Synthesis and synergistic, additive inhibitory effects of novel spiro derivatives against ringworm infections

Article abstract of DOI:10.1134/S106816201303014X

An environmentally benign solvent free synthesis of various spiro-1,4-dihydropyridines (1,4-DHPs) incorporating 2-oxindole/piperidines is performed in 5-8 min with reasonable purity in 80-90% yield under microwave irradiation using montmorillonite KSF as

Full text of DOI:10.1134/S106816201303014X

ISSN 1068ꢀ1620, Russian Journal of Bioorganic Chemistry, 2013, Vol. 39, No. 3, pp. 318–328. © Pleiades Publishing, Ltd., 2013.
Synthesis and Synergistic, Additive Inhibitory Effects of Novel Spiro
Derivatives against Ringworm Infections1
2
Gajanand Sharmaa, , Richa Sharmab, Meenakshi Sharmac, Anshu Dandiad, and Preeti Bansala
a Department of Chemical Sciences, Suresh Gyan Vihar University, Jaipur
b Department of Biotechnology and Food Science, Jayoti Vidyapeeth Women’s University, Jaipur
c Department of Botany, University of Rajasthan, Jaipur
d Anshu Dandia, Centre of Advanced Studies, Department of Chemistry, University of Rajasthan
Received May 14, 2012; in final form, November 12, 2012
Abstract—An environmentally benign solvent free synthesis of various spiroꢀ1,4ꢀdihydropyridines (1,4ꢀ
DHPs) incorporating 2ꢀoxindole/piperidines is performed in 5–8 min with reasonable purity in 80–90%
yield under microwave irradiation using montmorillonite KSF as an inorganic solid support. The reaction is
found to be general with respect to various cyclic carbonyl compounds, e.g. cyclohexanone, substituted
indoleꢀ2,3ꢀdione, and piperidinone derivatives. In our study, these compounds were also found effective
against dermatophytes and other fungal organisms. Our results suggest that novel spiro derivatives can be used
for the treatment of dermatophytosis or ringworm infections.
Keywords: montmorillonite KSF, microwave irradiation, MCRs, spiroꢀ1,4ꢀDHPs
DOI: 10.1134/S106816201303014X
2 1
The rapid assembly of molecular diversity is an logical activities such as HIV protease inhibition [12,
important goal of synthetic organic chemistry and one 13], MDR reversal [14–16], radioprotection [17],
of key paradigms of modern drug discovery. One vasodilaton [18], antitumor, bronchodilator, and
approach to address this challenge involves the use of hepatoprotective activities [19]. A large number of
multicomponent reactions (MCRs), in which three or publications is available on the synthesis of these bioꢀ
dynamic scaffolds [20].
more reactants are combined together in a single reacꢀ
tion flask to generate a product incorporating most of
the atoms contained in the starting material. Due to
their intrinsic atom economy, selectivity, simple proceꢀ
dures and equipment, time and energy saving, as well as
environmental friendliness, MCRs are gaining much
importance in both academia and industry [1–4].
Spirooxindole derivatives are also becoming key
building blocks for drug discovery as these templates
have been shown to exhibit a variety of interesting bioꢀ
logical activities, such as antioneoplastic [21], antibiꢀ
otic [22], cytostatic [23], monoamine transporter
inhibiting [24], bradykinin antagonist [25], and cell
cycle inhibiting activities [26]. Due to their structure,
they interact with a wide range of receptors and this
activity has resulted in significant interest in developꢀ
ing efficient methods to prepare spirocompounds. On
the other hand, spiropiperidines have also received
great attention because of their promising therapeutic
applications [27–30]. The spiro(indolineꢀ3,4'ꢀpiperiꢀ
dine) scaffold is a key structural feature in MKꢀ0677,
a potent peptidomimetic growth hormone secretaꢀ
gogue (GHS) [31], a serineꢀderived NK1 antagonist,
and a potent and selective melanocortin subtypeꢀ4
(MCꢀ4) receptor agonist [32]. It is also found in oxyꢀ
tocin, somatostatin, tachykinines, anaphylatoxin
chemotactic receptor ligands, and is considered as a
privileged structure for general Gꢀprotein coupled
receptor (GPCR) ligands [33].
Amlodipine [5, 8] is comparable—from a dynamic
point of view—to and nifedipine [6] and is in late stage
clinical evaluation for the onceꢀdaily treatment of
angina and hypertension [7]. Recent structureꢀactivity
assessment of a new generation of 1,4ꢀDHPs indicates
that the presence of oxypropanolamine moiety on
phenyl ring at positionꢀ4 of the DHP nucleus imparts
the agents with
βꢀ or αꢀ/βꢀadrenoceptor blocking
activities [9, 10]. In addition, Barnidipine and Furnidꢀ
ipine are well tolerated, as are other 1,4ꢀDHP calcium
channel anatagonists and vasodilators; headache,
flushing, and peripheral oedema account for most of
the adverse events reported [11]. Oedema is less freꢀ
quent than with amlodipine and nitredipine. Also its
use is not associated with reflex tachychardia. 1,4ꢀ
Dihydropyridine derivatives possess a variety of bioꢀ
To the best of our knowledge, no work has been
reported on the multicomponent synthesis of spiroꢀ
1,4ꢀDHPs incorporating Nꢀsubstituted piperidine or
1
The article is published in the original.
Corresponding author: eꢀmail: gnsharma2020@gmail.com.
2
318

SYNTHESIS AND SYNERGISTIC, ADDITIVE INHIBITORY EFFECTS
319
2ꢀoxindoline motif in a single molecular framework. moiety into a single framework may result in the proꢀ
Hence, promoted by these observations and in continꢀ duction of novel heterocycles with enhanced/altered
uation of our earlier interest on the green chemical bioactivity. Therefore, we herein report novel spiro
synthesis of biodynamic spiro and annulated derivaꢀ derivatives combining heterocyclic moieties with 1,4ꢀ
tives [34, 35] using nonꢀtraditional approach, an DHPs by the multicomponent reaction of cyclic carꢀ
attempt has been made to synthesize various spiroꢀ bonyl compounds
(1), βꢀketoester (2), and substituted
1,4ꢀDHP derivatives with the assumption that the anilines ( ), as depicted in Scheme, using environꢀ
3
incorporation of more than one bioactive heterocyclic mentally benign methodologies.
COOC2H5 CH3
2
H
H
O
O
+
NH2
O
1
X
3
COOC2H5 CH3
Mont. KSF MW
COOC2H5
CH3
N
X
CH3
COOC2H5
4
O
O
O
O
N
Y
=
O
N
H
O
1
N
CH3
CH2Ph
4d; X = 4ꢀCl, Y = H
4a; X = 4ꢀOC2H5 4b; X = 4ꢀCH3
4c; X = 4ꢀCl
4e; X = H Y = 5ꢀCH3
4f; X = 4ꢀCH3, Y = 4ꢀCl
Scheme.
A series of novel Nꢀsubstituted spiroꢀ1,4ꢀdihydropyꢀ under microwave irradiation and conventionally.
ridines (4a 4f) have been synthesized in one pot under However, the yield of the product was low when the
–
microwave irradiation using solventꢀfree conditions reaction was carried out conventionally in ethanol.
(Table 1). The reaction was performed under different The reaction was also performed under neat condiꢀ
conditions to find out the best method giving product in tions without adding any solvent or support, which
higher yield with operational simplicity. In the present could be expected to be the most economical method.
investigation, we study the synthesis of 3ꢀ(4ꢀethoxypheꢀ The reaction proceeded efficiently (~100% converꢀ
nyl)ꢀ2,4ꢀdimethylꢀ3ꢀazaspiro[5.5]undecaꢀ1,4ꢀdieneꢀ1,5ꢀ sion, indicated by TLC) but the yield of isolated crysꢀ
dicarboxylic acid diethyl ester (4a) via multicomponent talline product decreased to 72% due to the tedious
reaction of cyclohexanone
(1),
βꢀketoester (2), and
pꢀ
workꢀup procedure which requires trituration with
phenatidine (
in Table 2.
3
) varying the reaction parameters as shown petroleum ether followed by crystallization from
methanol.
Results reported in Table 2 evidence that the mulꢀ
ticomponent reaction of ( ), ( ), and (3a) occurred studied using different types of inorganic solid supꢀ
successfully in ethanol without using any catalyst both ports, e. g., montmorillonite KSF, neutral alumina,
To further improve the procedure, reaction was also
1
2
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320
SHARMA et al.
Table 1. Novel spiroꢀ1,4ꢀDHP derivatives
Reactants
Entry
Product
(1
)
(2
)
(3)
NH2
C2H5OOC
C2H5OOC
CH3
N
O
O
O
O
O
O
O
O
OC2H5
(4a
(4b
(4c
)
)
)
O
O
O
CH3
OC2H5
NH2
C2H5OOC
H3CN
CH3
N
CH3
N
CH3
C2H5OOC
CH3
CH3
NH2
O
C2H5OOC
PhH2CN
CH3
N
Cl
N
CH2Ph
C2H5OOC
CH3
Cl
CH3
NH2
O
C2H5OOC
O
O
O
O
O
O
N
Cl
(
4d
)
)
)
O
O
O
CH3
N
H
O
O
N
H
Cl
COOC2H5
CH3
O
NH2
C2H5OOC
H3C
N
(
4e
H3C
CH3
COOC H5
N
H
O
O
N
H
2
CH3
NH2
CH3
O
C2H5OOC
Cl
N
CH3
Cl
(
4f
CH3
COOC2H5
N
H
O
O
N
H
and silica gel. The montmorillonite KSF was found to
be the best solid support giving the maximum (90%)
yield of the required product reasonable purity (TLC)
with shortest time and easier workꢀup (Table 2). Howꢀ
ever, for spectral studies and elemental analyses, comꢀ
The threeꢀcomponent condensation of cyclic
ketones ), ꢀketoester ( ), and substituted anilines
) gave corresponding spiroꢀ1,4ꢀdihydropyridine
(1
β
2
(
3
derivatives incorporating indoline/piperiding ring.
The structure assigned for the reaction product is
established from analytical and spectral data. The IR
pounds (4a–4f) were recrystallized from methanol.
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SYNTHESIS AND SYNERGISTIC, ADDITIVE INHIBITORY EFFECTS
Table 2. Comparative results obtained in the synthesis of (4a) using classical method ( ) and microwave assistance (MW).
321
Δ
Exp.
Medium
EtOH
Mode of activation
Time, min
Temp.a,
°C
Yieldb, %
1
2
3
4
5
6
7
MW
MW
MW
MW
MW
MW
Δ
15
78
135
120
122
125
138
85
72
70
78
70
90
50
Neat
5
Neutral alumina
Acidic alumina
Silica gel
7
8
10
6
Mont. KSF
EtOH + AcONa
600–840
Reflux
Note: a
⎯
Final temperature is measured at the end of MW irradiation by introducing a glass thermometer in the reaction mixture.
b
⎯Isolated yield.
Table 3. Antifungal activity of compounds (the newly synthesized spiroꢀ1,4ꢀDHPs derivatives (4a
–4f)) against Trichophyꢀ
ton rubrum
Concentration of IZ of sample, IZ of a standard,
IZ of a standard,
clotrimazole, mm
Compound
AI
AI
compounds, %
mm
ketoconazole, mm
(
4a
)
100
100
100
100
100
100
68
72
82
80
79
78
60
60
60
60
60
60
1.1
1.2
1.3
1.3
1.3
1.3
36
36
36
36
36
36
1.8
2.0
2.2
2.2
2.1
2.1
(
4b)
(
(
(
4c
)
)
4d
4e)
(
4f)
spectrum of spiro compounds displayed characteristic
m
/
z
441 [M]+ (12.3%), along with base peak observed
m/z 269 (100%).
absorption band in the region of 1694–1724 cm–1 due at
to C = O vibrations. Aromatic and aliphatic C–H
absorption bands were observed at 3060–3080 and
Antidermatophytic activity of the newly syntheꢀ
sized spiroꢀ1,4ꢀDHPs derivatives 4a 4f was
2960–2985 cm–1, respectively. The aromatic skeletal
vibrations of C–C appeared at 1600, 1580, and
1450 cm–1 and the broad and intense absorption,
(
– )
screened using disc diffusion and MIC (minimum
inhibitory concentration) method on T. rubrum and
M. gypseum (etiological agent of dermatophytoses).
The results are presented in Tables 3 through 7 and
Fig. 1 through 7; they demonstrate the important antiꢀ
fungal activity of the compounds alone and in combiꢀ
nations. The diameters of the inhibition zones
obtained upon treatment with compounds and mixꢀ
ture of compounds at concentration of 100% was 68,
72, 82, 80, 79, and 78 mm against T. rubrum and 56,
69, 79, 78, 76, and 79 mm, against M. gypseum. Stanꢀ
dard reference drugs, i. e. clotrimazole and ketoconaꢀ
zole, showed inhibition zones of 36 and 60 mm against
1
occurred at 1595–1610 cm⎯ in all spectra, was
assigned to C=C stretching. 1H NMR spectra of comꢀ
pounds (4a–4f) exhibited one sharp singlet at
8.05 ppm due to NH proton along with a multiplet at
7.09–7.26 ppm for the aromatic protons. A triplet and
a quartet appeared at 1.15–1.28 ppm and 4.03–
4.10 ppm due to the presence of methyl and methylꢀ
ene protons of carbethoxy group, respectively. A sinꢀ
glet was found at 2.32 ppm due to the methyl protons.
The presence and position of NH was confirmed with
deuteration.
T. rubrum and 41 and 26 mm, against M. gypseum
,
Further, the structure of spiro compounds was also respectively. Inhibition zones of the mixture of comꢀ
supported by 13C NMR and mass spectra. In the 13C pounds were found to be higher than those of single
NMR spectrum of (4a) the quaternary Cꢀ6 spiro carꢀ compounds and reference antibiotics. The results
bon appeared at 84.67 ppm. The aromatic and carbonyl show that the compounds exhibited inhibitory effect
carbon resonated at 126.73–159.98 and 170.45 ppm, against T. rubrum at concentration of 1.6 to
respectively. Other signals were observed at 14.04– MIC of compounds against M. gypseum was found to
63.592 due to methyl and methylene carbon of carbeꢀ be within the range of 0.04 to 1.2 g/mL. Even after 4,
2 μg/mL.
μ
thoxy group. The signal of olefinic carbon of tetrahyꢀ 8, and 12 days interval, no growth was observed at that
dropyridine ring was observed at 114.71 ppm. The low concentrations and control taken without comꢀ
mass spectrum of (4a) showed molecular ion peak at pounds showed 100% growth of T. rubrum and M. gypꢀ
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SHARMA et al.
Table 4. Antifungal activity of compounds (the newly synthesized spiroꢀ1,4ꢀDHPs derivatives (4a–4f)) against Microsporum
gypseum
Concentration
of compounds,
%
IZ of a standard,
ketoconazole,
mm
IZ of a standard,
clotrimazole,
mm
IZ of sample,
mm
Compound
AI
AI
(
(
(
(
(
4a
4b
4c
4d
)
)
)
)
100
100
100
100
100
100
56
69
79
78
76
79
26
26
26
26
26
26
2.1
2.6
3.0
3.0
2.9
3.0
41
41
41
41
41
41
1.3
1.6
1.9
1.9
1.8
1.9
4e)
(
4f)
Table 5. Antifungal activity of mixture of compounds (the newly synthesized spiroꢀ1,4ꢀDHPs derivatives, (4a
–4f)) against
T. rubrum and M. gypseum
IZofastandard,
clotrimazole,
mm
Concentration IZ of sample, IZ of a standard,
Compound Test strain
AI
AI
of compounds, %
mm
ketoconazole, mm
Mixture of
compounds
T. rubrum
100
100
82
26
26
3.1
3.0
41
41
2.0
1.9
Mixture of
compounds
M. gypseum
79
Note: IZ, inhibition zone, in mm, including the diameter of disc, 6 mm; AI, activity index.
Table 6. MIC of compound (the newly synthesized spiroꢀ
1,4ꢀDHPs derivatives, (4a 4f)) against T. rubrum
Table 7. MIC of the compounds (the newly synthesized
spiroꢀ1,4ꢀDHPs derivatives, (4a–4f) against M. gypseum
–
Concentration of Growth visually inspected at different
Concentration
of compounds,
Growth visually inspected at different
concentrations of compounds
compounds,
μg/mL
concentrations of compounds
μg/mL
1
+4
+3
+2
0
+4
0.02
0.04
0.06
0.08
1.0
+1
0
+1
1.2
1.4
1.6
1.8
2
+3
+2
+2
0
0
0
0
0
0
0
0
0
0
0
1.2
0
0
Control without oil 1100% growth
100% growth
Control without oil 100% growth
100% growth
seum. We conclude that both, mixture of compounds
and single compounds can be used as antifungal agents
against T. rubrum and M. gypseum, the causal organꢀ
isms of dermatophytic infections.
medium, (iii) high yields, (iv) virtually no waste genꢀ
eration, and (v) ease of product isolation/purificaꢀ
tion—fulfill the triple bottomꢀline philosophy of
green chemistry and make the present methodology
environmentally benign.
CONCLUSION
Here, we describe an efficient, clean, and green
methodology for montmorillonite KSFꢀmediated
oneꢀpot synthesis of spiroꢀ1,4ꢀdihydropyridines. The
EXPERIMENTAL
Melting points were determined on a Toshniwal
advantages—(i) no need for additional reagent/cataꢀ apparatus and are reported uncorrected. The purity of
lyst, (ii) nonꢀinflammable and nontoxic reaction compounds was checked on thin layers of silica gel in
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SYNTHESIS AND SYNERGISTIC, ADDITIVE INHIBITORY EFFECTS
323
Fig. 1. Inhibition zone of clotrimazole against Trichophyton rubrum
.
Fig. 2. Inhibition zone of ketoconazole against M. gypseum.
various nonꢀaqueous solvent systems, e.g. benzene : respectively. TMS was used as an internal reference.
ethylacetate, 9 : 1, benzene : dichloromethane, 8 : 2. Mass spectra of representative compounds were
IR spectra (KBr) were recorded on a Shimadzu FT recorded on a Kratos 50 mass spectrometer at 70 eV.
1
IRꢀ8400S spectrophotometer and H NMR and 13C The microwaveꢀassisted reactions were carried out
NMR spectra were recorded on a Bruker DRXꢀ300 in a modified multimode MW oven (Panasonicꢀ
equipment using CDCl3 at 300.15 and 75.47 MHz NNꢀ781JF) equipped with inverter technology
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324
SHARMA et al.
Fig. 3. Inhibition zone of ketoconazole against Trichophyton rubrum.
Fig. 4. Inhibition zone of the novel synthesized spiroꢀ1, 4ꢀDHPs derivative (4c) against Trichophyton rubrum.
(generating fixed frequency throughout the After elimination of water, ethanol (25 mL) was added
required time) operating at 1000 W generating directly to the reaction mixture and refluxed for 15 h.
2450 MHz frequency.
Then the reaction mixture was poured into ice water,
the separated solid mass was extracted with diethyl
ether (50 mL), dried over magnesium sulfate, and then
concentrated. The solid product was treated with
methanol. The product was filtered and recrystallized
from ethyl acetate.
The synthesis of spiro compound (4a) was carried
out using different methods: (a) classical method, and
(b) microwaveꢀmediated synthesis.
(a) Classical Method
A mixture of 0.01 mol cyclohexanone
ethyl acetoacetate ( ), and 0.01 mol
3a), containing 1–2 g of fused sodium acetate, was
heated (without solvent) on steam bath for 10–12 h. 0.02 mol (
(
1
), 0.02 mol
(b) MicrowaveꢀMediated Synthesis
2
pꢀphenatidine
(
(i) Using polar solvent. A mixture of 0.01 mol (
1),
2), and 0.01 mol (3a) was put into a borosil
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SYNTHESIS AND SYNERGISTIC, ADDITIVE INHIBITORY EFFECTS
325
Fig. 5. Inhibition zone of the novel synthesized spiroꢀ1,4ꢀDHPs derivative (4f) against M. gypseum.
Fig. 6. Inhibition zone of the mixture of compounds: spiroꢀ1,4ꢀDHPs derivatives (4a–4f) against T. rubrum.
glass vessel containing 5 mL ethanol and irradiated the dark brownꢀcolored solid mass. After washing with
inside a microwave oven at 340 W. After every 2 min, petroleum ether, shiny crystals were isolated by filtraꢀ
an interval of 1 min without irradiation was allowed, to tion and found to be pure by TLC.
avoid excessive evaporation of solvent, until the comꢀ
(iii) Using inorganic solid support. A mixture of
pletion of the reaction (15 min, TLC). The reaction
0.01 mol (1), 0.02 mol (2), and 0.01 mol (3a) was
mixture was cooled and the product was filtered,
dried, and recrystallized from methanol.
adsorbed on inorganic solid supports, such as montꢀ
morillonite KSF (4 g), silica gel (4 g), or neutral aluꢀ
1), mina (4 g), via methanolic solution, and swirled for a
(ii) Neat reaction. A mixture of 0.01 mol (
0.02 mol (
2
), and 0.01 mol (3a) was irradiated under while followed by removal of solvent under gentle vacꢀ
neat conditions at 640 W under microwave irradiation uum. The dry powder thus obtained was placed into a
until the completion of the reaction (TLC). After tritꢀ pyrexꢀglass vessel and irradiated in a microwave oven
uration with petꢀether, 5 mL methanol was added to at power output of (640 W) for appropriate time
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SHARMA et al.
Fig. 7. Inhibition zone of the mixture of compounds: spiroꢀ1,4ꢀDHPs derivatives (4a–4f) against M. gypseum.
(TLC). The product was extracted with methanol and ppm): 0.93–2.35 (m, 8H, (CH2)4
,
and 6H,
found to pure by TLC.
(
⎯OCH2CH3)2, 2.21 (s, 6H, (CH3)2), 3.5 (s, 2H,
CH2Ph), 4.21 (q, 4H, (–OCH2CH3)2), 6.69–7.59 (m,
9H, ArH).
The compounds synthesized by various methods
were identified by their mixed melting point and specꢀ
tral studies. The results presented in Table 2 show that
the montmorillonite KSF was found to be the best
solid support for the synthesis of spiro compound (4a),
hence all other compounds listed in Table 1 were also
synthesized by microwave method using montmorilꢀ
lointe clay as inorganic solid support providing the
required product in pure form (TLC) with no need for
further purification. However, for spectral studies and
(
4d) Yield 88%; mp 180–181°C; reaction time,
6 min. Anal. Found: C, 65.02; H, 5.22; N, 5.32. Calcd.
C26H25ClN2: C, 64.93; H, 5.24; N, 5.28. IR (KBr) νmax
3298 (NH), 3018 (aromatic C–H), 2998 (aliphatic
C–H), 1705 (NHC=O), 1685 (C=O), 1610 (C=C).
1H NMR
(CDCl3) (δ, ppm): 1.22 (t, 6H,
(CH2CH3)2), 2.32(s, 6H, (CH3)2), 4.08 (q, 4H,
(CH2CH3)2), 7.09–7.26 (m, 8H, ArH), 8.05 (s, 1H,
NH).
elemental analyses, compounds (4a–4f) were further
recrystallized from methanol.
(
4a) Yield 92%; mp 48–50°C; reaction time,
7 min. Anal. Found: C, 70.50; H, 7.98; N, 3.013.
Calcd. C26H35NO5: C, 70.72; H, 7.99; N, 3.17. IR
(KBr) νmax 3080 (aromatic C–H), 2985 (aliphatic C–
(
4e) Yield 91%; mp 163–164°C; reaction time,
7 min. Anal. Found: C, 70.61; H, 6.12; N, 6.10. Calcd.
C27H28N2O5: C, 70.42; H, 6.13; N, 6.08. IR (KBr) νmax
3310 (NH), 3010 (aromatic C–H), 2994 (aliphatic
C–H), 1700 (NHC=O), 1689 (C=O), 1627 (C=C);
H), 1694 (C=O), 1595 (C=C). 1H NMR (CDCl3) (
δ,
ppm): 0.75–2.08 (m, 10H (CH2)5 and 9H, (CH3)3),
2.32 (s, 6H, (CH3)2), 3.91 (q, 2H, OCH), 4.03 (q, 4H,
O(CH2)2), 6.90–7.12 (m, 4H, ArH).
1H NMR (CDCl3) (
δ, ppm): 1.21 (s, 3H, CH3), 1.28
(t, 6H, (CH2CH3)2), 2.23 (s, 6H, (CH3)2, 3.91 (q, 4H,
(CH2CH3)2, 6.91–7.20 (m, 8H, ArH), 8.01 (s, 1H,
NH).
(
4b) Yield 89%; mp 138–140°C; reaction time,
5 min. Anal. Found: C, 70.69; H, 8.05; N, 6.60. Calcd.
C25H34N2O4: C, 70.39; H, 8.03; N, 6.57. IR (KBr) νmax
3086 (aromatic C–H), 2996 (aliphatic C–H), 1705
(
4f) Yield 94%; mp 140–144°C; reaction time,
1
(C=O), 1585 (C=C). H NMR (CDCl3) (
δ
, ppm):
7 min. Anal. Found: C, 65.63; H, 5.49; N, 5.70. Calcd.
C27H27ClN2O5: C, 65.52; H, 5.50; N, 5.66. IR (KBr)
νmax 3310 (NH), 3288 (NH), 3012 (aromatic C–H),
2987 (aliphatic C–H), 1702 (NHC=O), 1691 (C=O),
1617 (C=C). H NMR (CDCl3) (
3H, CH3), 1.28 (t, 6H, (CH2CH3)2, 2.35 (s, 6H,
(CH3)2, 3.89 (q, 4H, (CH2CH3)2, 6.86–7.32 (m, 7H,
ArH), 8.01(s, 1H, NH).
0.89–2.05 (m, 8H, (CH2)4 and (–OCH2CH3)2, 2.24 (s,
6H, (CH3)2), 2.31 (s, 3H, CH3), 3.1 (s, 3H, N–CH3),
4.01 (q, 4H, (–OCH2CH3)2), 6.78–7.04 (m, 4H, ArH).
(
4c) Yield 87%; mp 220–221°C; reaction time,
1
δ, ppm): 0.91 (s,
6 min. Anal. Found: C, 70.02; H, 6.75; N, 5.33. Calcd.
C30H35ClN2O4: C, 68.89; H, 6.74; N, 5.36. IR (KBr)
νmax 3078 (aromatic C–H), 2985 (aliphatic C–H),
1
1694 (C=O), 1595 (C=C). H NMR (CDCl3) (
δ,
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