Deep eutectic solvent: A simple, environmentally benign reaction media for regioselective synthesis of 2,3,4-trisubstituted 1H-pyrroles

Article abstract of DOI:10.1039/c5ra03270a

Choline hydroxide has been successfully employed as an efficient base as well as reaction media for the synthesis of 2,3,4-trisubstituted 1H-pyrroles from methyl 2-isocyanoacetate and α,β-unsaturated ketones. The choline hydroxide used is inexpensive, non-toxic, recyclable and environmentally friendly. Mild reaction conditions and an easy workup procedure are the striking features of this protocol. This transformation proceeds through the 1,4-conjugate addition of methyl 2-isocyanoacetate with α,β-unsaturated ketones followed by intramolecular cyclization-oxidation reaction.

Full text of DOI:10.1039/c5ra03270a

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PAPER
Deep eutectic solvent: a simple, environmentally
benign reaction media for regioselective synthesis
of 2,3,4-trisubstituted 1H-pyrroles†
Cite this: RSC Adv., 2015, 5, 35166
a
a
b
Hanuman P. Kalmode,‡ Kamlesh S. Vadagaonkar,‡ Kaliyappan Murugan,
c
ac
Sattey Prakash and Atul C. Chaskar‡*
Choline hydroxide has been successfully employed as an efficient base as well as reaction media for the
synthesis of 2,3,4-trisubstituted 1H-pyrroles from methyl 2-isocyanoacetate and a,b-unsaturated
ketones. The choline hydroxide used is inexpensive, non-toxic, recyclable and environmentally friendly.
Mild reaction conditions and an easy workup procedure are the striking features of this protocol. This
transformation proceeds through the 1,4-conjugate addition of methyl 2-isocyanoacetate with
a,b-unsaturated ketones followed by intramolecular cyclization–oxidation reaction.
Received 21st February 2015
Accepted 7th April 2015
DOI: 10.1039/c5ra03270a
www.rsc.org/advances
the challenge for a sustainable environment calls for clean
procedures that avoid the use of harmful organic solvents. One of
Introduction
Pyrroles are common structural motifs present in many natural the important principles of green chemistry is the elimination of
1
products. Moreover, they are employed as valuable intermedi- hazardous solvents in chemical synthesis, through which the use
2
ates in organic synthesis and also utilized in other important of expensive toxic solvents and the generation of waste can be
3

elds such as materials, medicinal chemistry and pharma- avoided. Many alternative solvents have been proposed including
4
cology. In addition, pyrroles nd promising application in water, supercritical uids and room temperature ionic liquids
5
13
organic semiconductors. Consequently, they appear to be (RTILs). Ionic liquids (ILs), which are organic salts with a
ꢀ
molecular scaffolds of considerable interest for synthetic melting point lower than 100 C, have attracted much attention in
chemists. The most frequently used methods for their prepa- recent years. They have some unusual properties, such as
ration are the classic Hantzsch, Knorr, Paal-Knorr procedures negligible vapor pressure, low inammability, high thermal
and Buchwald–Hartwig coupling. Although these methods stability, wide liquid temperature range, easy reusability and
have been used during the last century, there are signicant strong solvent power for both organic and inorganic substances.
drawbacks which have triggered the search for new methodol-
In this context, in recent years Paal-Knorr pyrrole synthesis
ogies, such as transition-metal-catalyzed cyclizations, cyclo- in deep eutectic solvents has been achieved in quantitative
addition reactions and MCRs. However, some of these new yields.
methods too have signicant limitations such as tedious synthesis catalyzed by acidic ionic liquid under microwave
14
6
7
8
9
15
10
11
12
16
Aydogan et al. reported Clauson-Kaas pyrrole
1
7
workup procedures, harsh reaction conditions, low yields, long irradiation.
Eco-compatible synthesis of functionalized
reaction times or the requirement of an inert atmosphere.
pyrrole was achieved in ionic liquid promoted multicompo-
1
8
All these aforementioned methods use large amounts of nent reaction. Synthesis of tetrasubstituted pyrroles by the
organic solvents, many of which are volatile, ammable and toxic. three-component condensation of acid chlorides, dia-
They are generally the largest single component by weight in most lkylacetylenedicarboxylates and amino acids in the presence of
reactions and are a clear target for concern. Due to the increase in various room-temperature ionic liquids as catalysts in water
1
9
environmental consciousness in chemical research and industry, were described. Polyethylene glycol (PEG) was found to be an
inexpensive, non-toxic and effective medium for the one pot
2
0
synthesis of highly functionalized pyrroles. A green and
practical method to synthesize novel N-(2-azetidinonyl)-2,5-
disubstituted pyrroles, has been developed by Bandyo-
a
Department of Dyestuff Technology, Institute of Chemical Technology, Mumbai
4
b
00019, India
21
National Taiwan University, Taipei 10617, Taiwan
padhyay et al. Despite of numerous diverse approaches
c
National Centre for Nanosciences and Nanotechnology, University of Mumbai,
towards the synthesis of substituted pyrroles, development of
an easy, atom-economic, environmentally benign synthetic
method still serve to be an attractive goal.
Thus, considering the literature reports and as a part of our
endeavors for the designing and development of simple and
Mumbai 400098, India. E-mail: achaskar25@gmail.com; Fax: +91-22-3361-1020;
Tel: +91-22-3361-2706
†
1
‡
Electronic supplementary information (ESI) available. See DOI:
0.1039/c5ra03270a
These authors contributed equally to this work.
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CuI and chalcone (2a), was carried out in the presence of
t
different bases such as Cs CO , K CO , NaOMe, K BuO and NaH
2
3
2
3
(Table 1, entries 1–5). All these bases produced methyl
4-benzoyl-3-phenyl-1H-pyrrole-2-carboxylate (3a) in low to
moderate yields (28–45%). Then we have screened the various
organic bases such as DBU, 2,6-lutidine, pyridine and triethyl-
amine (Table 1, entries 6–9) for the formation of 3a. DBU,
Scheme 1 General regioselective one-pot synthesis of 2,3,4-trisub-
stituted 1H-pyrrole.
2,6-lutidine and pyridine resulted in very low yields (10–18%) of
3
a whereas trace amount was observed in the case of triethyl-
22
green methodology for the synthesis of heterocycles, we herein
wish to report simple, efficient and regioselective synthesis of
novel 2,3,4-trisubstituted 1H-pyrroles from easily available
starting materials (Scheme 1).
amine. To obtain the highest yield of 3a, we have screened
various solvent such as water, MeOH, CH CN, THF and DCM in
the presence of choline hydroxide as a base in equimolar
amount (Table 1, entries 10–14). When we used water as a
solvent, 3a was obtained in 22% yield whereas in the case of
3
3
MeOH, CH CN, THF and DCM moderate yields (38–66%) of the
product were obtained.
Results and discussion
Initially, the reaction of methyl 2-isocyanoacetate (1) with
The formation of pyrrole (3a) was also studied in acidic,
1
,3-diphenyl-2-en-1-one (2a) was selected as a model reaction, neutral and basic deep eutectic solvents. In acidic deep eutectic
wherein the effect of different catalysts, bases and solvents were solvent such as ChCl : PTSA (Table 1, entry 15) no reaction was
investigated. The reaction of methyl 2-isocyanoacetate (1) with observed in 2 h. Similarly, the reaction in a mixture of choline
Table 1 Optimization of reaction conditions
d
Entry
Catalyst (mol%)
Base
Solvent
CH CN
DMF
MeOH
THF
Time (h)
Yield (%)
a
1
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
CuBr
Cs
2
CO
3
3
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
43
37
39
45
28
12
18
10
a
2
K
2
CO
3
a
3
NaOMe
a
t
4
K BuO
a
5
NaH
DBU
2,6-Lutidine
Pyridine
THF
a
6
CH
3
CN
a
7
DCM
DCM
a
8
a
9
NEt
3
CH
3
CN
Trace
22
a
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
ChOH
ChOH
ChOH
ChOH
Water
MeOH
a
a
a
a
b
b
b
b
b
b
b
b
b
c
66
44
49
38
N. R.
N. R.
78
89
34
44
24
27
30
CH
3
CN
THF
DCM
—
—
—
—
—
—
—
ChOH
ChCl : PTSA
ChCl : Urea
ChOH
ChOH
ChOH
ChOH
ChOH
ChOH
ChOH
1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
CuCl
CuBr
2
2
—
—
—
Cu(OAc)
CuI
2
ChOH
N. D.
a
Reaction conditions: methyl 2-isocyanoacetate 1 (1.0 mmol), 1,3-diphenyl-2-en-1-one 2a (1.0 mmol), catalyst (10 mol%) and base (1.0 mmol) in 5
b
mL of solvent for 2 h, open air. Reaction conditions: methyl 2-isocyanoacetate 1 (1.0 mmol), 1,3-diphenyl-2-en-1-one 2a (1.0 mmol), catalyst (10
mol%) and DES (3 mL), open air. Reaction conditions: methyl 2-isocyanoacetate 1 (1.0 mmol), 1,3-diphenyl-2-en-1-one 2a (1.0 mmol), catalyst (10
mol%) and DES (3 mL), under N
c
d
2
.
Isolated yields. N. R. ¼ No Reaction. N. D. ¼ Not Detected.
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a,b,c
Table 2 Scope of the formation of 2,3,4-trisubstituted 1H-pyrroles
a
b
Reaction conditions: methyl 2-isocyanoacetate 1 (1.0 mmol), chalcone 2 (1.0 mmol), catalyst (10 mol%) and DES (3 mL), open air. Isolated yields.
Time in minutes.
c
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chloride : urea DES (Table 1, entry 16), formation of 3a was not oxidation reaction to afford 2,3,4-trisubstituted 1H-pyrroles
observed. Then we tried the reaction of methyl 2-iso- (Table 2, entries 3t and 3u) in 68 and 80% yield, respectively.
cyanoacetate (1) with CuI and chalcone (2a) in choline
hydroxide as a base and reaction medium at room temperature
for 1 h, the formation of 3a was obtained in good yield (Table 1,
entry 17). Delighted with this result, we decided to monitor the
time required for completion of reaction. Aer varying time we
found that the said reaction proceeded for completion within
0.5 h which was then selected as the optimized time (Table 1,
entry 18). Various copper salts such as CuCl, CuBr, CuCl , CuBr
2
2
Scheme 2 Control experiment.
and Cu(OAc) were tested under this condition for their catalytic
2
activity but none of them was found to be as effective as CuI
(Table 1, entries 19–23). The formation of 3a was not detected
under N atmosphere (Table 1, entry 24), as oxygen present in
2
the open air drives oxidation of pyrroline to pyrrole. Therefore,
the synthesis of pyrrole (3a) by using CuI (10 mol%) as a cata-
lyst, choline hydroxide as a base and reaction media was found
to be the optimal reaction condition.
In order to investigate the scope and limitations of this novel
a,b-Unsaturated ketones with a 2-pyridyl substituent (4) and
greener protocol for the synthesis of 2,3,4-trisubstituted a 4-hydroxyphenyl substituent (5) at the b-position of chalcone
H-pyrroles, the reaction of methyl 2-isocyanoacetate (1) with do not undergo 1,4-conjugate addition followed by cyclization–
1
various a,b-unsaturated aromatic and aliphatic ketones (2) were oxidation reaction under these conditions (Scheme 2). This is
examined (Table 2). The reaction worked well and the due to the side reactions of catalyst and or base with the cor-
corresponding pyrroles were obtained in 60–90% yield within responding a,b-unsaturated ketones.
25–60 min. Chalcones bearing electron withdrawing nitro and
nitrile substituents on the phenyl ring of styryl portion offered Recyclability of choline hydroxide (ChOH)
excellent yields (88–90%) perhaps owing to the stability of
For large-scale operations, recovery and reuse of the DES is
olenic double bond (Table 2, entries 3b and 3c). a,b-Unsatu-
rated ketones bearing weakly activated or electron neutral
substituents on the phenyl ring of acetophenone (such as
methyl or halogens) portion and halogen substituents on the
phenyl ring of styryl portion offered good yields (78–85%) of
essential. In this context, the reaction between methyl 2-iso-
cyanoacetate (1) and chalcone (2a) was examined under opti-
mized reaction condition. Aer completion of reaction, the
reaction mixture was dissolved in water (10 mL) and the product
was extracted with ethyl acetate (3 ꢁ 10 mL). DES was recovered
by evaporation of aqueous layer under vacuum. The recovered
DES was then reused for the next run. As summarized in Table
2,3,4-trisubstituted 1H-pyrroles (Table 2, entries 3d, 3e, 3h, 3j
and 3k). The pyrroles (Table 2, entries 3f, 3g and 3i) were
obtained in 79–82% when chalcones bearing electron neutral or
weakly activated substituents (such as halogens) on the phenyl
ring of styryl portion were used.
3, DES can be recycled and reused up to four times without
signicant loss in activity.
Encouraged with these results in hand, we have tried the
reaction of methyl 2-isocyanoacetate (1) with methyl styryl Table 3 Recyclability study of DES for the synthesis of pyrrole (3a)
a,b
ketone under optimum condition and corresponding pyrrole
b
Entry
Number of cycles
Yield (%)
(3l) was obtained in 73% yield. Methyl styryl ketones bearing
methyl substituent (4-Me, 3-Me and 2-Me) on the phenyl ring of
styryl portion inuenced the outcome of the reaction (Table 2,
entries 3m, 3n and 3o). The steric hindrance near the double
bond of a,b-unsaturated ketones hampered the rate of reaction
and the yield of product (65–69%). The reactivity order was
observed to be p > m > o-isomer. Pyrroles 3p and 3q were
obtained in 71 and 73% yield, respectively by the use of methyl
styryl ketones consisting of halogen substituents (4-Br, 4-Cl) on
the phenyl ring of styryl portion. As expected, (E)-4-phenylbut-3-
1
2
3
4
5
Fresh, non recycled
First
Second
Third
Fourth
89
88
87
85
85
a
Reaction conditions: methyl 2-isocyanoacetate 1 (1.0 mmol), chalcone
a (1.0 mmol), catalyst (10 mol%) and DES (3 mL), open air. Isolated
b
2
yields.
en-2-one with an electron withdrawing –NO group on phenyl
ring required signicantly shorter reaction time (40 min) and
2
FT-IR analysis
offered a higher yield (78%) than that offered by its methoxy The compound having covalent bond absorbs various
Table 2, entries 3r and 3s) counterpart (55 min, 60%). Inter- frequencies of electromagnetic radiation in the infrared region
estingly, (E)-pent-3-en-2-one and diethyl maleate also under- of the electromagnetic spectrum. Infrared spectrum was used to
went the 1,4-conjugate addition followed by cyclization– determine structural information of
molecule. FT-IR
(
a
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spectroscopy was used to characterize ChOH before and aer
reaction. The absorption peak at around 3363 cm was the
Conclusions
ꢂ1
characteristic of –OH stretching frequency. The band at In conclusion, we have developed a simple, green and highly
ꢂ1
1
293 and 1085 cm results from C–N and C–O stretching. Also efficient protocol for the synthesis of 2,3,4-trisubstituted
ꢂ1
band at 951 and 862 cm was due to C–H bending frequency. 1H-pyrroles using deep eutectic solvent. The functional group
There was no change observed in the IR spectra of ChOH before tolerant regioselective synthesis offered good to excellent yields
the reaction and aer four runs (Fig. 1) so we can reuse it up to of the products at room temperature in very short time.
four cycles.
Fig. 1 FT-IR spectrum of (a) ChOH before reaction (blue curve) and (b) ChOH after four runs (red curve).
A
plausible mechanistic pathway of the reaction of 2,3,4-Trisubstituted 1H-pyrroles have strong applications in the
methyl 2-isocyanoacetate (1) and chalcone (2a) in choline eld of pharmaceuticals and agrochemicals.
hydroxide is depicted in Scheme 3. First the reaction of
methyl 2-isocyanoacetate (1) with copper iodide in choline
Experimental section
General methods
0
hydroxide gives a-cuprioisocyanide (A ). Then, 1,4-conjugate
0
addition of a-cuprioisocyanide (A ) with chalcone (2a)
followed by intramolecular cyclization gives a cyclic organo- Chemical reagents were obtained from commercial companies.
copper intermediate (B) which on copper hydrogen exchange All reactions were performed in round bottom ask and
affords 3,4-dihydro-2H-pyrrole (C). Oxidation of the latter monitored by TLC performed on aluminium plates (0.25 mm,
offers the methyl 4-benzoyl-3-phenyl-1H-pyrrole-2-carboxylate E. Merck) precoated with silica gel Merck 60 F-254. Developed
23
(3a).
TLC plates were visualized under a short-wavelength UV lamp.
Scheme 3 Proposed reaction mechanism.
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Reactions were conducted under open air and N
2
atmosphere in 2H), 7.65 (d, J ¼ 7.6 Hz, 2H), 7.50 (d, J ¼ 8.8 Hz, 2H), 7.37 (d, J ¼
1
3
solvents such as water, CH CN, MeOH, DCM, THF and DMF. 3.2 Hz, 1H), 7.19 (d, J ¼ 8.0 Hz, 2H), 3.73 (s, 3H), 2.38 (s, 3H);
C
3
1
13
Yields refer to spectroscopically ( H, C NMR) homogeneous NMR (100 MHz, CDCl ) d 190.19, 160.86, 146.96, 143.42, 140.89,
3
material obtained aer column chromatography. Column 136.07, 131.32, 130.08, 129.56, 129.10, 127.90, 125.09, 122.67,
chromatography was performed on silica gel (100–200 mesh 121.03, 51.99, 21.66; HRMS (ESI): calc. for [(C20
size) supplied by S. D. Fine Chemicals Limited, India. IR spectra [M + H] 365.1137, found 365.1111.
H
16
N
2
O
5
)H]
+
were recorded on a JASCO-FT/IR-4100 LE with attenuated total
reection (ATR) method. H and C NMR were recorded in carboxylate 3c. Off white solid, mp 182–184 C; IR (ATR) ~n
Methyl 4-(3-chlorobenzoyl)-3-(4-cyanophenyl)-1H-pyrrole-2-
1
13
ꢀ
ꢂ1
1
3 3
CDCl and CD
OD solution with a Br u¨ ker 400 and Agilent (cm ): 3273, 2234, 1727, 1707, 1644, 1517 and 746; H NMR
3
00 MHz spectrometers. Chemical shis (d) are reported rela- (400 MHz, CDCl ) d 9.57 (bs, 1H), 7.59 (distorted t, J ¼ 7.2 Hz,
3
tive to SiMe (d ¼ 0.0) as an internal standard. The number of 4H), 7.42 (distorted d, J ¼ 7.6 Hz, 4H), 7.31 (t, J ¼ 8.0, 7.2 Hz,
4
1
3
protons (n) for a given resonance is indicated by nH. Peak 1H), 3.75 (s, 3H); C NMR (100 MHz, CDCl ) d 189.12, 160.77,
3
multiplicities are designated by the following abbreviations: s, 140.31, 138.41, 134.46, 132.33, 131.21, 130.35, 129.78, 129.41,
singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, 128.17, 127.28, 124.48, 121.21, 119.12, 111.04, 52.06; HRMS
+
doublet of doublet; br, broad; J, coupling constant in Hz. High- (ESI): calc. for [(C20
H13ClN
2
O
3
)H] [M + H] 365.0693, found
resolution mass spectra were obtained by using positive as well 365.0665.
as negative electrospray ionization (ESI) by Time of Flight (TOF)
method.
Methyl 3-(4-uorophenyl)-4-(4-methylbenzoyl)-1H-pyrrole-2-
ꢀ
carboxylate 3d. White solid, mp 128–130 C; IR (ATR) ~n
ꢂ1
1
(
cm ): 3316, 1728, 1692, 1634, 1517, 1263 and 841; H NMR
General experimental procedure for the synthesis of choline
hydroxide
(400 MHz, CDCl ) d 9.56 (bs, 1H), 7.62 (d, J ¼ 7.2 Hz, 2H), 7.34 (s,
3
1H), 7.28 (distorted t, J ¼ 6.4, 6.0 Hz, 2H), 7.15 (d, J ¼ 7.2 Hz,
1
3
2
H), 6.95 (t, J ¼ 8.4, 8.0 Hz, 2H), 3.74 (s, 3H), 2.37 (s, 3H);
C
Choline chloride (1 mmol) and KOH (1 mmol) were dissolved in
methanol (10 mL) at room temperature. This mixture was
NMR (100 MHz, CDCl
3
) d 190.74, 162.26 (d, JC–F ¼ 248.3 Hz),
ꢀ
161.25, 143.01, 136.26, 132.04 (d, JC–F ¼ 8.0 Hz), 131.99, 131.45,
heated at 60 C for 12 h with constant stirring. Aer cooling to
1
2
29.65, 129.03, 128.88, 127.36, 125.34, 120.52, 114.40 (d, JC–F
¼
room temperature, the reaction mixture was ltered to remove
solid KCl. The obtained ltrate was concentrated under vacuum
to remove methanol and used without further purication.
1.4 Hz), 51.78, 21.64; HRMS (ESI): calc. for [(C H FNO )H]
2
0
16
3
+
[M + H] 338.1192, found 338.1163.
Methyl 3-(4-bromophenyl)-4-(4-methylbenzoyl)-1H-pyrrole-2-
ꢀ
carboxylate 3e. Pale yellow solid, mp 166–168 C; IR (ATR) ~n
General experimental procedure for the synthesis of
ꢂ1
1
(
(
(
cm ): 3262, 1730, 1692, 1636, 1504, 1261 and 754; H NMR
400 MHz, CDCl
) d 9.57 (bs, 1H), 7.62 (d, J ¼ 8.0 Hz, 2H), 7.39
d, J ¼ 8.0 Hz, 2H), 7.33 (d, J ¼ 2.4 Hz, 1H), 7.20–7.15 (dd, J ¼ 8.4,
2,3,4-trisubstituted 1H-pyrroles
3
A
round bottom ask was charged with methyl 2-iso-
cyanoacetate 1 (1.0 mmol), CuI (0.1 mmol), substituted chal-
cone 2 (1.0 mmol) and choline hydroxide (3 mL). The reaction
mixture was stirred at R.T. for appropriate time. Aer comple-
tion of reaction, the reaction mixture was dissolved in water
13
8
.0 Hz, 4H), 3.73 (s, 3H), 2.38 (s, 3H); C NMR (100 MHz, CDCl
d 190.57, 161.21, 143.10, 136.23, 132.21, 132.04, 131.21, 130.57,
29.64, 128.94, 127.49, 125.19, 121.59, 120.54, 51.84, 21.66;
3
)
1
+
HRMS (ESI): calc. for [(C H BrNO )H] [M + H] 398.0392,
2
0
16
3
(
1
10 mL) and the product was extracted with ethyl acetate (3 ꢁ
0 mL). The combined organic layer was dried over anhydrous
Na SO and concentrated under reduced pressure. The
found 400.0354.
Methyl 4-benzoyl-3-(4-bromophenyl)-1H-pyrrole-2-carboxylate
2
4
ꢀ
1
ꢂ1
3
f. Off white solid, mp 162–164 C; IR (ATR) ~n (cm ): 3275, 1723,
1
obtained crude product was puried by column chromatog-
raphy on silica gel (100–200 mesh size) with n-hexane : ethyl
acetate (75 : 25) as eluent to afford desired product 3a–3u.
3
695, 1632, 1505, 1262 and 732; H NMR (400 MHz, CDCl ) d 9.63
(
(
bs, 1H), 7.71 (d, J ¼ 7.6 Hz, 2H), 7.48 (t, J ¼ 7.2 Hz, 1H), 7.40–7.34
13
m, 5H), 7.19 (d, J ¼ 8.0 Hz, 2H), 3.73 (s, 3H); C NMR (100 MHz,
CDCl ) d 190.88, 161.20, 138.92, 132.28, 132.14, 132.03, 131.25,
3
Product characterization data
1
30.57, 129.42, 128.25, 127.87, 124.99, 121.63, 120.69, 51.87;
+
Methyl 4-benzoyl-3-phenyl-1H-pyrrole-2-carboxylate 3a. Off HRMS (ESI): calc. for [(C19
3
H14BrNO )H] [M + H] 384.0235, found
ꢀ
ꢂ1
white solid, mp 140–142 C; IR (ATR) ~n (cm ): 3256, 1724, 1694, 386.0194.
1
1
1
7
632, 1508, 1264 and 761; H NMR (400 MHz, CDCl ) d 9.82 (bs,
Methyl 4-benzoyl-3-(4-chlorophenyl)-1H-pyrrole-2-carboxylate
3
ꢀ
ꢂ1
H), 7.72 (dd, J ¼ 7.2, 1.2 Hz, 2H), 7.46 (t, J ¼ 7.4 Hz, 1H), 3g. Off white solid, mp 148–150 C; IR (ATR) ~n (cm ): 3276,
1
3
1
.36–7.32 (m, 5H), 7.29–7.23 (m, 3H), 3.74 (s, 3H); C NMR (100 1722, 1689, 1631, 1505, 1263 and 728; H NMR (400 MHz, CDCl
) d 191.20, 161.40, 138.97, 133.12, 132.49, 132.00, d 9.45 (bs, 1H), 7.71 (d, J ¼ 7.2 Hz, 2H), 7.48 (distorted t, J ¼ 7.2,
30.32, 129.41, 128.02, 127.74, 127.30, 127.21, 125.15, 120.44, 6.8 Hz, 1H), 7.36 (distorted t, J ¼ 7.6, 7.2 Hz, 3H), 7.25 (s, 4H),
3
)
MHz, CDCl
3
1
5
ꢂ
13
1.65; HRMS (ESI): calc. for [(C19
H
15NO
3
)H] [M + H] 306.1131, 3.75 (s, 3H); C NMR (100 MHz, CDCl
) d 190.89, 161.19, 138.91,
3
found 306.1130.
133.33, 132.27, 131.71, 131.63, 131.24, 129.42, 128.23, 127.78,
Methyl 4-(4-methylbenzoyl)-3-(4-nitrophenyl)-1H-pyrrole-2- 127.64, 125.08, 120.72, 51.86; HRMS (ESI): calc. for
ꢀ
+
carboxylate 3b. Pale yellow solid, mp 162–164 C; IR (ATR) ~n [(C19
H
14ClNO
)H] [M + H] 340.0740, found 340.0714.
3
ꢂ1
(
cm ): 3421, 1720, 1695, 1627, 1601, 1509, 1437, 1341 and 855;
Methyl 4-(3-chlorobenzoyl)-3-(4-chlorophenyl)-1H-pyrrole-2-
) d 9.81 (bs, 1H), 8.15 (d, J ¼ 8.4 Hz, carboxylate 3h. White solid, mp 110–112 C; IR (ATR) ~n
1
ꢀ
H NMR (400 MHz, CDCl
3
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ꢂ1
1
(
(
1
cm ): 3282, 1724, 1691, 1637, 1507, 1258 and 742; H NMR Hz, 1H), 7.10–7.08 (m, 2H), 3.65 (s, 3H), 2.36 (s, 3H), 1.99 (s, 3H);
1
3
400 MHz, CDCl ) d 9.66 (bs, 1H), 7.62 (s, 1H), 7.57 (d, J ¼ 7.6 Hz,
C NMR (100 MHz, CDCl ) d 194.51, 161.13, 137.05, 133.79,
3
131.49, 130.48, 128.28, 127.47, 127.05, 126.90, 126.01, 120.69,
3
1
3
H), 7.43 (d, J ¼ 8.0 Hz, 2H), 7.30–7.23 (m, 5H), 3.74 (s, 3H);
C
NMR (100 MHz, CDCl ) d 189.52, 161.11, 140.42, 134.30, 133.48, 51.46, 29.10, 21.32; HRMS (ESI): calc. for [(C H NO )–H]
3
15 15
3
ꢂ
1
1
[
32.10, 131.68, 131.42, 131.09, 129.61, 129.49, 127.83, 127.69, [M ꢂ H] 256.0973, found 256.0974.
27.34, 124.72, 120.88, 51.92; HRMS (ESI): calc. for Methyl 4-acetyl-3-(o-tolyl)-1H-pyrrole-2-carboxylate 3o. White
+
ꢀ
ꢂ1
(C19
H
13Cl
2
NO
3
)H] [M + H] 374.0350, found 374.0321.
solid, mp 162–164 C; IR (ATR) ~n (cm ): 3248, 1731, 1687, 1629,
1
Methyl 4-benzoyl-3-(4-uorophenyl)-1H-pyrrole-2-carboxylate 1502, 1255 and 774; H NMR (400 MHz, CDCl
3
) d 9.77 (bs, 1H),
ꢀ
ꢂ1
3
1
9
7
(
1
1
i. White solid, mp 128–130 C; IR (ATR) ~n (cm ): 3275, 1718, 7.61 (d, J ¼ 3.5 Hz, 1H), 7.27–7.16 (m, 3H), 7.11 (d, J ¼ 7.9 Hz,
1
13
686, 1631, 1510, 1264 and 734; H NMR (400 MHz, CDCl ) d 1H), 3.61 (s, 3H), 2.07 (s, 3H), 1.92 (s, 3H); C NMR (100 MHz,
3
.46 (bs, 1H), 7.69 (d, J ¼ 7.2 Hz, 2H), 7.45 (d, J ¼ 6.8 Hz, 1H), CDCl ) d 194.36, 161.19, 136.39, 134.05, 130.53, 129.53, 129.49,
3
1
3
.37–7.25 (m, 5H), 6.94 (t, J ¼ 8.0 Hz, 2H), 3.74 (s, 3H); C NMR 127.72, 126.72, 126.49, 125.26, 120.70, 51.52, 28.54, 19.94;
ꢂ
100 MHz, CD
3
OD) d 192.40, 162.10 (d, JC–F ¼ 243.7 Hz), 161.06, HRMS (ESI): calc. for [(C15
H15NO
3
)–H] [M ꢂ H] 256.0973,
39.18, 132.11 (d, JC–F ¼ 8.1 Hz), 131.86, 131.41, 129.92, 128.99, found 256.0972.
Methyl 4-acetyl-3-(4-bromophenyl)-1H-pyrrole-2-carboxylate
28.86, 127.90, 124.13, 120.83, 113.53 (d, JC–F ¼ 21.5 Hz), 50.47;
+
ꢀ
ꢂ1
HRMS (ESI): calc. for [(C19
H14FNO
3
)H] [M + H] 324.1036, found 3p. Off white solid, mp 150–152 C; IR (ATR) ~n (cm ): 3275,
1
3
24.1005.
1734, 1690, 1640, 1513, 1250 and 765; H NMR (400 MHz,
Methyl 4-(3-chlorobenzoyl)-3-(4-uorophenyl)-1H-pyrrole-2- CDCl ) d 9.89 (bs, 1H), 7.51 (d, J ¼ 3.3 Hz, 1H), 7.47 (d, J ¼ 8.5
3
ꢀ
13
carboxylate 3j. Off white solid, mp 104–106 C; IR (ATR) ~n Hz, 2H), 7.17 (d, J ¼ 8.5 Hz, 2H), 3.65 (s, 3H), 2.13 (s, 3H);
C
ꢂ1
1
(
(
1
2
J
7
1
[
cm ): 3296, 1715, 1686, 1637, 1513, 1260 and 739; H NMR NMR (100 MHz, CDCl ) d 193.76, 161.09, 132.88, 131.61, 130.63,
3
400 MHz, CDCl
3
) d 9.60 (bs, 1H), 7.61 (s, 1H), 7.55 (d, J ¼ 7.6 Hz, 129.90, 126.78, 126.19, 121.65, 120.96, 51.59, 28.92; HRMS (ESI):
ꢂ
H), 7.41 (d, J ¼ 3.2 Hz, 2H), 7.28 (s, 3H), 6.95 (t, J ¼ 8.8, 8.4 Hz, calc. for [(C14
H
12BrNO
3
)] [M] 321.0001 found 320.9922.
1
3
H), 3.74 (s, 3H); C NMR (100 MHz, CDCl
3
) d 189.74, 162.26 (d,
C–F ¼ 244.8 Hz), 161.18, 140.42, 134.24, 132.08, 132.05 (d, JC–F
Methyl 4-acetyl-3-(4-chlorophenyl)-1H-pyrrole-2-carboxylate
3q. Off white solid, mp 134–136 C; IR (ATR) ~n (cm ): 3278,
ꢀ
ꢂ1
¼
1
.9 Hz), 131.31, 129.55, 129.51, 128.79, 127.79, 127.34, 124.83, 1728, 1689, 1637, 1510, 1253 and 773; H NMR (400 MHz,
20.79, 114.46 (d, JC–F ¼ 21.3 Hz), 51.88; HRMS (ESI): calc. for CDCl ) d 9.67 (bs, 1H), 7.44 (d, J ¼ 3.3 Hz, 1H), 7.25 (d, J ¼ 8.3
3
+
13
(C H ClFNO )H] [M + H] 358.0656, found 358.0623.
Hz, 2H), 7.15 (d, J ¼ 8.2 Hz, 2H), 3.57 (s, 3H), 2.04 (s, 3H);
C
1
9
13
3
Methyl 3-(4-bromophenyl)-4-(3-chlorobenzoyl)-1H-pyrrole-2- NMR (100 MHz, CDCl ) d 193.71, 161.06, 133.45, 132.35, 131.28,
3
ꢀ
carboxylate 3k. White solid, mp 144–146 C; IR (ATR) ~n 129.90, 127.72, 126.62, 126.35, 121.01, 51.59, 28.93; HRMS (ESI):
ꢂ1
1
ꢂ
(
(
1
cm ): 3298, 1730, 1698, 1630, 1505, 1255 and 744; H NMR calc. for [(C14
400 MHz, CDCl Methyl 4-acetyl-3-(4-methoxyphenyl)-1H-pyrrole-2-carboxylate
) d 9.69 (bs, 1H), 7.62 (s, 1H), 7.56 (d, J ¼ 7.6 Hz,
H), 7.44–7.38 (m, 4H), 7.28 (t, J ¼ 7.6 Hz, 1H), 7.16 (d, J ¼ 8.4 3r. White solid, mp 132–134 C; IR (ATR) ~n (cm ): 3251, 1720,
3
H12ClNO )H] [M + H] 278.0585, found 278.0584.
3
ꢀ
ꢂ1
1
3
1
Hz, 2H), 3.74 (s, 3H); C NMR (100 MHz, CDCl
3
) d 189.48, 1694, 1625, 1501, 1254 and 763; H NMR (400 MHz, CDCl
3
) d 9.73
1
1
61.11, 140.43, 134.31, 132.10, 131.98, 131.93, 131.09, 130.63, (bs, 1H), 7.52 (d, J ¼ 3.5 Hz, 1H), 7.21 (d, J ¼ 8.8 Hz, 2H), 6.90 (d, J
1
3
29.63, 129.49, 127.89, 127.34, 124.65, 121.76, 120.85, 51.94; ¼ 8.7 Hz, 2H), 3.82 (s, 3H), 3.65 (s, 3H), 2.04 (s, 3H); C NMR
+
HRMS (ESI): calc. for [(C H BrClNO )H] [M + H] 417.9845, (100 MHz, CDCl ) d 194.53, 161.24, 159.00, 131.19, 131.05,
1
9
13
3
3
found 417.9822.
126.85, 126.34, 125.89, 120.75, 113.05, 55.09, 51.47, 29.09; HRMS
ꢂ
Methyl 4-acetyl-3-phenyl-1H-pyrrole-2-carboxylate 3l. White (ESI): calc. for [(C15
solid, mp 170–172 C; IR (ATR) ~n (cm ): 3250, 1728, 1697, 1638, 272.0923.
4
H14NO )–H] [M ꢂ H] 272.0922 found
ꢀ
ꢂ1
1
1
7
3
1
1
2
512, 1270 and 768; H NMR (400 MHz, CDCl
3
) d 9.81 (bs, 1H),
Methyl 4-acetyl-3-(4-nitrophenyl)-1H-pyrrole-2-carboxylate 3s.
ꢀ
ꢂ1
.54 (d, J ¼ 3.5 Hz, 1H), 7.37–7.34 (m, 3H), 7.30–7.28 (m, 2H), Pale yellow solid, mp 144–146 C; IR (ATR) ~n (cm ): 3415, 1724,
1
3
1
.63 (s, 3H), 2.02 (s, 3H); C NMR (100 MHz, CDCl ) d 194.43, 1698, 1632, 1605, 1513, 1443, 1345 and 858; H NMR (400 MHz,
3
61.27, 134.02, 131.33, 129.83, 127.56, 127.47, 126.80, 126.37, CDCl ) d 9.78 (bs, 1H), 8.20 (d, J ¼ 8.6 Hz, 2H), 7.56 (d, J ¼ 3.3 Hz,
3
ꢂ
13
20.79, 51.49, 29.06; HRMS (ESI): calc. for [(C H NO )] [M]
1H), 7.45 (d, J ¼ 8.6 Hz, 2H), 3.65 (s, 3H), 2.25 (s, 3H); C NMR
1
4
13
3
43.0895 found 243.0817.
3
(100 MHz, CDCl ) d 192.72, 160.67, 147.08, 141.28, 130.99,
Methyl 4-acetyl-3-(p-tolyl)-1H-pyrrole-2-carboxylate 3m. White 128.68, 126.98, 125.72, 122.54, 121.36, 51.77, 28.47; HRMS (ESI):
ꢀ
ꢂ1
ꢂ
solid, mp 184–186 C; IR (ATR) ~n (cm ): 3253, 1726, 1694, 1642, calc. for [(C14
H
N
O
)H] [M + H] 289.0825, found 289.0824.
12
2
5
1
1
7
3
1
5
516, 1268 and 765; H NMR (400 MHz, CDCl
3
) d 9.85 (bs, 1H),
Methyl 4-acetyl-3-methyl-1H-pyrrole-2-carboxylate 3t. White
ꢀ
ꢂ1
.52 (d, J ¼ 3.4 Hz, 1H), 7.24–7.15 (m, 4H), 3.64 (s, 3H), 2.37 (s, solid, mp 130–132 C; IR (ATR) ~n (cm ): 3254, 1732, 1690, 1633,
1
3
1
H), 2.03 (s, 3H); C NMR (100 MHz, CDCl ) d 194.61, 161.24, 1505, 1261 and 763; H NMR (400 MHz, CDCl ) d 9.47 (bs, 1H),
3
3
1
3
37.11, 131.55, 130.83, 129.70, 128.33, 126.81, 126.41, 120.69, 7.43 (d, J ¼ 3.4 Hz, 1H), 3.85 (s, 3H), 2.59 (s, 3H), 2.39 (s, 3H);
C
1.44, 29.10, 21.24; HRMS (ESI): calc. for [(C H NO )–H] [M ꢂ NMR (100 MHz, CDCl ) d 194.04, 162.02, 129.17, 127.20, 125.54,
1
5
15
3
3
ꢂ
H] 256.0973, found 256.0977.
121.16, 51.46, 28.25, 11.58; HRMS (ESI): calc. for [(C
9
H
11NO
3
)H]
ꢂ
Methyl 4-acetyl-3-(m-tolyl)-1H-pyrrole-2-carboxylate 3n. White [M + H] 182.0818, found 182.0817.
ꢀ
ꢂ1
solid, mp 170–172 C; IR (ATR) ~n (cm ): 3259, 1732, 1696, 1635,
3,4-Diethyl 2-methyl-1H-pyrrole-2,3,4-tricarboxylate 3u. Color-
) d 9.54 (bs, 1H), less oil; IR (ATR) ~n (cm ): 3247, 1676, 1655, 1499, 1443, 1259,
1
ꢂ1
1
508, 1260 and 772; H NMR (400 MHz, CDCl
.54 (d, J ¼ 3.5 Hz, 1H), 7.27 (d, J ¼ 7.5 Hz, 1H), 7.15 (d, J ¼ 7.6 and 898; H NMR (300 MHz, CDCl
3
1
7
3
) d 9.48 (bs, 1H), 7.49 (d, J
35172 | RSC Adv., 2015, 5, 35166–35174
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¼
3.3 Hz, 1H), 4.42 (q, J ¼ 7.2 Hz, 2H), 4.28 (q, J ¼ 7.2 Hz, 2H),
A. Maria Capelli, P. Cavallini, P. Cavanni, S. Davalli,
D. Donati, A. Feriani, S. Gehanne, M. Hamdan, M. Maffeis,
F. Maria Sabbatini, M. Elvira Tranquillini and M. V. Angela
Viziano, Farmaco, 2004, 59, 175–183; (u) B. D. Roth,
C. J. Blankley, A. W. Chucholowski, E. Ferguson,
M. L. Hoee, D. F. Ortwine, R. S. Newton, C. S. Sekerke,
D. R. Sliskovic and M. Wilson, J. Med. Chem., 1991, 34,
1
3
3
.86 (s, 3H), 1.39 (t, J ¼ 7.2 Hz, 3H), 1.32 (t, J ¼ 7.2 Hz, 3H);
C
NMR (75 MHz, CDCl ) d 165.34, 162.70, 160.21, 126.22,
3
1
23.51, 121.05, 116.73, 61.90, 60.71, 52.38, 29.85, 14.36;
+
HRMS (ESI): calc. for [(C12
found 292.0845.
6
H15NO )Na] [M + Na] 292.0796,
3
57–366; (v) S. M. Rokade, A. M. Garande, N. A. A. Ahmad
Acknowledgements
and P. M. Bhate, RSC Adv., 2015, 5, 2281–2284; (w)
N. A. A. Ahmad, S. M. Rokade, A. M. Garande and
P. M. Bhate, Tetrahedron Lett., 2014, 55, 5458–5461.
The nancial support from the Council of Scientic and
Industrial Research, New Delhi (sanction no. 01(2427)/10/
EMR-II dated 28/12/2010 and pool scheme no. 8644-A), India, to
carry out this work is gratefully acknowledged. H.P.K. and K.S.V.
thank Council of Scientic and Industrial Research and
University Grants Commission-Special Assistance Programme,
New Delhi respectively for award of Senior Research Fellow-
ships. A.C.C. thanks DST for offering Fast Track Project SB/FT/
CS-147/2013. The authors thank Prof. Prakash M. Bhate for his
generous support.
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