Facile one-pot three-component synthesis of diverse 2,3-disubstituted isoindolin-1-ones using ZrO2 nanoparticles as a reusable dual acid-base solid support under solvent-free conditions

Article abstract of DOI:10.1039/c6ra00870d

A facile one-pot three-component protocol for the synthesis of a series of multi-functionalized 2,3-disubstituted isoindolin-1-ones has been developed using ZrO₂ nanoparticles as a dual acid-base solid support under solvent-free conditions. The surface of the ZrO₂ nanoparticles, which is embedded with active hydroxyl groups, oxyanions and Zr⁴⁺ ions, efficiently catalyses the condensation of 2-carboxybenzaldehyde, aliphatic amines and a nucleophile (enamines/6-amino 1,3-dimethyluracil/1,3-cyclohexadiones/indole) to produce 2,3-disubstituted isoindolin-1-ones. Operational simplicity, reduced reaction time and temperature, elimination of solvent, high yields of products, wider substrate scope, utilization of ZrO₂ nanoparticles as a solid support, and its nearly undiminished catalytic activity after repeated applications, are the key features of the present methodology.

Full text of DOI:10.1039/c6ra00870d

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Facile one-pot three-component synthesis of diverse 2,3-
disubstituted isoindolin-1-ones using ZrO2 nanoparticles as a
reusable dual acid-base solid support under solvent-free
conditions
Kamalesh Debnath, Sayan Mukherjee, Chandan Bodhak and Animesh Pramanik*
Department of Chemistry, University of Calcutta, 92, A. P. C. Road, Kolkata-700 009, India;
Fax: +91ꢀ33ꢀ2351ꢀ9755; Tel: +91ꢀ33ꢀ2484ꢀ1647.
Eꢀmail: animesh_in2001@yahoo.co.in
Abstract: A facile oneꢀpot threeꢀcomponent protocol for the synthesis of a series of multiꢀ
functionalized 2,3ꢀdisubstituted isoindolinꢀ1ꢀones has been developed using ZrO2
nanoparticles as a dual acidꢀbase solid support under solventꢀfree conditions. The surface of
the ZrO2 nanoparticles which is embedded with active hydroxyl groups, oxyanions and Zr4+
ions efficiently catalyses the condensation of 2ꢀcarboxybenzaldehyde, aliphatic amines and a
nucleophile (enamines/6ꢀamino 1,3ꢀdimethyluracil /1,3ꢀcyclohexadiones/indole) to produce
2,3ꢀdisubstituted isoindolinꢀ1ꢀones. Operational simplicity, reduced reaction time and
temperature, elimination of solvent, high yields of the products, wider substrate scope, and
utilization of ZrO2 nanoparticles as solid support and its nearly undiminished catalytic
activity after repeated applications are the key features of the present methodology.
Introduction
The wedding of two emergent areas of chemical research of twenty first century,
nanocatalysis and green chemistry, holds the key to sustainability.1a In recent years, the metal
based nanoparticles (NPs) are being extensively used for the enhancement of efficiency of
organic synthesis.1 These extremely small size NPs have large surface area to volume ratio
which promotes enhanced catalysis. Moreover the nano catalysts make the reactions
operationally simpler and economical due to easy separation from the reaction mixtures.1a,d
1

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As a part of our research interest in exploring the catalytic performance of NPs in multiꢀ
component synthesis of biologically significant heterocycles,2 herein, we sought to explore
the catalytic activity and efficiency of ZrO2 NPs. The surface of ZrO2 NPs is embedded with
active hydroxyl groups, oxyanions and Zr4+ ions which attributes to the combined acidꢀbase
property.2d,3 This interesting dual nature of ZrO2 NPs has not been broadly explored,
especially, in multiꢀcomponent reactions under solventꢀfree conditions for the synthesis of
bioꢀactive building blocks.
The isoindoline scaffolds are very important because of their widespread occurrence
in numerous drug molecules of natural and synthetic origin.4 The synthesis of isoindolinꢀ1ꢀ
ones has attracted a great deal of attention since this core structure is present in many natural
products of profound biological potential such as zopiclone,5 pagoclone,6 nafodone7 and AKS
1868 (Fig. 1). Compounds with isoindolinꢀ1ꢀone structural motif are found in several
antimicrobial,9 antiꢀviral,10 anti HIV,11 antiarrhythmic,7 immunostimulant and anticancer12
agents. Despite of their immense pharmacological, industrial and synthetic importance,
comparatively less number of methodologies are reported in the literature for the synthesis of
isoindolineꢀ1ꢀones.13 On the other hand although these methods are helpful to construct the
biologically important scaffold, several factors such as prolonged reaction time, high reaction
temperature and presence of solvent in the synthesis restrict the ‘Green chemistry’ aspects.14
To the best of our knowledge, there is no efficient general protocol for the synthesis of
isoindolinꢀ1ꢀone scaffolds using green catalyst. With the objective of developing a benign,
clean, efficient and straightforward methodology for the synthesis of isoindolineꢀ1ꢀones,
herein, we wish to report our design by assembling the basic building blocks,
2ꢀcarboxybenzaldehyde (1), aliphatic amines (2) and a nucleophile (3) using ZrO2
nanoparticles as a reusable dual acidꢀbase solid support under solventꢀfree conditions
(Scheme 1).
2

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HO
O
Cl
N
H
N
O
N
O
H3C
N
O
N
N
N
N
Cl
N
O
O
O
Zopiclone
Pagoclone
Nafodone
HO
Cl
O
N
N
O
O
OH
AKS 186
an anticancer isoindolin-1-one
Figure 1. Representative pharmacologically important compounds with isoindolinꢀ1ꢀone
core.
CHO
ZrO2 NPs
D
+ R1 NH2
+
N R1
Solvent free
70-750C
D
COOH
O
2
3
1
1.0-2 h
4, when 3 = 3a
5, when 3 = 3b
6, when 3 = 3c
7, when 3 = 3d
O
N
O
O
H3C
R2
R2
R4
R4
O
N
NH2
N
H
NH
R3
O
CH3
3b
3a
3c
3d
Scheme 1: Synthesis of multiꢀfunctionalized isoindolinꢀ1ꢀone derivatives (4-7
)
Results and discussion
During our initial studies towards the development of ZrO2 NPs as a solid support for
the oneꢀpot threeꢀcomponent synthesis of isoindolinꢀ1ꢀones ( ) under solventꢀfree conditions,
we attempted to optimize the reaction conditions taking 2ꢀcarboxybenzaldehyde ( ), benzyl
) in 1:1:1 molar proportion
4
1
amine (
2
) and 5,5ꢀDimethylꢀ3ꢀpꢀtolylaminoꢀcyclohexꢀ2ꢀenone (3
3

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(Scheme 2). In this process, various parameters such as the effect of catalysts, solid supports,
temperature and solvents at different experimental conditions were investigated and the
results are summarised in Table 1. When the mixture of reactants 1, 2 and 3 was heated at
reflux in EtOH and DMF separately for 8 and 6 h respectively, the yield of the product 4a
was achieved up to ~60% (Table 1, entries 1 and 2). Under solventꢀfree conditions, the yield
of the product 4a improved marginally (~65%) within a reduced reaction time (~4 h) (Table
1, entry 3). A significant improvement of the yield of product 4a (~75%) was achieved with
further reduction of reaction time (~3 h) when the reaction was carried out in EtOH with the
addition of ZrO2 NPs as catalyst (20 mol%) (Table 1, entry 4). In presence of the same ZrO2
NPs catalyst (20 mol%), the yield of the product did not improve much upon changing the
reaction medium (e.g. H2O, CHCl3 and EtOHꢀH2O in 4:1 v/v) (Table 1, entries 5ꢀ7). These
results suggest that, the role of solvent is not so important to carry out the following
synthesis. In this context, when we tried to optimize the reaction conditions by eliminating
the solvent and using different solid supports (e.g. ZrO2 NPs, Silica gel of 60ꢀ120 mesh and
Fe3O4ꢀSiO2 NPs), the yield of the product 4a was enhanced (Table 1, entries 8ꢀ10). Next we
have done the optimization study taking basic alumina (500 mg) as solid support under the
same reaction condition. The yield of the product decreased slightly (~ 60%) with the
generation of several side products (Table 1, entry 11). It suggests that, the reaction profile is
not clear in presence of basic alumina as solid support. Gratifyingly, a cleaner reaction
profile with high yield of 4a (~85%) was observed when ZrO2 NPs (500 mg) was used as
solid support and the reaction mixture was stirred at 100 °C for 2 h (Table 1, entry 12). It is
envisioned that, the amphoteric nature (dual acid and base) of the ZrO2 NPs as solid support
helps to generate the best yield of the final product 4a and also the adsorption of the reactant
molecules on the solid surface of ZrO2 NPs increases the local concentration of the reactants
around the active sites considerably causing significant acceleration of the reaction rate. Then
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we carried out the optimization study to examine the influence of the stoichiometry of nano
ZrO2 (200 mgꢀ1.0 g) at different temperatures (50ꢀ100 ºC) for the best yield of 4a (Table 1,
entries 12ꢀ18). The study revealed that the best yield of the product 4a can be obtained when
the substrates 1, 2 and 3 taking 1.0 mmol each are allowed to react on the solid surface of
nano ZrO2 (250 mg) at 70 °C under solventꢀfree conditions (Table 1, entry 18).
With the optimized reaction condition in hand (Table 1, entry 18), next the scope and
generality of this protocol was assessed by employing various aliphatic amines and
nucleophiles (enamines/6ꢀamino 1,3ꢀdimethyluracil/1,3ꢀcyclohexadiones/indole) along with
2ꢀcarboxybenzaldehyde to obtain various isoindolinꢀ1ꢀones derivatives (Table 2). In all cases,
1
the formation of the final products (4-7) were confirmed by IR, H NMR, 13C NMR
spectroscopy, elemental analysis and also by matching the melting points of some of the
compounds with the reported values.13c, 16 The Xꢀray crystal structures of 4t and 5c (Fig. 2)
further confirm the formation of products without any ambiguity.
O
O
NH2
CHO
N
Catalyst
Solvent
H
+
+
NH
N
COOH
O
1
4a
2
3
Scheme 2: Optimization of the reaction conditions.
Table 1: Optimization of reaction conditions for the synthesis of 4a
Entry
Solvent
(5 ml)
EtOH
Catalyst/ Solid
Support
__
Loading
Time Temp.(°C) Yielda
(h)
(%)
1
2
3
4
5
6
__
__
8
reflux
reflux
reflux
reflux
reflux
reflux
60
DMF
__
__
6
4
3
3
3
58
65
75
72
70
__
__
EtOH
H2O
ZrO2 NPs
ZrO2 NPs
ZrO2 NPs
20 mol%
20 mol%
20 mol%
CHCl3
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7
8
9
EtOHꢀH2O (4:1)
ZrO2 NPs
20 mol%
500 mg
500 mg
3
2
2
reflux
100
75
85
70
__
__
ZrO2 NPs
Silica gel
100
(60ꢀ120 mesh)
Fe3O4ꢀSiO2 NPs
Basic alumina
ZrO2 NPs
100
100
80
10
11
12
__
__
__
500 mg
500 mg
500 mg
2
2
2
68
60
85
86
65
84
87
82
87
70
13
14
15
16
17
18
__
__
__
__
__
__
ZrO2 NPs
ZrO2 NPs
ZrO2 NPs
ZrO2 NPs
ZrO2 NPs
ZrO2 NPs
500 mg
500 mg
1000 mg
300 mg
200 mg
250 mg
2
2
2
2
2
2
50
70
70
70
70
aIsolated Yields (%)
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a
Table 2: Synthesis of multiꢀfunctionalized isoindolinꢀ1ꢀone derivatives (4-7
)
R2
R2
O
O
R3
N
H
CHO
ZrO2 NPs
R2
R1 NH2
+
+
N R1
NH
R3
R2
Solvent free
700C, 1.5 h
COOH
O
1
2
3a
4
CH3
O
F
Cl
O
O
O
O
N
N
N
H
N
H
H
H
N
N
N
N
O
O
O
O
4a (87%)
4b (85%)
4c (86%)
4d (90%)
Cl
Cl
Cl
F
Br
O
O
O
O
N
H
N
N
N
H
H
H
N
N
N
N
O
O
O
O
4h (79%)
4f (85%)
4g (81%)
4e (88%)
Cl
OH
CH3
O
O
O
O
N
H
N
N
H
N
H
H
CH3
F
N
N
O
N
N
O
O
O
4l (82%)
4i (80%)
4j (80%)
4k (78%)
Cl
Cl
O
F
O
O
O
N
H
N
H
N
N
H
H
F
N
O
F
N
N
N
O
O
O
4n (87%)
4m (84%)
4o (83%)
4p (79%)
O
O
Cl
O
O
O
N
N
H
H
N
H
N
H
N
F
N
N
O
N
O
O
O
4t (80%)
4q (81%)
4r (77%)
4s (83%)
O
F
N
H
N
O
4u (78%)
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O
H3C
O
N
CH3
N
O
N
H3C
O
CHO
ZrO2 NPs
NH2
+ R1 NH2
+
N
NH2
N R1
Solvent free
700C, 1.5 h
COOH
1
CH3
3b
2
O
5
O
O
O
O
N
N
N
N
N
N
N
N
O
O
O
O
NH2
NH2
NH2
NH2
F
N
CH3
N
N
N
O
O
O
O
5d (83%)
5a (85%)
5b (88%)
5c (80%)
R4
R4
O
O
CHO
ZrO2 NPs
OH
+ R1 NH2
+
R4
R4
N R1
Solvent free
750C, 1-1.5 h
O
COOH
O
2
1
6
3c
O
O
O
O
OH
N
OH
OH
OH
N
N
N
O
O
O
O
CH3
F
6d (87%)
6a (95%)
6b (92%)
6c (90%)
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NH
CHO
ZrO2 NPs
+ R1 NH2
+
N R1
Solvent free
700C, 2h
N
H
COOH
1
2
3d
7
O
NH
NH
NH
NH
N
N
N
O
N
O
O
O
7a (78%)
7b (83%)
7c (84%)
7d (80%)
CH3
F
aIsolated Yield (%)
Figure 2
.
Crystal structures of compounds 4t and 5c. Color code: red, oxygen; blue,
nitrogen; grey, carbon; white, hydrogen; greenishꢀyellow, fluorine (CCDC 1428628 and
1434728).
The ZrO2 NPs were prepared via solꢀgel method by condensation of ZrO2Cl2.8H2O
under basic medium (See †ESI for details) and analyzed by different spectroscopic (FTꢀIR,
UVꢀVis) and analytical (XRD, FEꢀSEM, HRꢀTEM) techniques. Scanning electron
microscopic (SEM) images taken at the operating voltage of 5.0 kV elucidate the morphology
of the freshly prepared and 5 times reused ZrO2 NPs. The SEM images show the formation of
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spherical and nearly uniform sized nanoparticles and also demonstrate that the grains of
different size form soft aggregates under the processing conditions (Fig. 3a and 3b). The
morphology and uniformity of particle size of freshly prepared and 5 times reused ZrO2 NPs
were further confirmed by high resolution transmission electron microscopy (HRꢀTEM)
study (Fig. 3c and 3d). The crystallite size of ZrO2 NPs in HRꢀTEM images is found to be
within the range of 6ꢀ14 nm.
(a)
(a)
(b)
(c)
(d)
Figure 3. SEM images of ZrO2 NPs (a) before reaction and (b) after 5 times applications in
reaction. HRTEM images of ZrO2 NPs (c) before use in reaction and (d) after five times
applications.
Elemental analyses of the asꢀsynthesized ZrO2 NPs were performed using EDX
equipped onto TEM. Quantitative EDX analysis showed that Zr and O are the main elemental
components (Fig. 4a). In the UVꢀVis spectrum (Fig. 4b) of freshly prepared ZrO2
nanoparticles, a maxima was observed at 259 nm, which is equivalent to a band gap of 4.76
eV. The powder Xꢀray diffraction pattern of the freshly prepared and reused ZrO2 NPs (Fig.
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4c) indicates the formation of tetragonal ZrO2 (tZrO2) NPs and its unchanged surface nature
after several reuses.14 The peaks at 2θ = 30.3°, 50.5° and 59.8° are assigned to the (101),
(112) and (103) reflection planes respectively which supports the purely tetragonal nature of
the synthesized NPs. The infrared spectrum of fresh ZrO2 was depicted in Fig. 4d. The fresh
ZrO2 showed a characteristic broad band at 3453cmꢀ1 and a broad band between 1600ꢀ1635
cmꢀ1, which are assigned to the O–H modes of chemisorbed water and/or terminated
hydroxides at the surface of the nanoparticles.15
1.6
(b)
(a)
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
UV-Vis spectra of Fresh ZrO2 NPs
200
250
300
350
400
Wavelength (nm)
(101)
(c)
(d)
(112)
(112)
(103)
(B)
(101)
(A)
(103)
20
40
60
80
2θ(Degree)
Figure 4. (a) TEMꢀEDX spectra of ZrO2 NPs, (b) UVꢀVis spectrum of ZrO2 NPs, (c) XRD
spectra of (A) freshly prepared ZrO2 NPs and (B) reused ZrO2 NPs after 5th cycle, (d) FTꢀIR
spectra of fresh ZrO2 NPs
A plausible mechanism for the formation of isoindolinꢀ1ꢀones derivatives 4-7 in
presence of ZrO2 NPs under solvent free condition has been depicted in scheme 3. The
surface of ZrO2 NPs is surrounded with active hydroxyl groups, oxyanions and Zr4+ ions
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which can act as dual acidꢀbase catalyst for the condensation reactions. Initially, Zr4+ ion of
ZrO2 NPs acts as strong Lewis acid acceptor and activates the carbonyl group to facilitate the
condensation between 2ꢀcarboxybenzaldehyde (
intermediate . Then ZrO2 NPs catalyse a Michael type addition between
to produce intermediate . Subsequently, the acidic and basic sites of ZrO2 NPs assist the
intermediate to undergo intramolecular electrophilic cyclization and tautomerization to
1
) and aliphatic amines (
2) to generate
8
8
and nucleophile 3
9
9
furnish the final products isoindolinꢀ1ꢀones 4-7
.
Zr4+
HO
O-
Zr4+
-O
ZrO2
O H
O-
NP's
Zr4+
O
O
O
H
Zr4+
O-
R
N
H
+
H2N R
2
HO
OH
D
O
8
3
1
O2-
H
D
NH
OH
D
N R
O
R
H
Zr4+
O
O
9
4-7
Scheme 3. Plausible mechanism for the formation of isoindolinꢀ1ꢀone derivatives 4-7
.
The reusability test of ZrO2 NPs was carried out separately for the synthesis of 4a and
5a under the optimized reaction conditions (Table 1, entry 17). At the end of the reactions,
the reaction mixtures were ultrasonicated with ethylacetate and ethanol to extract the products
4a and 7a from the surface of the solid support and the solid ZrO2 nanoparticles were
separated easily from the reaction mixture by simple decantation method. Then ZrO2 NPs
were washed three times with ethylacetate (3 x 5 mL), followed by washing with ethanol and
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chloroform, dried at room temperature under vacuum to eliminate residual solvents and used
for the next cycle. The recyclability test for the synthesis of 4a and 5a were performed with
the recovered catalyst upto five times. The result shows that ZrO2 NPs retains its initial
catalytic activity almost undiminished even after repeated applications (Fig. 5).
90
80
70
60
50
88 89
88 89
86 87
85 85
83 85
40
30
20
10
0
1
2
3
4
5
Number of Runs
Figure 5. Reusability test of ZrO2 NPs for the formation of 4a (blue bar) and 5a (green bar).
Conclusions
In summary, an efficient, green and sustainable methodology for the synthesis of a
series of biologically important multiꢀfunctionalized isoindolinꢀ1ꢀone derivatives has been
developed. The method involves oneꢀpot threeꢀcomponent condensation of
2ꢀcarboxybenzaldehyde, aliphatic amines and a nucleophile (enamines/6ꢀamino 1,3ꢀ
dimethyluracil /1,3ꢀcyclohexadiones/indole) in presence of ZrO2 nanoparticles as a reusable
dual acidꢀbase solid support under solventꢀfree conditions. The surface of the ZrO2
nanoparticles which is embedded with active hydroxyl groups, oxyanions and Zr4+ ions,
efficiently catalyses the condensation to produce 2,3ꢀdisubstituted isoindolinꢀ1ꢀones. This is a
promising approach from sustainable and practical chemistry viewpoints since the general
synthetic protocol offers several advantages including short reaction times, readily available
starting materials, recyclability of the catalyst and high isolated yields of the products. This
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simple, environmentally benign and convenient methodology may be useful in design and
synthesis of other biologically important molecules.
Experimental Section
General methods
Solvents and chemicals were purchased from commercial suppliers and used without
further purification. Catalyst and starting materials were prepared according to reported
procedure. Melting points were measured in open capillary tubes and were uncorrected.
JASCO FT/IRꢀ6300 spectrophotometer was used for IR spectra. 1H (300 MHz) and 13C NMR
(75 MHz) spectra were performed on Bruker instrument (300 MHz) in DMSOꢀd6. Elemental
analyses (C, H and N) were recorded using PerkinꢀElmer 240C elemental analyzer. The Xꢀ
ray diffraction data for crystallized compounds were collected with MoKα radiation at 296K
using the Bruker APEXꢀII CCD System. The morphological analysis of the resultant
nanoparticles was confirmed by HRTEM, using a HRTEM, JEOL JEM 2010 at an
accelerating voltage of 200kV and fitted with a CCD camera. The crystallinity of synthesized
ZrO2 nanoparticles was determined and confirmed by XRD analysis. The diffractogram was
documented from PANalytical, XPERTꢀPRO diffractrometer using Cuα (λ= 1.54060) as Xꢀ
ray source. ZEISS EvoꢀMA 10 Scanning Electron Microscope was used for SEM study.
General synthetic procedure for the preparation of compounds 4-7
An equimolar mixture of 2ꢀcarboxybenzaldehyde (1) (1.0 mmol), aliphatic amine (2)
(1.0 mmol) and a nucleophile (3a-d) (1.0 mmol) was dissolved in minimum quantity of
ethanol (0.5 ml) in a 50 ml round bottomed flask. Then the mixture was soaked on ZrO2
nanoparticles (250 mg) by stirring for 10 min and the solvent was removed under reduced
pressure at 50°C. The resulting solid mixture was stirred at 65ꢀ70°C in an oil bath for 1.0ꢀ2 h.
Progress of the reactions was monitored by thin layer chromatography (TLC). At the end of
the reaction, the products (4-7) were extracted from the surface of ZrO2 nanoparticles using
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ethylactetate, followed by ethanol under ultrasonication. The ZrO2 nanoꢀparticles were
separated by decantation method and the separated organic phase was collected in another
round bottom flask. The organic layer was concentrated by evaporating the solvent and then
it was purified by column chromatography on silica gel (60ꢀ120 mesh) using
ethylacetate/hexane (~2:3) as the eluent.
Characterization Data of 4a-u:
1
4a: White crystalline solid, m.p. 160ꢀ162°C; IR (KBr) 3321, 1689, 1616, 1560 cm–1; H
NMR (300 MHz, DMSOꢀd6) δH 7.83 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.42 (t, J =
7.5 Hz, 1H), 7.25 (d, J = 7.8 Hz, 3H), 7.20ꢀ7.16 (m, 3H), 6.87 (d, J = 7.5 Hz, 2H), 6.38 (s,
1H), 6.09 (d, J = 8.1 Hz, 2H), 5.62 (s, 1H), 4.85 (d, J = 14.7 Hz, 1H), 4.36 (d, J = 14.7 Hz,
1H), 2.32ꢀ2.24 (m, 1H), 2.16 (s, 3H), 2.12ꢀ2.06 (d, J = 16.5 Hz, 1H), 1.80 (d, J = 16.5 Hz,
13
1H), 1.65 (d, J = 16.5 Hz, 1H), 0.86 (s, 3H), 0.83 (s, 3H); C NMR (75MHz, DMSOꢀd6) δC
194.7, 168.2, 161.3, 145.7, 138.2, 136.8, 134.4, 132.7, 132.2, 130.0, 128.9, 128.8, 128.5,
127.5, 125.3, 124.6, 122.9, 103.1, 56.1, 50.1, 45.9, 40.8, 32.1, 30.1, 26.7, 21.1; C30H30N2O2
(450.57): calcd. C 79.97, H 6.71, N 6.22; found C 79.79, H 6.40, N 6.08.
1
4b: White crystalline solid, m.p. 148ꢀ150°C; IR (KBr) 3326, 1687, 1612, 1559 cm–1; H
NMR (300 MHz, DMSOꢀd6) δH 7.84 (d, J = 7.5 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.43 (t, J =
7.5 Hz, 1H), 7.28 (bs, 3H), 7.23ꢀ7.19 (m, 3H), 6.61 (d, J = 8.7 Hz, 2H), 6.41 (s, 1H), 6.18 (d,
J = 8.7 Hz, 2H), 5.52 (s, 1H), 4.85 (d, J = 14.4 Hz, 1H), 4.40 (d, J = 14.7 Hz, 1H), 3.65 (s,
3H), 2.28 (d, J = 16.8 Hz, 1H), 2.10 (d, J = 16.2 Hz, 1H), 1.80ꢀ1.61 (m, 2H), 0.88 (s, 3H),
0.85 (s, 3H); 13C NMR (75MHz, DMSOꢀd6) δC 194.6, 168.3, 161.8, 158.6, 145.8, 138.2,
132.6, 132.2, 129.7, 128.8, 128.8, 128.5, 127.5, 127.2., 124.5, 122.8, 114.6, 102.8, 56.2, 55.7,
50.0, 45.9, 40.7, 32.0, 30.1, 26.7; C30H30N2O3 (466.57): calcd. C 77.23, H 6.48, N 6.00;
found C 76.93, H 6.25, N 5.78.
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1
4c: White crystalline solid, m.p. 182ꢀ184°C; IR (KBr) 3332, 1689, 1615, 1562 cm–1; H
NMR (300 MHz, DMSOꢀd6) δH 7.84 (d, J = 7.5 Hz, 1H), 7.55ꢀ7.42 (m, 2H), 7.29ꢀ7.19 (m,
6H), 6.78 (t, J = 8.4 Hz, 2H), 6.40 (s, 1H), 6.21ꢀ6.16 (m, 2H), 5.51 (s, 1H), 4.87 (d, J = 14.4
Hz, 1H), 4.38 (d, J = 14.7 Hz, 1H), 2.28 (d, J = 16.5 Hz, 1H), 2.10 (d, J = 6.9 Hz, 1H), 1.78ꢀ
1.62 (m, 2H), 0.89 (s, 3H), 0.86 (s, 3H); 13C NMR (75MHz, DMSOꢀd6) δC 194.1, 167.6,
160.2, 145.0, 137.5, 132.3, 132.1, 131.5, 128.2, 128.0, 127.9, 127.8, 127.7, 126.9, 126.7,
126.6, 123.9, 122.2, 122.1, 115.8, 115.5, 103.1, 55.4, 49.4, 45.3, 40.1, 31.5, 29.4, 26.0;
C29H27FN2O2 (454.53): calcd. C 76.63, H 5.99, N 6.16; found C 76.93, H 6.10, N 5.98.
4d: White crystalline solid, m.p. 190ꢀ192°C; IR (KBr) 3299, 1688, 1683, 1615, 1566 cm–1;
1H NMR (300 MHz, DMSOꢀd6) δH 7.93 (d, J = 7.2 Hz, 1H), 7.62ꢀ7.50 (m, 2H), 7.35ꢀ7.25 (m,
6H), 7.12 (d, J = 8.7 Hz, 2H), 6.47 (s, 1H), 6.18 (d, J = 8.4 Hz, 2H), 5.57 (s, 1H), 4.94 (d, J =
14.7 Hz, 1H), 4.43 (d, J = 14.4 Hz, 1H), 2.33 (d, J = 16.5 Hz, 1H), 2.16 (d, J = 16.5 Hz, 1H),
1.88ꢀ1.72 (m, 2H), 0.96 (s, 3H), 0.94 (s, 3H); 13C NMR (75MHz, DMSOꢀd6) δC 194.6, 167.9,
159.6, 145.3, 137.8, 135.4, 132.5, 131.9, 129.2, 128.6, 128.5, 128.2, 127.3, 126.0, 124.3,
122.5, 104.0, 55.7, 49.9, 45.7, 40.4, 32.0, 29.8, 26.3; C29H27ClN2O2 (470.98): calcd. C 73.95,
H 5.78, N 5.95; found C 73.59, H 5.40, N 5.68.
1
4e: White crystalline solid, m.p. 220ꢀ222°C; IR (KBr) 3339, 1689, 1610, 1568 cm–1; H
NMR (300 MHz, DMSOꢀd6) δH 7.87 (d, J = 7.2 Hz, 1H), 7.54ꢀ7.47 (m, 2H), 7.28ꢀ7.19 (m,
6H), 7.01 (d, J = 4.8 Hz, 2H), 6.40 (s, 1H), 6.16 (s, 1H), 6.07 (s, 1H), 5.58 (s, 1H), 4.89 (d, J
= 14.7 Hz, 1H), 4.35 (d, J = 14.4 Hz, 1H), 2.31 (d, J = 16.8 Hz, 1H), 2.12 (d, J = 16.5 Hz,
1H), 1.85ꢀ1.68 (m, 2H), 0.90 (s, 3H), 0.89 (s, 3H); 13C NMR (75MHz, DMSOꢀd6) δC 194.6,
167.9, 159.6, 145.1, 138.0, 137.8, 134.6, 132.5, 131.9, 130.1, 128.7, 128.5, 128.3, 127.4,
126.3, 124.7, 124.4, 122.7, 122.5, 104.4, 55.7, 49.7, 45.7, 40.5, 32.1, 29.9, 26.2;
C29H27ClN2O2 (470.98): calcd. C 73.95, H 5.78, N 5.95; found C 73.61, H 5.47, N 5.75.
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4f: White crystalline solid, m.p. 210ꢀ212°C; IR (KBr) 3358, 1679, 1618, 1560 cm–1; 1H NMR
(300 MHz, DMSOꢀd6) δH 7.92 (d, J = 7.2 Hz, 1H), 7.60ꢀ7.47 (m, 2H), 7.39ꢀ7.35 (m, 3H),
7.32ꢀ7.28 (m, 3H), 7.25ꢀ7.22 (q, J1 = 7.2 Hz, J2 = 1.8 Hz, 1H), 7.14ꢀ7.09 (m, 2H), 6.55ꢀ6.52
(q, J1 = 7.5 Hz, J2 = 1.8 Hz, 1H), 6.48 (s, 1H), 5.86 (s, 1H), 4.87 (d, J = 14.7 Hz, 1H), 4.56 (d,
J = 14.4 Hz, 1H), 2.44 (d, J = 17.4 Hz, 1H), 2.27 (d, J = 16.8 Hz, 1H), 1.90ꢀ1.80 (m, 2H),
1.00 (s, 3H), 0.99 (s, 3H); 13C NMR (75MHz, DMSOꢀd6) δC 194.7, 168.2, 160.3, 144.8,
142.6, 134.3, 132.5, 131.8, 129.9, 129.5, 128.7, 128.6, 128.4, 127.4, 127.3, 127.0, 126.9,
124.5, 122.9, 104.5, 55.5, 49.8, 45.7, 40.8, 32.2, 29.7, 26.4; C29H27ClN2O2 (470.98): calcd. C
73.95, H 5.78, N 5.95; found C 73.68, H 5.50, N 5.60.
1
4g: White crystalline solid, m.p. 228ꢀ230°C; IR (KBr) 3284, 1689, 1622, 1565 cm–1; H
NMR (300 MHz, DMSOꢀd6) δH 7.85 (d, J = 7.5 Hz, 1H), 7.56ꢀ7.46 (m, 2H), 7.28ꢀ7.20 (m,
6H), 6.89ꢀ6.83 (m, 1H), 6.39 (s, 1H), 6.23ꢀ6.20 (m, 1H), 6.10ꢀ6.06 (m, 1H), 5.45 (s, 1H), 4.89
(d, J = 14.4 Hz, 1H), 4.34 (d, J = 14.4 Hz, 1H), 2.30 (d, J = 16.5 Hz, 1H), 2.12 (d, J = 16.8
13
Hz, 1H), 1.78ꢀ1.55 (m, 2H), 0.90 (s, 3H), 0.89 (s, 3H); C NMR (75MHz, DMSOꢀd6) δC
194.6, 167.9, 159.7, 145.1, 137.9, 133.4, 132.5, 131.8, 128.7, 128.6, 128.3, 127.5, 127.4,
125.0, 124.9, 124.3, 122.5, 121.5, 121.3, 117.0, 116.7, 104.3, 55.8, 49.8, 45.8, 40.4, 32.0,
29.8, 26.3; C29H26ClFN2O2 (488.98): calcd. C 71.23, H 5.36, N 5.73; found C 70.93, H 5.40,
N 5.55.
1
4h: White crystalline solid, m.p. 210ꢀ212°C; IR (KBr) 3393, 1685, 1610, 1567 cm–1; H
NMR (300 MHz, DMSOꢀd6) δH 7.89ꢀ7.85 (m, 1H), 7.85ꢀ7.43 (m, 2H), 7.27ꢀ7.17 (m, 8H),
6.42ꢀ6.38 (m, 1H), 6.10ꢀ6.03 (m, 2H), 5.55 (d, J = 12.0 Hz, 1H), 4.92ꢀ4.88 (m, 1H), 4.41ꢀ
4.36 (m, 1H), 2.34ꢀ2.25 (m, 1H), 2.16ꢀ2.06 (m, 2H), 1.81ꢀ1.69 (m, 1H), 0.91ꢀ0.85 (m, 6H);
13C NMR (75MHz, DMSOꢀd6) δC 194.3, 167.5, 159.5, 144.9, 137.5, 135.5, 132.2, 131.9,
128.2, 127.9, 127.0, 125.9, 124.0, 122.2, 119.4, 103.8, 55.4, 49.4, 45.4, 40.2, 31.7, 29.5, 26.0;
C29H27BrN2O2 (515.44): calcd. C 67.58, H 5.28, N 5.43; found C 67.25, H 5.05, N 5.22.
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4i: White crystalline solid, m.p. 178ꢀ180°C; IR (KBr) 3380, 3274, 1693, 1539 cm–1; 1H NMR
(300 MHz, DMSOꢀd6) δH 7.84 (d, J = 7.5 Hz, 1H), 7.50 (t, J = 7.5 Hz, 1H), 7.40 (t, J = 7.5
Hz, 1H), 7.28ꢀ7.13 (m, 7H), 6.89ꢀ6.84 (m, 1H), 6.63 (d, J = 8.1 Hz, 1H), 6.42 (s, 1H), 5.90 (s,
1H), 5.73 (d, J = 7.8 Hz, 1H), 5.58 (s, 1H), 4.81 (d, J = 15.0 Hz, 1H), 4.43 (d, J = 14.4 Hz,
1H), 2.23 (d, J = 16.5 Hz, 1H), 2.05 (d, J = 16.5 Hz, 1H), 1.94 (d, J = 17.7 Hz, 1H), 1.74 (d, J
= 17.1 Hz, 1H), 0.87 (s, 3H), 0.80 (s, 3H); 13C NMR (75MHz, DMSOꢀd6) δC 195.1, 168.4,
161.3, 157.7, 145.3, 137.7, 137.3, 132.7, 131.5, 129.8, 128.8, 128.4, 128.1, 127.4, 124.4,
122.6, 116.0, 113.9, 112.2, 102.6, 56.0, 49.8, 45.6, 40.5, 31.9, 29.7, 26.4; C29H28N2O3
(452.54): calcd. C 76.97, H 6.24, N 6.19; found C 76.80, H 5.95, N 6.10.
4j: White crystalline solid, m.p. 148ꢀ150°C; IR (KBr) 3348, 1680, 1600, 1559 cm–1; 1H NMR
(300 MHz, DMSOꢀd6) δH 7.72 (d, J = 7.5 Hz, 1H), 7.49ꢀ7.44 (m, 1H), 7.38ꢀ7.33 (m, 1H),
7.23ꢀ7.15 (m, 6H), 7.12ꢀ7.08 (m, 3H), 6.47ꢀ6.45 (m, 2H), 6.37 (s, 1H), 4.67 (d, J = 14.4 Hz,
1H), 4.45 (s, 1H), 4.41ꢀ4.37 (m, 1H), 3.91ꢀ3.84 (m, 1H), 3.77ꢀ3.70 (m, 1H), 2.26 (d, J = 16.6
Hz, 1H), 2.10 (d, J = 16.5 Hz, 1H), 1.90 (d, J = 16.8 Hz, 1H), 1.71 (d, J = 16.5 Hz, 1H), 0.91
(s, 3H), 0.89 (s, 3H); 13C NMR (75MHz, DMSOꢀd6) δC 193.4, 167.8, 162.6,145.7, 137.7,
136.4, 132.1,131.7, 128.8, 128.5, 128.2, 128.1, 127.7, 127.3, 126.1, 124.1, 122.6, 101.4, 55.7,
49.4, 46.6, 45.3, 39.2, 31.4, 29.7, 27.0; C30H30N2O2 (450.57): calcd. C 79.97, H 6.71, N 6.22;
found C 79.72, H 6.50, N 6.01.
1
4k: White crystalline solid, m.p. 218ꢀ220°C; IR (KBr) 3336, 1686, 1617, 1557 cm–1; H
NMR (300 MHz, DMSOꢀd6) δH 7.91 (d, J = 7.2 Hz, 1H), 7.61ꢀ7.48 (m, 2H), 7.35 (d, J = 7.2
Hz, 1H), 7.26 (d, J = 7.5 Hz, 2H), 7.08 (d, J = 7.2 Hz, 2H), 6.97 (d, J = 7.2 Hz, 2H), 6.48 (s,
1H), 6.21 (d, J = 7.2 Hz, 2H), 5.64 (s, 1H), 4.81 (d, J = 14.4 Hz, 1H), 4.52 (d, J = 14.4 Hz,
1H), 2.36ꢀ2.33 (m, 4H), 2.26 (s, 3H), 2.18ꢀ2.05 (m, 1H), 1.95 (d, J = 16.8 Hz, 1H), 1.84 (d, J
= 16.8 Hz, 1H), 0.98 (s, 3H), 0.97 (s, 3H); 13C NMR (75MHz, DMSOꢀd6) δC 194.4, 168.0,
160.4, 145.6, 136.8, 136.4, 134.8, 134.2, 132.3, 131.9, 129.6, 128.9, 128.6, 128.4, 125.1,
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124.1, 122.6, 102.9, 55.7, 50.0, 45.2, 40.5, 31.9, 29.7, 26.6, 21.1, 20.8; C31H32N2O2 (464.59):
calcd. C 80.14, H 6.94, N 6.03; found C 79.93, H 6.81, N 5.85.
4l: White crystalline solid, m.p. 186ꢀ188°C; IR (KBr) 3293, 1686, 1625, 1571 cm–1; 1H NMR
(300 MHz, DMSOꢀd6) δH 7.84ꢀ7.81 (d, J = 7.2 Hz, 1H), 7.51ꢀ7.43 (m, 2H), 7.25ꢀ7.20 (m,
3H), 7.03ꢀ6.98 (m, 2H), 6.89ꢀ6.82 (m, 2H), 6.34 (s, 1H), 6.17 (s, 1H), 6.16ꢀ6.08 (m, 1H), 5.52
(s, 1H), 4.64 (d, J = 14.4 Hz, 1H), 4.43 (d, J = 14.7 Hz, 1H), 2.27 (d, J = 16.5 Hz, 1H), 2.12
(d, J = 16.5 Hz, 1H), 1.87 (s, 2H), 0.90 (s, 6H); 13C NMR (75MHz, DMSOꢀd6) δC 194.7,
167.9, 163.7, 160.5, 159.3, 145.1, 138.0, 134.7, 133.6, 132.6, 131.7, 130.3, 130.2, 130.1,
128.8, 126.3, 124.6, 124.3, 122.7, 115.2, 114.9, 104.4, 55.4, 50.0, 44.7, 40.7, 32.2, 29.7, 26.5;
C29H26ClFN2O2 (464.59): calcd. C 71.23, H 5.36, N 5.73; found C 71.04, H 5.11, N 5.48.
1
4m: White crystalline solid, m.p. 192ꢀ194°C; IR (KBr) 3346, 1681, 1614, 1563 cm–1; H
NMR (300 MHz, DMSOꢀd6) δH 7.79 (d, J = 7.5 Hz, 1H), 7.57ꢀ7.41 (m, 2H), 7.35ꢀ7.28 (m,
3H), 7.20ꢀ7.18 (m, 3H), 6.99ꢀ6.93 (m, 2H), 6.56ꢀ6.53 (m, 2H), 6.43 (s, 1H), 4.64ꢀ4.45 (m,
3H), 4.04ꢀ3.84 (m, 2H), 2.35 (d, J = 16.2 Hz, 1H), 2.22 (d, J = 16.5 Hz, 1H), 2.08 (d, J = 16.8
Hz, 1H), 1.95 (d, J = 16.8 Hz, 1H), 1.02 (s, 3H), 1.00 (s, 3H); 13C NMR (75MHz, DMSOꢀd6)
δC 193.6, 167.9, 163.7, 162.3, 160.5, 145.7, 136.5, 133.4, 132.2, 131.7, 130.4, 130.3, 128.8,
128.3, 127.8, 126.1, 124.1, 122.6, 115.1, 114.8, 101.3, 55.4, 49.6, 46.6, 44.4, 39.3, 31.5, 29.5,
27.3; C30H29FN2O2 (468.56): calcd. C 76.90, H 6.24, N 5.98; found C 76.67, H 6.03, N 5.78.
1
4n: White crystalline solid, m.p. 212ꢀ214°C; IR (KBr) 3391, 1677, 1617, 1569 cm–1; H
NMR (300 MHz, DMSOꢀd6) δH 7.64 (d, J = 6.9 Hz, 1H), 7.28ꢀ7.20 (m, 2H), 7.09ꢀ7.00 (m,
3H), 6.70ꢀ6.64 (m, 2H), 6.16 (s, 1H), 4.32ꢀ4.29 (m, 2H), 3.70 (s, 1H), 2.58ꢀ2.39 (m, 2H),
2.12ꢀ2.05 (m, 2H), 1.88ꢀ1.80 (m, 1H), 1.65ꢀ1.60 (m, 1H), 0.83ꢀ0.79 (m, 6H), 0.72ꢀ0.67 (m,
2H), 0.54ꢀ0.50 (m, 2H), 0.45ꢀ0.43 (m, 3H); 13C NMR (75MHz, DMSOꢀd6) δC 193.2, 167.7,
163.6, 162.4, 160.3, 145.8, 133.6, 133.5, 132.2, 131.6, 130.3, 130.2, 128.1, 123.8, 122.6,
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114.9, 114.6, 100.2, 55.5, 49.6, 44.2, 42.3, 39.4, 31.4, 29.4, 27.4, 19.0, 13.3; C27H31FN2O2
(434.54): calcd. C 74.63, H 7.19, N 6.45; found C 74.35, H 6.95, N 6.18.
1
4o: White crystalline solid, m.p. 192ꢀ194°C; IR (KBr) 3278, 1683, 1624, 1574 cm–1; H
NMR (300 MHz, DMSOꢀd6) δH 7.86 (d, J = 7.2 Hz, 1H), 7.59ꢀ7.54 (m, 1H), 7.50ꢀ7.45 (m,
1H), 7.36 (d, J = 7.2 Hz, 1H), 7.13ꢀ7.07 (m, 2H), 6.54 (s, 1H), 6.44ꢀ6.42 (m, 2H), 5.82 (s,
1H), 3.89ꢀ3.85 (m, 1H), 3.07ꢀ3.02 (m, 1H), 2.42 (s, 2H), 2.34 (d, J = 17.1 Hz, 1H), 2.22 (d, J
= 16.8 Hz, 1H), 1.66ꢀ1.59 (m, 2H), 1.36ꢀ1.29 (m, 2H), 1.07 (s, 3H), 1.06 (s, 3H), 0.91 (t, J =
7.2 Hz, 3H); 13C NMR (75MHz, DMSOꢀd6) δC 194.9, 167.9, 159.4, 145.2, 138.3, 134.8,
132.2, 131.9, 130.2, 128.5, 126.4, 124.9, 123.9, 123.1, 122.6, 104.6, 54.7, 50.0, 40.9, 40.5,
32.6, 30.3, 28.4, 27.8, 20.1, 13.7; C26H29ClN2O2 (436.97): calcd. C 71.46, H 6.69, N 6.41;
found C 71.20, H 6.43, N 6.26.
4p: White crystalline solid, m.p. 202ꢀ204°C; IR (KBr) 1705, 1693, 1650 cm–1; 1H NMR (300
MHz, DMSOꢀd6) δH 7.84 (d, J = 6.6 Hz, 1H), 7.56ꢀ7.54 (m, 1H), 7.49ꢀ7.47 (m, 1H), 7.35 (d,
J = 7.2 Hz, 1H), 6.99ꢀ6.94 (m, 1H), 6.63ꢀ6.61 (m, 1H), 6.47ꢀ6.43 (m, 2H), 5.71 (s, 1H), 3.89ꢀ
3.85 (m, 1H), 3.06ꢀ3.01 (m, 1H), 2.40 (s, 2H), 2.28ꢀ2.11 (m, 2H), 1.63ꢀ1.61 (m, 2H), 1.33ꢀ
1.31 (m, 2H), 1.06 (s, 6H), 0.94ꢀ0.88 (m, 3H); 13C NMR (75MHz, DMSOꢀd6) δC 194.8,
167.8, 159.5, 158.1, 154.8, 145.2, 133.6, 132.2, 131.8, 128.4, 127.7, 125.4, 125.3, 123.8,
122.5, 121.6, 121.4, 117.1, 116.8, 104.4, 54.6, 49.9, 40.8, 40.4, 32.4, 30.3, 28.4, 27.7, 20.1,
13.6; C26H28ClFN2O2 (454.96): calcd. C 68.64, H 6.20, N 6.16; found C 68.46, H 6.01, N
5.92.
1
4q: White crystalline solid, m.p. 188ꢀ190°C; IR (KBr) 3340, 1688, 1615, 1563 cm–1; H
NMR (300 MHz, DMSOꢀd6) δH; 1H NMR (300 MHz, DMSOꢀd6) 7.87 (d, J = 7.5 Hz, 1H),
7.60ꢀ7.55 (m, 1H), 7.50ꢀ7.46 (m, 1H), 7.40 (d, J = 7.5 Hz, 1H), 7.08 (t, J = 8.1 Hz, 1H), 6.67ꢀ
6.63 (m, 1H), 6.48 (s, 1H), 6.14 (d, J = 7.2 Hz, 1H), 6.01 (s, 1H), 5.80 (s, 1H), 3.85ꢀ3.80 (m,
1H), 3.68 (s, 3H), 3.13ꢀ3.09 (m, 1H), 2.54ꢀ2.42 (m, 3H), 1.98ꢀ1.94 (m, 2H), 1.67ꢀ1.60 (m,
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2H), 1.41ꢀ1.24 (m, 3H), 0.92 (t, J = 7.2 Hz, 3H); 13C NMR (75MHz, DMSOꢀd6) δC 195.3,
167.8, 162.2, 160.0, 145.4, 138.0, 132.0, 129.8, 128.3, 123.8, 122.7, 117.2, 111.6, 111.0,
104.5, 55.2, 54.8, 40.4, 36.5, 30.4, 27.7, 21.6, 20.1, 13.7; C25H28N2O3 (404.50): calcd. C
74.23, H 6.98, N 6.93; found C 73.93, H 6.60, N 6.78.
1
4r: White crystalline solid, m.p. 160ꢀ162°C; IR (KBr) 3350, 1684, 1612, 1566 cm–1; H
NMR (300 MHz, DMSOꢀd6) δH 7.77 (d, J = 7.5 Hz, 1H), 7.54ꢀ7.49 (m, 1H), 7.44ꢀ7.39 (m,
1H), 7.31ꢀ7.27 (m, 2H), 7.23ꢀ7.13 (m, 4H), 7.07 (d, J = 7.5 Hz, 2H), 6.53ꢀ6.50 (m, 2H), 6.47
(s, 1H), 4.73 (d, J = 15.0 Hz, 1H), 4.44 (d, J = 14.4 Hz, 1H), 4.35 (s, 1H), 3.90ꢀ3.75 (m, 2H),
2.43ꢀ2.40 (m, 1H), 2.31 (s, 3H), 2.24ꢀ2.16 (m, 2H), 1.96ꢀ1.78 (m, 3H); 13C NMR (75MHz,
DMSOꢀd6) δC 194.1, 167.8, 163.7, 145.7, 136.8, 136.4, 134.8, 132.0, 131.8, 128.8, 128.6,
128.5, 127.9, 127.7, 127.2, 124.0, 122.6, 102.6, 55.8, 46.6, 45.0, 36.0, 25.9, 21.1, 20.7;
C29H28N2O2 (436.54): calcd. C 79.79, H 6.46, N 6.42; found C 79.57, H 6.27, N 6.31.
4s: White crystalline solid, m.p. 194ꢀ196°C; IR (KBr) 3318, 1684, 1617, 1559 cm–1; 1H NMR
(300 MHz, DMSOꢀd6) δH 7.93 (d, J = 7.2 Hz, 1H), 7.63ꢀ7.51 (m, 2H), 7.39ꢀ7.28 (m, 3H),
7.13 (d, J = 8.4 Hz, 2H), 6.95 (t, J = 8.4 Hz, 2H), 6.48 (s, 1H), 6.21 (d, J = 8.4 Hz, 2H), 5.52
(s, 1H), 4.90 (d, J = 14.4 Hz, 1H), 4.44 (d, J = 14.7 Hz, 1H), 2.55ꢀ2.49 (m, 1H), 2.33ꢀ2.22 (m,
1H), 2.17ꢀ2.12 (m, 1H), 1.98ꢀ1.88 (m, 1H), 1.82ꢀ1.81 (m, 2H); 13C NMR (75MHz, DMSOꢀ
d6) δC 195.2, 167.9, 161.4, 145.2, 135.3, 133.9, 133.8, 132.5, 132.0, 131.8, 130.3, 130.2,
129.3, 128.7, 125.8, 124.3, 122.7, 115.1, 114.8, 105.1, 55.7, 44.9, 36.4, 27.4, 21.3;
C27H22ClFN2O2 (460.92): calcd. C 70.36, H 4.81, N 6.08; found C 70.18, H 4.58, N 5.91.
4t: White crystalline solid, m.p. 120ꢀ122°C; IR (KBr) 3296, 1682, 1623, 1578 cm–1; 1H NMR
(300 MHz, DMSOꢀd6) δH 7.88 (t, J = 7.2 Hz, 1H), 7.86ꢀ7.40 (m, 3H), 7.03ꢀ6.99 (m, 2H),
6.52ꢀ6.45 (m, 3H), 5.43 (d, J = 6.0 Hz, 1H), 3.89ꢀ3.82 (m, 1H), 3.18ꢀ3.12 (m, 1H), 2.56ꢀ2.55
(m, 2H), 2.46ꢀ2.41 (m, 2H), 2.27 (d, J = 7.8 Hz, 3H), 1.98ꢀ1.96 (m, 2H), 1.70ꢀ1.65 (m, 2H),
1.42ꢀ1.35 (m, 2H), 0.98ꢀ0.91 (m, 3H); 13C NMR (75MHz, DMSOꢀd6) δC 195.2, 167.9, 162.6,
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145.5, 136.6, 134.3, 132.0, 129.7, 128.3, 125.2, 123.8, 122.7, 103.9, 54.9, 40.4, 36.6, 30.4,
27.7, 21.6, 20.8, 20.1, 13.7; C25H28N2O2 (388.50): calcd. C 77.29, H 7.26, N 7.21; found C
77.45, H 7.40, N 7.10.
1
4u: White crystalline solid, m.p. 162ꢀ164°C; IR (KBr) 3360, 1685, 1611, 1561 cm–1; H
NMR (300 MHz, DMSOꢀd6) δH 7.77 (d, J = 6.6 Hz, 1H), 7.55ꢀ7.40 (m, 3H), 7.29ꢀ7.24 (m,
5H), 6.88ꢀ6.82 (m, 1H), 6.49ꢀ6.45 (m, 3H), 5.25 (s, 1H), 4.88 (d, J = 14.7 Hz, 1H), 4.38 (d, J
= 14.1 Hz, 1H), 4.26 (m, 1H), 3.89ꢀ3.69 (m, 2H), 2.43 (d, J = 16.2 Hz, 1H), 2.27ꢀ2.12 (m,
13
2H), 1.88ꢀ1.77 (m, 3H); C NMR (75MHz, DMSOꢀd6) δC 194.3, 167.8, 163.6, 145.7, 137.9,
132.1, 131.7, 130.4, 129.3, 128.8, 128.5, 128.2, 128.0, 127.9, 127.8, 127.3, 126.2, 124.1,
122.6, 115.9, 115.6, 102.7, 56.0, 45.9, 45.5, 35.9, 25.8, 20.6; C28H25FN2O2 (440.50): calcd. C
76.34, H 5.72, N 6.36; found C 76.03, H 5.50, N 6.28.
Characterization Data of 5a-d:
1
5a: White crystalline solid, m.p. 200ꢀ202°C; IR (KBr) 3450, 1684, 1619, 1496 cm–1; H
NMR (300 MHz, DMSOꢀd6) δH 7.69 (d, J = 6.9 Hz, 1H), 7.49ꢀ7.41 (m, 2H), 7.26ꢀ7.20 (m,
6H), 7.05 (s, 2H), 5.69 (s, 1H), 4.56 (d, J = 15.3 Hz, 1H), 4.38 (d, J = 15.0 Hz, 1H), 3.34 (s,
3H), 2.79 (s, 3H); 13C NMR (75MHz, DMSOꢀd6) δC 168.0, 159.5, 154.5, 151.1, 147.1, 138.5,
133.1, 131.3, 128.4, 128.2, 127.4, 127.1, 122.7, 122.2, 80.5, 57.2, 44.1, 30.4, 27.1;
C21H20N4O3 (376.40): calcd. C 67.01, H 5.36, N 14.88; found C 66.85, H 5.10, N 14.48.
1
5b: White crystalline solid, m.p. 142ꢀ144°C; IR (KBr) 3459, 1682, 1619, 1496 cm–1; H
NMR (300 MHz, DMSOꢀd6) δH 7.74 (d, J = 7.2 Hz, 1H), 7.55ꢀ7.52 (m, 1H), 7.47ꢀ7.42 (m,
1H), 7.36 (d, J = 7.2 Hz, 1H), 7.14 (d, J = 7.8 Hz, 2H), 7.00 (d, J = 7.8 Hz, 2H), 6.30 (s, 1H),
4.72 (d, J = 14.4 Hz, 1H), 4.43 (d, J = 14.7 Hz, 1H), 4.27 (s, 2H), 3.37 (s, 3H), 3.11 (s, 3H),
2.26 (s, 3H); 13C NMR (75MHz, DMSOꢀd6) δC 167.8, 162.9, 151.5, 150.7, 144.4, 137.1,
134.0, 132.5, 131.5, 128.8, 128.6, 128.3, 123.8, 123.1, 81.8, 56.9, 44.9, 28.5, 28.4, 21.0;
C22H22N4O3 (390.43): calcd. C 67.68, H 5.68, N 14.35; found C 67.44, H 5.49, N 14.18.
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5c: White crystalline solid, m.p. 180ꢀ182°C; IR (KBr) 3446, 1682, 1629 cm–1; 1H NMR (300
MHz, DMSOꢀd6) δH 7.73 (d, J = 7.5 Hz, 1H), 7.60ꢀ7.54 (m, 1H), 7.48ꢀ7.42 (m, 1H), 7.38 (d,
J = 7.5 Hz, 1H), 7.29ꢀ7.25 (m, 2H), 6.90 (t, J = 8.4 Hz, 2H), 6.29 (s, 1H), 4.55 (s, 2H), 4.38
(s, 2H), 3.37 (s, 3H), 3.18 (s, 3H); 13C NMR (75MHz, DMSOꢀd6) δC 167.7, 163.6, 162.8,
160.4, 151.5, 150.6, 144.2, 132.8, 132.6, 131.2, 130.1, 130.0, 128.8, 123.7, 123.1, 115.0,
114.7, 81.4, 56.5, 44.1, 28.6, 28.4; C21H19FN4O3 (394.39): calcd. C 63.95, H 4.86, N 14.21;
found C 63.70, H 4.62, N 14.02.
1
5d: White crystalline solid, m.p. 160ꢀ162°C; IR (KBr) 3342, 1691, 1631, 1591 cm–1; H
NMR (300 MHz, DMSOꢀd6) δH 7.68 (d, J = 7.5 Hz, 1H), 7.59ꢀ7.55 (m, 1H), 7.48ꢀ7.41 (m,
2H), 6.33 (s, 1H), 4.56 (s, 2H), 3.80ꢀ3.75 (m, 1H), 3.41 (s, 3H), 3.39 (s, 3H), 2.97ꢀ2.93 (m,
1H), 1.61ꢀ1.53 (m, 2H), 1.32ꢀ1.25 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H); 13C NMR (75MHz,
DMSOꢀd6) δC 168.0, 163.0, 151.8, 151.0, 144.5, 132.4, 131.6, 128.8, 123.5, 123.2, 81.3, 56.0,
40.1, 30.2, 29.0, 28.5, 20.0, 13.6 ; C18H22N4O3 (342.39): calcd. C 63.14, H 6.48, N 16.36;
found C 62.97, H 6.29, N 16.15.
Characterization Data of 6a-d:
6a: White milky powder, m.p. 220 (reported)13c/216ꢀ218 (observed)°C; IR (KBr) 3422, 1700,
1653 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 10.99 (bs, 1H), 7.59 (d, J = 7.2 Hz, 1H), 7.43ꢀ
7.29 (m, 2H), 7.23ꢀ7.09 (m, 6H), 5.60 (s, 1H), 4.75 (d, J = 15.0 Hz, 1H), 3.95 (d, J = 15.0 Hz,
1H), 2.21 (s, 2H), 1.97ꢀ1.89 (m, 2H), 0.89 (s, 3H), 0.88 (s, 3H); C23H23NO3 (361.43): calcd.
C 76.43, H 6.41, N 3.88; found C 76.10, H 6.29, N 3.69.
6b: White milky powder, m.p. 247 (reported)13c/242ꢀ244 (observed)°C; IR (KBr) 2957, 1708,
1609 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 7.44 (t, J = 7.2 Hz, 1H), 7.34 (d, J = 7.2 Hz,
1H), 7.29ꢀ7.21 (m, 2H), 7.09ꢀ7.03 (m, 4H), 5.93 (s, 1H), 4.74 (d, J = 14.7 Hz, 1H), 4.07 (d, J
= 15.0 Hz, 1H), 2.35ꢀ2.28 (m, 5H), 1.28ꢀ1.25 (m, 2H), 1.06 (s, 3H), 1.03 (s, 3H); C24H25NO3
(375.46): calcd. C 76.77, H 6.71, N 3.73; found C 76.40, H 6.42, N 3.61.
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6c: White milky powder, m.p. 229 (reported)13c/230ꢀ232 (observed)°C; IR (KBr) 3200, 1710,
1620 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 10.97 (bs, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.39ꢀ
7.27 (m, 2H), 7.16ꢀ7.08 (m, 3H), 7.03ꢀ6.97 (m, 2H), 5.58 (s, 1H), 4.60 (d, J = 15.0 Hz, 1H),
4.06 (d, J = 15.0 Hz, 1H), 2.30ꢀ2.15 (m, 2H), 2.01ꢀ1.97 (m, 2H), 1.70ꢀ1.64 (m, 2H);
C21H18FNO3 (351.37): calcd. C 71.78, H 5.16, N 3.99; found C 71.45, H 5.01, N 3.68.
1
6d: White milky powder, m.p. 226ꢀ228°C; IR (KBr) 3229, 1705, 1650 cm–1; H NMR (300
MHz, DMSOꢀd6) δH 7.46 (t, J = 6.9 Hz, 1H), 7.27ꢀ7.24 (m, 3H), 6.01 (s, 1H), 3.78ꢀ3.71 (m,
1H), 2.83ꢀ2.74 (m, 1H), 2.47ꢀ2.28 (m, 3H), 1.55ꢀ1.50 (m, 2H), 1.42ꢀ1.38 (m, 3H), 1.09 (s,
3H), 1.06 (s, 3H), 0.87 (t, J = 7.2 Hz, 3H); 13C NMR (75MHz, DMSOꢀd6) δC 185.8, 170.0,
146.6, 132.0, 131.2, 127.2, 122.5, 121.8, 107.6, 54.8, 49.1, 44.6, 39.9, 32.0, 29.9, 28.2, 28.1,
19.9, 13.6; C20H25NO3 (327.41): calcd. C 73.37, H 7.70, N 4.28; found C 73.05, H 7.50, N
4.13.
Characterization Data of 7a-d:
7a: White powder, m.p. 209.4–211.2 (reported)16/206ꢀ208(observed)°C, IR (KBr) 3252, 1664
cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 8.88 (s, 1H), 8.02ꢀ8.00 (m, 1H), 7.49ꢀ7.37 (m, 3H),
7.25ꢀ7.11 (m, 8H), 6.89ꢀ6.66 (m, 2H), 5.61 (m, 1H), 5.38ꢀ5.33 (m, 1H), 3.83ꢀ3.78 (m, 1H);
13C NMR (75MHz, DMSOꢀd6) δC 167.5, 146.8, 138.0, 137.4, 132.2, 131.8, 128.9, 128.6,
127.9, 127.5, 126.9, 125.2, 123.9, 123.2, 122.1, 119.4, 118.3, 112.4, 109.1, 57.8, 43.3;
C23H18N2O (338.40): calcd. C 81.63, H 5.36, N 8.28; found C 81.93, H 5.40, N 8.48.
7b: White powder, m.p. 200ꢀ202°C, IR (KBr) 3270, 1669 cm–1; 1H NMR (300 MHz, DMSOꢀ
d6) δH 11.26 (s, 1H), 7.87ꢀ7.84 (m, 1H), 7.56ꢀ7.50 (m, 3H), 7.39 (d, J = 8.1 Hz, 1H), 7.26ꢀ
7.23 (m, 1H), 7.12ꢀ7.00 (m, 5H), 6.77 (t, J = 7.2 Hz, 1H), 6.58ꢀ6.56 (m, 1H), 5.72 (s, 1H),
5.02 (d, J = 15.3 Hz, 1H), 3.73 (d, J = 15.3 Hz, 1H), 2.25 (s, 3H); 13C NMR (75MHz,
DMSOꢀd6) δC 166.5, 145.9, 136.5, 135.7, 134.0, 131.3, 130.9, 128.6, 127.7, 127.0, 125.9,
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124.3, 123.0, 122.2, 120.9, 118.5, 117.4, 111.5, 108.2, 56.8, 42.1, 20.1; C24H20N2O (352.42):
calcd. C 81.79, H 5.72, N 7.95; found C 81.45, H 5.60, N 7.83.
1
7c: Isolated as gummy liquid; H NMR (300 MHz, DMSOꢀd6) δH 11.30 (s, 1H), 7.90ꢀ7.88
(m, 1H), 7.59 (s, 1H), 7.51ꢀ7.49 (m, 2H), 7.41 (d, J = 8.1 Hz, 1H), 7.25ꢀ7.17 (m, 3H), 7.10ꢀ
7.02 (m, 3H), 6.76 (t, J = 7.2 Hz, 1H), 6.70 (s, 1H), 5.77 (s, 1H), 5.00 (d, J = 15.3 Hz, 1H),
3.88 (d, J = 15.3 Hz, 1H); 13C NMR (75MHz, DMSOꢀd6) δC 167.6, 163.3, 160.1, 146.9,
137.5, 134.3, 134.2, 132.3, 131.8, 130.1, 130.0, 128.7, 126.9, 125.2, 123.9, 123.2, 121.9,
119.4, 118.4, 115.7, 115.4, 112.4, 109.1, 57.9, 42.8; C23H17FN2O (356.39): calcd. C 77.51, H
4.81, N 7.86; found C 77.29, H 4.60, N 7.80.
7d: White powder, m.p. 208.2–208.8 (reported)16/206ꢀ208(observed)°C, IR (KBr) 3218,
1672 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 11.24 (s, 1H), 7.80ꢀ7.75 (m, 1H), 7.66 (s, 1H),
7.50ꢀ7.48 (m, 2H), 7.38 (d, J = 8.1 Hz, 1H), 7.28ꢀ7.24 (m, 1H), 7.01 (t, J = 7.2 Hz, 1H), 6.77ꢀ
6.72 (m, 1H), 6.57 (s, 1H), 5.95 (s, 1H), 3.75ꢀ3.66 (m, 1H), 2.80ꢀ2.75 (m, 1H), 1.46ꢀ1.44 (m,
2H), 1.21ꢀ1.17 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H); 13C NMR (75MHz, DMSOꢀd6) δC 167.3,
146.8, 137.3, 132.3, 131.9, 128.5, 126.7, 125.3, 123.7, 122.9, 121.8, 119.3, 118.4, 112.3,
109.6, 57.9, 39.3, 30.2, 19.9, 13.9; C20H20N2O (304.39): calcd. C 78.92, H 6.62, N 9.20;
found C 78.69, H 6.48, N 9.07.
Acknowledgements
K.D. and S.M. thank UGC, New Delhi, India for offering them Senior Research Fellowship
(SRF) and Junior Research Fellowship (JRF) respectively. The financial assistance of CSIR,
New Delhi is gratefully acknowledged [Major Research Project, No. 02(0007)/11/EMRꢀII].
Crystallography was performed at the DSTꢀFIST, Indiaꢀfunded Single Crystal Diffractometer
Facility at the Department of Chemistry, University of Calcutta. We also acknowledge Center
for Research in Nanoscience and Nanotechnology (CRNN), University of Calcutta for
instrumental facilities.
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Facile one-pot three-component synthesis of diverse 2,3-
disubstituted isoindolin-1-ones using ZrO2 nanoparticles as a
reusable dual acid-base solid support under solvent-free
conditions
Kamalesh Debnath, Sayan Mukherjee, Chandan Bodhak and Animesh Pramanik*
Department of Chemistry, University of Calcutta, 92, A. P. C. Road, Kolkata-700 009, India;
Fax: +91-33-2351-9755; Tel: +91-33-2484-1647.
E-mail: animesh_in2001@yahoo.co.in
A series of multi-functionalized 2,3-disubstituted isoindolin-1-ones has been synthesized
using ZrO2 nanoparticles as a dual acid-base solid support under solvent-free conditions.