of respective amine 2 (0.5 mmol), dialkylacet-
ylene dicarboxylate 1 (0.56 mmol), and propargylic alcohol 3 (0.5
mmol) in toluene (3 mL) was added I2 (10 mol%). The reaction mix-
ture was heated slowly to reflux for 3 h. After completion of the re-
action as monitored by TLC (hexane–EtOAc, 5:1), the mixture was
cooled to r.t. and diluted with EtOAc (10 mL). The EtOAc layer was
washed with sat. aq Na2S2O3 (2 × 2 mL), followed by H2O (5 mL)
and brine (5 mL). The residue was dried (Na2SO4), concentrated un-
der reduced pressure, and subjected to column chromatography
(hexane–EtOAc, 10:1) to afford the corresponding pentasubstituted
pyrroles 4 (Table 2).
Dimethyl 5-Benzyl-4-(4-fluorophenyl)-1-phenyl-1H-pyrrole-
2,3-dicarboxylate (4c)
Following the general procedure, the crude residue was subjected to
column chromatography (hexane–EtOAc, 10:1) to give 4c (188 mg,
85%) as a dark brownish oil.
IR (neat): 1730, 1798, 1601, 1450 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.32 (dd, J = 7.80, 5.50 Hz, 2 H),
7.10–7.05 (m, 6 H), 7.05– 7.01 (t, J = 8.80 Hz, 2 H), 6.90 (d,
J = 7.80 Hz, 2 H), 6.66–6.60 (m, 2 H), 3.74 (s, 5 H), 3.64 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 166.3, 163.5, 160.2, 138.5, 138.3,
135.2, 131.3, 130.0, 129.3, 129.1, 128.2, 128.1, 127.8, 127.6, 126.1,
115.3, 115.0, 52.1, 51.8, 30.4.
Dimethyl 5-Benzyl-1,4-diphenyl-1H-pyrrole-2,3-dicarboxylate
(4a)
Following the general procedure, the crude residue was subjected to
column chromatography (hexane–EtOAc, 10:1) to give 4a (185 mg,
88%) as a brownish oil.
MS (ESI): m/z = 444 [M + H] +, 466 [M + Na]+.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1045–1050

1048
N. Bhunia, B. Das
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Anal. Calcd C27H22FNO4: C, 73.13; H, 5.00; N, 3.16. Found: C,
73.21; H, 4.96; N, 3.21.
13C NMR (50 MHz, CDCl3): δ = 167.2, 159.5, 136.4, 135.5, 133.6,
131.0, 130.1, 129.9, 128.5, 128.4, 128.0, 127.9, 127.8, 126.5, 126.1,
121.4, 113.6, 55.5, 52.1, 51.6, 30.5.
Dimethyl 5-Benzyl-4-(4-fluorophenyl)-1-(p-tolyl)-1H-pyrrole-
2,3-dicarboxylate (4d)
MS (ESI): m/z = 490 [M + H]+, 513 [M + Na]+.
Following the general procedure, the crude residue was subjected to
column chromatography (hexane–EtOAc, 10:1) to give 4d (176 mg,
78%) as a brownish oil.
IR (neat): 1739, 1695, 1605, 1451 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.33 (dd, J = 7.70, 5.52 Hz, 2 H),
7.11–7.06 (m, 5 H), 7.05–7.01 (t, J = 8.80 Hz, 2 H), 6.90 (d,
J = 7.70 Hz, 2 H), 6.68–6.63 (m, 2 H), 3.75 (s, 5 H), 3.65 (s, 3 H),
2.36 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 166.4, 162.2 (d, J = 285.96 Hz),
160.0, 138.6, 138.3, 135.3, 131.3, 130.0, 129.5, 129.1, 128.2, 128.0,
127.9, 127.6, 126.1, 115.3, 115.0, 52.0, 51.7, 29.9, 21.1.
Anal. Calcd for C28H24ClNO5: C, 68.64; H, 4.94; N, 2.86. Found: C,
68.71; H, 4.89; N, 2.89.
Dimethyl 5-Benzyl-4-(4-methoxyphenyl)-1-(p-tolyl)-1H-pyr-
role-2,3-dicarboxylate (4h)
Following the general procedure, the crude residue was subjected to
column chromatography (hexane–EtOAc, 8:1) to give 4h (153 mg,
77%) as a brownish oil.
IR (neat): 1724, 1592, 1497, 1446 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.30–7.28 (m, 4 H), 7.10–7.07 (m,
3 H), 6.88 (d, J = 8.8 Hz, 2 H), 6.71 (d, J = 8.3 Hz, 2 H), 6.61–6.65
(m, 2 H), 3.79 (s, 2 H), 3.73 (s, 3 H), 3.61 (s, 3 H), 2.47 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 166.7, 160.3, 138.6, 136.7, 135.7,
130.5, 130.3, 129.3, 129.0, 128.9, 128.0, 125.9, 123.3, 122.0, 113.5,
55.2, 52.1, 51.6, 30.2, 21.1.
MS (ESI): m/z = 458 [M + H]+, 480 [M + Na]+.
Anal. Calcd for C28H24FNO4: C, 73.51; H, 5.29; N, 3.06. Found: C,
73.66; H, 5.22; N, 2.11.
MS (ESI): m/z = 470 [M + H]+, 492 [M + Na]+.
Dimethyl 5-Benzyl-4-(4-fluorophenyl)-1-(4-methoxyphenyl)-
1H-pyrrole-2,3-dicarboxylate (4e)
Following the general procedure, the crude residue was subjected to
column chromatography (hexane–EtOAc, 12:1) to give 4e (191 mg,
81%) as a light yellowish oil.
Anal. Calcd for C29H27NO5: C, 74.18; H, 5.80; N, 2.98. Found: C,
74.22; H, 5.77; N, 3.01.
Dimethyl 5-Benzyl-1,4-di-p-tolyl-1H-pyrrole-2,3-dicarboxyl-
ate(4i)
Following the general procedure, the crude residue was subjected to
column chromatography (hexane–EtOAc, 8:1) to give 4i (165 mg,
75%) as a colorless oil.
IR (neat): 1735, 1709, 1602, 1463 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.37–7.31 (m, 3 H), 7.11–7.07 (m,
2 H), 7.03 (t, J = 8.80 Hz, 2 H), 6.92 (d, J = 8.83 Hz, 2 H), 6.78 (d,
J = 8.80 Hz, 2 H), 6.69–6.65 (m, 2 H), 3.80 (s, 3 H), 3.75 (s, 5 H),
3.65 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 166.2, 163.5, 160.3, 159.5, 138.4,
135.4, 131.4, 131.2, 130.1, 129.5, 128.9, 128.1, 127.9, 129.1, 124.4,
123.9, 119.0, 115.3, 115.08, 114.0, 113.6, 55.3, 52.1, 51.7, 29.6.
IR (neat): 1732, 1598, 1501, 1450 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.41–7.20 (m, 6 H), 7.08–7.01 (m,
3 H), 6.91–6.82 (m, 2 H), 6.69–6.64 (m, 2 H), 3.77 (s, 2 H), 3.70 (s,
3 H), 3.62 (s, 3 H), 2.36 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 167.2, 160.7, 138.7, 136.8, 135.9,
130.6, 130.4, 128.8, 128.5, 128.2, 127.9, 125.6, 123.3, 122.0, 52.0,
51.5, 30.4, 21.1, 21.1.
MS (ESI): m/z = 474 [M + H]+, 496 [M + Na]+.
Anal. Calcd for C28H24FNO4: C, 71.03; H, 5.11; N, 2.96. Found: C,
71.13; H, 5.07; N, 2.99.
MS (ESI): m/z = 454 [M + H]+, 475 [M + Na]+.
Dimethyl 5-Benzyl-4-(4-chlorophenyl)-1-(p-tolyl)-1H-pyrrole-
2,3-dicarboxylate (4f)
Following the general procedure, the crude residue was subjected to
column chromatography (hexane–EtOAc, 9:1) to give 4f (186 mg,
80%) as a yellowish oil.
Anal. Calcd for C29H27NO4: C, 76.80; H, 6.00; N, 3.09. Found: C,
76.89; H, 5.99; N, 3.11.
Dimethyl 5-Benzyl-1-(4-methoxyphenyl)-4-(p-tolyl)-1H-pyr-
role-2,3-dicarboxylate(4j)
Following the general procedure, the crude residue was subjected to
column chromatography (hexane–EtOAc, 15:1) to give 4j (187 mg,
82%) as a yellowish oil.
IR (neat): 1731, 1591, 1499, 1452 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.32 (d, J = 7.0, 4.0 Hz, 4 H),
7.13–7.08 (m, 5 H), 6.9 (d, J = 7.0 Hz, 2 H), 6.70–6.65 (m, 2 H),
3.78 (s, 5 H), 3.65 (s, 3 H), 2.48 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 166.5, 160.5, 139.0, 138.5, 135.3,
135.0, 133.2, 132.3, 131.1, 129.4, 128.9, 128.7, 128.5, 126.2, 123.3,
122.5, 121.4, 52.0, 51.8, 30.0, 21.1.
IR (neat): 1724, 1592, 1497, 1446 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.31–7.27 (m, 4 H), 7.10–7.06 (m,
3 H), 6.88 (d, J = 8.8 Hz, 2 H), 6.71 (d, J = 8.3 Hz, 2 H), 6.61–6.65
(m, 2 H), 3.79 (s, 2 H), 3.73 (s, 3 H), 3.61 (s, 3 H), 2.47 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 166.7, 160.3, 138.6, 136.7, 135.7,
130.5, 130.3, 129.3, 129.0, 128.9, 128.0, 125.9, 123.3, 122.0, 113.5,
55.2, 52.1, 51.6, 30.5, 21.1.
MS (ESI): m/z = 474 [M + H]+, 496 [M + Na]+.
Anal. Calcd for C28H24ClNO4: C, 70.96; H, 5.10; N, 2.96. Found: C,
70.99; H, 5.01; N, 2.83.
MS (ESI): m/z = 470 [M + H]+, 492 [M + Na]+.
Dimethyl 5-Benzyl-4-(4-chlorophenyl)-1-(4-methoxyphenyl)-
1H-pyrrole-2,3-dicarboxylate (4g)
Following the general procedure, the crude residue was subjected to
column chromatography (hexane–EtOAc, 15:1) to give 4g (198 mg,
82%) as a yellowish oil.
Anal. Calcd for C29H27NO5: C, 74.18; H, 5.80; N, 2.98. Found: C,
74.22; H, 5.77; N, 3.01.
Dimethyl 5-Benzyl-4-phenyl-1-(p-tolyl)-1H-pyrrole-2,3-dicar-
boxylate (4k)
Following the general procedure, the crude residue was subjected to
column chromatography (hexane–EtOAc, 8:1) to give 4k (175 mg,
85%) as a brownish oil.
IR (neat): 1729, 1590, 1496, 1447 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.33–7.29 (m, 4 H), 7.13–7.08 (m,
3 H), 6.91 (d, J = 9.0 Hz, 2 H), 6.77 (d, J = 8.30 Hz, 2 H), 6.66 (m,
2 H), 3.81 (s, 2 H), 3.76 (s, 3 H), 3.64 (s, 3 H).
IR (neat): 1737, 1624, 1530, 1453 cm–1.
Synthesis 2013, 45, 1045–1050
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of Pentasubstituted Pyrroles
IR (neat): 1717, 1565, 1491, 1449, 1296 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.52–7.42 (m, 4 H), 7.40–7.22 (m,
6 H), 3.73 (s, 3 H), 3.63 (s, 3 H), 2.42–2.30 (m, 2 H), 1.18–1.03 (m,
3 H), 1.01–0.83 (m, 5 H), 0.79 (t, J = 6.6 Hz, 3 H).
13C NMR (200 MHz, CDCl3): δ = 166.8, 160.2, 137.9, 133.8, 129.1,
129.5, 128.1, 128.7, 128.0, 126.9, 122.6, 122.2, 120.6, 111.4, 52.1,
51.4, 31.2, 29.5, 29.0, 28.7, 28.2, 24.3, 22.4, 13.9.
1049
1H NMR (200 MHz, CDCl3): δ = 7.40–7.21 (m, 6 H), 7.09–7.01 (m,
3 H), 6.92–6.82 (m, 2 H), 6.70–6.62 (m, 2 H), 3.77 (s, 2 H), 3.70 (s,
3 H), 3.61 (s, 3 H), 2.36 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 166.5, 160.2, 138.4, 137.9, 131.6,
129.5, 129.1, 128.6, 128.4, 128.3, 128.22, 128.1, 128.0, 127.9,
127.8, 127.6, 127.0, 125.9, 30.5, 21.1.
MS (ESI): m/z = 440 [M + H]+, 462 [M + Na]+.
Anal. Calcd C28H25NO4: C, 76.52; H, 5.73; N, 3.19. Found: C,
76.55; H, 5.69; N, 3.21.
MS (ESI): m/z = 434 [M + H]+, 456 [M + Na]+.
Anal. Calcd for C27H31NO4: C, 74.80; H, 7.21; N, 3.23. Found: C,
74.85; H, 7.16; N, 3.27.
Dimethyl 5-Benzyl-1-(4-chlorophenyl)-4-phenyl-1H-pyrrole-
2,3-dicarboxylate(4l)
Following the general procedure, the crude residue was subjected to
column chromatography (hexane–EtOAc, 10:1) to give 4l (193 mg,
86%) as a colorless oil.
Dimethyl 5-Heptyl-1-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-
2,3-dicarboxylate (4p)
Following the general procedure, the crude residue was subjected to
column chromatography (hexane–EtOAc, 15:1) to give 4p (197 mg,
86%) as a yellowish oil.
IR (neat): 1728, 1612, 1522, 1443, 1254 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.40–7.35 (m, 4 H), 7.23 (d,
J = 8.30 Hz, 1 H), 7.12–7.05 (m, 6 H), 6.90 (d, J = 9.06 Hz, 1 H),
6.68–6.63 (m, 2 H), 3.80 (s, 3 H), 3.75 (s, 5 H), 3.65 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 166.5, 160.0, 138.1, 136.9, 135.5,
134.5, 133.1, 129.4, 129.2, 128.6, 128.3, 128.1, 129.9, 127.2, 126.2,
123.8, 122.7, 116.1, 52.4, 51.6, 29.5.
IR (neat): 1732, 1628, 1531, 1450 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.40–7.29 (m, 5 H), 7.21 (d,
J = 9.06 Hz, 2 H), 6.98 (d, J = 8.30 Hz, 2 H), 3.87 (s, 3 H), 3.73 (s,
3 H), 3.65 (s, 3 H), 2.37 (t, J = 8.30 Hz, 2 H), 1.22–1.07 (m, 3 H),
1.05–0.89 (m, 5 H), 0.79 (t, J = 7.55 Hz, 3 H).
13C NMR (200 MHz, CDCl3): δ = 166.8, 160.3, 159.9, 138.3, 133.9,
130.6, 129.5, 129.0, 128.5, 128.1, 126.8, 122.4, 122.1, 121.4, 113.8,
55.3, 52.0, 51.5, 31.3, 29.6, 29.1, 28.8, 28.2, 24.3, 22.4, 13.9.
MS (ESI): m/z = 460 [M + H]+, 482 [M + Na]+.
Anal. Calcd for C27H22ClNO4: C, 70.51; H, 4.82; N, 3.05. Found: C,
70.66; H, 4.76; N, 3.11.
MS (ESI): m/z = 464 [M + H]+, 476 [M + Na]+.
Anal. Calcd for C28H33NO5: C, 72.55; H, 7.18; N, 3.02. Found: C,
72.59; H, 7.11; N, 3.07.
Dimethyl 5-Benzyl-1-(4-fluorophenyl)-4-phenyl-1H-pyrrole-
2,3-dicarboxylate (4m)
Following the general procedure the crude residue was subjected to
column chromatography (hexane–EtOAc, 10:1) to give 4m (180
mg, 82%) as a dark brownish oil.
IR (neat): 1725, 1582, 1490, 1438 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.43–7.28 (m, 5 H), 7.11–7.07 (m,
3 H), 6.94 (d, J = 6.0 Hz, 4 H), 6.68–6.64 (m, 2 H), 3.79 (s, 2 H),
3.76 (s, 3 H), 3.64 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 166.6, 162.2 (d, J = 285.96 Hz),
160.0, 138.1, 135.6, 133.6, 133.2, 129.7, 128.9, 128.8, 129.6, 129.6,
128.3, 128.1, 127.8, 127.2, 126.1, 115.5, 115.2, 52.1, 51.6, 30.5.
Dimethyl 5-Heptyl-4-phenyl-1-(p-tolyl)-1H-pyrrole-2,3-dicar-
boxylate (4q)
Following the general procedure, the crude residue was subjected to
column chromatography (hexane–EtOAc, 10:1) to give 4q (174 mg,
79%) as a brownish oil.
IR (neat): 1725, 1621, 1527, 1442 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.40–7.31 (m, 5 H), 7.30–7.22 (m,
2 H), 7.17 (d, J = 8.30 Hz, 2 H), 3.73 (s, 3 H), 3.64 (s, 3 H), 2.43 (s,
3 H), 2.37 (t, J = 7.55 Hz, 2 H), 1.22–1.05 (m, 3 H), 1.03–0.89 (m,
5 H), 0.79 (t, J = 6.79 Hz, 3 H).
MS (ESI): m/z = 444 [M + H]+, 466 [M + Na]+.
13C NMR (50 MHz, CDCl3): δ = 167.8, 160.3, 138.6, 138.0, 135.4,
134.0, 129.5, 129.4, 128.9, 128.1, 127.7, 126.9, 122.5, 52.1, 51.5,
31.3, 29.6, 29.1, 28.7, 28.2, 24.3, 22.3, 22.4, 21.2, 13.9.
Anal. Calcd for C27H22FNO4: C, 73.13; H, 5.00; N, 3.16. Found: C,
73.19; H, 5.18; N, 3.21.
MS (ESI): m/z = 448 [M + H]+, 470 [M + Na]+.
Dimethyl 1,5-Dibenzyl-4-(p-tolyl)-1H-pyrrole-2,3-dicarboxyl-
ate (4n)
Following the general procedure, the crude residue was subjected to
column chromatography (hexane–EtOAc, 10:1) to give 4n (195 mg,
87%) as a colorless oil.
Anal. Calcd for C28H33NO4: C, 75.14; H, 7.43; N, 3.13. Found: C,
75.19; H, 7.34; N, 3.21.
Diethyl 5-Benzyl-1-(4-methoxyphenyl)-4-phenyl-1H-pyrrole-
2,3-dicarboxylate (4r)
Following the general procedure, the crude residue was subjected to
column chromatography (hexane–EtOAc, 10:1) to give 4r (179 mg,
76%) as a yellowish oil.
IR (neat): 1740, 1630, 1604, 1441 cm–1.
1H NMR (200 MHz, CDCl3): δ = 7.31–7.18 (m, 8 H), 7.12 (d,
J = 8.22 Hz, 2 H), 7.00 (d, J = 7.40 Hz, 2 H), 6.91 (d, J = 8.22 Hz,
2 H), 5.35 (s, 2 H), 3.87 (s, 2 H), 3.76 (s, 6 H), 2.33 (s, 3 H).
IR (neat): 1728, 1612, 1522, 1443 cm–1.
13C NMR (50 MHz, CDCl3): δ = 167.0, 160.7, 138.0, 137.3, 136.7,
134.4, 130.3, 129.2, 129.0, 128.7, 128.6, 127.6, 127.1, 126.5, 125.7,
124.1, 122.9, 120.5, 52.1, 51.6, 48.7, 30.2, 21.1.
1H NMR (200 MHz, CDCl3): δ = 7.44–7.27 (m, 5 H), 7.10–7.03 (m,
3 H), 6.91 (d, J = 8.83 Hz, 2 H), 6.77 (d, J = 8.83 Hz, 2 H), 6.70–
6.64 (m, 2 H), 4.21 (q, J = 7.75 Hz, 2 H), 4.09 (q, J = 7.75 Hz, 2 H),
3.80 (s, 3 H), 3.78 (s, 2 H), 1.17 (t, J = 7.72 Hz, 3 H), 1.12 (t,
J = 7.72 Hz, 3 H).
13C NMR (50 MHz, CDCl3): δ = 164.5, 159.4, 138.6, 135.5, 133.3,
132.0, 131.6, 130.5, 129.6, 129.0, 128.2, 128.0, 127.5, 127.8, 127.3,
127.0, 126.0, 113.6, 63.0, 61.0, 60.4, 55.3, 29.6, 14.1, 14.0.
MS (ESI): m/z = 454 [M + H]+, 476 [M + Na]+.
Anal. Calcd for C29H27NO4: C, 76.80; H, 6.00; N, 3.09. Found: C,
76.85; H, 5.96; N, 3.11.
Dimethyl 5-Heptyl-1,4-diphenyl-1H-pyrrole-2,3-dicarboxylate
(4o)
Following the general procedure, the crude residue was subjected to
column chromatography (hexane–EtOAc, 9:1) to give 4o (175 mg,
82%) as a colorless oil.
MS (ESI): m/z = 484 [M + H]+, 503 [M + Na]+.
Anal. Calcd for C30H29NO5: C, 74.52; H, 6.04; N, 2.90. Found: C,
74.56; H, 6.01; N, 2.95.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1045–1050

1050
N. Bhunia, B. Das
PAPER
(7) Some recent examples: (a) Shiner, C. M.; Taner, T. D.
Acknowledgment
Tetrahedron 2005, 61, 11628. (b) Minetto, G.; Raveglia, L.
F.; Sega, A.; Taddei, M. Eur. J. Org. Chem. 2005, 34, 5277.
(c) Larionov, O. V.; de Meijire, A. Angew. Chem. Int. Ed.
2005, 44, 5664. (d) Istrate, F. M.; Gagosz, F. Org. Lett.
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Angew. Chem. Int. Ed. 2008, 47, 5430. (g) Plaskon, A. S.;
Ryabukhin, S. V.; Volochnyuk, D. M.; Shivanyuk, A. N.;
Tolmachev, A. A. Tetrahedron 2008, 64, 5933.
(h) Brichacek, M.; Njardarson, J. T. Org. Biomol. Chem.
2009, 7, 1760. (i) Lu, Y.; Fu, X.; Chen, H.; Du, X.; Jia, X.;
Liu, Y. Adv. Synth. Catal. 2009, 351, 129. (j) Wang, J-Y.;
Wang, X-P.; Yu, Z-S.; Yu, W. Adv. Synth. Catal. 2009, 351,
2063.
The authors thank CSIR, New Delhi for financial assistance.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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Synthesis 2013, 45, 1045–1050
© Georg Thieme Verlag Stuttgart · New York