Lithium hydroxide mediated synthesis of 3,4-disubstituted pyrroles

Article abstract of DOI:10.1039/c3ra42569j

LiOH·H₂O in ethanol was found to be an effective reagent for the synthesis of 3,4-disubstituted pyrrole derivatives by the van Leusen method. In situ formation of chalcones from aromatic aldehydes and enolisable ketones, and their subsequent reaction with tosylmethyl isocyanide resulted in the formation and precipitation of pyrrole derivatives from the reaction medium, in good yields. The solvation effect of the polar medium facilitates the reaction. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ra42569j

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Lithium hydroxide mediated synthesis of 3,4-
disubstituted pyrroles
Cite this: DOI: 10.1039/c3ra42569j
Ratnesh Sharma,a Kapil Kumar,a Mangilal Chouhan,a Vikas Groverb and Vipin
A. Nair*a
LiOH?H2O in ethanol was found to be an effective reagent for the synthesis of 3,4-disubstituted pyrrole
derivatives by the van Leusen method. In situ formation of chalcones from aromatic aldehydes and
enolisable ketones, and their subsequent reaction with tosylmethyl isocyanide resulted in the formation
and precipitation of pyrrole derivatives from the reaction medium, in good yields. The solvation effect of
the polar medium facilitates the reaction.
Received 25th May 2013,
Accepted 12th June 2013
DOI: 10.1039/c3ra42569j
www.rsc.org/advances
conditions. Pyrroles, which are inherently susceptible to air
and acidic environments, usually require a tedious work-up
Introduction
The pyrrole skeleton is an integral part of many natural and
biologically active compounds1 with antibacterial,2 antifun-
gal,3 antiviral,4 antiinflammatory,5 and anticancer6 properties.
Syntheses of pyrrole derivatives involve two types of strategies:
(a) condensation reactions of a-aminocarbonyl compounds
and activated ketones (Knorr pyrrole synthesis7) or a-halocar-
bonyl compounds, b-keto esters and ammonia (Hantzsch
pyrrole synthesis8) or 1,4-dicarbonyl compounds and primary
amines (Paal–Knorr synthesis9) and (b) functionalization of
pyrrole by substitution reactions.10 Condensation reactions
have several drawbacks like non-availability of suitable
starting materials, multistep syntheses, functional group
incompatibility, lack of regiospecificity and involvement of
harsh reagents and conditions. Various new strategies have
been developed which involve rapid and convergent techni-
ques but the use of expensive reagents still mitigates the
advantages. Based on our interests on heterocyclic compounds
and reaction methodology,11 we decided to reinvestigate the
van Leusen reaction12 for the synthesis of pyrroles from
tosylmethyl isocyanide (TosMIC). Under basic conditions,
TosMIC reacts with a,b-unsaturated ketones, esters or nitriles
to give 3-acyl pyrroles, pyrrole-3-carboxylates and 3-cyanopyr-
roles respectively.13 The reaction involves the generation of the
TosMIC anion by sodium hydride in a solvent mixture of
diethyl ether–dimethyl sulfoxide followed by the reaction of
the anion with a,b-unsaturated carbonyl compounds. The
product is usually isolated by extraction into an organic
medium followed by chromatographic purification. The
reaction affords modest yields under the typical experimental
and purification process. Our efforts resulted in a simple one-
pot procedure both for chalcone14 formation from aromatic
aldehydes and enolisable ketones and the subsequent cyclo-
condensation to form pyrrole. The advantage also lies in the
fact that the product is precipitated from the reaction medium
when formed, due to low solvation and dynamic effects of the
solvent employed. Also the use of a greener solvent and milder
reaction conditions is environmentally benign, and avoiding
the hassle of isolation/purification makes it cost-effective.
Results and discussion
In a model reaction acetophenone (1.0 eq) was reacted with
benzaldehyde (1.0 eq) in the presence of LiOH?H2O (0.1 eq) in
ethanol medium to afford 1,3-diphenylprop-2-enone by an
aldol condensation between the enolate and the electrophile
(Scheme 1). After 30 min, the reaction underwent completion,
as monitored by TLC. To the same flask TosMIC (1.1 eq) and
an additional equivalent of LiOH?H2O (1.2 eq) was introduced.
aDepartment of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research, Sector 67, Mohali, Punjab, 160062, India.
E-mail: vn74nr@yahoo.com; vnair@niper.ac.in
bCentral Instrumentation Laboratory, National Institute of Pharmaceutical
Scheme 1 Synthesis of phenyl(4-phenyl-1H-pyrrol-3-yl)methanone.
Education and Research, Sector 67, Mohali, Punjab, 160062, India
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As the reaction progressed, a white solid precipitated from the
reaction medium. Upon completion of the reaction, the
product obtained was filtered, washed with water and ethanol,
and characterized as phenyl(4-phenyl-1H-pyrrol-3-yl)metha-
none.
recorded on a Bruker Maxix TOF mass spectrometer. Melting
points are uncorrected.
Typical procedure for the synthesis of aryl(4-aryl-1H-pyrrol-3-
yl)methanone
A mixture of benzaldehyde (1.0 mmol), acetophenone (1.0
mmol) and lithium hydroxide monohydrate (0.1 mmol) in
ethanol (3 mL) was stirred at RT. The progress of the reaction
was monitored by TLC. Upon completion, lithium hydroxide
monohydrate (1.1 mmol) and tosylmethyl isocyanide (1.2
mmol) were added and stirred. As the reaction progressed,
the product precipitated. The precipitate was filtered, and
washed with water and cold ethanol, successively. The product
was characterized by spectroscopic methods.
The base, LiOH?H2O, has appreciable covalent character
due to the small size of the Li+ ion. This property slows down
the release of OH2 ions as compared to other alkali metal
hydroxides. In polar solvents, the Li–O bond provides a strong
contribution to the solute–solvent interaction. Solvents often
affect the reaction equilibrium by preferentially stabilizing
either the reactants or the products, often referred to as the
solvation effect. Polar solvents can accelerate the reaction if
ionized species are generated from unionized starting materi-
als. The solvated ionized species being stable in polar medium
modulates the reaction effectively with the chalcone.
Subsequent to the reaction, the solubility decreases, due to
the loss of charge. The low solvation and the dynamic effect of
the solvent leads to the precipitation of the pyrrole derivatives
from the solution. This favors the equilibrium towards
completion of reaction, and isolation of the product without
the difficulties of purification. While precipitation of the final
product was witnessed with aromatic substrates, the aliphatic
a,b-unsaturated carbonyls tended to polymerize in presence of
the base.
(4-(3,4-Dimethoxyphenyl)-1H-pyrrol-3-yl)(phenyl)methanone
(3aa)
1
White solid; mp 225–227 uC; H NMR (DMSO-d6, 400 MHz) d
11.59 (brs, 1H), 7.70 (d, J = 7.3 Hz, 2H), 7.55–7.41 (m, 3H), 7.19
(s, 1H), 7.04–6.82 (m, 4H), 3.72 (s, 3H), 3.67 (s, 3H); 13C NMR
(DMSO-d6, 100MHz) d 190.5, 147.9, 147.1, 140.1, 131.4, 128.9,
128.0, 127.9, 127.0, 125.3, 120.5, 120.4, 119.1, 112.8, 111.4,
55.4, 55.3; ESI-HRMS(m/z): [M + Na]+ calcd. for C19H17NNaO3,
330.1106, found 330.1106.
(4-(4-Nitrophenyl)-1H-pyrrol-3-yl)(phenyl)methanone (3ab)
1
Brown solid; mp 218–220 uC; H NMR (DMSO-d6, 400 MHz) d
Apart from solvation, dynamic solvent effects also play a
significant role in the reaction rate. The optimized conditions
were generalized by reacting substituted benzaldehydes and
acetophenones (Table 1). The scope of the reaction was also
examined on cinnamaldehyde and thiophene-2-carboxalde-
hyde, which afforded good yields.
11.91 (brs, 1H), 8.13 (d, J = 8.2 Hz, 2H), 7.71 (d, J = 7.2 Hz, 2H),
7.65 (d, J = 8.2 Hz, 2H), 7.61–7.47 (m, 3H), 7.33 (d, J = 13.8 Hz,
2H); 13C NMR (DMSO-d6, 100 MHz) d 190.1, 145.1, 142.6, 139.5,
131.8, 129.3, 129.0, 128.9, 128.3, 123.3, 123.1, 121.8, 120.6; ESI-
HRMS(m/z): [M + Na]+ calcd. for C17H12N2NaO3, 315.0746,
found 315.0746.
A plausible mechanism for the reaction is depicted in
Scheme 2. LiOH?H2O abstracts a proton from the methylene
group of TosMIC to generate a carbanion which is stabilized by
the sulfonyl group. The intermediate, a 1,3-dipole, undergoes
[3 + 2] cycloaddition reaction to afford the cycloadduct II.
Elimination of lithium p-toluene sulfinate mediated by the
base leads to the formation of a C-3 substituted pyrrole
derivative III. Finally, a 1,3-hydride shift occurs to afford the
desired product IV. The b-substituent of the electrophile ends
up at the C-4 position of the pyrrole ring.
Phenyl(4-phenyl-1H-pyrrol-3-yl)methanone (3ac)
1
White solid; mp 230–232 uC; H NMR (DMSO-d6, 400 MHz) d
11.65 (brs, 1H), 7.73 (d, J = 7.2 Hz, 2H), 7.58–7.44 (m, 3H), 7.37
(d, J = 7.3 Hz, 2H), 7.27–7.22 (m, 3H), 7.18–7.14 (m, 1H), 7.08
(d, J = 1.7 Hz, 1H); 13C NMR (DMSO-d6, 100 MHz) d 190.3,
139.9, 135.2, 131.5, 128.9, 128.3, 128.1, 128.0, 127.7, 125.6,
125.4, 120.5, 119.6; ESI-HRMS(m/z): [M + Na]+ calcd. for
C
17H13NNaO, 270.0895, found 270.0892.
(4-(2-Chlorophenyl)-1H-pyrrol-3-yl)(phenyl)methanone (3ad)
1
White solid; mp 233–235 uC; H NMR (DMSO-d6, 400 MHz) d
11.67 (brs, 1H), 7.71–7.69 (m, 2H), 7.55–7.52 (m, 1H), 7.46–7.21
(m, 7H), 6.98–6.97 (m, 1H); 13C NMR (DMSO-d6, 100 MHz) d
190.2, 139.9, 135.4, 133.2, 132.3, 131.9, 129.4, 129.2, 128.5,
128.2, 127.0, 126.9, 122.6, 122.6, 120.7; ESI-HRMS(m/z): [M +
Na]+ calcd. for C17H12ClNNaO, 304.0505, found 304.0505.
Experimental section
All the reagents were purchased from commercial sources and
used as such without further purification. Solvents were
distilled and dried before use. The 1H and 13C NMR spectra
were recorded at 400 MHz and 100 MHz, respectively on a
Bruker Avance DPX 400 (400 MHz) spectrometer in CDCl3/
DMSO-d6 using TMS as an internal standard. The chemical
(4-(4-Chlorophenyl)-1H-pyrrol-3-yl)(phenyl)methanone (3ae)
1
White solid; mp 290–292 uC; H NMR (DMSO-d6, 400 MHz) d
1
shifts (d) for H and 13C are given in ppm relative to residual
11.64 (brs, 1H), 7.68 (d, J = 7.6 Hz, 2H), 7.55–7.21 (m, 8H), 6.96
(s, 1H); 13C NMR (DMSO-d6, 100 MHz) d 190.3, 139.9, 135.3,
133.2, 132.2, 131.9, 129.4, 129.2, 128.6, 128.3, 127.1, 126.9,
122.6, 122.5, 120.7; ESI-HRMS(m/z): [M + Na]+ calcd. for
C17H12ClNNaO, 304.0505, found 304.0505.
signals of the solvent. Coupling constants are given in Hz. The
following abbreviations are used to indicate the multiplicity: s,
singlet; d, doublet; t, triplet; td, triple doublet; dt, double
triplet; q, quartet; m, multiplet; brs, broad signal. HRMS were
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Table 1 Synthesis of 3,4-disubstituted pyrroles
Starting Materials
ArCHO
Entry
ArCOCH3
Product
Yield (%)
80
1
2
78
3
4
5
82
85
83
6
7
79
84
8
9
80
83
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Table 1 (Continued)
Starting Materials
ArCHO
Entry
ArCOCH3
Product
Yield (%)
88
10
11
12
81
83
13
14
15
87
75
82
16
17
81
78
18
76
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Table 1 (Continued)
Starting Materials
ArCHO
Entry
ArCOCH3
Product
Yield (%)
78
19
20
21
87
83
128.2, 126.1, 125.4, 122.9, 121.3, 119.8, 118.2, 116.5, 112.0,
55.7, 55.6; ESI-HRMS(m/z): [M + Na]+ calcd. for C19H17NNaO3,
330.1106, found 330.1109.
(4-(4-Fluorophenyl)-1H-pyrrol-3-yl)(phenyl)methanone (3af)
1
White solid; mp 211–213 uC; H NMR (DMSO-d6, 400 MHz) d
11.64 (brs, 1H), 7.73–7.70 (m, 2H), 7.58–7.37 (m, 5H), 7.22 (d, J
= 2.0 Hz, 1H), 7.10–7.04 (m, 3H); 13C NMR (DMSO-d6, 100
MHz) d 190.7, 140.4, 132.1, 131.9, 130.6, 130.6, 129.3, 128.7,
128.6, 124.8, 120.9, 120.2, 115.0, 114.7; ESI-HRMS(m/z): [M +
Na]+ calcd. for C17H12FNNaO, 288.0801, found 288.0808.
(4-(4-(Dimethylamino)phenyl)-1H-pyrrol-3-yl)(phenyl)
methanone (3ai)
1
Yellow solid; mp 245–247 uC; H NMR (DMSO-d6, 400 MHz) d
11.48 (brs, 1H), 7.72–7.43 (m, 5H), 7.22 (d, J = 8.8 Hz, 2H), 7.13
(d, J = 2.0 Hz, 1H), 6.93 (d, J = 1.9 Hz, 1H), 6.63 (d, J = 8.8 Hz,
2H), 2.86 (s, 6H); 13C NMR (DMSO-d6, 100 MHz) d 190.8, 149.2,
140.8, 131.8, 129.4, 129.3, 128.6, 128.2, 126.2, 123.9, 120.8,
118.8, 112.5, 40.8; ESI-HRMS(m/z): [M + Na]+ calcd. for
C19H18N2NaO, 313.1317, found 313.1317.
(4-(4-Bromophenyl)-1H-pyrrol-3-yl)(phenyl)methanone (3ag)
1
White solid; mp 242–244 uC; H NMR (DMSO-d6, 400 MHz) d
11.69 (brs, 1H), 7.73 (d, J = 7.0 Hz, 2H), 7.56 (d, J = 6.0 Hz, 1H),
7.49–7.43 (m, 4H), 7.33 (d, J = 7.0 Hz, 2H), 7.23 (s, 1H), 7.13 (s,
1H); 13C NMR (DMSO-d6, 100 MHz) d 190.7, 140.3, 135.0, 132.0,
131.0, 130.8, 129.4, 128.9, 128.7, 124.6, 120.8, 120.5, 119.2; ESI-
HRMS(m/z): [M + Na]+ calcd. for C17H12BrNNaO, 348.0000,
found 348.0008.
(4-(4-Methoxyphenyl)-1H-pyrrol-3-yl)(phenyl)methanone (3aj)
1
White solid; mp 225–227 uC; H NMR (DMSO-d6, 400 MHz) d
11.56 (brs, 1H), 7.72–7.70 (m, 2H), 7.57–7.43 (m, 3H), 7.32–7.28
(m, 2H), 7.17 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 2.0 Hz, 1H), 6.84–
6.80 (m, 2H), 3.73 (s, 3H); 13C NMR (DMSO-d6, 100 MHz) d
190.8, 158.0, 140.6, 131.9, 129.9, 129.3, 128.6, 128.4, 128.1,
125.6, 120.8, 119.5, 113.6, 55.4; ESI-HRMS(m/z): [M + Na]+
calcd. for C18H15NNaO2, 300.1000, found 300.1009.
(4-(2,5-Dimethoxyphenyl)-1H-pyrrol-3-yl)(phenyl)methanone
(3ah)
1
White solid; mp 213–215 uC; H NMR (DMSO-d6, 400 MHz) d
11.47 (brs, 1H), 7.66–7.64 (m, 2H), 7.48–7.34 (m, 3H), 7.17 (d, J
= 2.0 Hz, 1H), 6.93 (d, J = 2.0 Hz, 1H), 6.79 (dd, J = 2.6 Hz, 0.8
Hz, 1H), 6.69–6.64 (m, 2H), 3.68 (s, 3H), 3.34 (s, 3H); 13C NMR
(DMSO-d6, 100 MHz) d 190.8, 153.3, 150.6, 139.8, 131.7, 129.2,
(4-(3,4-Dimethoxyphenyl)-1H-pyrrol-3-yl)(4-methoxyphenyl)
methanone (3ba)
1
White solid; mp 239–241 uC; H NMR (DMSO-d6, 400 MHz) d
11.51 (brs, 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 1.8 Hz, 1H),
7.04–6.81 (m, 6H), 3.80 (s, 3H), 3.71 (s, 3H), 3.66 (s, 3H); 13C
NMR (DMSO-d6, 100 MHz) d 189.9, 162.5, 148.5, 147.5, 133.0,
131.7, 128.6, 127.1, 125.6, 121.2, 120.7, 119.1, 113.8, 113.2,
112.1, 56.0, 55.8, 55.8; ESI-HRMS(m/z): [M + Na]+ calcd. for
C
20H19NNaO4, 360.1212, found 360.1212.
Scheme 2 Plausible mechanism for the 1,3-dipolar cycloaddition.
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3H), 7.18–7.14 (m, 1H), 7.08 (d, J = 1.7 Hz, 1H); 13C NMR
(DMSO-d6, 100 MHz) d 189.6, 139.4, 135.5, 131.6, 131.4, 128.8,
128.8, 128.2, 126.2, 125.9, 125.7, 120.7, 120.2; ESI-HRMS(m/z):
[M + Na]+ calcd. for C17H12BrNNaO, 348.0000, found 348.0001.
(4-Methoxyphenyl)(4-(4-nitrophenyl)-1H-pyrrol-3-yl)
methanone (3bb)
Light yellow solid; mp 252–254 uC; 1H NMR (DMSO-d6, 400
MHz) d 11.81 (brs, 1H), 8.12 (d, J = 7.78 Hz, 2H), 7.84–7.77 (m,
2H), 7.66–7.59 (m, 2H), 7.38–7.28 (m, 2H), 7.03 (d, J = 7.78 Hz,
2H), 3.83 (s, 3H); 13C NMR (DMSO-d6, 100 MHz) d 189.5, 162.8,
145.5, 143.2, 132.4, 131.9, 129.1, 128.6, 123.7, 123.6, 122.0,
121.4, 114.0, 55.9; ESI-HRMS(m/z): [M + Na]+ calcd. for
C18H14N2NaO4, 345.0851, found 345.0851.
(4-Fluorophenyl)(4-phenyl-1H-pyrrol-3-yl)methanone (3fc)
1
White solid; mp 227–229 uC; H NMR (DMSO-d6, 400 MHz) d
11.65 (brs, 1H), 7.83–7.76 (m, 2H), 7.35–7.07 (m, 9H); 13C NMR
(DMSO-d6, 100 MHz) d 189.4, 163.3, 136.9, 135.6, 132.2, 132.1,
128.8, 128.3, 128.2, 126.1, 125.9, 120.9, 120.1, 115.6, 115.4; ESI-
HRMS(m/z): [M + Na]+ calcd. for C17H12FNNaO, 288.0801,
found 288.0801.
(4-Methoxyphenyl)(4-phenyl-1H-pyrrol-3-yl)methanone (3bc)
1
White solid; mp 218–220 uC; H NMR (DMSO-d6, 400 MHz) d
11.55 (brs, 1H), 7.75 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 17.3 Hz, 2H),
7.25–7.12 (m, 4H), 7.07 (d, J = 1.8 Hz, 1H), 6.98 (d, J = 8.7 Hz,
2H), 3.81 (s, 3H); 13C NMR (DMSO-d6, 100 MHz) d 189.7, 162.6,
135.8, 132.8, 131.8, 128.6, 128.2, 127.2, 125.9, 125.7, 121.2,
119.6, 113.9, 55.8; ESI-HRMS(m/z): [M + Na]+ calcd. for
C18H15NNaO2, 300.1000, found 300.1009.
(E)-Phenyl(4-styryl-1H-pyrrol-3-yl)methanone (3ak)
1
Brownish solid; mp 175–177 uC; H NMR (CDCl3, 400 MHz) d
8.83 (brs, 1H), 7.81–7.79 (m, 2H), 7.70 (d, J = 16.5 Hz, 1H),
7.55–7.42 (m, 5H), 7.36–7.11 (m, 5H), 6.92 (d, J = 16.5 Hz, 1H);
13C NMR (CDCl3, 100 MHz) d 192.2, 140.5, 138.0, 131.5, 129.1,
128.5, 128.2, 127.7, 127.4, 127.0, 126.3, 124.5, 122.0, 121.5,
116.6; ESI-HRMS(m/z): [M + Na]+ calcd. for C19H15NNaO,
296.1051, found 296.1057.
(4-(2-Chlorophenyl)-1H-pyrrol-3-yl)(4-methoxyphenyl)
methanone (3bd)
1
White solid; mp 225–227 uC; H NMR (DMSO-d6, 400 MHz) d
Phenyl(4-(thiophen-2-yl)-1H-pyrrol-3-yl)methanone (3al)
11.60 (brs, 1H), 7.71 (d, J = 6.9 Hz, 2H), 7.35–7.20 (m, 5H),
6.98–6.95 (m, 3H), 3.80 (s, 3H); 13C NMR (DMSO-d6, 100MHz) d
189.0, 162.4, 135.5, 133.1, 132.3, 132.3, 131.5, 129.4, 128.1,
127.0, 125.9, 122.7, 122.5, 120.5, 113.8, 55.8; ESI-HRMS(m/z):
[M
334.0611.
1
Creamy white solid; mp 231–233 uC; H NMR (DMSO-d6, 400
MHz) d 11.72 (brs, 1H), 7.74–7.72 (m, 2H), 7.59–7.56 (m, 1H),
7.50–7.46 (m, 2H), 7.32 (d, J = 4.4 Hz, 2H), 7.21–7.19 (m, 2H),
6.98–6.96 (m, 1H); 13C NMR (DMSO-d6, 100 MHz) d 190.5,
140.5, 137.3, 132.0, 129.3, 129.0, 128.7, 127.4, 125.6, 124.3,
120.7, 120.3, 118.6; ESI-HRMS(m/z): [M + Na]+ calcd. for
C15H11NNaOS, 276.0459, found 276.0453.
+
Na]+ calcd. for C18H14ClNNaO2, 334.0611, found
(4-(4-Chlorophenyl)-1H-pyrrol-3-yl)(4-methoxyphenyl)methanone
(3be)
1
White solid; mp 248–250 uC; H NMR (DMSO-d6, 400 MHz) d
11.62 (brs, 1H), 7.75 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.6 Hz, 2H),
7.29 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 1.8 Hz, 1H), 7.11 (d, J = 1.8
Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H); 13C NMR (DMSO-
d6, 100 MHz) d 189.6, 162.6, 134.7, 132.7, 131.8, 130.6, 130.3,
128.2, 127.7, 124.4, 121.1, 120.1, 113.9, 55.9; ESI-HRMS(m/z):
Conclusions
A mild and efficient procedure was developed for the synthesis
of 3,4-disubstituted pyrrole derivatives from tosylmethyl
isocyanide and in situ formed chalcones by
procedure. The solvation and dynamic effects of the medium
resulted in the precipitation of the product from the reaction.
a one-pot
[M
334.0611.
+
Na]+ calcd. for C18H14ClNNaO2, 334.0611, found
(4-Phenyl-1H-pyrrol-3-yl)(p-tolyl)methanone (3cc)
1
White solid; mp 242–244 uC; H NMR (DMSO-d6, 400 MHz) d
Acknowledgements
11.59 (brs, 1H), 7.65 (d, J = 8.1 Hz, 2H), 7.36–7.06 (m, 9H), 2.36
(s, 3H); 13C NMR (DMSO-d6, 100 MHz) d 190.5, 142.1, 137.7,
135.8, 129.6, 129.2, 128.7, 128.2, 128.0, 126.0, 125.8, 121.1,
119.9, 21.5; ESI-HRMS(m/z): [M + Na]+ calcd. for C18H15NNaO,
284.1051, found 284.1056.
Research funding from the Department of Science and
Technology (DST) and a research fellowship to R. S. from the
Council of Scientific and Industrial Research (CSIR) are
gratefully acknowledged.
(4-Chlorophenyl)(4-phenyl-1H-pyrrol-3-yl)methanone (3dc)
1
White solid; mp 231–233 uC; H NMR (DMSO-d6, 400 MHz) d
Notes and references
11.69 (brs, 1H), 7.73 (d, J = 5.0 Hz, 2H), 7.51 (d, J = 6.7 Hz, 2H),
7.36–7.08 (m, 7H); 13C NMR (DMSO-d6, 100 MHz) d 189.5,
139.1, 136.7, 135.6, 131.2, 128.8, 128.7, 128.7, 128.2, 126.1,
125.9, 120.7, 120.2; ESI-HRMS(m/z): [M + Na]+ calcd. for
C17H12ClNNaO, 304.0505, found 304.0505.
1 G. P. Bean, In Pyrroles, ed. R. A. Jones, Wiley, New York,
1990, p. 105.
2 (a) G. Sbardella, A. Mai, M. Artico, R. Loddo, M. G. Setzuc
and P. La Collac, Bioorg. Med. Chem. Lett., 2004, 14, 1537; (b)
M. V. Raimondi, S. Cascioferro, D. Schillaci and S. Petruso,
Eur. J. Med. Chem., 2006, 41, 1439; (c) M. Biava, G.
C. Porretta, G. Poce, D. Deidda, R. Pompei, A. Tafi and
F. Manetti, Bioorg. Med. Chem., 2005, 13, 1221.
(4-Bromophenyl)(4-phenyl-1H-pyrrol-3-yl)methanone (3ec)
1
White solid; mp 210–212 uC; H NMR (DMSO-d6, 400 MHz) d
11.69 (brs, 1H), 7.65 (s, 4H), 7.36–7.34 (m, 2H), 7.26–7.23 (m,
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3 R. Di Santo, A. Tafi, R. Costi, M. Botta, M. Artico, F. Corelli,
M. Forte, F. Caporuscio, L. Angiolella and A. T. Palamara, J.
Med. Chem., 2005, 48, 5140.
2039; (f) R. Sharma, M. Chouhan, D. Sood and V. A. Nair,
Appl. Organomet. Chem., 2011, 25, 305; (g) B. Liegault and
K. Fagnou, Organometallics, 2008, 27, 4841.
4 M. Bialer, B. Yagen, R. Mechoulam and Y. Becker, J. Med.
Chem., 1980, 23, 1144.
11 (a) V. Kumar, P. Raghavaiah, S. M. Mobin and V. A. Nair,
Org. Biomol. Chem., 2010, 8, 4960; (b) V. Kumar and V.
A. Nair, Tetrahedron Lett., 2010, 51, 966; (c) G. L. Khatik,
R. Khurana, V. Kumar and V. A. Nair, Synthesis, 2011, 3123;
(d) V. Kumar, G. L. Khatik and V. A. Nair, Synlett, 2011,
2997; (e) M. Chouhan, K. R. Senwar, R. Sharma, V. Grover
and V. A. Nair, Green Chem., 2011, 13, 2553; (f) V. Kumar,
A. Pal, G. L. Khatik and V. A. Nair, Tetrahedron: Asymmetry,
2012, 23, 434; (g) G. L. Khatik, V. Kumar and V. A. Nair, Org.
Lett., 2012, 14, 2442; (h) M. Chauhan, R. Sharma and V.
A. Nair, Org. Lett., 2012, 14, 5672; (i) V. Kumar, K. Kumar,
A. Pal, G. L. Khatik and V. A. Nair, Tetrahedron, 2013, 69,
1747.
¨
5 (a) G. Dannhardt, W. Kiefer, G. Kramer, S. Maehrlein, U. Nowe
and B. Fiebich, Eur. J. Med. Chem., 2000, 35, 499; (b) S. Laufer,
J. Augustin, G. Dannhardt and W. Kiefer, J. Med. Chem., 1994,
37, 1894; (c) I. K. Khanna, R. M. Weier, P. W. Collins, J.
M. Miyashiro, C. M. Koboldt, A. W. Veenhuizen, J. L. Currie,
K. Seibert and P. C. Isakson, J. Med. Chem., 1997, 40, 1619.
6 (a) K.-I. Wakabayashi, K. Imai, H. Miyachi, Y. Hashimoto
and A. Tanatani, Bioorg. Med. Chem., 2008, 16, 6799; (b)
H. Lee, J. Lee, Y. Shin, W. Jung, J.-H. Kim, K. Park, S. Ro, H.-
H. Chung and J. S. Koh, Bioorg. Med. Chem. Lett., 2001, 11,
2963.
7 L. Knorr, Ber., 1884, 17, 1635.
8 A. Hantzsch, Ber., 1890, 23, 1474.
9 (a) C. Paal, Ber., 1885, 18, 367; (b) L. Knorr, Ber., 1885, 18,
299.
10 (a) J. R. Garabatos-Perera, B. H. Rotstein and A. Thompson,
J. Org. Chem., 2007, 72, 7382; (b) G. Fridkin and W.
D. Lubell, Org. Lett., 2008, 10, 849; (c) D. T. Gryko, D. Gryko
and C.-H. Lee, Chem. Soc. Rev., 2012, 41, 3780; (d) J.
S. Lindsey, Acc. Chem. Res., 2010, 43, 300; (e) R. Sharma,
M. Chouhan and V. A. Nair, Tetrahedron Lett., 2010, 51,
12 D. van Leusen and A. M. van Leusen, Org. React., 2003, 57,
419 and references cited therein.
13 (a) A. M. van Leusen, H. Siderius, B. E. Hoogenboom and
D. van Leusen, Tetrahedron Lett., 1972, 13, 5337; (b) D. H.
R. Barton, J. Kervagoret and S. Z. Zard, Tetrahedron, 1990,
46, 7587; (c) D. van Leusen, E. van Echten and A. M. van
Leusen, J. Org. Chem., 1992, 57, 2245.
14 S. Bhagat, R. Sharma, D. M. Sawant, L. Sharma and A.
K. Chakraborti, J. Mol. Catal. A: Chem., 2006, 244, 20.
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