Site-selective multicomponent synthesis of densely substituted 2-oxo dihydropyrroles catalyzed by clean, reusable, and heterogeneous TiO2 nanopowder

Article abstract of DOI:10.1016/j.tetlet.2012.12.109

An efficient method for the synthesis of densely substituted 2-oxo dihydropyrroles has been demonstrated by clean, reusable, and heterogeneous catalyst titanium dioxide (TiO₂) nanopowder by the four component coupling reaction of dialkyl but-2-ynedioate, two different amines, and an aldehyde. The reaction is site-selective with respect to aromatic and aliphatic amines. Environmentally benign reaction procedure, excellent yields, tolerance of varieties of functionalities in the reactants, a wide variety of products and reusability of the catalyst make the methodology highly beneficial for the synthesis of polyfunctional dihydropyrroles. Copyright

Full text of DOI:10.1016/j.tetlet.2012.12.109

Tetrahedron Letters 54 (2013) 1371–1379
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Site-selective multicomponent synthesis of densely substituted 2-oxo
dihydropyrroles catalyzed by clean, reusable, and heterogeneous TiO2
nanopowder
Sunil Rana a, Mike Brown b, Arghya Dutta c, Asim Bhaumik c, Chhanda Mukhopadhyay a,
⇑
a Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata 700009, India
b Bruker BioSpin, 2700 Technology Forest Drive, Woodlands, TX 77381, USA
c Department of Materials Science, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the synthesis of densely substituted 2-oxo dihydropyrroles has been demon-
strated by clean, reusable, and heterogeneous catalyst titanium dioxide (TiO2) nanopowder by the four
component coupling reaction of dialkyl but-2-ynedioate, two different amines, and an aldehyde. The
reaction is site-selective with respect to aromatic and aliphatic amines. Environmentally benign reaction
procedure, excellent yields, tolerance of varieties of functionalities in the reactants, a wide variety of
products and reusability of the catalyst make the methodology highly beneficial for the synthesis of poly-
functional dihydropyrroles.
Received 28 September 2012
Revised 22 December 2012
Accepted 24 December 2012
Available online 4 January 2013
Keywords:
Multicomponent synthesis
2-Oxo dihydropyrroles
Site selectivity
Ó 2012 Elsevier Ltd. All rights reserved.
TiO2 nanopowder
2-Oxo dihydropyrroles are an important class of nitrogen con-
taining five-membered heterocycles. They are the building blocks
of many natural products like bilirubins1 and indolocarbazole alka-
loids.2 They have also been used as the inhibitors of HIV integrase,3
cardiac cyclic AMP phosphodiesterase,4 vascular endothelial
growth factor receptors,5 pesticides,6 herbicides7 and also as anti
tumor agent.8 They are also considered as a precursor of pyrrolizi-
dine alkaloids.9 Structures of some biologically important dihydro-
pyrrol-2-one are shown in Figure 1. General methods for the
preparation of this useful structural motif include multicomponent
Multicomponent reactions (MCRs) are very popular for their
efficiency to produce structurally diverse, synthetically novel,
and biologically important molecules in pot, atom, and step eco-
nomic ways.16 In recent years much attention has been given on
the design and use of environment-friendly catalysts to reduce
the amount of toxic waste.17 Nano scale metal oxides are highly
effective for the destruction of hazardous chemicals and as cata-
lysts for many organic transformations.18
Herein, we describe a new, easy, and general procedure for the
synthesis of 2-oxo-2,5-dihydro-1H-pyrrole-4-carboxylic acid alkyl
esters by the multicomponent reaction of dialkyl acetylenedicar-
boxylate, aldehyde, and amines catalyzed by reusable TiO2 nano-
powder. In search of a more efficient and environmentally benign
catalyst, a series of experiments were performed with the standard
reaction of diethyl acetylenedicarboxylate, 3,4-dimethylaniline,
propionaldehyde, and isopropyl amine (Scheme 1). The results are
depicted in Table 1. Among various Lewis acids it was found that
titanium dioxide nanopowder was the most effective and
10 mol % of it was sufficient to complete the reaction within 3 h in
refluxing dichloromethane with maximum yield. The reaction did
not proceed smoothly in the absence of the catalysts and only a trace
of the product was formed which could not be separated. To find out
the best medium for the reaction, we also performed the standard
reaction with different solvents like MeOH, EtOH, ACN, DMF,
DCM, and THF. DCM in refluxing condition was found to be the best
reaction medium for the reaction. The stoichiometric ratio of
1:1:1.1:1.2 (acetylenedicarboxylate:amine-1:aldehyde:amine-2)
reaction of acetylene, imine, and CO2,10 reaction of
imine with CO,11 combination of
-cyanomethyl-b-ketoesters and
a,b-unsaturated
a
alcohols,12 reaction of isocyanides, dialkyl acetylenedicarboxylates,
and benzoyl chlorides.13 Recently, Zhu et al. synthesized this core
by the one pot reaction of dialkyl acetylenedicarboxylate, amine,
and aldehyde.14a There are also few other synthetic methods avail-
able in the literature for the synthesis of the dihydropyrrole moi-
ety.14b,15 However, these methods have many limitations in
terms of the use of expensive and corrosive catalysts, multi-step
procedures, product-diversity, and lower yields. Hence, develop-
ment of new, versatile, simple, high-yielding, and environmentally
benign protocol for one-pot multicomponent synthesis of highly
substituted dihydropyrrole scaffolds is still in demand.
⇑
Corresponding author. Tel.: +91 33 23371104.
E-mail address: cmukhop@yahoo.co.in (C. Mukhopadhyay).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.109

1372
S. Rana et al. / Tetrahedron Letters 54 (2013) 1371–1379
F
O
N
N
HO2C
CO2H
N
O
OH
MeO
O
HDPO
NH
HN
H
N
O
O
N
H
NH
HN
Rolipram
O
O
N
N
H3C
H
Bilirubin
H3CO
NHCH3
Staurosporine
Figure 1. Some biologically important dihydropyrrole 2-ones.
NH2
CO2Et
EtO2C
HN
catalyst
iC3H7NH2
+
CH CH CHO
+
+
3
2
DCM, Reflux, 3h
(1.1mmol)
(1.2 mmol)
O
N
CO2Et
(1 mmol)
iC3H7
(1 mmol)
(5v)
Scheme 1.
with both electron withdrawing and donating substituents (like
Cl, Br, NO2, OMe, Me groups) at different positions of the aromatic
ring resulted in good to excellent yields. The yield was also very
high with aliphatic aldehydes and heteroaromatic aldehyde like
pyridine-2-carboxaldehyde. With aliphatic aldehydes, the reaction
was completed even at room temperature (25–28 °C) under stir-
ring. Use of aniline, substituted anilines, heteroaromatic amine,
and aliphatic amines increased the diversity of the products. No
product was however obtained with two different aromatic
amines. Dimethyl acetylenedicarboxylate and diethyl acetylenedi-
carboxylate were used as the but-2-ynedioate part and both of
them are equally efficient for this reaction. One of the main advan-
tages of this methodology is that 4-nitro benzaldehyde also yielded
the product though with lower yield (Table 2, entries 14 and 17)
which was not obtained by Zhu et al.14a
Table 1
Screening of catalysts for the synthesis of multifunctional dihydropyrroles
(Scheme 1)a
Entry
Catalyst (10 mol %)
Isolated yield (%)
Time (h)
1
2
3
4
5
6
7
8
Boric acid + glycerol (1 drop)
FeCl3
TsOH
AcOH
SiO2
Al2O3 (acidic)
H3PO4–SiO2
H3PW12O40
Commercial TiO2 (10)
TiO2 nanopowder (10)
TiO2 nanopowder (5)
TiO2 nanopowder (15)
TiO2 nanopowder (10)
None
60
46
58
65
37
31
66
78
83
91
82
90
91
Trace
12
12
12
12
12
12
12
12
12
12
12
12
3
9
10
11
12
13
14
We did not get compound ‘6’ with the combination of diethyl
acetylenedicarboxylate, 3,4-dimethyl aniline, isopropyl amine,
and propionaldehyde but instead got 5v (Scheme 2). The site selec-
tivity of the amines also plays a vital role in this reaction and has
been explained in the mechanism part.
12
a
Diethyl acetylenedicarboxylate (1 mmol), 3,4-dimethyl aniline (1 mmol), iso-
propyl amine (1.2 mmol), propionaldehyde (1.1 mmol), and 5 ml DCM were taken
in a 25 ml round bottomed flask. The resulting mixture was then refluxed for the
mentioned period of time in the presence of various catalysts.
A mechanistic rationale exhibiting the probable sequence of
events is given in Scheme 3. At first, amine-1 (R2NH2) reacts with
dialkyl acetylenedicarboxylate through 1,4-addition reaction to
form enamine (A). Activation of the ester-carbonyl group by TiO2
facilitates this Michael addition step. ‘A’ then undergoes nucleo-
philic attack to aldehyde to form ‘B’ which then eliminates water
by E1CB mechanism to form D through the conjugate base C. Then
in the presence of 10 mol % TiO2 nanopowder in refluxing DCM was
found to be the optimum conditions for the maximum yield of the
reaction.19
After the standardization of the reaction condition, a variety of
aldehydes and amines were used (Table 2). Aromatic aldehydes

S. Rana et al. / Tetrahedron Letters 54 (2013) 1371–1379
1373
Table 2
TiO2 nanopowder catalyzed multicomponent synthesis of fully substituted dihydropyrroles
H
N
R1O2C
R2
R1O2C
CO2R1
TiO2 nanopowder (10 mol%)
DCM, reflux, 3h
1 (1 mmol)
R3
O
H2N
CHO
R2
N
R3
NH2
R4
(1 mmol)
2
3 (1.1 mmol)
R4
(5a-5w)
(1.2 mmol)
4
Entry
1
2
3
4
Product
Yield (%)
O
H
N
MeO
O
N
1
1a
2a
3a
4a
86
5a
O
H
N
MeO
O
N
2
1a
2a
3b
4a
85
Br
5b
O
H
N
OMe
MeO
O
N
3
1a
2c
3c
4b
88
O2N
MeO
Cl
5c
OMe
O
H
N
MeO
O
4
5
6
1a
1a
1a
2b
2a
2b
3d
3e
3e
4c
4a
4c
84
87
86
N
OMe
5d
O
H
N
MeO
O
N
5e
O
H
N
MeO
O
N
Cl
5f
O
H
N
Cl
MeO
O
N
7
1a
2d
3f
4d
84
5g
Cl
(continued on next page)

1374
S. Rana et al. / Tetrahedron Letters 54 (2013) 1371–1379
Table 2 (continued)
Entry
1
2
3
4
Product
Yield (%)
O
H
N
MeO
O
8
1a
2b
3b
4e
88
N
Br
5h
Me
O
H
N
MeO
9
1a
1a
2e
2b
3g
3e
4f
90
87
O
N
MeO
5i
O
H
N
MeO
10
4g
O
N
Cl
5j
N
O
H
N
MeO
11
12
1a
1a
2f
3a
4e
4e
90
88
O
N
5k
O
H
N
MeO
MeO
O
2a
3h
N
5l
O
H
N
13
14
1a
1a
2e
2g
3h
3i
4g
4f
87
62
O
N
5m
O
H
N
MeO
OMe
O
N
O2N
5n
O
H
N
MeO
15
16
1a
1a
2c
2e
3h
3j
4h
4h
92
88
O
N
N
5o
O
H
N
MeO
O
5p
O
H
N
MeO
17
1a
2e
3i
4g
64
O
N
O2N
5q

S. Rana et al. / Tetrahedron Letters 54 (2013) 1371–1379
1375
Table 2 (continued)
Entry
1
2
3
4
Product
Yield (%)
O
H
N
OMe
5r
MeO
18
19
1a
2c
3k
4h
87
85
O
N
O
H
N
EtO
1b
2e
3l
4e
O
N
N
5s
O
H
N
OMe
EtO
20
21
1b
1b
2c
3j
3j
4h
4e
86
83
O
N
5t
O
H
N
Br
EtO
O
2h
N
5u
O
H
N
EtO
22
23
1b
1b
2i
3j
4h
4g
91
88
O
N
5v
O
H
N
EtO
O
2a
3k
N
N
5w
EtO2C
CO2Et
MeO2C
NH2
CO2Me
1a
1b
NH2
NH2
NH2
NH2
NH2
NH2
NH2
N
NH2
OMe
OMe
Cl
Br
2d/4d
2f
2g
2a/4a 2b/4c 2c/4b
2e
2h
2i
CHO
CHO
CHO
CHO
CHO
CHO
CHO
CHO
OMe
NO2
Br
NO2
OMe
OMe
Cl
CH3CHO
3a
3e
3f
3g
3i
3b
3d
3h
3c
NH2
NH2
NH2
CHO
N
NH2
CH3CH2CH2CHO
CH3CH2CHO
3j
3k
4f
4h
3l
4e
4g

1376
S. Rana et al. / Tetrahedron Letters 54 (2013) 1371–1379
iC3H7
NH2
EtO2C
HN
EtO2C
HN
CO2Et
nano TiO2 (10 mol%)
DCM, reflux, 3h
nano TiO2 (10 mol%)
iC3H7NH2
+
+ CH3CH2CHO
+
O
O
N
DCM, reflux, 3h
N
CO2Et
iC3H7
(5v)
(6)
Scheme 2. Scope of the multicomponent synthesis of densely functionalized dihydropyrrole showing the site selectivity of the amines.
CO2R1
H2
N
R1O2C
[1,4-addition]
R2
R1O2C
H
HN
R2
_
+
/
H
H
H2N
R2
(A)
O
+
CO2R1
C
(Amine-1)
nano
TiO2
nano
TiO2
C
R1O
O
R3
nano
TiO2
R1O
O
_
+ H
H
nano
nano
TiO2
TiO2
R2
N
R2
H
N
R1O2C
R1O2C
R1O2C
N
R2
_
_
+
H2O
H
H
CO2R1
(C)
CO2R1
CO2R1
R3
R3
(D)
OH2
HO
(B)
R3
R4
nano
TiO2
H2N
(Amine-2)
_
H
+
H
R1O2C
HN
R2
R1O2C
H
N
R2
_
R1OH
nano
TiO2
OR1
+
R3
O
NH
R4
R3
(regenerated)
N
O
R4
nano
TiO2
Scheme 3. Probable mechanism for the synthesis of densely substituted 2-oxodihydropyrrole.
amine-2 (R4NH2) attacks the highly conjugated intermediate D
through 1,4-addition reaction and finally amidation reaction leads
to cyclization by the elimination of R1OH to form the final product.
Lewis acidic character of Ti4+ promotes the nucleophilic attack on
the aldehyde by making it more electrophilic. Negative charge on
the conjugate base C is stabilized by the CO2R1 group, the conju-
gated imine part, and also by TiO2. Elimination of R1OH is also facil-
itated by Ti4+. Higher concentration of Ti4+ on the surface of the
TiO2 nanoparticles (due to higher surface area) makes it a more
efficient catalyst than commercially available TiO2 in this reaction.
TiO2 facilitating all the steps and giving stability to the intermedi-
ates, plays an important role in controlling the mechanism and
deciding the site selectivity. Intermediates B, C, and D are more sta-
bilized when R2 is aromatic due to extended conjugation with the
aromatic ring and the 1,4-addition of amine-2 to the intermediate
D is facilitated when R4 is aliphatic as aliphatic amine is more
nucleophilic than aromatic amine. The mechanism, therefore, fa-
vors R2 as aromatic and R4 as aliphatic.
That the reaction goes through the intermediate enamine dies-
ter has been proved by isolating the intermediate A as the major
product (structure of the enamine diester has been confirmed by
NMR and given in the Supplementary data) from the reaction mix-
ture after 1 h of the standard reaction. The catalyst being heteroge-
neous the reaction can be quenched at any time simply by filtering
out the catalyst from the reaction mixture. We then performed the
standard reaction by refluxing the isolated enamine diester A, pro-
pionaldehyde, and isopropylamine in DCM in the presence of
10 mol % TiO2 and product 5v was obtained with the same yield
as that of the standard reaction (Scheme 4). The detailed procedure
has been given in the Supplementary data.
The reaction occurred even at room temperature when aliphatic
aldehydes were taken as the aldehyde component. This may be due
to the fact that aliphatic aldehydes are more electrophilic than
aromatic aldehydes. Nucleophilicity of amine-2 is very much
important for the success of this reaction. When 4-nitro aniline
and 3-nitro aniline were used separately as amine-2 then we did

S. Rana et al. / Tetrahedron Letters 54 (2013) 1371–1379
1377
NH2
NH2
CO2Et
CO2Et
TiO2 nanopowder (10 mol%)
other products
+
+
EtO2C
NH
DCM, reflux, 1h
CO2Et
CH3CH2CHO
(A)
EtO2C
HN
NH2
TiO2 nanopowder (10 mol%)
DCM, reflux, 3h
(A) + CH CH CHO
+
3
2
O
N
5v
Scheme 4. Proof of the involvement of the intermediate enamine diester for the formation of 2-oxo dihydropyrrole.
not get the desired products. In the standard reaction, when all the
reactants were added simultaneously then more nucleophilic
isopropyl amines acted as amine-2 and 3,4-dimethyl aniline as
amine-1 (Scheme 2). In general, aliphatic amines are more nucleo-
philic than aromatic amines and as in the last step of the reaction
nucleophilicity of the amine is very important for the elimination
of R1OH, aliphatic amine acts as amine-2 in the competition with
aromatic amine. Again due to extended conjugation the enamine
diester formed in the first step by the aromatic amine is more sta-
ble than that of aliphatic amine. So, only the compound 5v was
formed selectively. In a similar fashion, where aromatic amines
and aliphatic amines were involved in the reaction aromatic
amines acted as amine-1 and aliphatic amines acted as amine-2.
All the synthesized compounds were unknown to the best of
our knowledge and were characterized by NMR, IR, CHN analysis
and melting points (for the solid compounds). The spectral and
analytical data of the two of the representative compounds have
been cited in this manuscript20 while those for the remaining com-
pounds are given in the Supplementary data. The final structure
was confirmed by an X-ray crystallography study of a single crystal
of dihydropyrrole 5p (Table 2, entry 16) and is given below in
Figure 2. Intermolecular hydrogen bonding is observed between
N1H1 of one molecule and O3 of another.
TiO2 nanopowder was prepared by the gel combustion meth-
od.21 It was characterized by TEM (Figure 3), BET surface area
determination (Figure 4) and powder X-ray diffraction analysis
(Figure 5). From X-ray diffraction study characteristic peaks due
to the crystal planes (101), (004), (200), (105), (211), (204)
(116), (220), and (215) and their respective 2h values correspond
to the rutile structure of TiO2 which are in agreement with the
standard JCPDS value. From nitrogen adsorption isotherm study
specific surface area of TiO2 nanopowder was found to be
69.51 m2 gÀ1. HR TEM analysis revealed that the material has
blocky crystals, which are composed of 20–35 nm size TiO2
nanoparticles.
In addition, a catalytic recycle experiment (Table 3) was done
with the standard reaction. After the completion of the reaction,
as indicated by TLC, the catalyst was recovered by filtration. The
Figure 2. Structure of dihydropyrrole 5p by the single crystal X-ray diffraction (Table 2, entry 16) (CCDC 866193) showing the intermolecular H bonding (distance 2.205 Å).

1378
S. Rana et al. / Tetrahedron Letters 54 (2013) 1371–1379
Table 3
Recycling of the catalyst for the four-component coupling reaction of diethyl
acetylenedicarboxylate, 3,4-dimethyl aniline, propionaldehyde, and isopropyl amine
(product 5v)
Run
Time (h)
Yield (%) (isolated)
1
2
3
4
5
6
3
3
3
3
3
3
91
90
90
90
89
84
advantages such as higher yields, shorter reaction time, simpler
work-up, recovery and reusability of catalyst, and tolerance of a
wide range of functional groups in the starting materials with no
side products.
Acknowledgements
One of the authors (S.R.) thanks the Council of Scientific and
Industrial Research, New Delhi, for his fellowship (SRF). We
acknowledge the grant received from UGC funded Major project,
F. No. 37-398/2009 (S.R.) dated 11-01-2010.
Figure 3. Average particle diameter (20–35 nm) and the pore size between two
particles by the HR TEM analysis of TiO2 nanoparticle.
Supplementary data
300
Adsorption Points
Desorption Points
Spectral and analytical data of all the compounds in Table 2
along with the copies of 1H and 13C NMR are given in the Supple-
mentary Section. Copies of 1H and 13C NMR of the crude products
(when mixed amines were used) are also provided in the supple-
mentary section. Supplementary data associated with this article
can be found, in the online version, at http://dx.doi.org/10.1016/
j.tetlet.2012.12.109.
250
BET Surface Area 69.51 m2g-1
Pore Volume 0.3979 ccg-1
200
150
100
50
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Lowe, D. J. Synth. Commun. 2005, 35, 2453; (e) Goh, W. K.; Iskander, G.; Black, D.
S.; Kumar, N. Tetrahedron Lett. 2007, 48, 2287; (f) Ghelfi, F.; Stevens, C. V.;
Laureyn, I.; Meenen, E. V.; Rogge, T. M.; Buyck, L. D.; Nikitin, K. V.; Grandi, R.;
Libertini, E.; Pagnonia, U. M.; Schenettia, L. Tetrahedron 2003, 59, 1147; (g)
Mase, N.; Nishi, T.; Takamori, Y.; Yoda, H.; Takabe, K. Tetrahedron: Asymmetry
1999, 10, 4469.
20
30
40
50
60
70
80
2θ in degrees
Figure 5. powdered XRD study of TiO2 nanoparticle.
recovered TiO2 was then washed with DCM for five times, dried,
and reused for the standard reaction for up to six cycles with a
slight decrease in the yield of the reaction.
In conclusion, we have proved the utility of nanopowder TiO2 in
synthesizing the site-selective 2-oxo dihydropyrroles in good to
excellent yields. Three new C–N bonds and one new C–C bond
are formed in a single operation. This protocol offers several
16. (a)Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; WILEY-VCH Verlag
GmbH & Co., KGaA: Weinheim, 2005; (b) Cariou, C. C. A.; Clarkson, G. J.;
Shipman, M. J. Org. Chem. 2008, 73, 9762; (c) Kupchan, S. M.; Komoda, Y.; Court,
W. A.; Thomas, G. J.; Smith, R. M.; Karim, A.; Gilmore, C. J.; Haltivanger, R. C.;

S. Rana et al. / Tetrahedron Letters 54 (2013) 1371–1379
1379
Bryan, R. F. J. Am. Chem. Soc. 1972, 94, 1354; (d) Armstrong, R. W.; Combs, A. P.;
Tempest, P. A.; Brown, S. D.; Keating, T. A. Acc. Chem. Res. 1996, 29, 123; (e)
Zhou, L.; Bohle, D. S.; Jiang, H. F.; Li, C. J. Synlett 2009, 937; (f) Ren, G.; Zhang, J.;
Duan, Z.; Cui, M.; Wu, Y. Aust. J. Chem. 2009, 62, 75; (g) Mukhopadhyay, C.;
Rana, S.; Butcher, R. J. Tetrahedron Lett. 2011, 52, 4153.
20. (a)
carboxylic acid methyl ester (5a) (Table 2, entry 1): Yield 86%; White solid;
mp: 156–158 °C (EtOAc);
max (KBr)/cmÀ1 3247, 3033, 2921, 1694, 1651, 1523,
2-Oxo-5-phenyl-1-p-tolyl-3-p-tolylamino-2,5-dihydro-1H-pyrrole-4-
m
1437, 1390, 1353, 1253, 1203, 1126, 1022 and 812; 1H NMR (300 MHz, CDCl3)
dH: 8.05 (1H, s, NH), 7.24 (2H, d, J = 8.4 Hz, ArH), 7.18–7.10 (5H, m, ArH), 7.06–
6.93 (6H, m, ArH), 5.68 (1H, s, C5-H), 3.46 (3H, s, CO2Me), 2.25 (3H, s, Me), 2.14
(3H, s, Me); 13C NMR (75 MHz, CDCl3) dC: 164.8, 163.9, 142.7, 137.1, 135.9,
135.4, 134.6, 134.0, 129.4, 129.0, 128.4, 128.0, 127.6, 123.2, 122.8, 108.3, 63.2,
51.0, 21.0, 20.9; Anal. Calcd for C26H24N2O3; C: 75.71; H: 5.86; N: 6.79. Found:
C: 75.93; H: 5.75; N: 6.71. (b) 3-(3,4-Dimethyl-phenylamino)-5-ethyl-1-
isopropyl-2-oxo-2,5-dihydro-1H-pyrrole-4-carboxylic acid ethyl ester (5v)
(Table 2, entry 22): Yield 91%; White solid; mp: 82–84 °C (EtOAc); mmax
(KBr)/cmÀ1 3260, 2973, 2931, 2878, 1701, 1630, 1534, 1443, 1356, 1296, 1185,
1106, 1047 and 872; 1H NMR (300 MHz, CDCl3) dH: 7.94 (1H, s, NH), 7.03 (1H, d,
J = 7.8 Hz, ArH), 6.90–6.80 (2H, m, ArH), 4.42 (1H, t, J = 3.0 Hz, C5-H), 4.19–4.00
(3H, m, OCH2 and NCH), 2.22 (6H, s, 2 Â CH3), 1.98–1.88 (2H, m, CH2), 1.41 (3H,
d, J = 6.9 Hz, CH3), 1.34 (3H, d, J = 6.9 Hz, CH3), 1.15 (3H, t, J = 7.2 Hz, CH3), 0.71
(3H, t, J = 7.2 Hz, CH3); 13C NMR (75 MHz, CDCl3) dC: 164.9, 164.7, 144.0, 136.8,
136.3, 132.5, 129.3, 123.8, 120.1, 105.6, 59.7, 58.0, 45.8, 22.6, 20.4, 19.7, 19.1,
14.0, 5.7; Anal. Calcd for C20H28N2O3; C: 69.74; H: 8.19; N: 8.13. Found: C:
69.99; H: 8.07; N: 8.15%.
17. (a) Clark, J. H. Acc. Chem. Res. 2002, 35, 791–797; (b) Mukhopadhyay, C.; Ray, S.
Tetrahedron 2011, 67, 7936; (c) Karmakar, B.; Chowdhury, B.; Banerji, J. Catal.
Commun. 2010, 11, 601; (d) Karmakar, B.; Banerji, J. Tetrahedron Lett. 2011, 52,
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(f) Mukhopadhyay, C.; Rana, S. Catal. Commun. 2009, 11, 285.
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Interscience: New York, 2001. Chapter 7; (b) Choudary, B. M.; Kantam, M. L.;
Ranganath, K. V. S.; Mahender, K. J. Am. Chem. Soc. 2004, 126, 3396; (c)
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Kumar, K. B. S.; Sridhar, C. Adv. Synth. Catal. 2005, 347, 1212.
19. General procedure for the synthesis of fully substituted 2-
oxodihydropyrrole: But-2-ynedioate (1 mmol), primary amine (aromatic)
(1 mmol), aldehyde (1.1 mmol), another primary amine (aliphatic/aromatic)
(1.2 mmol) and 10 ml dichloromethane were taken in a 25 ml round bottomed
flask. To the resulting mixture 0.1 mmol TiO2 nanopowder was added and the
reaction mixture was refluxed for 3 h on a hot water bath. After the completion
of the reaction, as indicated by TLC, the catalyst was recovered by filtration.
DCM was pumped out using a rotary evaporator. The crude product was then
purified through recrystallization from ethylacetate and petroleum ether
mixture. In few cases the products were purified by column chromatography
using silica gel (60–120 mesh) with 10% ethyl acetate in petroleum ether (60–
80 °C) as eluant. The catalyst was reused for the next reactions after washing it
with dichloromethane.
21. Procedure for the synthesis of nanopowder TiO2: At first titanium nitrate was
synthesized by the hydrolysis of titanium isopropoxide with nitric acid. Then it
was mixed with glycine in the mol ratio of 1:2. The mixture was then dissolved
in deionised water and homogenized. The pH of the solution was maintained
between 6 and 8 by using NH4OH. It was then heated on a hot plate up to
300 °C. During heating, the solution became more viscous, then it became solid
paste and after that, combustion occurred. After combustion was completed,
products were calcinated at 700 °C for 1 h in flowing oxygen to remove of
volatile organic species for the formation of crystalline oxides.