Synthesis of tetra-substituted pyrroles, a potential phosphodiesterase 4B inhibitor, through nickel(II) chloride hexahydrate catalyzed one-pot four-component reaction

Article abstract of DOI:10.1016/j.tetlet.2012.05.133

A wide variety of tetra-substituted pyrrole derivatives were synthesized through one-pot four-component condensation reaction of aromatic aldehydes, benzylamines, β-ketoesters, and nitroalkanes in the presence of 10 mol % NiCl₂·6H₂O in good yields. Some of them exhibit properties as potential inhibitors of phosphodiesterase 4B (PDE4B) through docking studies.

Full text of DOI:10.1016/j.tetlet.2012.05.133

Tetrahedron Letters 53 (2012) 4145–4150
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of tetra-substituted pyrroles, a potential phosphodiesterase 4B
inhibitor, through nickel(II) chloride hexahydrate catalyzed one-pot
four-component reaction
Abu T. Khan a, , Mohan Lal a, Prasanta Ray Bagdi a, R. Sidick Basha a, Parameswaran Saravanan b,
⇑
Sanjukta Patra b
a Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781 039, India
b Department of Biotechnology, Indian Institute of Technology Guwahati, Guwahati 781 039, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A wide variety of tetra-substituted pyrrole derivatives were synthesized through one-pot four-compo-
nent condensation reaction of aromatic aldehydes, benzylamines, b-ketoesters, and nitroalkanes in the
presence of 10 mol % NiCl2ꢀ6H2O in good yields. Some of them exhibit properties as potential inhibitors
of phosphodiesterase 4B (PDE4B) through docking studies.
Received 16 March 2012
Revised 26 May 2012
Accepted 29 May 2012
Available online 9 June 2012
Ó 2012 Elsevier Ltd. All rights reserved.
This work is dedicated to my mentor,
Professor Dr. R. R. Schmidt on the occasion
of his 77th birthday
Keywords:
Multicomponent reactions
b-Ketoesters
Nickel(II) chloride hexahydrate
Tetra-substituted pyrroles
Docking studies
Phosphodiesterase 4B inhibitor
In recent times, multicomponent reactions (MCRs) have been
extensively utilized in organic synthesis, combinatorial and medic-
inal chemistry due to their simplicity and high selectivity, good
yield, superior atom-economy, high variability, less time consum-
ing and avoidance of costly purification processes.1
roles and their derivatives through multicomponent reactions
(MCRs). Phosphodiesterase (PDE) are enzymes that play vital roles
in regulating the cellular levels of cyclic adenosine monophosphate
(cAMP) and cyclic guanosine monophosphate (cGMP), secondary
messengers that mediate several biological processes with re-
sponse to extracellular signals.11 The inhibition of PDE leads to
higher levels of cyclic nucleotides. They also have therapeutic po-
tential such as anti-inflammators, anti-asthmatics, vasodilators,
antidepressants, antithrombiotics and cognitive function enhanc-
ers.12,13 The existing therapies serve as symptomatic treatment
and PDE inhibitors prevent progression of several diseases and pro-
vide better relief for symptoms.14 Due to their wide range of biolog-
ical activities, the synthesis of these compounds under different
reaction conditions is highly desirable.
Pyrrole and its derivatives are naturally occurring compounds
and some of their synthetic strategies have been reviewed re-
cently.2 They also display a wide range of biological activities such
as antibacterial, antiviral, anticonvulsant, anticancer, and antioxi-
dant.3 Some of them are promising lead molecule for cholesterol
lowering agent. In addition, they are also useful in building blocks
which are extensively used in material science.4 The synthesis of
pyrroles and their derivatives is usually achieved by employing
well-known Hantzsch5 or Knorr6 or Paal Knorr7 reaction. Recently,
tetra-substituted pyrrole derivatives were reported by Jana and co-
workers by employing four-component reaction catalyzed by
FeCl38 or palladium mediated Suzuki coupling based MCR.9 Menen-
dez and his co-workers reviewed10 recently the synthesis of pyr-
Nickel salts are commonly used in coupling reaction.15 A few
years ago, we had demonstrated anhydrous NiCl2 as an useful Lewis
acid for chemoselective thioacetalization of aldehydes16a and
deprotection of tetrahydropyranyl ether as well as tert-butyldi-
methylsilyl ether using a combination of catalytic amount of
NiCl2ꢀ6H2O and 1,2-ethanthiol.16b Recently, other research groups
have shown the efficacy of anhydrous NiCl2 for multicomponent
⇑
Corresponding author. Tel.: +91 361 2582305; fax: +91 361 2582349.
E-mail address: atk@iitg.ernet.in (A.T. Khan).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.133

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A. T. Khan et al. / Tetrahedron Letters 53 (2012) 4145–4150
aldehydes namely 2-formylthiophene and furan-2-carbaldehyde,
O
Ar CHO
+
R3
respectively and the desired products 5h and 5i (Table 2, entries
8 and 9) were isolated in 58% and 55% yields, respectively. Further,
the scope of the present protocol was elongated with other amines
such as cyclohexylamine, 4-methylbenzylamine, and furfurylamine
with methylacetoacetate and 4-chlorobenzaldehyde. All these reac-
tions went smoothly and also provided the products 5j–l (Table 2,
entries 10–12) in good yields under similar reaction conditions.
Similarly, the reactions were also verified with different b-ketoest-
ers namely ethylacetoacetate, tert-butylacetoacetate, allylacetoace-
tate with benzylamine and 4-chlorobenzaldehyde, respectively and
the required products 5m–o (Table 2, entries 13–15) were isolated
in good yields. Finally, the reactions were also studied with acetyl-
acetone, benzylamine, and 4-chlorobenzaldehyde or 4-bromobenz-
aldehyde in a similar manner and the desired products 5p and 5q
(Table 2, entries 16 and 17) were isolated in 56% and 60% yields,
respectively. It was observed that aniline also reacts with acetylace-
tone and benzaldehyde under identical conditions and the product
5r was obtained in 52% yield (Table 2, entries 18). Further, the scope
of the reaction was also verified with chiral benzyl amines such as
(R)-1-phenylethanamine or (S)-1-phenylethanamine under similar
conditions and the preferred products 5s and 5t were isolated in
76% and 72% yields (Table 2, entry 19 and 20) respectively. Simi-
larly, the reaction of (R)-1-phenylethanamine, ethylacetoacetate,
and 4-fluorobenzaldehyde gave the product 5u in 75% yield (Table
2, entry 21). Similarly, an aldehyde containing electron-withdraw-
ing group such as o-nitrobenzaldehyde also provided the product
5v in 65% yield (Table 2, entry 22) on reaction with (S)-1-phenyle-
thanamine and ethylacetoacetate in a similar manner.
The scope of the present protocol was further scrutinized with
other nitroalkane namely nitroethane with benzylamine, methy-
lacetoacetate, and 4-methyl benzaldehyde and the product 5w
was obtained in 60% yield (Scheme 2). These successful results
clearly indicate that the present protocol is also extendable to a
wide variety of substrates.
The formation of various tetra-substituted pyrroles can be ratio-
nalized as follows: Initially, amine reacts with b-ketoester to pro-
duce enamine A in the presence of Lewis acid NiCl2ꢀ6H2O. We
assume that nitroalkane reacts with benzylamine to generate carb-
anion B which reacts with the NiCl2ꢀ6H2O activated aromatic alde-
hyde to form nitrostyrene C,20 as shown in Scheme 3.
Subsequently, the enamine A reacts with nitrostyrene C to provide
Michael adduct D. The intermediate D undergoes concomitant
cyclization with the elimination of NiO, NO, and HCl to provide
Ar
R2
O
O
•
10 mol% NiCl2 6H2O
R1 NH2
R3
reflux
Me
N
R2
NO2
R1
R1 = Ph/PhCH2/cyclohexyl/furfuryl/chiral amines
R2 = H/Me
R3 = Me/OMe/OEt/OC(CH3)3/O-allyl
Scheme 1. Synthesis of tetra-substituted pyrrole derivatives.
reactions (MCRs).17 As a part of our ongoing research interest to find
out new catalysts on MCRs for the synthesis of various heterocyclic
compounds18, we perceived nickel(II) chloride hexahydrate might
be a useful catalyst for the synthesis of highly substituted pyrroles.
Herein, we wish to report a simple and useful synthetic protocol for
the synthesis of tetra-substituted pyrroles by employing
NiCl2ꢀ6H2O as a catalyst through one-pot four-component conden-
sation reaction of aromatic aldehydes, benzylamines, b-ketoesters
or 1,3-diketone, and nitroalkanes as shown in Scheme 1.
With this goal in mind, a mixture of methylacetoacetate
(1 mmol), benzylamine (1 mmol) and NiCl2ꢀ6H2O (0.1 mmol) in
of nitromethane (1 mL) was stirred at room temperature with 4-
chlorobenzaldehyde to give the desired product 5a in 78% yield.
The efficacy of the other catalysts was also scrutinized by carrying
out similar set of reactions in the presence of other catalysts such
as Fe2(SO4)3, ZnCl2, NiCl2 and NiCl2ꢀ6H2O under identical condi-
tions and the results are summarized in Table 1. Among them,
NiCl2ꢀ6H2O is found to be the most effective catalyst for the syn-
thesis of tetra-substituted pyrrole derivatives. In the above trans-
formation, nitroalkane plays a dual role of a solvent as well as a
reactant.
After optimization of the reaction conditions, the next reaction
was carried out with a mixture of benzylamine, methylacetoace-
tate, benzaldehyde and nitromethane in presence of 10 mol % of
NiCl2ꢀ6H2O under identical reaction conditions and it afforded the
desired product 5b in 72% yield (Table 2, entry 2). Due to these suc-
cessful results, various aromatic aldehydes having substituents
such as Me, MeO, NO2, F, and Br in the aromatic ring were examined
with benzylamine and methylacetoacetate in the presence of the
same amount of catalyst in similar reaction conditions and the
products 5c–g (Table 2, entries 3–7) were obtained in good yields.
The same methodology was further extended with heteroaromatic
Table 1
Optimization of reaction conditions for the synthesis of tetra-substituted pyrrolea
Cl
O
CHO
NH2
MeO
Me
O
O
Catalyst
reflux
CH3NO2
+
+
+
OMe
N
4
Cl
1a
2a
3a
5a
.
Entry
Catalyst
Fe2(SO4)3
ZnCl2
Catalytic amount (mol %)
Time (h)
12
12
12
13
Yieldb (%)
1
2
3
4
5
6
10
10
10
5
10
15
40
45
49
60
78
77
NiCl2
NiCl2ꢀ6H2O
NiCl2ꢀ6H2O
NiCl2ꢀ6H2O
10
10
a
The reactions were performed using 1 mmol scale with benzylamine (1a), methylacetoacetate (2a) and 4-chlorobenzaldehyde (3a)
respectively in 1 mL of nitromethane under reflux conditions.
b
Isolated yield.

A. T. Khan et al. / Tetrahedron Letters 53 (2012) 4145–4150
4147
Table 2
Synthesis of tetra-substituted pyrrole derivatives from various aromatic aldehydes, b-ketoesters amines and nitroalkanes19
O
Ar
CHO
3
+
R3
Ar
O
O
.
10 mol% NiCl2 6H2O
R1 NH2
R3
reflux
Me
N
1
2
R1
CH3NO2
4
5
Entry
R1
Ar
R3
Time/h
Producta
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H5CH2
C6H11
4-Cl-C6H4
C6H5
4-Me-C6H4
4-OMe-C6H4
4-NO2-C6H4
4-F-C6H4
4-Br-C6H4
2-Thiophen
2-Furan
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
8
9
8
8
9
8
8
12
11
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
78
72
75
65
70
76
73
58
55
74
4-Cl-C6H4
5j
11
4-Cl-C6H4
OMe
10
5k
72
CH2
O
12
13
14
4-MeC6H4CH2
C6H5CH2
C6H5CH2
4-Cl-C6H4
4-Cl-C6H4
4-Cl-C6H4
OMe
OEt
OC(CH3)3
9
10
11
5l
5m
5n
70
78
76
15
16
17
18
C6H5CH2
C6H5CH2
C6H5CH2
C6H5
4-Cl-C6H4
4-Cl-C6H4
4-Br-C6H4
C6H5
12
8
9
5o
5p
5q
5r
75
56
60
52
O
Me
Me
Me
10
19
20
21
22
4-Me-C6H4
4-Me-C6H4
4-F-C6H4
OMe
OMe
OEt
6
5s
5t
76
72
75
65
NH2
NH2
NH2
NH2
7
8
5u
5v
2-NO2-C6H4
OEt
10
a
The reactions were performed using 1 mmol of amines (1), 1 mmol of b-ketoesters (2) or 1,3-diketone, and 1 mmol of aromatic aldehydes (3) in 1 mL nitromethane under
reflux conditions.
b
Isolated yield.
Me
O
O
O
OMe
MeO
Me
NH2
10 mol% NiCl2 6H2O
reflux
+
CH3CH2NO2
Me
N
Me
CHO
5w
Scheme 2. Synthesis of fully substituted pyrrole.
the final product 5, since the intermediate ‘enamine A’ can react21
as a ‘di-nucleophile.’ The pH of the reaction mixture was 2-3 during
reaction time indicating the generation of HCl in the medium. To
prove the mechanism, we have carried out an experiment with a
mixture of b-ketoester, benzylamine, aromatic aldehyde, and nitro-
methane in the presence of 10 mol % NiO. We have obtained tetra-
substituted pyrrole derivative 5b in 70% yield. From this observa-
tion we believe that the NiO generated in the reaction is further
participating in the catalytic cycle for the formation of the product.
The structure of compound 5k was confirmed by single XRD
crystallographic data22 and the ORTEP diagram of substituted pyr-
role 5k is shown in Fig. 1.
In support of the mechanism, the by product, NiO was charac-
terized through X-ray diffraction (XRD) analysis. A representative
XRD pattern of the product NiO is given in Supplementary data.
Structure-based docking study is a viable method for the iden-
tification of hits and enriching the lead identification phase of the
pharmaceutical industry.23 The synthesized compounds especially

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A. T. Khan et al. / Tetrahedron Letters 53 (2012) 4145–4150
NiCl2.6H2O
NiCl2.6H2O
O
O
O
R1NH2
R2
+
NO2
CH3NO2
R3
Ar
H
B
R1NH2
R1
O
H
Ar
R3
O
O
R2
NH
O
H2O
+
HCl
N
R2
+
O
R3
Ar
N
O
NH
A
C
R1
Cl
Ni
D
Imine-enamine
tautomerization
O
O
O
H
R3
Ar
R2
N
Ar
R3
Ar
R3
R2
O
N
-NO,NiO
-HCl
R2
N
O
N
NH
R1
O
Cl
R1
Cl
O
Ni
R1
F
Ni
E
5
Scheme 3. Plausible mechanism for the formation of substituted pyrrole derivatives.
residues of the active site pocket mainly Ile410 and Phe446. The
best hit, 5b had similar interaction mode and hydrophobic contacts
with Pro396 and Phe414 also contributed to the binding as shown
in Fig. 2 (predicted free energy of binding: ꢁ0.29 kcal/mol). The
compounds bound near to the invariant Gln443 which could be
exploited to design non-selective PDE inhibitors.
The docking provides insight into designing selective inhibitors
for PDE4 which are provided in Table 4. The contact residues of the
synthesized derivatives from the docking studies are analyzed for
their conservation within PDE family used in the current study.
Significant differences observed in the contact residues are: (i)
Tyr403 whose counterpart are Histidine, Glutamine, Serine and
Alanine in PDE1, PDE3, PDE5, PDE7, and PDE9, respectively; (ii)
Met431 whose counterpart are Threonine, Phenyalanine, Aspar-
tate, Leucine, and Phenyalanine in PDE1, PDE3, PDE5, PDE7 and
PDE9, respectively.
Partial differences are also observed in the contact residues as
shown in Table 4 which can be exploited to design selective
inhibitors.
The compounds bound near to the invariant Gln443 which
could be exploited to design non-selective PDE inhibitors. Design
of lead molecules interacting with Asn395, Pro396, and Thr407
can be designed for dual inhibitors against PDE family and lead
molecules with strong interactions towards Tyr403 and Met431
can be designed to selectively inhibit PDE4 family.
Figure 1. ORTEP diagram of compound of 5k (CCDC 848584).
the top hits formed hydrogen bond with hydroxyl group of Tyr233
and also a conserved interaction with Phe446 as shown in Table
p
3. The interactions were also stabilized by the hydrophobic
Table 3
Compounds with comparable inhibition efficiency of reference compound (PDB ligand ID: 20A)
Entry
Product
Score
Poseview H-bond
Poseview
p-interaction
Poseview hydrophobic contact residues
1
2
3
4
5
6
7
8
5b
5f
5h
5r
5a
5c
5j
5q
5m
20A
5g
ꢁ8.29
ꢁ8.22
ꢁ8
Y233-O1
Y233-O1
Y233-O1
F446[2]
F446[2]
F446[2]
F446[2]
F446
I410, F414, F446, P396, N395, Y403
N395 P396, I410, F414, F446
I410, F414, F446
N395, Y403, T407, M431, I410, F414, F446
Y233, L393, N395, I410, F446
Y233, N395, I410, F414, S442, F446
I410, N395, F414, F446
M431, I410, F414, F446
M431, I410, F446
I410, M431, F446
M431, I410, F446
ꢁ7.99
ꢁ7.97
ꢁ7.96
ꢁ7.9
H234-O
F446
F446[2], F414
F446[2]
F446[3]
F446
ꢁ7.87
ꢁ7.84
ꢁ7.76
ꢁ7.72
9
10
11
Q443
F446[3]

A. T. Khan et al. / Tetrahedron Letters 53 (2012) 4145–4150
4149
Figure 2. Interaction mode of the best hit (5b) with PDE4B in (a) 3D and (b) 2D view.
Table 4
Contact residues of synthesized pyrrole derivatives from the docking studies provide insight to design selective inhibitors for PDE4
PDE Type
PDB Id
Contact residues of synthesized derivatives
PDE4B*
PDE1
PDE3
PDE5
PDE7
3D3P
1TAZ
1SO2
1UHO
1ZKL
2HD1
1FOJ
Y233
N395
P396
Y403
T407
I410
L
F414
M431
F446
H
G
A
H
H
Q
S
T
F
D
L
I
A
S
A
V
V
L
PDE9
F
E
A
Y
F
PDE4B2B
PDE4D
PDE4D2
1MKD
1OYN
⁄Numbering according to the PDE4B (PDB Id: 3D3P) (Residues interacting with the synthesized derivatives in the docking studies are highlighted in bold and corresponding
identical residue in other family are not shown).
In summary, we have demonstrated the use of a four-compo-
nent reaction for the synthesis of tetra-substituted pyrroles start-
ing from amines, b-ketoesters or 1,3-dicarbonyl compounds,
aromatic aldehydes or heteroaromatic aldehydes, and nitroalkanes
using NiCl2ꢀ6H2O as catalyst in moderate to good yields. The reac-
tion proceeds through the formation of enamine and nitrostyrene
followed by Michael addition and subsequently, it undergoes intra-
molecular cyclization to afford pyrroles derivatives. The binding
study of the synthesized pyrrole derivatives indicates their poten-
tial as inhibitors of phosphodiesterase 4B (PDE4B) enzymes.
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.05.133.
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dichloromethane. The filtrate was washed with water and dried over
anhydrous sodium sulfate. The organic extract was concentrated and the
crude residue was finally purified through a silica gel column chromatography.
The final product was obtained by eluting with ethyl acetate and hexane
mixture (5:95). Spectral data: Methyl 4-(4-chlorophenyl)-1-(furan-2-ylmethyl)-
2-methyl-1H-pyrrole-3-carboxylate (5k): Yield = 0.237 g (72%), yellow solid, mp
98 °C, IR (KBr) mmax 2925, 2854, 1698, 1527, 1488, 1438, 1415, 1283, 1193,
1147, 1089, 1070, 1014 cmꢁ1 1H NMR (400 MHz, CDCl3): d 2.51 (s, 3H), 3.59 (s,
;
3H), 4.91 (s, 2H), 6.17 (dd, J = 0.8, 7.2 Hz, 1H), 6.26 (dd, 1.6, 3.2 Hz, 1H), 6.49 (s,
1H), 7.19 (br s, 4H), 7.66 (s, 1H); 13C NMR (100 MHz, CDCl3): d 11.6, 29.9, 43.7,
50.7, 108.7, 110.7, 120.2, 125.2, 127.8, 130.6, 132.1, 134.4, 136.7, 143.1, 149.6,
166.1. Anal. calcd for C18H16ClNO3 (329.77) C, 65.56; H, 4.89; N, 4.25%; found C,
65.48; H, 4.78; N, 4.18%. Allyl 1-benzyl-4-(4-chlorophenyl)-2-methyl-1H-pyrrole-
3-carboxylate (5o): Yield = 0.274 g (75%), oily liquid, IR (KBr) mmax 3027, 2932,
1697, 1524, 1486, 1451, 1420, 1277, 1203, 1182, 1143, 1091, 1056, cmꢁ1 1H
;
15. (a) Terao, J.; Todo, H.; Watanabe, H.; Ikumi, A.; Kambe, N. Angew. Chem., Int. Ed.
2004, 43, 6180–6182; (b) Lee, K.; Counceller, C. M.; Stambuli, J. P. Org. Lett.
2009, 11, 1457–1459.
16. (a) Khan, A. T.; Mondal, E.; Sahu, P. R.; Islam, S. Tetrahedron Lett. 2003, 44, 919–
922; (b) Khan, A. T.; Islam, S.; Choudhary, L. H.; Ghosh, S. Tetrahedron Lett.
2004, 45, 9617–9621.
17. (a) Samai, S.; Nandi, G. C.; Singh, M. S. Tetrahedron Lett. 2010, 51, 5555–5558;
(b) Zhang, X.-N.; Li, Y.-X.; Zhang, Z.-H. Tetrahedron 2011, 67, 7426–7430.
18. (a) Khan, A. T.; Lal, M.; Ali, S.; Khan, M. M. Tetrahedron Lett. 2011, 52, 5327–
5332; (b) Khan, A. T.; Das, D. K.; Khan, M. M. Tetrahedron Lett. 2011, 52, 4539–
4542; (c) Khan, A. T.; Khan, M. M. Tetrahedron Lett. 2011, 52, 3455–3459; (d)
Khan, A. T.; Khan, M. M.; Bannuru, K. K. R. Tetrahedron 2010, 66, 7762–7772; (e)
Khan, A. T.; Lal, M.; Khan, M. M. Tetrahedron Lett. 2010, 51, 4419–4424.
NMR (400 MHz, CDCl3): d 2.46 (s, 3H), 4.61 (d, J = 4.8 Hz, 2H), 5.03 (s, 2H), 5.11
(d, J = 11.6 Hz, 2H), 5.78-5.88 (m, 1H), 6.55 (s, 1H), 7.05 (d, J = 7.6 Hz, 2H), 7.24–
7.34 (m, 7H); 13C NMR (100 MHz, CDCl3): d 11.8, 50.7, 64.5, 110.8, 117.7, 120.8,
125.3, 126.7, 127.8, 128.0, 129.1, 130.7, 132.1, 132.7, 134.5, 136.7, 137.1, 165.4.
Anal. calcd for C22H20ClNO2 (365.85) C, 72.22; H, 5.51; N, 3.83%; found C, 72.13;
H, 5.42; N, 3.76%. (R)-methyl 2-methyl-1-(1-phenylethyl)-4-(p-tolyl)-1H-pyrrole-
3-carboxylate (5s): Yield = 0.253 g (76%), oily liquid, ½a D20
ꢂ
ꢁ58.8o (c 1.5, CHCl3);
IR (KBr) mmax 2990, 2984, 2851, 1701, 1527, 1437, 1412, 1277, 1214, 1189,
1149, 1118, 1079, 1027 cmꢁ1 1H NMR (400 MHz, CDCl3): d 1.74 (d, J = 7.2 Hz,
;
3H), 2.28 (s, 3H), 2.36 (s, 3H), 3.58 (s, 3H), 5.27 (q, J = 6.8 Hz, 1H), 6.63 (br s,
1H), 6.99 (d, J = 7.6 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 7.16–7.25 (m, 5H); 13C NMR
(100 MHz, CDCl3): d 11.5, 21.2, 22.2, 50.5, 55.2, 110.7, 116.9, 125.9, 127.6,
128.5, 128.9, 129.0, 133.2, 135.6, 136.5, 142.2, 166.5. Anal. calcd for C22H23NO2
(333.42) C, 79.25; H, 6.95; N, 4.20; found C, 79.05; H, 6.82; N, 4.05.
20. Gairaud, C. B.; Lappin, G. R. J. Org. Chem. 1953, 18, 1–3.
21. Zhong, C.; Liao, T.; Tuguldur, O.; Shi, X. Org. Lett. 2010, 12, 2064–2067.
22. Complete crystallographic data of 5k (CCDC no. is 848584) for the structural
analysis have been deposited with the Cambridge Crystallographic Data
Centre. Copies of this information may be obtained free of charge from the
Director, Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: +44 1223 336033, e-mail: deposit@ccdc.cam.ac.uk or via:
www.ccdc.cam.ac.uk).
19. General Procedure for the Synthesis of Pyrrole: To
a mixture of an amine
(1 mmol) and b-ketoester (1 mmol) in nitromethane (1 mL) was added
10 mol % NiCl2ꢀ6H2O and kept for stirring at room temperature. The solid
precipitate appeared after 10 minutes and then aromatic aldehyde (1 mmol)
was added into it. Subsequently, the reaction mixture was kept for refluxing in
a heated oil-bath with constant stirring. After completion of the reaction as
monitored by TLC, the reaction mixture was brought to room temperature and
the excess nitromethane was removed in a rotary evaporator. Then, the crude
residue was dissolved in 25 mL of dichloromethane and the solid particle was
removed by filtration. The precipitate was further washed with 2 mL of
23. Lyne, P. D. Drug Discov. Today 2002, 7, 1047–1055.