ZrO2 nanoparticles as a reusable solid dual acid-base catalyst for facile one-pot synthesis of multi-functionalized spirooxindole derivatives under solvent free condition

Article abstract of DOI:10.1039/c5ra16259a

A two-step one-pot protocol for the facile synthesis of biologically important spirooxindole derivatives such as spiro[4H-pyran-3,3′-oxindoles] and spiro[indoline-3,4′(1H′)-pyrano-[2,3-c]pyrazol-2-ones has been developed. In this method ZrO₂ na

Full text of DOI:10.1039/c5ra16259a

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ZrO2 nanoparticles as a reusable solid dual acid-base catalyst for
facile one-pot synthesis of multi-functionalized spirooxindole
derivatives under solvent free condition
Chandan Bodhak, Ashis Kundu 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 twoꢀstep oneꢀpot protocol for the facile synthesis of biologically important
spirooxindole derivatives such as spiro[4Hꢀpyranꢀ3,3′ꢀoxindoles] and spiro[indolineꢀ3,4′(1H′)ꢀ
pyranoꢀ[2,3ꢀc]pyrazolꢀ2ꢀones has been developed. In this method ZrO2 nanoparticles have been
utilized as a reusable solid dual acidꢀbase catalyst to get quick access to the multiꢀfunctionalized
spirooxindole derivatives under solvent free condition at room temperature. The main advantages
of this method are the operational simplicity, reduced reaction time, elimination of solvents, high
yield of the products, convenient work up procedure and employment of nontoxic and recyclable
ZrO2 nano catalyst. All these factors make the present method economical, green and
sustainable.
Introduction:
The practices of green chemistry hold the key to build an environmentally sustainable
society.1 In recent time, metal based nanoparticles (NPs) in the form of nano catalysts have
emerged as viable alternatives to conventional materials in various fields of chemistry and
attracted the interest of chemists in exploration new green synthetic pathways.2 The metal based
NPs are known to be promising materials for heterogeneous catalysts in a variety of organic
transformations.3 The surface of ZrO2 NPs is reported to contain active hydroxyl groups,
1

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oxyanions and Zr4+ ions which can act as dual acidꢀbase catalyst.4 This interesting property of
ZrO2 NPs has not been explored as yet under solvent free condition, especially in important
multicomponent reactions for synthesis of bioꢀactive building blocks. In continuation of our
research work on the synthesis of isatin based heterocycles5 and development of green synthetic
methodologies,5b,5c,6 herein, we explore the potential of nontoxic ZrO2 NPs as heterogeneous
catalyst in multicomponent reactions. Moreover the study will provide valuable insights into the
mechanism of the reaction and the mode of catalytic activity of ZrO2 NPs which will help in
expanding the scope of the catalyst in new synthetic design.
The indole ring system is probably the most ubiquitous heterocyclic moiety found in a
large number of bioactive natural products and medicinal agents.7 The spirooxindole derivatives
also occupy a special place in organic and medicinal chemistry since they exhibit diverse
biological and pharmacological activities. To name a few, spirotryprostatin A and B, for
instance, are wellꢀknown microtubule assembly inhibitors (Fig. 1).8 Isopteropodine and
pteropodine are found to act as Muscarinic M1 and serotonin receptor modulators (Fig. 1).9 MKꢀ
0677 is bioactive as nonpeptidyl growthꢀhormone secretagogues.10 In light of their unique
structural features along with the important biological activities, spirooxindole derivatives have
drawn considerable attention to synthetic chemists for their preparation.11 While a number of
methods for the synthesis of spirooxindole derivatives have been documented in the literature,
the development of new routes for efficient construction of the spirooxindole core with diverse
functionalized structures remains desired. Therefore we wish to report herein a facile oneꢀpot
synthesis of two series of spirooxindole derivatives such as spiro[4Hꢀpyranꢀ3,3′ꢀoxindoles] (4)
and spiro[indolineꢀ3,4′(1H′)ꢀpyranoꢀ[2,3ꢀc]pyrazolꢀ2ꢀones (7) through the condensation of isatin
(1) and malononitrile (2) with cyclohexaneꢀ1,3ꢀdiones (3) and ethylacetoacetate (5) and
2

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hydrazines (6) in presence of ZrO2 nano catalyst under solventꢀfree condition at room
temperature (Scheme 1).
N
N
H
H
O
O
O
O
H
N
N
O
O
N
NH
O
H
Spirotryprostatin B
Spirotryprostatin A
H3C
H3C
O
O
H
N
N
H
O
H
H
H
H
O
O
O
O
O
N
H
N
H
Isopteropodine
Pteropodine
Figure 1. Some spirooxindole based biologically active natural products
O
O
O
R2
R2
OEt
5
+
O
NHNH2
R3
3
6
O
X
O
ZrO2 NPs
ZrO2 NPs
Solvent free
Stirring, RT,
1 min
N
R1
Solvent free
Stirring, RT,
1 min
1
CN
2
CN
R2
R2
R3
H2N
O
H2N
NC
O
N
N
R1 = Alkyl/ Aryl
R2 = H, Me
NC
X
O
O
O
X
N
R3 = H, Ph
N
R1
4
R1
7
Scheme 1: Synthesis of spiro[4Hꢀpyranꢀ3,3′ꢀoxindoles] (4) and spiro[indolineꢀ3,4′(1H′)ꢀpyranoꢀ
[2,3ꢀc]pyrazolꢀ2ꢀone derivatives (7)
3

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Results and discussion:
During the optimization studies towards the development of ZrO2 as nano catalyst
for oneꢀpot synthesis of spirooxindole derivatives, two different set of reactions such as
condensation of isatin (1), malononitrile (2) and dimedone (3) and condensation of isatin (1),
malononitrile (2), ethylacetoacetate (5) and hydrazine (6) were chosen as model reactions
(Scheme 2). In these processes various parameters such as the effect of catalysts, solid supports
and solvents at different experimental conditions have been examined (Table 1). In the initial
investigation, two reaction mixtures, taking the reactants 1.0 mmole each in ethanol, were stirred
at room temperature. Under this conditions the condensation of isatin (1), malononitrile (2) and
dimedone (3) afforded the product 4a in ~70% yield and condensation of isatin (1), malononitrile
(2), ethylacetoacetate (5) and hydrazine (6) furnished the product 7a in ~74% yield within 10
minutes (Scheme 2; Table 1, entry 1). These reactions were found to be twoꢀstep oneꢀpot
processes where the reactants 1 and 2 were added initially and then after two minutes the
remaining reactants (3 or 5 and 6) were added sequentially. When the same reactions were
carried out in water medium the product 4a and 7a were formed in ~65 and 62% yield
respectively (Table 1, entry 2). The low yield of the products was due to low solubility of the
reactants in water medium. Employment of 10 mol% Et3N or piperidine as catalyst enhanced the
products formation slightly in EtOH medium at room temperature (Table 1, entries 3 and 4).
Addition of various acid catalysts (20 mol%) such as lactic acid, formic acid and pꢀTSA in EtOH
medium not only showed insignificant reaction catalysis but also gradual lowering of products
yield with increase of acidity (Table 1, entries 5ꢀ7). The presence of organocatalyst Lꢀproline (20
mol%) in EtOH medium also could not enhance the products yield significantly at room
temperature (Table 1, entry 8). Surprisingly when ZrO2 NPs (20 mol%) were used as catalyst in
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EtOH and water medium substantial catalysis was observed in both cases producing 4a and 7a in
good yields within 5 minutes (Table 1, entries 9 and 10).
In quest of greener conditions, subsequently both the reactions were performed under
solvent free condition without using any catalyst. In this condition no product was formed even
after stirring the reaction mixtures for 20 minutes at room temperature (Table 1, entry 11). Then
the feasibility of the reactions under solvent free condition was examined in presence of various
strong solid acid catalysts such as pꢀTSA (20 mol%), SSA (200 mg), PEGꢀOSO3H (200 mg) and
Melamine sulfonic acid (250 mg) (Table 1, entries 12ꢀ15). To our delight, we observed that the
selected solid acids can catalyze the condensation reactions significantly under solvent free
condition at room temperature. In search of better yield, reduced reaction time and cleaner
reaction profile, next 20 mol% ZrO2 NPs was employed as catalyst for the reactions under
solvent free condition. Gratifyingly, in this case the product 4a and 7a were formed in high yield,
~86 and 91% respectively on stirring the reaction mixtures for 5 minutes at room temperature
(Table 1, entry 16). Then we carried out the optimization study to examine the influence of the
stoichiometry of ZrO2 NPs (20ꢀ5 mol%) under solvent free condition for the best yield of
product 4a and 7a (Table 1, entries 16ꢀ18). The study revealed that the best yield of the product
4a and 7a can be obtained when the reactants are allowed to react on the solid surface of ZrO2
NPs (5.0 mol%) at room temperature just for 1 minute under solventꢀfree condition (Table 1,
entry 18). It is envisioned that, the adsorption of the reactant molecules on the large surface area
of ZrO2 NPs increases the local concentration around the active sites and accelerates the reaction
rate remarkably.
With the optimized condition in hand, next the scope and generality of this protocol was
assessed by employing various isatins, cyclohexaneꢀ1,3ꢀdiones and hydrazines (Scheme 1). The
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results show that the optimized methodology (Table 1, entry 18) tolerates a wide spectrum of
substrates to produce multiꢀfunctionalized spirooxindole derivatives 4aꢀs and 7aꢀw in good to
excellent yields (Table 2 and 3). The formation of the final products 4 and 7 was confirmed by
1
IR, H NMR, 13C NMR spectroscopy, elemental analysis and also by matching the melting
points of some of the compounds with the reported values.11aꢀi The determination of the Xꢀray
crystal structures of 4n and 7e further corroborates the products formation (Fig. 2 and 3).
Figure 2. Crystal structure of compound 4n. Color code: red, oxygen; blue, nitrogen; grey,
carbon; white, hydrogen (CCDC 1409892).†
O
O
O
O
Me
Me
OEt
H
N
H2N
NC
H2N
NC
5
O
O
+
Me
Me
O
NH2
N
H2N
O
N
6
3
H
1
O
O
O
Catalyst
Solvent
+
CN
NH
Catalyst
Solvent
NH
4a
7a
CN
2
Scheme 2: Optimization of the reaction conditions
6

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Table 1: Optimization of reaction conditions for the synthesis of 4a and 7aa
Entry Solvent
(5.0 ml)
Catalyst
Catalyst
Load
Time
(min)
Yieldb (%)
4a
7a
1
2
3
EtOH
H2O
__
__
__
__
10
15
10
70
74
65
74
62
76
EtOH
Et3N
10 mol%
4
5
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
__
Piperidine
Lactic acid
Formic acid
pꢀTSA
10 mol%
20 mol%
20 mol%
20 mol%
20 mol%
20 mol%
20 mol%
__
10
15
15
15
15
5
78
76
70
68
72
87
86
__
68
60
65
63
86
84
84
79
77
71
69
73
88
85
__
67
61
63
67
91
90
90
6
7
8
Lꢀproline
ZrO2 NPs
ZrO2 NPs
__
9
10
11
12
13
14
15
16
17
18
5
20
15
5
__
pꢀTSA
20 mol%
200 mg
200 mg
200 mg
20 mol%
10 mol%
5 mol%
__
SSA
__
PEGꢀOSO3H
15
10
1
__
Melamine sulfonic
acid (MSA)
ZrO2 NPs
__
ZrO2 NPs
1
__
__
ZrO2 NPs
1
aAll the reactions were carried out at room temperature taking the reactants in 1.0 mmol each
bIsolated yields.
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Table 2: Library synthesis of spiro[4Hꢀpyranꢀ3,3′ꢀoxindoles] compounds 4a-sa
H2N
NC
H2N
NC
H2N
NC
O
O
H2N
NC
O
O
O
Cl
O
Br
O
O2N
O
O
O
O
O
NH
NH
NH
NH
4d (81%)
4a (84%)
4c (80%)
4b (88%)
H2N
H2N
O
O
H2N
O
H2N
O
NC
NC
NC
NC
O
I
O
O
O
O
F
O
N
O
O
NH
O
N
NH
4e (89%)
4f (85%)
4g (82%)
4h (90%)
H2N
O
H2N
H2N
H2N
O
O
NC
NC
NC
NC
O
O
O
O
O
O
O
O
N
N
N
N
4i (92%)
4j (87%)
4l (91%)
4k (88%)
Br
H2N
O
H2N
O
H2N
NC
O
H2N
O
NC
NC
O
O
NC
O
N
O
O
O
Cl
N
O
N
O
H2C 11
N
4m (86%)
4n (84%)
4o (92%)
4p (88%)
H2N
O
H2N
NC
H2N
NC
O
O
NC
O
O
O
Br
O
O
O
N
N
N
4q (82%)
aIsolated yields
4r (89%)
4s (90%)
Br
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Figure 3. Crystal structure of compound 7e. Color code: red, oxygen; blue, nitrogen; grey,
carbon; white, hydrogen; purple, iodine (CCDC 1411963). †
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Table 3: Library synthesis of spiro[indolineꢀ3,4′(1H′)ꢀpyranoꢀ[2,3ꢀc]pyrazolꢀ2ꢀone derivatives
7a-wa
H
N
H
N
H
N
H
N
H2N
NC
O
H2N
NC
O
H2N
NC
O
H2N
NC
O
N
N
N
N
O
Cl
O
O
Br
O
F
NH
NH
NH
NH
7b (86%)
7a (90%)
7d (84%)
7c (87%)
H
N
H2N
O
H
H
N
H
H2N
NC
O
H2N
NC
O
N
H2N
NC
O
N
N
N
N
N
NC
O
O
O
O2N
O
I
N
N
NH
NH
7f (80%)
7g (83%)
7h (90%)
7e (92%)
H
H
H
H
H2N
NC
O
H2N
NC
O
H2N
NC
O
N
H2N
NC
O
N
N
N
N
N
N
N
O
O
O
O
N
N
N
N
7i (84%)
7j (86%)
7l (88%)
7k (92%)
H
N
H2N
NC
O
H
H2N
NC
O
N
N
H2N
NC
O
H2N
NC
O
N
N
N
N
N
O
O
O
N
O
N
N
NH
7m (89%)
7p (87%)
7n (94%)
7o (83%)
Br
H
H2N
NC
O
N
H2N
NC
O
H2N
NC
O
N
N
N
H2N
NC
O
N
N
N
N
O
Cl
O
Cl
O
O
N
Br
Br
N
N
N
7s (86%)
7r (79%)
7t (82%)
Br
7q (85%)
Br
H
N
H2N
NC
O
N
H2N
NC
O
N
H2N
NC
O
N
N
N
O
N
O
Cl
O
N
NH
7u (88%)
7v (91%)
7w (84%)
Br
aIsolated yields
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The morphology of the prepared ZrO2 NPs has been determined from scanning electron
microscopic (SEM) study. The SEM images indicate the formation of spherical and nearly
uniform sized ZrO2 NPs (Fig. 4a and 4b). The morphology and uniformity of particle size of
ZrO2 NPs were further characterized by highꢀresolution transmission electron microscopic
(HRTEM) images, before (Fig. 4c) and after five times applications (Fig. 4d) at an accelerating
voltage of 200 kV. Elemental analyses of the asꢀsynthesized ZrO2 NPs were performed at EDX
equipped onto HRTEM and found to be quite consistent (Fig. 5). Further the characterization of
asꢀsynthesized ZrO2 NPs has been carried out by powder XRD study. The XRD patterns of
freshly prepared ZrO2 NPs and after five times reused ZrO2 NPs are displayed in Fig. 6. The
powder Xꢀray diffraction pattern of the catalyst indicates the formation of tetragonal ZrO2
(tZrO2) NPs.12 No characteristics changes in the peaks are observed after 5 times reuse of the
ZrO2 NPs which suggests that the arrangement of the catalyst remains unchanged after the
reusability test.13 Further characterization of ZrO2 NPs catalyst was confirmed by FTꢀIR and UVꢀ
visible studies (Supporting Information).
Figure 4. SEM images of ZrO2 NPs (a) before reaction and (b) after 5 times applications in
reaction. HRTEM images of ZrO2 NPs (c) before reaction and (d) after five times applications.
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Figure 5. TEMꢀEDX of ZrO2 NPs
Figure 6. XRD spectra of (A) freshly prepared ZrO2 NPs and (B) reused ZrO2 NPs after 5th cycle
Mechanism:
A plausible mechanism for the formation of spirooxindoles 4 and 7 using ZrO2 NPs under
solvent free condition has been described in scheme 3. The surface of ZrO2 NPs is decorated
with active hydroxyl, oxide and Zr4+ ions4 which can act as dual acidꢀbase catalyst for the
condensation reactions. On adsorption of the reactant molecules on the solid surface of ZrO2 NPs
the local concentration of the reactants around the active sites increases significantly causing
acceleration of the reaction rate. Initially, malononitrile (2) condenses with isatins (1) via
Knoevenagel condensation to form a common intermediate (I) promoted by acidꢀbase catalysis
of ZrO2 NPs as shown in Scheme 3. Then the intermediate I undergoes Michael type
condensation with the pyrazole intermediate (II) derived in situ from ethylacetoacetate (5) and
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hydrazine (6) to form the intermediate III (Scheme 3a). Subsequently the acidic and basic sites
of ZrO2 NPs assist the intermediate III to undergo intraꢀmolecular electrophilic cyclization
followed by tautomerization, to afford the desired spirooxindoles 7. Similarly the intermediate I
undergoes Michael type addition with the enol form of cyclohexaneꢀ1,3ꢀdiones (IV) to furnish
spirooxindoles 4 through the formation of intermediate V (Scheme 3b).
(a)
Zr4+
OEt
5
O-
Zr4+
O
O
HO
-O
X
O
H
O
O
ZrO2
N
R1
O-
1
H
N
Zr4+
H
HN
H
N
6
HO
R3
O-
N
2
H
NC
CN
O
X
O
O
N
N
N
R3
N
R3
H
N
(II)
(I)
R1
O2-
Zr4+
O
H
R3
N
H2N
NC
R3
N
N
O
N
N
O
X
NC
X
H
O
O
N
R1
N
R1
7
O2-
(III)
ZrO2
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(b)
4+Zr
O-
Zr4+
O
HO
O-
R2 R2
O
H
ZrO2
X
O
O-
O
O
N
R1
1
Zr4+
H
3
N
HO
O-
H
N
2
R2 R2
NC
CN
O
X
H O
O
(IV)
N
(I)
R1
O2-
O
H
Zr4+
O
R2
R2
R2
R2
H2N
NC
O
N
NC
X
X
O
O
H
N
O
O
O2-
R1
N
R1
4
(V)
ZrO2
Scheme 3. Plausible mechanism for the formation of (a) spirooxindoles
spirooxindoles
7 and (b)
4
The reusability test of ZrO2 NPs was carried out separately for the synthesis of 4a and 7a
under the optimized reaction conditions (Table 1, entry 18). At the end of the reactions, the
reaction mixtures were ultrasonicated with ethylacetate 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), dried at room temperature under vacuum to eliminate residual solvents
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and used for the next cycle. The condensation reactions for the synthesis of 4a and 7a were
performed with the recovered catalyst upto five times. The result shows that there is indeed
substantial retention of initial catalytic activity of ZrO2 NPs even after repeated applications (Fig.
7).
Figure 7. Reusability of ZrO2 NPs for the formation of 4a (red bar) and 7a (light green bar).
Conclusions
In summary, we have developed an efficient, ecoꢀfriendly and sustainable methodology
to get quick access to several multiꢀfunctionalized spirooxindole derivatives such as spiro[4Hꢀ
pyranꢀ3,3′ꢀoxindoles] and spiro[indolineꢀ3,4′(1H′)ꢀpyranoꢀ[2,3ꢀc]pyrazolꢀ2ꢀones under solventꢀ
free condition at room temperature. The method involves twoꢀstep oneꢀpot condensation of
isatins, malononitrile, cyclohexane 1,3ꢀdiones and pyrazoles in presence of ZrO2 nanoparticles as
a solid dual acidꢀbase catalyst. To the best our knowledge this is the first example where ZrO2
nanoparticles have been exploited as a solid supported dual acidꢀbase catalyst in important
condensation reactions for synthesis of bioꢀactive building blocks. The significant advantages of
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this methodology are the use of solventꢀfree reaction conditions, employment of simple and
easily available starting materials and reagents, operational simplicity of the reaction and the use
of a nontoxic and recyclable catalyst. All these factors make the present method economical,
green and sustainable.
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 Xꢀray 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, XPERTꢀ
PRO diffractrometer using Cuα (λ= 1.54060) as Xꢀray source. Hitachi Sꢀ3400N Scanning
Electron Microscope was used for SEM.
General synthetic procedure for the preparation of compounds 4:
An equimolar mixture of isatins (1) (1.0 mmol) and malononotrile (2) (1.0 mmol) was dissolved
in minimum quantity of chloroform (3 ml) in a 100 ml round bottom flask and to this mixture
ZrO2 NPs (5.0 mol%) were added and mixed thoroughly. Then the solvent was removed from
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the mixture under vacuum to get a semi liquid mixture. Subsequently cyclohexaneꢀ1,3ꢀdiones
(1.0 mmol) were added and the resulting mixture was stirred at room temperature for 1ꢀ2
minutes. The progress of the reaction was monitored by thin layer chromatography (TLC). At the
end of the reaction, ethylacetate was added to the reaction mixture and the product was extracted
from the solid support by ultrasonication. The ZrO2 NPs were separated by decantation method
and the separated organic phase was collected in another round bottom flask. Then the organic
layer was evaporated to get the crude mass. Pure products
4 were obtained from the isolated
crude mass through column chromatography on silica gel using ethylacetate/hexane (~1:1) as the
eluent.
General synthetic procedure for the preparation of compounds 7:
To an equimolar mixture of isatins (1) (1.0 mmol) and malononotrile (2) (1.0 mmol) in a 100 ml
round bottom flask, ZrO2 NPs (5 mol %) were added and mixed thoroughly. Then to this semi
liquid mixture hydrazines (1.0 mmol) and ethylacetoacetate (1.0 mmol) were added sequentially
and the resulting mixture was stirred at room temperature for 1ꢀ2 minutes. The progress of the
reaction was monitored by thin layer chromatography (TLC). At the end of the reaction,
ethylacetate was added to the reaction mixture and the product was extracted from the solid
support by ultrasonication. The ZrO2 NPs were separated by decantation method and the
separated organic phase was collected in another round bottom flask. Then the organic layer was
evaporated to get the crude mass. Pure products
through column chromatography on silica gel using ethylacetate/hexane (~1:1) as the eluent.
Recycle procedure of catalyst ZrO2 NPs
7 were obtained from isolated crude mass
:
At the end of the reactions for the preparation of 4a and 7a as described above, the
reaction mixtures were ultrasonicated with ethylacetate to extract the products 4a and 7a from
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the surface of the solid support and the solid ZrO2 NPs were separated easily from the reaction
mixture by simple decantation method. Then ZrO2 NPs were washed three times with
ethylacetate (3 x 5 mL), dried at room temperature under vacuum to eliminate residual solvents
and used for the next cycle. The reactions for the synthesis of 4a and 7a were performed upto
five times with the catalyst ZrO2 NPs recovered after each cycle.
Characterization Data of 4a-s:
4a: White amorphous solid (yield 84%); mp: 288ꢀ292oC. IR (KBr) 3389, 3299, 2950, 2195,
1
1743, 1165, 1648, 1482 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 10.24 (s, 1H), 7.11 (s, 2H,
NH2), 7.07ꢀ6.98 (m, 1H), 6.87ꢀ6.62 (m, 3H), 2.39 (s, 2H), 2.09ꢀ1.95 (m, 2H), 0.91 (s, 3H), 0.88
(s, 3H); 13C NMR (75 MHz, DMSOꢀd6) δC 195.3, 178.4, 164.5, 159.2, 142.5, 134.8, 128.6,
123.4, 122.1, 117.7, 111.2, 109.6, 58.0, 50.4, 47.2, 32.3, 28.0, 27.5; C19H17N3O3 (335.35): calcd.
C 68.05, H 5.11, N 12.53%; found C 67.80, H 5.05, N 12.38%.
4b: White amorphous solid (yield 88%); mp: 296ꢀ298oC. IR (KBr) 3364, 3248, 3172, 2193,
1
1718, 1680, 1472 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 10.54 (s, 1H), 7.31 (s, 2H, NH2),
7.19ꢀ7.16 (dd, J1 = 8.1 Hz, J2 = 1.5 Hz, 1H), 7.09 (s, 1H), 6.79 (d, J = 8.4 Hz, 1H), 2.54 (d, J =
13
7.5 Hz, 2H), 2.14 (s, 2H), 1.01 (s, 6H); C NMR (75 MHz, DMSOꢀd6) δC 195.5, 178.2, 165.0,
159.3, 141.5, 136.8, 128.5, 126.1, 123.7, 117.6, 111.0, 110.6, 57.2, 50.4, 47.5, 32.4, 27.9, 27.6;
C19H16ClN3O3 (369.80): calcd. C 61.71, H 4.36, N 11.36%; found C 61.50, H 4.25, N 11.19%.
4c: White amorphous solid (yield 80%); mp: >300oC. IR (KBr) 3358, 3242, 2189, 1740, 1695,
1
1483 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 10.54 (s, 1H), 7.31 (bs, 2H), 7.21 (bs, 2H), 6.78
(bs, 1H), 2.56 (d, J = 10.5 Hz, 2H), 2.16 (s, 2H), 1.03 (s, 6H); 13C NMR (75 MHz, DMSOꢀd6) δC
195.5, 178.1, 165.0, 159.3, 141.9, 137.2, 131.3, 126.4, 117.6, 113.7, 111.6, 110.6, 57.2, 50.4,
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47.5, 32.4, 28.0, 27.6; C19H16BrN3O3 (414.25): calcd. C 55.09, H 3.89, N 10.14%; found C
54.98, H 3.75, N 10.09%.
4d: Yellow amorphous solid (yield 81%); mp: 296ꢀ298oC. IR (KBr) 3364, 3248, 2185, 1735,
1
1683, 1539, 1465 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 11.19 (s, 1H), 8.16 (d, J = 6.9 Hz,
1H), 7.97 (s, 1H), 7.47 (s, 2H, NH2), 7.03 (d, J = 8.7 Hz, 1H), 2.70ꢀ2.56 (m, 2H), 2.17 (d, J = 5.7
Hz, 2H), 1.03 (s, 6H); 13C NMR (75 MHz, DMSOꢀd6) δC 195.7, 179.0, 165.6, 159.5, 149.1,
142.8, 135.8, 126.2, 119.2, 117.4, 110.2, 109.8, 56.4, 50.2, 47.4, 32.5, 28.1, 27.4; C19H16N4O5
(380.35): calcd. C 60.00, H 4.24, N 14.73%; found C 59.96, H 4.16, N 14.69%.
4e: White amorphous solid (yield 89%); mp: >300oC. IR (KBr) 3354, 3263, 2187, 1718, 1691,
1
1480 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 10.41 (s, 1H), 7.37ꢀ7.34 (dd, J1 = 7.8 Hz, J2 =
1.2 Hz, 1H), 7.19 (bs, 3H), 6.53 (d, J = 8.1 Hz, 1H), 2.35 (d, J = 8.7 Hz, 2H), 2.03 (s, 2H), 0.89
(s, 6H); 13C NMR (75 MHz, DMSOꢀd6) δC 195.4, 177.8, 164.9, 159.2, 142.3, 137.4, 137.1,
131.7, 117.5, 112.1, 110.4, 84.7, 57.2, 50.3, 47.2, 32.3, 27.9, 27.5; C19H16IN3O3 (461.25): calcd.
C 49.47, H 3.50, N 9.11%; found C 49.41, H 3.38, N 9.01%.
4f: White amorphous solid (yield 85%); mp: 292ꢀ294oC. IR (KBr) 3357, 3289, 3147, 2194,
1
1726, 1659, 1603, 1474 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 10.32 (s, 1H), 7.18 (s, 2H),
13
6.86ꢀ6.81 (m, 2H), 6.66 (m, 1H), 2.42 (s, 2H), 2.03 (s, 2H), 0.90 (s, 6H); C NMR (75 MHz,
DMSOꢀd6, F coupled 13C spectra) δC 195.3, 178.4, 164.8, 160.1, 159.2, 157.0, 138.6, 136.5,
117.5, 114.9, 114.6, 111.4, 111.1, 110.7, 110.3, 110.2, 57.3, 50.3, 47.7, 32.3, 27.4; C19H16FN3O3
(353.34): calcd. C 64.58, H 4.56, N 11.89%; found C 64.48, H 4.50, N 11.80%.
4g: White amorphous solid (yield 82%); mp: 298ꢀ300oC. IR (KBr) 3352, 3278, 2190, 1720,
1
1652, 1603, 1469 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 7.62ꢀ7.59 (m, 2H), 7.54ꢀ7.49 (m,
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1H), 7.38 (m, 4H), 7.23ꢀ7.16 (m, 2H), 7.11ꢀ6.98 (m, 1H), 6.67 (d, J = 7.5 Hz, 1H), 2.56 (s, 2H),
13
2.20 (d, J = 11.4 Hz, 2H), 1.06 (s, 3H), 1.04 (s, 3H); C NMR (75 MHz, DMSOꢀd6) δC 195.6,
176.5, 164.8, 159.2, 143.6, 135.1, 133.6, 130.0, 128.8, 128.5, 127.0, 123.8, 123.4, 117.6, 111.2,
108.9, 57.5, 50.2, 47.0, 32.4, 28.0, 27.4; C25H21N3O3 (411.45): calcd. C 72.98, H 5.14, N
10.21%; found C 72.89, H 5.08, N 10.13%.
4h: White amorphous solid (yield 90%); mp: 258ꢀ260oC. IR (KBr) 3360, 3265, 2185, 1718,
1
1670, 1605, 1472 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 7.29ꢀ7.24 (m, 3H), 7.07ꢀ6.93 (m,
3H), 3.14 (s, 3H), 2.58 (s, 2H), 2.12 (d, J = 7.2 Hz, 2H), 1.04 (s, 3H), 1.00 (s, 3H); 13C NMR (75
MHz, DMSOꢀd6) δC 195.2, 176.9, 164.6, 159.2, 143.9, 133.9, 128.7, 123.1, 122.8, 117.5, 111.1,
108.5, 57.6, 50.3, 46.8, 32.3, 27.9, 27.4, 26.7; C20H19N3O3 (349.38): calcd. C 68.75, H 5.48, N
12.03%; found C 68.67, H 5.38, N 11.95%.
4i: Yellowish white amorphous solid (yield 92%); mp: 232ꢀ236oC. IR (KBr) 3356, 3260, 3156,
2190, 1740, 1697, 1578, 1465 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 7.31 (s, 2H, NH2), 7.22
(t, J = 7.5 Hz, 1H), 7.07 (d, J = 6.9 Hz, 1H), 6.98 (m, 1H), 6.88 (d, J = 7.8 Hz, 1H), 5.87ꢀ5.80
(m, 1H), 5.44 (d, J = 17.4 Hz, 1H), 5.16 (d, J = 10.5 Hz, 1H), 4.32ꢀ4.24 (m, 2H), 2.59 (s, 2H),
13
2.14 (d, J = 9.9 Hz, 2H), 1.04 (s, 3H), 1.01 (s, 3H); C NMR (75 MHz, DMSOꢀd6) δC 195.2,
176.6, 164.7, 159.2, 143.0, 133.9, 132.1, 128.6, 123.2, 122.7, 117.6, 117.0, 111.0, 109.2, 57.6,
50.3, 46.9, 42.3, 32.3, 27.9, 27.4; C22H21N3O3 (375.42): calcd. C 70.38, H 5.64, N 11.19%; found
C 70.27, H 5.61, N 11.10%.
4j: Yellowish white amorphous solid (yield 87%); mp: 270ꢀ272oC. IR (KBr) 3364, 3256, 3160,
1
2187, 1715, 1695, 1480 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 7.55ꢀ7.53 (m, 2H), 7.41ꢀ7.31
(m, 5H), 7.18ꢀ7.13 (m, 2H), 7.04ꢀ7.01 (m, 1H), 6.74 (d, J = 7.8 Hz, 1H), 4.96 (m, 2H), 2.65 (s,
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2H), 2.25ꢀ2.20 (m, 2H), 0.96 (s, 6H); 13C NMR (75 MHz, DMSOꢀd6) δC 195.4, 177.1, 164.9,
159.4, 143.0, 136.6, 134.0, 128.8, 128.7, 127.5, 123.3, 123.0, 117.8, 111.1, 109.3, 57.7, 50.3,
47.0, 43.7, 32.4, 28.0, 27.4; C26H23N3O3 (425.47): calcd. C 73.39, H 5.45, N 9.88%; found C
73.28, H 5.41, N 9.79%.
4k: White amorphous solid (yield 88%); mp: 280ꢀ282oC. IR (KBr) 3360, 3250, 3172, 2192,
1
1720, 1690, 1475 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 7.15ꢀ7.08 (m, 3H), 6.95ꢀ6.81 (m,
3H), 3.59ꢀ3.58 (m, 2H), 2.37 (s, 2H), 2.09ꢀ1.91 (m, 2H), 1.04 (t, J = 6.9 Hz, 3H), 0.92 (s, 3H),
0.90 (s, 3H); 13C NMR (75 MHz, DMSOꢀd6) δC 194.9, 176.1, 164.3, 158.9, 142.5, 133.9, 128.4,
123.0, 122.3, 117.1, 110.8, 108.3, 57.4, 50.0, 46.4, 34.4, 32.0, 27.7, 27.1, 12.1; C21H21N3O3
(363.40): calcd. C 69.41, H 5.82, N 11.56%; found C 69.38, H 5.73, N 11.48%.
4l: Yellowish white amorphous solid (yield 91%); mp: 244ꢀ246oC. IR (KBr) 3317, 3237, 3209,
3155, 2949, 2189, 1724, 1661, 1599 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 7.52ꢀ7.48 (m, 4H),
7.36 (s, 2H, NH2), 7.18ꢀ7.09 (m, 2H), 7.00ꢀ6.95 (m, 1H), 6.74 (d, J = 7.50 Hz, 1H), 4.90 (s, 2H),
13
2.62 (s, 2H), 2.25ꢀ2.10 (m, 2H), 1.05 (s, 3H), 1.02 (s, 3H); C NMR (75 MHz, DMSOꢀd6) δC
195.7, 177.4, 165.2, 159.6, 143.0, 136.4, 134.2, 131.9, 130.2, 129.0, 123.7, 123.3, 121.0, 118.0,
111.3, 109.5, 57.9, 50.6, 47.2, 43.4, 32.6, 28.3, 27.7; C26H22BrN3O3 (504.37): calcd. C 61.91, H
4.40, N 8.33%; found C 61.82, H 4.37, N 8.25%.
4m: White amorphous solid (yield 86%); mp: 184ꢀ186oC. IR (KBr) 3381, 3281, 3137, 2914,
2189, 1706, 1671, 1591, 1465 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 7.14ꢀ7.08 (m, 3H), 6.93ꢀ
6.84 (m, 3H), 3.54ꢀ3.49 (m, 2H), 3.23 (bs, 4H), 2.38 (s, 2H), 2.00 (d, J = 11.4 Hz, 2H), 1.48ꢀ1.46
(m, 2H), 1.12ꢀ1.06 (bs, 14 H), 0.91 (s, 3H), 0.88 (s, 3H), 0.73 (t, 3H); 13C NMR (75 MHz,
DMSOꢀd6) δC 195.1, 176.7, 164.6, 159.3, 143.5, 134.1, 128.7, 123.3, 122.5, 117.5, 111.2, 107.7,
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57.8, 50.4, 46.8, 32.3, 31.7, 29.4, 29.3, 29.1, 28.0, 27.5, 27.3, 26.7, 22.5, 14.4; C31H41N3O3
(503.67): calcd. C 73.92, H 8.20, N 8.34%; found C 73.86, H 8.15, N 8.28%.
4n: Yellowish white amorphous solid (yield 84%); mp: 228ꢀ230oC. IR (KBr) 3379, 3291, 3155,
2933, 2189, 1706, 1661, 1599, 1482 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 7.32ꢀ7.26 (m, 3H),
7.09ꢀ7.00 (m, 3H), 4.59ꢀ4.43 (m, 2H), 3.25 (s, 1H), 2.58 (s, 2H), 2.19ꢀ2.06 (m, 2H), 1.03 (s, 3H),
1.00 (s, 3H); 13C NMR (75 MHz, DMSOꢀd6) δC 195.2, 176.1, 164.7, 159.3, 142.2, 133.8, 128.7,
123.4, 123.2, 117.3, 111.0, 109.3, 78.1, 74.8, 57.3, 50.3, 46.8, 32.4, 29.6, 28.0, 27.5; C22H19N3O3
(373.40): calcd. C 70.76, H 5.13, N 11.25%; found C 70.69, H 5.01, N 11.18%.
4o: White amorphous solid (yield 92%); mp: 252ꢀ254oC. IR (KBr) 3390, 3272, 2923, 2189,
2126, 1716, 1692, 1591, 1478 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 7.21ꢀ7.11 (m, 3H), 7.05ꢀ
13
6.92 (m, 3H), 4.49ꢀ4.34 (m, 2H), 3.25 (s, 1H), 2.58 (bs, 2H), 2.13 (bs, 2H), 1.84 (bs, 2H); C
NMR (75 MHz, DMSOꢀd6) δC 194.9, 175.9, 166.2, 158.8, 141.8, 133.6, 128.3, 123.2, 122.8,
116.9, 111.7, 108.8, 77.8, 74.4, 57.0, 46.5, 36.3, 29.2, 26.8, 19.8; C20H15N3O3 (345.35): calcd. C
69.56, H 4.38, N 12.17%; found C 69.48, H 4.31, N 12.10%.
4p: Yellowish white amorphous solid (yield 88%); mp: 274ꢀ276oC. IR (KBr) 3424, 3281, 3165,
2958, 2189, 1716, 1581, 1474 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 7.33 (s, 2H, NH2), 7.24
(bs, 1H), 7.21 (s, 1H), 6.85 (d, J = 8.1 Hz, 1H), 5.82ꢀ5.72 (m, 1H), 5.38 (d, J = 17.1 Hz, 1H),
5.11 (d, J = 10.5 Hz, 1H), 4.32ꢀ4.26 (m, 2H), 2.64ꢀ2.60 (bs, 2H), 2.22ꢀ2.18 (bs, 2H), 1.90 (bs,
13
2H); C NMR (75 MHz, DMSOꢀd6) δC 195.3, 176.2, 166.8, 158.9, 141.5, 135.8, 131.5, 128.1,
126.5, 123.4, 117.2, 116.8, 111.2, 110.3, 56.6, 46.8, 42.1, 36.3, 26.8, 19.7; C20H16ClN3O3
(381.81): calcd. C 62.91, H 4.22, N 11.01%; found C 62.85, H 4.15, N 10.92%.
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4q: Yellowish white amorphous solid (yield 82%); mp: 258ꢀ260oC. IR (KBr) 3315, 3236, 3150,
2946, 2192, 1724, 1692, 1590, 1465 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 7.47ꢀ7.40 (m, 4H),
7.28 (s, 2H, NH2), 7.12ꢀ7.06 (m, 2H), 6.94ꢀ6.89 (m, 1H), 6.68 (d, J = 7.5 Hz, 1H), 4.84 (s, 2H),
13
2.65 (bs, 2H), 2.22ꢀ2.20 (bs, 2H), 1.94ꢀ1.90 (bs, 2H); C NMR (75 MHz, DMSOꢀd6) δC 195.2,
176.8, 166.5, 158.8, 142.4, 135.8, 133.7, 131.2, 129.6, 128.3, 123.2, 122.7, 120.4, 117.4, 111.7,
108.7, 57.3, 46.7, 42.7, 36.3, 26.8, 19.8; C24H18BrN3O3 (476.32): calcd. C 60.52, H 3.81, N
8.82%; found C 60.48, H 3.75, N 8.78%.
4r: White amorphous solid (yield 89%); mp: 294ꢀ296oC. IR (KBr) 3348, 3272, 2195, 1718,
1
1675, 1605, 1470 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 7.58ꢀ7.54 (m, 2H), 7.46ꢀ7.35 (m,
5H), 7.15ꢀ7.13 (m, 2H), 7.02ꢀ6.97 (m, 1H), 6.62 (d, J = 7.8 Hz, 1H), 2.65 (bs, 2H), 2.24 (bs, 2H),
1.91 (bs, 2H); 13C NMR (75 MHz, DMSOꢀd6) δC 195.8, 176.7, 166.8, 159.1, 143.7, 135.2, 133.8,
130.1, 128.9, 128.5, 127.1, 124.0, 123.5, 117.7, 112.4, 108.9, 57.7, 47.1, 36.7, 27.1, 20.2;
C23H17N3O3 (383.39): calcd. C 72.05, H 4.47, N 10.96%; found C 71.89, H 4.39, N 10.88%.
4s: White amorphous solid (yield 90%); mp: 282ꢀ284oC. IR (KBr) 3361, 3289, 3147, 2199,
1716, 1671, 1599, 1474 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 7.48 (d, J = 6.9 Hz, 2H), 7.41ꢀ
7.39 (m, 2H), 7.34ꢀ7.29 (m, 5H), 6.66 (d, J = 8.1 Hz, 1H), 2.69 (bs, 2H), 2.28 (bs, 2H), 1.99 (bs,
13
2H); C NMR (75 MHz, DMSOꢀd6) δC 194.2, 175.3, 165.8, 157.7, 140.8, 134.9, 134.6, 132.6,
129.8, 127.2, 126.1, 125.9, 124.9, 116.1, 113.2, 110.0, 109.6, 55.5, 45.7, 42.2, 35.1, 25.7, 18.5;
C24H18BrN3O3 (476.32): calcd. C 60.52, H 3.81, N 8.82%; found C 60.48, H 3.75, N 8.71%.
Characterization Data of 7a-w:
7a: White amorphous solid (yield 90%); mp: 278ꢀ280oC. IR (KBr) 3338, 3136, 2182, 1711,
1
1643, 1584 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 12.26 (s, 1H), 10.57 (s, 1H), 7.21 (s, 2H,
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NH2), 7.17 (s, 1H), 7.01ꢀ6.92 (m, 2H), 6.86 (d, J =7.5 Hz, 1H), 1.48 (s, 3H); 13C NMR (75 MHz,
DMSOꢀd6) δC 178.4, 162.9, 155.6, 141.9, 135.1, 133.1, 129.3, 124.9, 122.9, 119.1, 110.1, 95.8,
55.6, 47.7, 9.3; C15H11N5O2 (293.28): calcd. C 61.43, H 3.78, N 23.88%; found C 61.38, H 3.65,
N 23.78%.
7b: White amorphous solid (yield 86%); mp: 294ꢀ296oC. IR (KBr) 3386, 3348, 3141, 2182,
1
1715, 1644, 1582 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 12.32 (s, 1H), 10.73 (s, 1H), 7.27
13
(bs, 3H), 7.11 (s, 1H), 6.90 (d, J =8.1 Hz, 1H), 1.56 (s, 3H); C NMR (75 MHz, DMSOꢀd6) δC
178.1, 162.9, 155.6, 140.8, 135.2, 129.3, 126.9, 125.0, 119.0, 111.6, 95.1, 55.0, 48.0, 9.4;
C15H10ClN5O2 (327.72): calcd. C 54.97, H 3.08, N 21.37%; found C 54.88, H 2.97, N 21.28%.
7c: White amorphous solid (yield 87%); mp: 278ꢀ280oC. IR (KBr) 3323, 3148, 2195, 1730,
1637, 1610, 1593 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 12.31 (s, 1H), 10.62 (s, 1H), 7.27 (s,
13
2H, NH2), 7.10ꢀ7.04 (m, 1H), 7.00ꢀ6.97 (m, 1H), 6.91ꢀ6.87 (m, 1H), 1.56 (s, 3H); C NMR (75
MHz, DMSOꢀd6, F coupled 13C spectra) δC 178.4, 162.9, 157.4, 155.6, 147.8, 138.2, 135.2,
135.0, 119.0, 116.0, 115.7, 112.8, 112.5, 111.1, 95.3, 55.2, 48.3, 9.4; C15H10FN5O2 (311.27):
calcd. C 57.88, H 3.24, N 22.50%; found C 57.79, H 3.15, N 22.43%.
7d: Brown amorphous solid (yield 84%); mp: 282ꢀ284oC. IR (KBr) 3348, 3138, 2181, 1712,
1
1644, 1609, 1582 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 12.24 (bs, 1H), 10.66 (s, 1H), 7.32
13
(d, J = 7.5 Hz, 1H), 7.20 (s, 2H, NH2), 7.14 (s, 1H), 6.78 (d, J = 7.8 Hz, 1H), 1.48 (s, 3H); C
NMR (75 MHz, DMSOꢀd6) δC 177.9, 162.9, 155.5, 141.2, 135.5, 135.2, 132.1, 127.7, 119.0,
114.5, 112.1, 95.1, 55.0, 47.9, 9.4; C15H10BrN5O2 (372.17): calcd. C 48.41, H 2.71, N 18.82%;
found C 48.33, H 2.65, N 18.78%.
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7e: White amorphous solid (yield 92%); mp: >300oC. IR (KBr) 3399, 3346, 3127, 2180, 1713,
1
1643, 1583 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 12.33 (s, 1H), 10.73 (s, 1H), 7.59 (d, J =
8.1 Hz, 1H), 7.34 (s, 1H), 7.29 (s, 2H, NH2), 6.77 (d, J = 8.4 Hz, 1H), 1.59 (s, 3H); 13C NMR (75
MHz, DMSOꢀd6) δC 177.8, 162.9, 155.6, 141.7, 138.0, 135.8, 135.2, 133.2, 119.0, 112.6, 95.3,
85.7, 55.1, 47.8, 9.5; C15H10IN5O2 (419.17): calcd. C 42.98, H 2.40, N 16.71%; found C 42.91, H
2.35, N 16.65%.
7f: White amorphous solid (yield 80%); mp: 228ꢀ232oC. IR (KBr) 3449, 3306, 3189, 2187,
1
1690, 1646, 1592 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 12.40 (s, 1H), 7.64ꢀ7.59 (m, 2H),
7.52ꢀ7.48 (m, 1H), 7.43ꢀ7.28 (m, 5H), 7.21ꢀ7.12 (m, 2H), 6.80 (d, J = 7.5 Hz, 1H), 1.65 (s, 3H);
13C NMR (75 MHz, DMSOꢀd6) δC 176.0, 162.5, 155.3, 142.6, 135.1, 134.2, 131.8, 129.9, 129.2,
128.4, 126.6, 124.9, 123.9, 118.5, 109.1, 95.1, 55.2, 47.3, 9.2; C21H15N5O2 (369.37): calcd. C
68.28, H 4.09, N 18.96%; found C 68.19, H 3.95, N 18.88%.
7g: Yellowish white amorphous solid (yield 83%); mp: 240ꢀ244oC. IR (KBr) 3457, 3138, 2195,
1
1713, 1648, 1326, 1589 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 12.40 (s, 1H), 11.35 (s, 1H),
13
8.25ꢀ8.22 (m, 1H), 7.92 (s, 1H), 7.41 (s, 2H, NH2), 7.15 (d, J = 8.7 Hz, 1H), 1.59 (s, 3H); C
NMR (75 MHz, DMSOꢀd6) δC 178.8, 163.1, 155.7, 148.2, 143.5, 135.4, 134.2, 126.7, 120.6,
118.8, 110.6, 94.5, 54.4, 47.9, 9.5; C15H10N6O4 (338.27): calcd. C 53.26, H 2.98, N 24.84%;
found C 53.18, H 2.85, N 24.78%.
7h: Yellowish white amorphous solid (yield 90%); mp: 244ꢀ246oC. IR (KBr) 3392, 3328, 3167,
1
2194, 1697, 1641, 1589, 1494, 1403 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 12.32 (s, 1H),
7.35ꢀ7.29 (m, 3H), 7.13ꢀ7.03 (m 3H), 5.90ꢀ5.81 (m, 1H), 5.32ꢀ5.18 (m, 2H), 4.44ꢀ4.30 (m, 2H),
1.48 (s, 3H); 13C NMR (75 MHz, DMSOꢀd6) δC 176.5, 163.0, 155.7. 142.5, 135.2, 132.3, 132.0,
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129.4, 124.8, 123.6, 119.0, 117.6, 109.7, 95.6, 55.5, 47.4, 42.3, 9.5; C18H15N5O2 (333.34): calcd.
C 64.86, H 4.54, N 21.01%; found C 64.78, H 4.45, N 20.88%.
7i: Yellow amorphous solid (yield 84%); mp: 250ꢀ254oC. IR (KBr) 3306, 3177, 2195, 1698,
1
1639, 1595, 1493 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 12.28 (bs, 1H), 7.34ꢀ7.23 (m, 3H),
13
7.14ꢀ7.02 (m, 3H), 3.67 (bs, 2H), 1.63ꢀ1.59 (m, 2H), 1.45 (s, 3H), 0.92 (m, 3H); C NMR (75
MHz, DMSOꢀd6) δC 176.6, 162.8, 155.6, 142.7, 135.0, 132.3, 129.3, 124.6, 123.3, 118.8, 109.1,
95.6, 55.5, 47.2, 41.5, 21.0, 11.4, 9.3; C18H17N5O2 (335.35): calcd. C 64.47, H 5.11, N 20.88%;
found C 64.38, H 5.05, N 20.72%.
7j: Yellowish white amorphous solid (yield 86%); mp: 262ꢀ264oC. IR (KBr) 3315, 3227, 2182,
1718, 1657, 1595, 1517 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 12.31 (bs, 1H), 7.36ꢀ7.29 (bs,
13
3H), 7.10 (bs, 3H), 3.21(s, 3H), 1.46 (s, 3H); C NMR (75 MHz, DMSOꢀd6) δC 176.7, 163.0,
155.6, 143.4, 135.1, 132.3, 129.5, 124.6, 123.6, 119.0, 109.1, 95.7, 55.2, 47.4, 26.7, 9.3;
C16H13N5O2 (307.30): calcd. C 62.53, H 4.26, N 22.79%; found C 62.48, H 4.15, N 22.68%.
7k: White amorphous solid (yield 92%); mp: 260ꢀ262oC. IR (KBr) 3385, 3337, 3139, 2189,
1702, 1638, 1589, 1495 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 12.27 (bs, 1H), 7.34ꢀ7.30 (m,
1H), 7.22 (s, 2H, NH2), 7.13 (d, J = 7.8 Hz, 1H), 7.06ꢀ7.02 (m, 2H), 3.76ꢀ3.73 (m, 2H), 1.46 (s,
3H), 1.16 (t, J = 6.6 Hz, 3H); 13C NMR (75 MHz, DMSOꢀd6) δC 176.3, 162.9, 155.7, 142.3,
135.2, 132.6, 129.4, 124.8, 123.4, 118.8, 109.1, 95.6, 55.5, 47.3, 34.9, 13.0, 9.4; C17H15N5O2
(321.33): calcd. C 63.54, H 4.71, N 21.79%; found C 63.48, H 4.63, N 21.70%.
7l: Yellowish white amorphous solid (yield 88%); mp: 254ꢀ258oC. IR (KBr) 3328, 3163, 2923,
2188, 1715, 1643, 1540, 1470 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 12.33 (s, 1H), 7.43 (d, J
= 6.9 Hz, 2H), 7.36ꢀ7.26 (m, 6H), 7.15ꢀ7.04 (m, 3H), 5.06ꢀ4.91 (m, 2H), 1.38 (s, 3H); 13C NMR
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(75 MHz, DMSOꢀd6) δC 177.1, 163.1, 155.7, 142.4, 136.5, 135.2, 132.3, 129.4, 129.0, 127.9,
124.8, 123.7, 119.1, 109.8, 95.6, 55.4, 47.5, 43.6, 9.3; C22H17N5O2 (383.40): calcd. C 68.92, H
4.47, N 18.27%; found C 68.88, H 4.35, N 18.21%.
7m: White amorphous solid (yield 89%); mp: 258ꢀ262oC. IR (KBr) 3397, 3331, 3272, 2914,
1
2189, 2128, 1716, 1644, 1591, 1482 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 12.29 (s, 1H),
7.39ꢀ7.34 (m, 1H), 7.28 (s, 2H, NH2), 7.18 (d, J = 7.8 Hz, 1H), 7.13ꢀ7.09 (m, 2H), 4.68ꢀ4.49 (m,
13
2H), 3.25 (s, 1H), 1.46 (s, 3H); C NMR (75 MHz, DMSOꢀd6) δC 176.2, 163.1, 155.5, 141.4,
135.4, 132.2, 129.4, 124.8, 124.0, 118.8, 109.8, 95.6, 78.3, 74.8, 54.9, 47.4, 29.5, 9.5;
C18H13N5O2 (331.32): calcd. C 65.25, H 3.95, N 21.14%; found C 65.18, H 3.88, N 21.08%.
7n: Yellowish brown amorphous solid (yield 94%); mp: 224ꢀ226oC. IR (KBr) 3342, 3130, 2184,
1
1715, 1646, 1590 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 10.72 (s, 1H), 7.75 (d, J = 7.8 Hz,
2H), 7.56 (s, 2H, NH2), 7.50ꢀ7.45 (m, 2H), 7.33ꢀ7.22 (m, 2H), 7.14 (d, J = 7.2 Hz, 1H), 7.01ꢀ
13
6.96 (m, 1H), 6.91 (d, J = 7.8 Hz, 1H), 1.50 (s, 3H); C NMR (75 MHz, DMSOꢀd6) δC 177.9,
161.4, 145.3, 144.3, 142.0, 137.6, 132.5, 129.8, 129.6, 126.9, 125.3, 123.0, 120.5, 118.3, 110.2,
96.7, 56.6, 48.2, 12.1; C21H15N5O2 (369.37): calcd. C 68.28, H 4.09, N 18.96%; found C 68.19,
H 4.01, N 18.88%.
7o: Yellowish brown amorphous solid (yield 83%); mp: 140ꢀ142oC. IR (KBr) 3451, 3299, 3157,
2923, 2197, 2119, 1706, 1653, 1530, 1482 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 7.80 (d, J =
7.5 Hz, 2H), 7.69 (s, 2H, NH2), 7.55ꢀ7.50 (m, 2H), 7.46ꢀ7.34 (m, 2H), 7.31ꢀ7.24 (m, 2H), 7.16 (t,
J = 7.2 Hz, 1H), 4.76ꢀ4.57 (m, 2H), 3.32 (s, 1H), 1.51 (s, 3H); 13C NMR (75 MHz, DMSOꢀd6) δC
175.6, 161.6, 145.3, 144.4, 141.5, 137.6, 131.7, 129.8, 127.0, 125.2, 124.1, 120.6, 118.0, 110.0,
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96.5, 78.1, 75.0, 55.8, 47.9, 29.7, 12.3; C24H17N5O2 (407.42): calcd. C 70.75, H 4.21, N 17.19%;
found C 70.69, H 4.15, N 17.10%.
7p: White amorphous solid (yield 87%); mp: 158ꢀ162oC. IR (KBr) 3317, 3192, 2914, 2199,
1716, 1661, 1599, 1492 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 12.31 (s, 1H), 7.51 (d, J = 8.4
13
Hz, 2H), 7.37ꢀ7.26 (m, 5H), 7.09ꢀ7.03 (m, 3H), 4.94ꢀ4.91 (m, 2H), 1.34 (s, 3H); C NMR (75
MHz, DMSOꢀd6) δC 177.1, 163.0, 155.7, 142.2, 136.1, 135.2, 132.3, 131.9, 130.3, 129.4, 124.9,
123.8, 121.1, 119.1, 109.7, 95.5, 55.4, 47.4, 43.0, 9.4; C22H16BrN5O2 (462.29): calcd. C 57.16, H
3.49, N 15.15%; found C 57.09, H 3.41, N 15.09%.
7q: Yellowish brown amorphous solid (yield 85%); mp: 190ꢀ192oC. IR (KBr) 3299, 3182, 2914,
2189, 1706, 1644, 1618 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 7.82ꢀ7.77 (m, 2H), 7.68 (s, 2H,
NH2), 7.56ꢀ7.48 (m, 4H), 7.42ꢀ7.24 (m, 5H), 7.13ꢀ7.08 (m, 2H), 5.02ꢀ4.91 (m, 2H), 1.36 (s, 3H);
13C NMR (75 MHz, DMSOꢀd6) δC 176.6, 161.3, 145.4, 144.3, 142.3, 137.6, 136.0, 131.9, 131.8,
130.4, 129.9, 127.1, 125.3, 124.0, 121.2, 120.6, 118.4, 109.9, 96.4, 56.3, 47.9, 43.1, 12.2;
C28H20BrN5O2 (538.39): calcd. C 62.46, H 3.74, N 13.01%; found C 62.38, H 3.65, N 12.88%.
7r: Yellow amorphous solid (yield 78%); mp: 178ꢀ180oC. IR (KBr) 3391, 3324, 3155, 2195,
1692, 1637, 1585, 1494 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 7.78 (d, J = 7.8 Hz, 2H), 7.70
(s, 2H, NH2), 7.53ꢀ7.48 (m, 2H), 7.44ꢀ7.32 (m, 3H), 7.10 (d, J = 8.1 Hz, 1H), 5.89ꢀ5.80 (m, 1H),
5.33ꢀ5.19 (m, 2H), 4.48ꢀ4.32 (m, 2H), 1.52 (s, 3H); 13C NMR (75 MHz, DMSOꢀd6) δC 175.4,
161.2, 145.2, 143.8, 141.0, 137.3, 133.6, 131.2, 129.5, 129.3, 127.6, 126.7, 125.1, 120.4, 117.9,
117.6, 111.1, 95.5, 55.4, 47.7, 42.2, 12.0; C24H18ClN5O2 (443.88): calcd. C 64.97, H 4.09, N
15.78%; found C 64.89, H 4.02, N 15.65%.
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7s: White amorphous solid (yield 86%); mp: 272ꢀ274oC. IR (KBr) 3390, 3320, 3158, 2199,
1
1697, 1643, 1588, 1493 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 12.37 (s, 1H), 7.42ꢀ7.36 (m,
3H), 7.23 (s, 1H), 7.08 (d, J = 8.4 Hz, 1H), 5.87ꢀ5.79 (m, 1H), 5.31ꢀ5.18 (m, 2H), 4.45ꢀ4.35 (m,
13
2H), 1.54 (s, 3H); C NMR (75 MHz, DMSOꢀd6) δC 174.7, 161.5, 154.1, 139.7, 133.7, 132.8,
130.1, 127.8, 126.2, 123.4, 117.3, 116.2, 109.7, 93.3, 53.2, 46.1, 40.8, 8.0; C18H14ClN5O2
(367.78): calcd. C 58.78, H 3.84, N 19.04%; found C 58.70, H 3.79, N 18.88%.
7t: White amorphous solid (yield 82%); mp: 196ꢀ198oC. IR (KBr) 3350, 3268, 2923, 2187,
2126, 1710, 1653, 1589, 1479 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 7.72 (d, J = 6.6 Hz, 2H),
7.65 (s, 2H, NH2), 7.58ꢀ7.54 (m, 2H), 7.46 (bs, 2H), 7.30 (bs, 1H), 7.15 (d, J = 6.6 Hz, 1H),
13
4.69ꢀ4.52 (m, 2H), 3.28 (s, 1H), 1.48 (s, 3H); C NMR (75 MHz, DMSOꢀd6) δC 175.1, 161.5,
145.3, 144.0, 140.6, 137.4, 134.1, 132.4, 129.7, 128.1, 126.9, 120.6, 117.8, 115.9, 111.9, 95.7,
77.6, 75.1, 55.2, 47.9, 29.7, 12.2; C24H16BrN5O2 (486.32): calcd. C 59.27, H 3.32, N 14.40%;
found C 59.18, H 3.25, N 14.38%.
7u: White amorphous solid (yield 88%); mp: 200ꢀ204oC. IR (KBr) 3361, 3299, 3182, 3129,
1
2968, 2189, 1698, 1644, 1599, 1492 cm–1; H NMR (300 MHz, DMSOꢀd6) δH 12.32 (s, 1H),
7.38ꢀ7.33 (m, 1H), 7.28 (s, 2H, NH2), 7.18 (d, J = 7.8 Hz, 1H), 7.12ꢀ7.05 (m, 2H), 3.77 (bs, 2H),
3.59ꢀ3.56 (m, 2H), 1.91ꢀ1.86 (m, 2H), 1.77ꢀ1.75 (bs, 2H), 1.48 (s, 3H); 13C NMR (75 MHz,
DMSOꢀd6) δC 176.6, 162.7, 155.6, 142.5, 136.9, 132.2, 129.3, 124.7, 123.4, 118.7, 109.1, 95.4,
55.4, 47.2, 34.7, 29.7, 26.0, 25.6, 9.3; C19H18BrN5O2 (428.28): calcd. C 53.28, H 4.24, N
16.35%; found C 53.20, H 4.15, N 16.28%.
7v: Brownish white amorphous solid (yield 80%); mp: 228ꢀ232oC. IR (KBr) 3451, 3326, 3192,
2189, 1706, 1653, 1572, 1519 cm–1; 1H NMR (300 MHz, DMSOꢀd6) δH 10.74 (s, 1H), 7.76 (d, J
29