Alum-catalyzed synthesis of 3-(1H-pyrrol-2-yl)-2H-chromen-2-ones: A water-peg 400 binary solvent mediated, one-pot, three-component protocol

Article abstract of DOI:10.1055/s-0032-1318494

A novel, one-pot, three-component condensation reaction of 3-(bromoacetyl)coumarin, acetylacetone, and an amine using the inexpensive, environmentally benign, and mild catalyst alum as an efficient catalyst and the water-PEG 400 binary solvent system gives 3-(1-aryl-4-acetyl-5-methyl-1H-pyrrol- 2-yl)-2H-chromen-2-ones, a new heterocyclic scaffold containing both the coumarin and pyrrole nuclei in a single molecule, in good to excellent yields. This methodology offers several advantages: simple procedure, excellent yields, short reaction times, and green aspects such as avoiding toxic catalysts and solvents. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0032-1318494

PAPER
▌1191
paper
Alum-Catalyzed Synthesis of 3-(1H-Pyrrol-2-yl)-2H-chromen-2-ones:
A Water–PEG 400 Binary Solvent Mediated, One-Pot, Three-Component
Protocol
3-(1H-Pyrrol-2-yl)-2H-chromen-2-ones
Gargi Pal, Sanjay Paul, Asish R. Das*
Department of Chemistry, University of Calcutta, Kolkata 700009, India
Fax +91(33)23519754; E-mail: ardchem@caluniv.ac.in; E-mail: ardas66@rediffmail.com
Received: 16.01.2013; Accepted after revision: 04.03.2013
MeO
O
Abstract: A novel, one-pot, three-component condensation reac-
tion of 3-(bromoacetyl)coumarin, acetylacetone, and an amine us-
ing the inexpensive, environmentally benign, and mild catalyst
O
alum as an efficient catalyst and the water–PEG 400 binary solvent
O
O
O
system gives 3-(1-aryl-4-acetyl-5-methyl-1H-pyrrol-2-yl)-2H-
chromen-2-ones, a new heterocyclic scaffold containing both the
coumarin and pyrrole nuclei in a single molecule, in good to excel-
lent yields. This methodology offers several advantages: simple
procedure, excellent yields, short reaction times, and green aspects
such as avoiding toxic catalysts and solvents.
NMeBn
pachyrrhizine (I)
MeO
MeO
O
O
AP2238 (II)
Key words: pyrrole derivatives, coumarin, alum, binary solvent,
green protocol
O
HN
NO2
N
The coumarin (2H-chromen-2-one) skeleton is an impor-
tant heterocyclic motif due to its presence in many syn-
thetically challenged and pharmaceutically active
compounds. As a privileged scaffold, coumarin is a ubiq-
uitous subunit in many natural products with unique
physical1 and remarkable biological activity, including
anti-HIV,2,3 antitumor, antihypertension, antiarrhythmia,
anti-inflammatory, antiosteoporosis, antiseptic, analgesic,
and anticoagulant activity.4 In the last few years, much at-
tention has focused on the synthesis of new biologically
active coumarin derivatives. In particular, the 3-substitut-
ed coumarin scaffold has been the focal point of recent
studies as it constitutes an important class of biologically
active compounds such as carbochromen (coronary heart
disease treatment),5 pachyrrhizine (I, mosquitocidal activ-
ity),6 warfarin (anticoagulant),7 and AP2238 (II, anti-
Alzheimer drug candidate)8 (Figure 1). Accordingly, in-
teresting applications of 3-substituted coumarin deriva-
tives in the health sciences have promoted their
preparation as an interesting topic in synthetic organic
chemistry.
R
III
Figure 1 Biologically active coumarin and pyrrole derivatives
pyrroles are in the spotlight as they display antibacterial,11
antiviral (also anti-HIV-1),2,3 anti-inflammatory,12,13 and
antioxidant14 activity and also inhibit cytokine-mediated
diseases.15–18
Both the coumarin and pyrrole systems exhibit diverse
biological properties. It was thought that linking these two
active pharmacophores would produce novel molecular
templates that are likely to exhibit interesting biological
properties. The paramount therapeutic significance of the
coumarin and pyrrole systems inspired us to develop effi-
cient protocols for the synthesis of new diversified pyrrole
derivatives linked with a coumarin moiety (Figure 2). A
number of methods have been reported for the synthesis
of pyrrole. However, no reports are available in literature
to date for the synthesis of pyrrole derivatives linked with
a coumarin moiety. The traditional methods for the syn-
thesis of pyrrole derivatives are: Knorr,19 Paal–Knorr,20
and Hantzsch reactions.21 A survey in the literature re-
vealed that most traditional as well as recently developed
methods for the synthesis of pyrrole derivatives involved
the use of hazardous metal catalysts, toxic chlorinated sol-
vents, considerable amounts of acids, or harsh reaction
conditions such as microwave irradiation,22 whereas ap-
proaches for preparing heterocyclic systems containing a
highly acid- and base-sensitive coumarin unit under mild
reaction conditions are narrow in scope.
Among various synthetic and naturally occurring hetero-
cyclic structures, the pyrrole core containing molecular
framework is the most prevalent. Pyrroles are found in a
wide spectrum of natural products and bioactive mole-
cules,9 including the highly efficient drug Atorvastatin
Calcium,10a as well as important anti-inflammatants,10b
antitumor agents,10c immunosuppressants,10d and an anti-
proliferative agent III (Figure 1). 1,2,3,5-Tetrasubstituted
SYNTHESIS 2013, 45, 1191–1200
Advanced online publication: 19.03.2013
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DOI: 10.1055/s-0032-1318494; Art ID: SS-2013-N0053-OP
© Georg Thieme Verlag Stuttgart · New York

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G. Pal et al.
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Table 1 Evaluation of Various Catalyst Systemsa
Entry
Catalyst
Time (h)
Yieldb (%)
N
R
1
2
–
24
12
12
12
12
12
12
12
12
12
12
7
14
10
10
15
23
28
49
41
39
40
48
81
O
O
ZnCl2
SiO2
3
Figure 2 Diversified coumarin-linked pyrrole derivatives
4
ZnO
In continuation of our research program dedicated to the
design and synthesis of novel heterocyclic systems,23 we
began our investigational journey with the objective of
developing a clean, efficient, and straightforward method-
ology utilizing an inexpensive, nontoxic, and environ-
mentally benign catalyst that has been used for the
synthesis of several heterocyclic molecules.24 We like to
report a direct synthesis of various highly substituted pyr-
role derivatives. The synthesis of pyrrole-substituted cou-
marin systems has been performed by assembling the
basic building blocks using alum as the key and efficient
catalyst.
5
MgO
6
FeCl3
zeolite
alumina
PTSA
AcOH
PEG-SO3H
alum
7
8
9
10
11
12
a Reaction conditions: 1a (1 mmol), 2a (1 mmol), 3b (1 mmol), cata-
lyst (15 mol%), PEG 400–H2O (1:1, 5 mL), 70 °C.
b Isolated yields of pure products.
For the optimization studies, we chose 3-(bromoace-
tyl)coumarin (1a), acetylacetone (2a), and p-anisidine
(3b) as the substrates for the one-pot, three-component
condensation reaction (Scheme 1). To establish the opti-
mal conditions, we used a wide variety of Lewis acids
(ZnCl2, silica gel, ZnO, MgO, FeCl3, zeolite, alumina, al-
um), organo acid catalysts (PTSA, AcOH), and polymer-
supported PEG-OSO3H to carry out the key transforma-
tion and to obtain the corresponding substituted pyrrole
ring (Table 1). It was evident that the reaction proceeded
very slowly in the absence of a catalyst and the expected
product was isolated in low yield after heating the reaction
mixture in PEG 400–H2O mixture (1:1, 5 mL) for about
24 hours at 70 °C (entry 1). We then examined Lewis
acids such as zinc chloride, silica gel, zinc oxide, magne-
sium oxide, and iron(III) chloride (entries, 2–6), but they
were not efficient catalysts in this reaction and the product
4b was obtained in poor yields. Using zeolite, alumina, or-
gano acid catalysts (PTSA, AcOH) and polymer-support-
ed PEG-SO3H (entry 7–11) was more efficient, but alum
proved to be most efficient catalyst giving 4b in 81% yield
in seven hours (entry 12).
ticomponent reaction (Table 2). The catalyst showed
moderate catalytic activity in water and PEG 400. The
best catalytic activity was observed in the water–PEG 400
binary solvent system, compared to other organic solvents
(THF, toluene, MeCN, MeOH). The catalytic activity of
alum was maximum in aqueous media due to its very high
solubility in water, but the poor solubility of the reactants
diminished the yield of the desired product. To obtain a
high yielding clean protocol, the polarity of the solvent
was optimized by employing water as a cosolvent with
PEG 400 in different proportions. The reaction (Scheme
1) was performed in pure PEG 400 and then the polarity
was adjusted with water for better results. The results
summarized in Table 2 clearly demonstrate that PEG 400–
water (3:2) mixture produced the optimum polarity of the
solvent at which the reaction took place at faster rate. This
also revealed that quantity of the catalyst played a vital
role in realizing the optimum product yield. An increase
in the amount of alum from 5 to 15 mol% increased the
yield of 4b to a great extent (58–91%, Table 2).
Next we sought to optimize the conditions (catalyst load-
ing and solvents) for the catalyst alum in this reaction. The
effect of the solvent is very much pronounced in the mul-
Further examination of the reaction conditions revealed
that the yields largely depended on the reaction tempera-
MeO
NH2
O
O
O
O
catalyst
Br
+
+
N
PEG 400/H2O
70 °C
O
O
OMe
O
O
4b
1a
2a
3b
Scheme 1 Synthesis of pyrrole derivatives linked with coumarin
Synthesis 2013, 45, 1191–1200
© Georg Thieme Verlag Stuttgart · New York

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3-(1H-Pyrrol-2-yl)-2H-chromen-2-ones
1193
ture (Figure 3). At 70 °C the reaction proceeded well and
gave the maximum yield (91%) of the desired product 4b.
The rate of the reaction was very slow at temperatures be-
low 70 °C, probably due to the unavailability of activation
energy, and at a higher temperature there might be some
sort of polymerization of the intermediate or the starting
material resulting poor yields of the desired product.
Table 2 Optimization of the Catalyst Concentration and Solvent
Systema
Entry
Alum
(mol%)
Solvent
Time
(h)
Yieldb
(%)
1
2
15
15
15
15
15
15
15
15
15
15
5
THF
12
12
12
12
12
12
7
trace
trace
trace
25
toluene
3
MeCN
Figure 3 Effect of temperature on the reaction of 3-(bromoace-
tyl)coumarin, acetylacetone, and p-anisidine in PEG 400–H2O (3:2)
4
MeOH
5
PEG 400
48
The efficiency of the above reaction protocol encouraged
us to develop a novel, one-pot, three-component synthetic
route for the synthesis of highly functionalized pyrrole de-
rivatives linked with a coumarin moiety under thermal
conditions. As shown in Table 3, a range of electronically
divergent aromatic amines are tolerated under these con-
ditions. In addition, our methodology has been applied
successfully to acid and base sensitive compounds such as
heteroaromatic amines and aliphatic amines. To scrutinize
the scope, limitations, and generality of this protocol, we
also utilized two (bromoacetyl)coumarin derivatives [3-
(bromoacetyl)coumarin and 3-(bromoacetyl)-7-methoxy-
coumarin] for the synthesis of a number of diversified
pyrroles linked with a coumarin moiety. All the synthe-
sized compounds were characterized by 1H and 13C NMR,
IR, and HRMS spectral data. The structure of the pyrrole-
linked coumarin derivative 4c was also confirmed explic-
itly by X-ray crystal structure analysis (Figure 4).25
6
H2O
35
7
PEG 400–H2O (1:1)
PEG 400–H2O (3:2)
PEG 400–H2O (3:1)
PEG 400–H2O (4:1)
PEG 400–H2O (3:2)
PEG 400–H2O (3:2)
PEG 400–H2O (3:2)
81
8
5
91
9
6
65
10
11
12
13
7
60
8
58
10
20
8
62
5
90
a Reaction conditions: 1a (1 mmol), 2a (1 mmol), 3b (1 mmol), alum,
solvent (5 mL), 70 °C.
b Isolated yield.
Table 3 Substrate Scopea
R2
N
O
O
O
Alum
Br
R2 NH2
+
O
+
PEG 400/H2O (3:2)
70 °C
R1
O
O
R1
O
O
1
2
3
4
Entry
Product
Time (h)
Yield (%)
N
1
5
90
O
O
O
4a
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1191–1200

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G. Pal et al.
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Table 3 Substrate Scopea (continued)
R2
N
O
O
O
O
Alum
Br
R2 NH2
+
O
+
PEG 400/H2O (3:2)
70 °C
R1
O
R1
O
O
1
2
3
4
Entry
Product
Time (h)
Yield (%)
MeO
N
2
5
91
O
O
O
O
O
O
4b
Cl
N
O
3
6
89
O
O
O
4c
F
N
O
4
6
89
4d
Br
N
O
5
6
90
4e
Cl
MeO
N
O
6
6
87
O
O
4f
N
O
7
5
89
O
O
4g
Synthesis 2013, 45, 1191–1200
© Georg Thieme Verlag Stuttgart · New York

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3-(1H-Pyrrol-2-yl)-2H-chromen-2-ones
1195
Table 3 Substrate Scopea (continued)
R2
N
O
O
O
Alum
Br
R2 NH2
+
O
+
PEG 400/H2O (3:2)
70 °C
R1
O
O
R1
O
O
1
2
3
4
Entry
Product
Time (h)
Yield (%)
N
8
6
88
O
O
O
4h
N
N
O
9
7
84
O
O
4i
S
N
O
10
4
85
O
O
4j
N
O
11
5
89
O
O
4k
N
O
12
5.5
87
O
O
4l
N
13
5
83
O
MeO
O
O
4m
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1191–1200

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G. Pal et al.
PAPER
Table 3 Substrate Scopea (continued)
R2
N
O
O
O
O
Alum
Br
R2 NH2
+
O
+
PEG 400/H2O (3:2)
70 °C
R1
O
R1
O
O
1
2
3
4
Entry
Product
Time (h)
Yield (%)
MeO
N
14
5
85
O
O
O
MeO
O
O
O
O
4n
Cl
N
15
5.5
86
MeO
O
4o
F
N
O
16
5.5
84
MeO
4p
a Reaction conditions: 1 (1 mmol), 2 (1 mmol), 3 (1 mmol), alum (15 mol%), PEG 400–H2O (3:2, 5 mL), 70 °C.
With these outstanding results in hand, we are now in a
position to propose the mechanistic pathway, namely the
insight into the three-component tandem cyclization
(Scheme 2). The first step of the alum-catalyzed, three-
component coupling reaction involved condensation of β-
dicarbonyl 2 and amine derivatives 3 for the formation of
β-enaminone IV. Alum (specifically Al3+, the active and
key component of the catalyst) has shown excellent cata-
lytic activity in promoting the reaction to the desired prod-
uct by enhancing the electrophilicity of the β-dicarbonyl
2; that is, it prevents the premature attack of amine nu-
cleophile to the activated α-C of (bromoacetyl)coumarin
1, otherwise it may lead to the formation of a new class of
compounds V. Subsequently the intermediate β-enami-
none IV underwent alum-catalyzed nucleophilic attack at
the α-C (Al3+ polarizes the Br atom) of (bromoacetyl)cou-
marin 1 to generate a new intermediate VI that experien-
ces sequential intramolecular cyclization followed by
dehydration to fabricate the target molecule. In presence
of water–PEG 400 binary solvent mixture the problem of
solubility of the organic compounds not only diminished,
but an enhancement of the catalytic activity was also ob-
Figure 4 ORTEP diagram of the single-crystal X-ray structure of 3-
[4-acetyl-1-(4-chlorophenyl)-5-methyl-1H-pyrrol-2-yl]-2H-chro-
men-2-one (4c) (CCDC 900676)
Synthesis 2013, 45, 1191–1200
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3-(1H-Pyrrol-2-yl)-2H-chromen-2-ones
1197
served. Probably this is due to the co-ordination of the hy- ly (Scheme 2). The FT-IR spectra (Figure 5) of PEG-400
droxy group of PEG 400 with Al3+, the active species of and PEG-400–alum mixture clearly indicates the coordi-
the catalyst and it constructs a macromolecular cavity. By nation of the hydroxy group of PEG 400 with Al3+ and in
taking the advantage of the formation of macromolecular turn formation of a macromolecular cavity. The peak at
cavity, the building blocks of the targeted pyrrole deriva- 3398 cm–1 (due to the OH group) of PEG-400 was re-
tives are in the close vicinity to the catalyst so that alum placed by a broad peak at 2400–3600 cm–1 of PEG-400–
catalyzes the multicomponent coupling reaction efficient- alum mixture (Figure 5). The formation of a β-enaminone
H
H
Al3+
O
Br
O
O
O
O
O
O
O
O
R2
O
O
HN
R2
2
NH2
– H2O
1
IV
O
O
O
O
R1
3
O
O
O
Br
x
R1
O
n
1
OH
H
– HBr
N
R2
R1
O
O
V
R2
3+Al
HN
O
R2
O
N
R1
O
O
– H2O
O
VI
R1
O
O
Scheme 2 Plausible mechanism for the formation of pyrrole derivatives linked with coumarin
Figure 5 FT-IR spectra of PEG-400 (PEG) and PEG-400, alum (PEG-Al) inclusion complex
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1191–1200

1198
G. Pal et al.
PAPER
1H NMR (300 MHz, CDCl3): δ = 7.65 (s, 1 H), 7.48 (d, J = 7.5 Hz,
2 H), 7.36 (d, J = 8.1 Hz, 1 H), 7.28–7.23 (m, 3 H), 6.99 (d, J = 8.7
intermediate in the actual reaction pathway was estab-
lished successfully by performing the reaction between
(bromoacetyl)coumarin and β-enaminone, obtained from
the reaction (alum-catalyzed) of m-toluidine and acetyl-
acetone under identical experimental conditions.
Hz, 2 H), 6.89 (s, 1 H), 3.87 (s, 3 H), 2.39 (s, 3 H), 2.38 (s, 3 H). 13
C
NMR (75 MHz, CDCl3): δ = 195.5, 160.0, 159.5, 153.4, 138.8,
135.6, 131.4, 130.8, 127.7, 127.4, 124.4, 124.3, 123.0, 119.7, 118.4,
116.6, 114.6, 55.6, 30.4, 13.0.
HRMS: m/z [M + H]+ calcd for C23H20NO4: 374.1392; found:
374.1392.
In conclusion, the present study represents the first exam-
ple of the direct synthesis of novel compounds containing
pyrrole-substituted coumarin molecules via three-compo-
nent condensation of 3-(bromoacetyl)coumarin, acetyl-
acetone, and an aromatic amine utilizing alum, an
inexpensive, efficient, nontoxic, and mild Lewis acid cat-
alyst. This simple, environmentally benign and conve-
nient methodology extends the scope towards a wide
range of novel compounds possessing an important struc-
tural subunit of a variety of biologically active molecules,
which would surely attract the attention of the biological
as well as pharmaceutical industries.
3-[4-Acetyl-1-(4-chlorophenyl)-5-methyl-1H-pyrrol-2-yl]-2H-
chromen-2-one (4c)
White crystalline solid; yield: 0.336 g (89%); mp 200 °C.
IR (KBr): 1232.3, 1403.8, 1494.9, 1637.4, 1719.6 (OC=O), 3059.6
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.65 (s, 1 H), 7.26–7.53 (m, 8 H),
6.91 (s, 1 H), 2.39 (s, 3 H), 2.38 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 195.8, 161.0, 153.4, 139.0, 137.0,
135.0, 134.4, 131.0, 129.7, 127.7, 127.5, 124.4, 124.0, 123.4, 122.6,
119.6, 118.9, 116.6, 30.4, 13.0.
HRMS: m/z [M + H]+ calcd for C22H17ClNO3: 378.0897; found:
378.0894.
1H and 13C NMR spectral were recorded on a Bruker-Advance Dig-
ital 300 MHz and 75 MHz instruments with TMS as internal stan-
dard. IR spectra were recorded in KBr pellets in reflection mode on
a Perkin Elmer RX-1 FTIR spectrophotometer. HRMS were ob-
tained using a QTOFMICRO YA263 mass spectrometer. Suitable
single crystal of compound 4c was mounted on a Bruker-AXS
SMART APEX II diffractometer equipped with a graphite mono-
chromator. All reactions were monitored by TLC carried out on
Merck aluminum-backed silica gel plates coated with silica gel G
under UV light and also by exposure to I2 vapor. Melting points
were determined on a Köfler Block apparatus and are uncorrected.
Synthetic grade chemicals from Sigma-Aldrich, Spectrochem and
E-Merck were used for the organic reactions. For column chroma-
tography, Spectrochem 100–200 mesh silica gel was used. All the
solvents used in the reaction were distilled and dried (Na2SO4).
3-[4-Acetyl-1-(4-fluorophenyl)-5-methyl-1H-pyrrol-2-yl]-2H-
chromen-2-one (4d)
White crystalline solid; yield: 0.321 g (89%); mp 188 °C.
IR (KBr): 1219.6, 1509.4, 1659.9, 1713.5 (OC=O), 3037.3 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.65 (s, 1 H), 7.48 (d, J = 7.2 Hz,
2 H), 7.36–7.15 (m, 6 H), 6.89 (s, 1 H), 2.37 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 195.8, 163.9, 161.0, 160.6, 153.4,
139.0, 135.2, 134.5, 130.9, 128.3, 128.2, 127.5, 124.4, 124.1, 123.1,
122.8, 119.6, 118.7, 116.6, 116.3, 30.4, 12.9.
HRMS: m/z [M + H]+ calcd for C22H17FNO3: 362.1192; found:
362.1192.
3-[4-Acetyl-1-(4-bromophenyl)-5-methyl-1H-pyrrol-2-yl]-2H-
chromen-2-one (4e)
White crystalline solid; yield: 0.380 g (90%); mp 199 °C.
IR (KBr): 1235.2, 1492.9, 1636.9, 1713.1 (OC=O), 3419.6 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.03–7.73 (m, 9 H), 6.83 (s, 1 H),
Pyrrole-Substituted Coumarins; General Procedure
A mixture of 3-(bromoacetyl)coumarin (1, 1 mmol), acetylacetone
(2, 1 mmol), amine derivative 3 (1 mmol), and alum (15 mol%) in
PEG 400–H2O (3:2, 5 mL) was stirred at 70 °C. After completion of
the reaction (TLC monitoring), the mixture was cooled and extract-
ed with EtOAc (3 × 10 mL). Removal of the solvent under reduced
pressure and purification of the crude product by column chroma-
tography (silica gel 100–200 mesh) provided pure products. All
compounds were characterized by 1H, 13C NMR, FT-IR, and HRMS
analysis.
2.32 (s, 3 H), 2.31 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 195.4, 162.4, 153.4, 139.1, 132.7,
131.1, 128.0, 127.5, 124.4, 124.0, 122.5, 122.4, 120.1, 119.6, 119.1,
116.6, 30.4, 13.0.
HRMS: m/z [M + Na]+ calcd for C22H16BrNNaO3: 444.0211; found:
444.0217.
3-(4-Acetyl-5-methyl-1-phenyl-1H-pyrrol-2-yl)-2H-chromen-2-
one (4a)
3-[4-Acetyl-1-(3-chloro-4-methoxyphenyl)-5-methyl-1H-pyr-
rol-2-yl]-2H-chromen-2-one (4f)
White crystalline solid; yield: 0.355 g (87%); mp 214 °C.
IR (KBr): 1058.2, 1258.8, 1500.2, 1724.3 (OC=O), 2929.5 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.62 (s, 1 H), 7.45 (d, J = 7.2 Hz,
White crystalline solid; yield: 0.309 g (90%); mp 185 °C.
IR (KBr): 1064.0, 1231.2, 1498.9, 1636.5, 1714.9 (OC=O), 3064.3
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.61 (s, 1 H), 7.20–7.48 (m, 9 H),
6.89 (s, 1 H), 2.36 (s, 3 H), 2.34 (s, 3 H).
2 H), 6.91–7.38 (m, 5 H), 6.84 (s, 1 H), 3.93 (s, 3 H), 2.45 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 195.4, 153.4, 138.9, 135.2, 130.8,
129.4, 128.4, 127.4, 126.4, 124.3, 122.7, 119.7, 118.6, 116.5, 30.4,
13.1.
HRMS: m/z [M + H]+ calcd for C22H18NO3: 344.1287; found:
344.1281.
13C NMR (75 MHz, CDCl3): δ = 195.8, 161.0, 153.4, 139.0, 137.0,
135.1, 134.0, 131.0, 128.6, 127.7, 127.5, 124.4, 124.1, 123.1, 122.6,
119.6, 118.7, 116.5, 56.4, 30.4, 13.0.
HRMS: m/z [M + H]+ calcd for C23H19ClNO4: 408.1003; found:
408.1006.
3-[4-Acetyl-1-(4-methoxyphenyl)-5-methyl-1H-pyrrol-2-yl]-
2H-chromen-2-one (4b)
White crystalline solid; yield: 0.336 g (91%); mp 220 °C.
3-[4-Acetyl-5-methyl-1-(4-tolyl)-1H-pyrrol-2-yl]-2H-chromen-
2-one (4g)
White crystalline solid; yield: 0.318 g (89%); mp 196 °C.
IR (KBr): 1238.6, 1405.7, 1662.9, 1703.9 (OC=O), 3042.6 cm–1.
IR (KBr): 1029.1, 1238.0, 1510.7, 1654.8, 1709.8 (OC=O), 3421.0
cm–1.
Synthesis 2013, 45, 1191–1200
© Georg Thieme Verlag Stuttgart · New York

PAPER
3-(1H-Pyrrol-2-yl)-2H-chromen-2-ones
1199
1H NMR (300 MHz, CDCl3): δ = 7.62 (s, 1 H), 7.16–7.49 (m, 8 H),
6.88 (s, 1 H), 2.40 (s, 3 H), 2.36 (s, 3 H), 2.35 (s, 3 H).
IR (KBr): 1231.5, 1420.9, 1607.6, 1720.5 (OC=O), 2380.3, 3046.0
cm–1.
13C NMR (75 MHz, CDCl3): δ = 195.7, 161.0, 153.3, 139.2, 138.7,
138.4, 135.8, 135.3, 130.1, 127.3, 127.1, 126.1, 125.2, 124.3, 122.7,
119.6, 118.4, 116.4, 30.4, 21.1, 13.1.
1H NMR (300 MHz, CDCl3): δ = 8.08 (s, 1 H), 7.88–6.38 (m, 4 H),
6.79 (s, 1 H), 3.75–3.70 (m, 1 H), 2.33 (s, 3 H), 2.31 (s, 3 H), 2.29–
2.18 (m, 4 H), 1.87–1.72 (m, 6 H).
HRMS: m/z [M + H]+ calcd for C23H20NO3: 358.1443; found:
358.1441.
13C NMR (75 MHz, CDCl3): δ = 196.1, 160.6, 152.6, 142.7, 132.2,
128.6, 128.3, 128.1, 127.0, 124.3, 122.5, 113.7, 106.8, 45.0, 41.0,
37.1, 33.3, 31.2, 27.1, 20.0, 13.2.
HRMS: m/z [M + H]+ calcd for C22H24NO3: 350.1751; found:
350.1758.
3-[4-Acetyl-5-methyl-1-(3-tolyl)-1H-pyrrol-2-yl]-2H-chromen-
2-one (4h)
White crystalline solid; yield: 0.315 g (88%); mp 192 °C.
IR (KBr): 1240.0, 1503.1, 1638.6, 1717.1 (OC=O), 3049.7 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.65 (s, 1 H), 6.93–7.56 (m, 8 H),
3-(4-Acetyl-5-methyl-1-phenyl-1H-pyrrol-2-yl)-7-methoxy-2H-
chromen-2-one (4m)
White crystalline solid; yield: 0.310 g (83%); mp 184 °C.
6.92 (s, 1 H), 2.37–2.43 (m, 9 H).
IR (KBr): 1233.0, 1612.3, 1721.9 (OC=O), 3456.3 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.97 (s, 1 H), 7.19–7.55 (m, 4 H),
13C NMR (75 MHz, CDCl3): δ = 195.8, 161.0, 153.4, 139.6, 138.8,
138.5, 135.2, 130.8, 129.2, 127.4, 127.0, 124.4, 123.5, 123.0, 122.8,
119.7, 118.5, 116.6, 30.4, 21.3, 13.1.
6.79–6.89 (m, 5 H), 4.85 (s, 3 H), 3.81–3.87 (m, 6 H).
HRMS: m/z [M + H]+ calcd for C23H20NO3: 358.1443; found:
358.1446.
13C NMR (75 MHz, CDCl3): δ = 196.1, 162.3, 161.4, 155.2, 149.4,
138.5, 135.3, 129.4, 126.4, 122.9, 122.5, 120.7, 118.8, 114.4, 113.2,
112.7, 100.6, 100.4, 69.3, 30.4, 13.2.
HRMS: m/z [M + H]+ calcd for C23H20NO4: 374.1392; found:
374.1390.
3-[4-Acetyl-5-methyl-1-(pyridin-3-yl)-1H-pyrrol-2-yl]-2H-
chromen-2-one (4i)
White crystalline solid; yield: 0.244 g (84%); mp 171 °C.
IR (KBr): 1176.0, 1613.4, 1715.5 (OC=O), 3365.3 cm–1.
3-[4-Acetyl-1-(4-methoxyphenyl)-5-methyl-1H-pyrrol-2-yl]-7-
methoxy-2H-chromen-2-one (4n)
1H NMR (300 MHz, CDCl3): δ = 8.45–8.40 (m, 1 H), 8.26 (s, 1 H),
8.10 (s, 1 H), 7.59–7.24 (m, 6 H), 6.84 (s, 1 H), 2.60 (s, 3 H), 2.58
(s, 3 H).
White crystalline solid; yield: 0.330 g (85%); mp 201 °C.
IR (KBr): 1506.3, 1497.8, 1616.1, 1715.6 (OC=O), 3409.2 cm–1.
13C NMR (75 MHz, CDCl3): δ = 191.0, 159.6, 152.8, 150.3, 140.5,
136.5, 130.9, 128.1, 124.6, 121.0, 119.8, 118.7, 116.3, 113.9, 112.9,
106.0, 29.0, 13.0.
HRMS: m/z [M + H]+ calcd for C22H17N2O3: 345.1234; found:
345.1236.
1H NMR (300 MHz, CDCl3): δ = 7.59 (s, 1 H), 6.82–7.37 (m, 8 H),
3.85 (s, 3 H), 3.84 (s, 3 H), 2.35 (s, 3 H), 2.34 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 195.0, 162.2, 161.4, 159.4, 154.9,
140.6, 139.4, 135.6, 131.4, 129.3, 128.4, 127.6, 126.9, 122.6, 120.8,
118.6, 114.5, 113.3, 112.6, 100.6, 55.8, 30.3, 13.0.
HRMS: m/z [M + H]+ calcd for C24H22NO5: 404.1498; found:
404.1497.
3-[4-Acetyl-5-methyl-1-(thiophen-2-ylmethyl)-1H-pyrrol-2-yl]-
2H-chromen-2-one (4j)
Yellow amorphous solid; yield: 0.311 g (85%); mp 62 °C.
3-[4-Acetyl-1-(4-chlorophenyl)-5-methyl-1H-pyrrol-2-yl]-7-
methoxy-2H-chromen-2-one (4o)
White crystalline solid; yield: 0.351 g (86%); mp 210 °C.
IR (KBr): 1240.3, 1530.6, 1648.3, 1721.2 (OC=O), 2410.3, 3010.6
cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.13 (s, 1 H), 7.65–7.20 (m, 5 H),
IR (KBr): 1237.2, 1496.8, 1612.7, 1716.3 (OC=O), 3407.0 cm–1.
6.82–6.78 (m, 3 H), 5.38 (s, 2 H), 2.11 (s, 3 H), 2.08 (s, 3 H).
1H NMR (300 MHz, CDCl3): δ = 6.85–7.61 (m, 9 H), 3.90 (s, 3 H),
2.39 (s, 3 H), 2.36 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 196.3, 162.1, 161.6, 155.4, 139.0,
138.5, 132.7, 131.0, 127.9, 127.5, 124.4, 122.5, 122.3, 119.6, 116.6,
113.5, 112.8, 101.0, 56.0, 30.4, 13.0.
13C NMR (75 MHz, CDCl3): δ = 196.0, 164.3, 152.8, 144.8, 136.1,
132.7, 129.0, 124.6, 122.8, 122.7, 122.3, 117.0, 115.4, 113.3, 105.5,
47.1, 31.1, 10.2.
HRMS: m/z [M + H]+ calcd for C21H18NO3S: 364.1002; found:
364.1002.
HRMS: m/z [M + H]+ calcd for C23H19ClNO4: 408.1003;
found:408.1005.
3-(4-Acetyl-1-benzyl-5-methyl-1H-pyrrol-2-yl)-2H-chromen-2-
one (4k)
3-[4-Acetyl-1-(4-fluorophenyl)-5-methyl-1H-pyrrol-2-yl]-7-
methoxy-2H-chromen-2-one (4p)
White crystalline solid; yield: 0.329 g (84%); mp 212 °C.
IR (KBr): 1220.0, 1506.3, 1614.2, 1715.3 (OC=O), 2925.0 cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.49 (s, 1 H), 6.74–7.29 (m, 8 H),
Yellow amorphous solid; yield: 0.318 g (89%); mp 45 °C.
IR (KBr): 1180.3, 1546.9, 1654.6, 1719.2 (OC=O), 2346.3, 3030.0
cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.48–7.05 (m, 8 H), 6.85–6.77 (m,
2 H), 6.70 (s, 1 H), 5.09 (s, 2 H), 2.46 (s, 3 H), 2.38 (s, 3 H).
3.78 (s, 3 H), 2.27 (s, 3 H), 2.26 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 199.6, 165.3, 158.4, 146.9, 143.2,
141.8, 136.6, 133.7, 133.6, 132.7, 132.3, 131.5, 130.5, 129.4, 126.3,
125.3, 123.8, 121.3, 118.4, 53.0, 33.4, 16.9.
HRMS: m/z [M + H]+ calcd for C23H20NO3: 358.1448; found:
358.1443.
13C NMR (75 MHz, CDCl3): δ = 196.0, 163.8, 162.3, 161.4, 155.2,
139.5, 135.3, 134.6, 128.4, 122.9, 122.5, 120.5, 119.1, 116.5, 116.3,
113.2, 112.7, 100.6, 56.1, 30.4, 13.1.
HRMS: m/z [M + Na]+ calcd for C23H18ClNNaO4: 414.1118; found:
414.1118.
3-(4-Acetyl-1-cyclohexyl-5-methyl-1H-pyrrol-2-yl)-2H-chro-
men-2-one (4l)
Yellow amorphous solid; yield: 0.304 g (87%); mp 57 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1191–1200

1200
G. Pal et al.
PAPER
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Acknowledgement
We acknowledge the financial support from University of Calcutta.
G.P thanks CSIR, New Delhi, India, for her fellowship (Grant No.
09/028(0792)/2010 EMR-I). S.P. thanks U.G.C., New Delhi, India,
for the grant of Junior Research fellowship. Crystallography was
performed at the DST-FIST, India-funded Single Crystal Diffracto-
meter Facility at the Department of Chemistry, University of Cal-
cutta.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
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nnfomartit
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Synthesis 2013, 45, 1191–1200
© Georg Thieme Verlag Stuttgart · New York