Acetic acid mediated regioselective synthesis of 2,4,5-trisubstituted thiazoles by a domino multicomponent reaction

Article abstract of DOI:10.1039/c9nj01717h

Acetic acid mediated regioselective synthesis of novel 2,4,5-trisubstituted thiazole derivatives has been reported by a domino reaction of thiosemicarbazide and aldehydes/ketones/isatin, to generate thiosemicarbazones (in situ) followed by addition of arylglyoxal and active methylene/activated C-H acids/pyrazole/indole in ethanol at 80 °C. The products are obtained in high yields by a simple work up. Metal free, short reaction time and high yields are some merits of this methodology.

Full text of DOI:10.1039/c9nj01717h

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Acetic acid mediated regioselective synthesis
of 2,4,5-trisubstituted thiazoles by a domino
Cite this:DOI: 10.1039/c9nj01717h
multicomponent reaction†
Mohit Saroha and Jitender M. Khurana
*
Received 3rd April 2019,
Accepted 8th May 2019
Acetic acid mediated regioselective synthesis of novel 2,4,5-trisubstituted thiazole derivatives has been
reported by a domino reaction of thiosemicarbazide and aldehydes/ketones/isatin, to generate thio-
semicarbazones (in situ) followed by addition of arylglyoxal and active methylene/activated C–H acids/
pyrazole/indole in ethanol at 80 1C. The products are obtained in high yields by a simple work up. Metal
free, short reaction time and high yields are some merits of this methodology.
DOI: 10.1039/c9nj01717h
rsc.li/njc
have reported ZnCl
and imidazoline-2-ones by the reaction of phenylglyoxal and
Thiazole scaffolds are present in a number of medicinally nucleophiles with urea and N,N-dimethyl urea, respectively.
2
mediated synthesis of dihydropyrimidinone
Introduction
2
0a
relevant compounds e.g., sulfathiazole (I) is a short-acting sulfa Imidazo[1,2-b]pyrazole and imidazo[1,2-a]azine have been reported
1
20b,c
drug which exhibits antibacterial activity, abafungin (II) is a by a glyoxal based multicomponent reaction.
2
broad-spectrum potent antifungal agent, compound III behaves
as a nonsteroidal anti-inflammatory agent, compound IV exhibits methodologies have evolved for the synthesis of biologically
antimicrobial activity, compound V is cytotoxic, and nizatidine active heterocycles. In continuation of our efforts to develop
VI) is a successful drug for the treatment of peptic ulcers and efficient and green methodologies to construct biologically and
gastroesophageal disease (Fig. 1). Many other 2-hydrazinyl medicinally important molecules, we decided to investigate
substituted thiazole motifs are known to show activities such as the synthesis of trisubstituted thiazoles by one-pot three com-
A literature survey revealed that in recent years, various
3
4a
4b
21
(
4
c
22
5
6
7
antimicrobial, antitumour, antibacterial and antifungal, anti- ponent condensation of thiosemicarbazones, arylglyoxal and
inflammatory, antimycobacterial, and anticancer.
8
9
10
activated C–H acids.
Various methods have been reported for the synthesis of 1,3-
3
thiazoles; e.g., condensation of 1-alkynyl(phenyl)-l -iodanes
1
1
and thioamides/thioureas, synthesis of thiazole amino acid
derivatives by modified Hantzsch reaction, and organocatalytic
Results and discussion
12
epoxidation of nitrostyrene followed by condensation with In this paper, we report regioselective synthesis of novel 2,4,5-
13
thioamides. Condensation of arylglyoxals, cyclic 1,3-dicarbonyls trisubstituted thiazoles by one-pot condensation of arylthiose-
14
and thioamides under exposure to microwaves at 130 1C, domino micarbazones (generated in situ), arylglyoxal and activated C–H
reaction between 1,1,3,3-tetramethylguanidine, acetylenic esters and acids like 4-hyroxycoumarin, dimedone, cyclohexane-1,3-dione,
15
aryl isothiocyanates, and one-pot tandem cyclization of aldehydes 4-hydroxy-6-methyl-2-pyrone, cyclopentane-1,3-dione, 3-methyl-
and cysteine esters as N and S sources in the presence of I /TBHP 1H-pyrazol-5(4H)-one, 1,3-dimethylbarbituric acid, methyl 5-hydroxy-
2
16
have also been used for the synthesis of thiazoles. Catalyst free 1-phenyl-1H-pyrazole-3-carboxylate and indole in the presence
visible light mediated synthesis of multi-functionalized thiazoles by of acetic acid as a catalyst. The reaction conditions were optimized
1
7
the reaction of phenacyl bromide and substituted thiourea,
by attempting reaction of equimolar amounts of thiosemicarbazide
(1a), piperonaldehyde (2a), phenylglyoxal (3a) and 4-hydroxy-
1
8
catalyst free intramolecular cyclization of N-allylbenzothioamide
and NBS-mediated sequential reaction of 1,3-dicarbonyl compounds coumarin (4a) under different conditions. Initially, the reaction
19
with mercaptonitrile salts have also been reported. Balalaie et al. was attempted by heating thiosemicarbazide (1a) and pipero-
naldehyde (2a) in ethanol at 80 1C in the presence of 10 mol% of
p-toluenesulphonic acid (p-TSA). After the disappearance of the
reactants (B30 min), phenylglyoxal (3a) and 4-hydroxycoumarin
Department of Chemistry, University of Delhi, Delhi-110007, India.
E-mail: jmkhurana1@yahoo.co.in, jmkhurana@chemistry.du.ac.in;
(
4a) were added to the reaction mixture and the progress of the
Fax: +91 11 27667624; Tel: +91 11 2766772
Electronic supplementary information (ESI) available. See DOI: 10.1039/c9nj01717h reaction was monitored by TLC using chloroform : methanol
†
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Fig. 1 Some medicinally important thiosemicarbazide and 1,3-thiazole skeletons.
Table 1 Optimization of the reaction conditions for the synthesis of of glacial acetic acid at 80 1C. The reactions were complete in
a
compound 5a
120 min and gave varying yields of the product (5a) from 76% to
b
c
82% (Table 1, entries 3–6). Therefore, it can be inferred from
the results shown in Table 1 that the optimized reaction
conditions for the synthesis of trisubstituted thiazole is one-pot
four component condensation in ethanol at 80 1C in the presence
of 10 mol% glacial acetic acid.
Entry
Catalyst
Solvent
Time (min)
Yield (%)
1
2
3
4
5
6
pTSA
EtOH
EtOH
MeOH
DCM
EG
PEG-400
120
60
120
120
120
120
85
92
76
78
81
82
CH
CH
CH
CH
CH
3
3
3
3
3
COOH
COOH
COOH
COOH
COOH
After the optimization of the reaction conditions, reactions
of thiosemicarbazide (1), piperonaldehyde (2a) and phenylglyoxal
a
Reaction conditions: thiosemicarbazide (1) (1.0 mmol), aldehyde (2a)
(3a) were attempted with different nucleophiles such as 4-hydroxy-6-
(
1.0 mmol), phenylglyoxal (1.0 mmol), 4-hydroxycoumarin (4a) (1.0 mmol)
b
c
and solvent (5 mL). 10 mol% catalyst. Isolated yield.
methyl-2-pyrone (4b), dimedone (4c), cyclohexane-1,3-dione (4d),
pentane-1,3-dione (4e), 1,3-dimethylbarbituric acid (4f), 3-methyl-
1
H-pyrazol-5-ol (4g), methyl 5-hydroxy-1-phenyl-1H-pyrazole-3-
95 : 5, v/v) as an eluent. The reaction was found to be completed carboxylate (4h) and indole (4i) in ethanol in the presence of
after 120 min. The product was separated and identified as 10 mol% glacial acetic acid at 80 1C and phenylglyoxal and
E)-3-(2-(2-(benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-4-phenyl- nucleophiles (activated C–H acids) were added in the same pot
thiazol-5-yl)-4-hydroxy-2H-chromen-2-one (5a) in 85% yield after the disappearance of aldehyde at B30 min as monitored
Table 1, entry 1). The reaction was then repeated in ethanol by TLC. All the reactions were complete in 1–2 h and gave the
(
(
(
using glacial acetic acid as a catalyst. To our delight, the reaction corresponding trisubstituted thiazoles (5b–5i) in high yields
was complete in 60 min, and the product 5a was isolated in 92% (Scheme 2) (Table 2). Subsequently, we also attempted reactions
yield (Scheme 1) (Table 1, entry 2).
with different aldehydes/ketones under similar conditions. All
Reactions were then attempted in different solvents like the reactions were complete in 1–3 h and gave the corres-
methanol, DCM, EG and PEG-400 in the presence of 10 mol% ponding products in good yields (Table 2, entries 5j–5p).
Scheme 1
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a,b
Table 2 Synthesis of 2,4,5-trisubstituted thiazoles
a
Reaction conditions: thiosemicarbazide (1a) (1.0 mmol), aldehyde/ketone/isatin (1.0 mmol), arylglyoxal (1.0 mmol) and nucleophile (Nu) (4a–4i)
b
(1.0 mmol) in 10 mol% AcOH in 5 mL of ethanol. Isolated yields are given in brackets.
Reactions using substituted phenylglyoxal also yielded the corres- proceeded smoothly and were complete in 1 h yielding the
ponding thiazoles in high yields (Table 2, entries 5q–5r). corresponding 4-hydroxy-3-(4-phenyl-2-(arylamino)thiazol-5-yl)-
The above protocol was also examined for the one-pot three 2H-chromen-2-one (Scheme 3).
component condensation of equimolar amounts of phenyl-
The proposed mechanism for the formation of thiazoles is
glyoxal and 4-hydroxycoumarin with phenylthiourea & 4-tolyl- depicted in Scheme 4. The reaction involves initial condensation
thiourea in place of thiosemicarbazone in ethanol in the of aldehydes/ketones/isatin and thiosemicarbazide to give thio-
2
3
presence of 10 mol% glacial acetic acid at 80 1C. The reactions semicarbazone (A). The condensation between phenylglyoxal
Scheme 2 Synthesis of 2,4,5-trisubstituted thiazoles.
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Scheme 3 Synthesis of 2,4,5-trisubstituted thiazoles.
apparatus and are uncorrected. IR (neat) spectra were recorded
on a SHIMADZU spectrophotometer and the values are expressed
À1
1
13
as nmax cm . The H NMR and C NMR spectra were recorded
on a Jeol JNM ECX-400P at 400 and 100 MHz respectively, using
TMS as an internal standard. The chemical shift values are recorded
on d scale and the coupling constants (J) are in Hz. Mass spectral
data were recorded on an Agilent 6200 Q-TOf (ESI-HRMS) mass
spectrometer.
General procedure for the synthesis of 2,4,5-trisubstituted
thiazoles (5a–5t)
A mixture of thiosemicarbazide (1) (1.0 mmol), aldehyde/ketone/
isatin (2) (1.0 mmol), glacial acetic acid (10 mol%) and 5 mL of
ethanol was taken in a 50 mL round bottomed flask mounted
over a magnetic stirrer. The reactants were stirred magnetically
in an oil-bath maintained at 80 1C and the progress of the
reaction was monitored by TLC (eluent: chloroform : methanol,
95 : 5, v/v). After disappearance of the carbonyl compound (B30
min), arylglyoxal (1.0 mmol) and nucleophile (4a–4i) (1.0 mmol)
were added to the reaction mixture and the heating was
continued. The progress of the reaction was monitored by TLC
(eluent: chloroform : methanol, 95 : 5, v/v) for the disappearance of
Scheme 4 Proposed mechanism for the synthesis of 2,4,5-trisubstituted
arylglyoxal. After completion of the reaction, the mixture was
cooled to room temperature. A solid product separated out which
was filtrated at pump. The solid residue was washed with ethanol
thiazoles.
with cyclo-1,3-dione gives intermediate B which undergoes
Michael addition with A followed by tautomerization to give C.
Intramolecular cyclization followed by loss of water gives the
1
13
(5 mL). The products were characterized by IR, H NMR, C NMR
14
and HRMS.
desired product 5.
Spectral data
(
E)-3-(2-(2-(Benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-4-
phenylthiazol-5-yl)-4-hydroxy-2H-chromen-2-one (5a). Off white
Conclusions
À1
solid; m.p. 256–259 1C; IR (nmax cm ) (neat): 3183, 1676, 1603,
1
In conclusion, we have reported a facile one-pot metal free
regioselective sequential synthesis of 2,4,5-trisubstituted thiazoles
by condensation of aldehydes/ketones/isatin, thiosemicarbazide,
phenylglyoxal and active methylene compounds/activated C–H
acids in ethanol in the presence of glacial acetic acid (10 mol%)
in excellent yields at 80 1C. The 2,4,5-trisubstituted thiazoles could
also be obtained by replacing thiosemicarbazone, formed in situ,
with arylthiourea.
1
1
7
495, 1260, 1086, 750; H NMR (400 MHz, DMSO-d
6
) d 12.10 (bs,
H, OH), 7.94 (s, 1H, CH imine), 7.85 (d, J = 8.0 Hz, 1H, ArH),
.67–7.60 (m, 1H, ArH), 7.54 (d, J = 7.1 Hz, 2H, ArH), 7.41–7.30
(m, 2H, ArH), 7.25 (t, J = 7.5 Hz, 2H, ArH), 7.18 (t, J = 7.2 Hz, 2H,
ArH), 7.06 (d, J = 8.1 Hz, 1H, ArH), 6.91 (d, J = 8.0 Hz, 1H, ArH),
1
3
6
1
1
1
2 6
.01 (s, 2H, OCH O); C NMR (100 MHz, DMSO-d ) d 168.2,
64.1, 161.9, 153.2, 149.0, 148.5, 141.9, 135.9, 133.5, 129.4,
28.7, 127.6, 124.7, 124.4, 122.7, 116.9, 116.3, 110.8, 109.0,
05.1, 102.0, 97.4; HRMS (ESI) calcd for
26 17 3 5
C H N O S
+
+
[
M + H] : 484.0967, found: 484.0963 [M + H] .
Experimental
(
E)-3-(2-(2-(Benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-4-
All the chemicals were commercially available and purchased phenylthiazol-5-yl)-4-hydroxy-6-methyl-2H-pyran-2-one (5b). Off
À1
from Sigma-Aldrich or Merck and used as received. Thin layer white solid; m.p. 180–182 1C; IR (nmax cm ) (neat): 2970, 2945, 1742,
1
chromatography (GF-254) was used to monitor reaction progress. 1584, 1371, 1252, 1032, 692; H NMR (400 MHz, DMSO-d
6
) d 11.95
Melting points were measured on Buchi M-560 melting point (bs, 1H, OH), 7.93 (s, 1H, CH imine), 7.53 (d, J = 7.3 Hz, 2H, ArH),
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.30 (t, J = 7.6 Hz, 2H, ArH), 7.26–7.17 (m, 2H, ArH), 7.08 (100 MHz, DMSO-d
Paper
7
6
) d 166.4, 159.4, 148.4, 148.0, 146.0, 140.9,
(
d, J = 8.2 Hz, 1H, ArH), 6.94 (d, J = 8.2 Hz, 1H, ArH), 6.06 (s, 3H, 138.6, 135.9, 129.1, 128.2, 127.2, 127.0, 122.1, 112.2, 108.6,
1
3
OCH O + CH alkene), 2.21 (s, 3H, CCH ), C NMR (100 MHz, 104.7, 101.5, 94.2, 10.5; HRMS (ESI) calcd for C H N O S
DMSO-d ) d 172.6, 168.6, 167.5, 163.6, 163.3, 149.0, 148.5, [M + H] : 420.1130, found: 420.1113 [M + H] .
2
3
21 17 5 3
+
+
6
1
1
C
41.5, 136.4, 129.5, 128.6, 127.7, 127.4, 122.6, 111.8, 109.0,
(E)-Methyl 4-(2-(2-(benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-
05.0, 101.9, 100.5, 94.1, 21.6; HRMS (ESI) calcd for 4-phenylthiazol-5-yl)-5-hydroxy-1-phenyl-1H-pyrazole-3-carboxylate
+
+
À1
23
H
17
N
3
O
5
S [M + H] : 448.0967, found: 448.0958 [M + H] .
(5h). White solid; m.p. 246–248 1C; IR (nmax cm ) (neat): 1715,
1
(
E)-2-(2-(2-(Benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-4- 1601, 1445, 1246, 1031, 760; H NMR (400 MHz, DMSO-d
6
) d 12.01
phenylthiazol-5-yl)-3-hydroxy-5,5-dimethylcyclohex-2-enone (5c). (bs, 1H, OH), 7.94 (s, 1H, CH imine), 7.71 (d, J = 7.6 Hz, 2H, ArH),
À1
Yellow solid; m.p. 179–180 1C; IR (nmax cm ) (neat): 3460, 2968, 7.60–7.45 (m, 4H, ArH), 7.35 (t, J = 7.4 Hz, 1H, ArH), 7.30–7.21
1
1
742, 1369, 1225, 1034; H NMR (400 MHz, DMSO-d ) d 7.91 (s, (m, 2H, ArH), 7.21–7.13 (m, 2H, ArH), 7.11–7.03 (m, 1H, ArH), 6.91
6
1
H, CH imine), 7.53 (d, J = 7.3 Hz, 2H, ArH), 7.34–7.12 (m, 4H, (d, J = 8.1 Hz, 1H, ArH), 6.02 (s, 2H, OCH O), 3.59 (s, 3H, COOCH );
2
3
13
ArH), 7.06 (d, J = 7.8 Hz, 1H, ArH), 6.93 (d, J = 7.8 Hz, 1H, ArH),
C NMR (100 MHz, DMSO-d ) d 167.5, 162.3, 152.3, 149.0, 148.5,
6
6
.05 (s, 2H, OCH
COCH CMe
), 1.03 (s, 6H, 2 Â CH
d 172.2, 166.7, 148.3, 148.0, 146.9, 140.6, 136.1, 129.2, 127.9, 127.1,
22.0, 113.1, 108.6, 106.5, 104.5, 101.5, 56.1, 31.5, 28.1, 21.1, 18.6;
2
O), 2.32 (bs, 2H, COCH
2
CMe
2
), 1.90 (bs, 2H, 141.6, 141.0, 138.4, 136.1, 129.7, 129.5, 128.6, 127.9, 127.7, 123.0,
13
2
2
3
); C NMR (100 MHz, DMSO-d
6
)
122.7, 110.2, 109.0, 105.1, 102.0, 96.5, 52.0; HRMS (ESI) calcd for
+
+
C
28
H
21
N
5
O
5
S [M + Na] : 562.1161, found: 562.1162 [M + Na] .
(E)-2-(2-(Benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-5-(1H-
23 3 4
HRMS (ESI) calcd for C25H N O S [M + H] : 462.1488, found: indol-3-yl)-4-phenylthiazole (5i). White solid; m.p. 231–232 1C; IR
1
+
+
À1
462.1476 [M + H] .
(n
cm ) (neat): 2914, 1628, 1493, 1443, 1246, 1028, 737;
max
1
(
E)-2-(2-(2-(Benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-4-
H NMR (400 MHz, DMSO-d ) d 11.35 (s, 1H, NH), 7.94 (s, 1H,
6
phenylthiazol-5-yl)-3-hydroxycyclohex-2-enone (5d). Yellow solid; CH imine), 7.58–7.48 (m, 2H, ArH), 7.40 (d, J = 8.1 Hz, 2H, ArH),
À1
m.p. 226–228 1C; IR (nmax cm ) (neat): 3007, 2970, 1742, 1646, 7.25–6.99 (m, 7H, ArH), 6.94–6.82 (m, 2H, ArH), 5.99 (s, 2H,
1
13
1
368, 1227, 1028; H NMR (400 MHz, DMSO-d
imine), 7.63 (d, J = 7.3 Hz, 2H, ArH), 7.35 (t, J = 7.6 Hz, 2H, ArH), 148.5, 145.1, 141.4, 136.8, 136.4, 129.5, 128.5, 128.2, 127.5, 126.6,
.26 (d, J = 7.8 Hz, 2H, ArH), 7.12 (d, J = 7.8 Hz, 1H, ArH), 6.99 126.0, 122.5, 122.2, 119.9, 115.6, 112.4, 109.0, 106.6, 105.1, 101.9,
6 2 6
) d 7.97 (s, 1H, CH OCH O); C NMR (100 MHz, DMSO-d ) d 172.7, 166.1, 148.9,
7
(
+
d, J = 8.2 Hz, 1H, ArH), 6.10 (s, 2H, OCH
COCH CH CH CO); C NMR (100 MHz, DMSO-d ) d 172.2, [M + H] 439.1243.
2
O), 2.18–1.90 (m, 6H, HRMS (ESI) calcd for C25
18 4 2
H N O S [M + H] : 439.1229, found:
13
+
2
2
2
6
166.7, 148.4, 148.1, 146.5, 140.6, 136.2, 129.2, 128.1, 126.9,
(E)-5-(2-(2-(3,4-Dihydroxybenzylidene)hydrazinyl)-4-phenyl-
1
22.1, 113.5, 108.6, 107.8, 104.6, 101.5, 21.1, 20.3; HRMS (ESI) calcd thiazol-5-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5j).
+
+
À1
for C23
H
19
N
3
O
4
S [M + H] : 434.1175, found: 434.1164 [M + H] .
White solid; m.p. 4300 1C; IR (nmax cm ) (neat): 3456, 3100,
1
(
E)-2-(2-(2-(Benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-4- 1657, 1560, 1435, 1277, 754; H NMR (400 MHz, DMSO-d
6
) d 8.06
phenylthiazol-5-yl)-3-hydroxycyclopent-2-enone (5e). Yellow solid; (s, 1H, CH imine), 7.55 (d, J = 9.7 Hz, 2H, ArH), 7.42–7.08 (m, 5H,
À1
m.p. 252–253 1C; IR (nmax cm ) (neat): 3408, 3009, 1740, 1628, ArH), 6.97 (s, 1H, ArH), 6.07 (s, 2H, OCH
1
2
O), 3.09 (s, 6H, 2 Â
) d 161.1, 152.0, 148.4,
CH imine), 7.53 (q, J = 8.2 Hz, 2H, ArH), 7.23 (m, 4H, ArH), 7.07 145.9, 132.7, 128.1, 127.5, 124.9, 120.8, 117.3, 115.7, 112.6, 27.7;
1
13
6 3 6
447, 1250, 1034, 602; H NMR (400 MHz, DMSO-d ) d 7.90 (s, 1H, NCH ), C NMR (100 MHz, DMSO-d
+
(
q, J = 7.8 Hz, 1H, ArH), 6.92 (d, J = 8.2 Hz, 1H, ArH), 6.03 (s, 2H, HRMS (ESI) calcd for C H N O S [M + H] : 466.1185, found:
OCH O), 2.53–2.43 (bs, 4H, COCH CH CO); C NMR (100 MHz, 466.1192 [M + H] .
22 19 5 5
13
+
2
2
2
DMSO-d
6
) d 172.2, 166.8, 148.4, 148.0, 140.9, 136.2, 129.1,
(E)-3-(2-(2-(4-Chlorobenzylidene)hydrazinyl)-4-phenylthiazol-
1
2
28.0, 127.2, 127.0, 110.5, 109.4, 108.6, 104.6, 101.5, 30.5, 5-yl)-4-hydroxy-2H-chromen-2-one (5k). Off white solid; m.p.
+
À1
1.1; HRMS (ESI) calcd for C22
H
17
N
3
O
4
S [M + H] : 420.1018, 268–270 1C; IR (nmax cm ) (neat): 3165, 1676, 1605, 1526,
+
1
found: 420.0999 [M + H] .
6
1086, 752, 692; H NMR (400 MHz, DMSO-d ) d 12.32 (bs, 1H,
(
E)-5-(2-(2-(Benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-4- OH), 8.01 (s, 1H, CH imine), 7.86 (d, J = 6.6 Hz, 1H, ArH), 7.63 (d,
phenylthiazol-5-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione J = 8.5 Hz, 3H, ArH), 7.58–7.51 (m, 2H, ArH), 7.47–7.40 (m, 2H,
À1
(
5f). Yellow solid; m.p. 4300 1C; IR (nmax cm ) (neat): 2970, 1741, ArH), 7.40–7.36 (m, 1H, ArH), 7.36–7.30 (m, 1H, ArH), 7.29–7.22
1
13
1
8
7
674, 1557, 1369, 1225, 762; H NMR (400 MHz, DMSO-d ) d (m, 2H, ArH), 7.18 (t, J = 7.3 Hz, 1H, ArH); C NMR (100 MHz,
6
.36 (s, 1H, CH imine), 7.53–7.41 (m, 4H, ArH), 7.29 (dd, J = 15.8, DMSO-d
.1 Hz, 4H, ArH), 6.32 (s, 2H, OCH ), 133.9, 133.5, 129.5, 128.8, 128.1, 127.6, 124.8, 124.5, 116.9, 116.3,
O), 3.08 (s, 6H, 2 Â NCH
) d 161.0, 151.9, 149.1, 148.0, 128.3, 111.2, 97.4; HRMS (ESI) calcd for C25
6
) d 168.1, 164.0, 161.9, 153.2, 149.6, 140.7, 135.8, 134.2,
2
3
1
3
+
C NMR (100 MHz, DMSO-d
6
3 3
H16ClN O S [M + H] : 474.0679,
+
+
1
28.1, 127.7, 127.5, 123.4, 108.6, 105.0, 101.7, 27.8; HRMS (ESI) calcd found: 474.0678 [M + H] and 476.0658 [M + H + 2] .
+
+
for C23
H
19
N
5
O
5
S [M + H] : 478.1185, found: 478.1192 [M + H] .
(E)-3-(2-(2-(3,4-Dimethoxybenzylidene)hydrazinyl)-4-phenyl-
(
E)-4-(2-(2-(Benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-4- thiazol-5-yl)-4-hydroxy-2H-chromen-2-one (5l). Off white solid;
À1
phenylthiazol-5-yl)-3-methyl-1H-pyrazol-5-ol (5g). White solid; m.p. 254–256 1C; IR (n
m.p. 258–269 1C; IR (n
439, 1251, 1036; H NMR (400 MHz, DMSO-d
cm ) (neat): 3441, 3144, 1674, 1587,
cm ) (neat): 3167, 2972, 1742, 1562, 1528, 1462, 1092, 820; H NMR (400 MHz, DMSO-d ) d 8.07–7.97
6
max
1
À1
max
1
1
6
) d 11.27 (s, 2H, (s, 1H, CH imine), 7.92–7.79 (m, 2H, ArH), 7.65–7.48 (m, 3H,
OH, NH), 7.92 (s, 1H, CH imine), 7.55 (s, 2H, ArH), 7.37–6.89 ArH), 7.39–7.20 (m, 4H, ArH), 7.14 (d, J = 8.0 Hz, 1H, ArH), 6.94
1
3
(
2 3
m, 6H, ArH), 6.04 (s, 2H, OCH O), 1.75 (s, 3H, CCH ), C NMR (d, J = 8.2 Hz, 1H, ArH), 6.82–6.58 (m, 1H, ArH), 3.74 (s, 6H,
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1
3
2
1
1
1
 OCH
3
); C NMR (100 MHz, DMSO-d
6
) d 168.3, 166.5, 165.4, (m, 2H, ArH), 7.18 (s, 1H, ArH), 7.13–7.03 (m, 3H, ArH),
13
2
64.2, 162.0, 153.2, 152.8, 150.8, 149.5, 147.5, 143.3, 135.1, 6.90 (d, J = 8.0 Hz, 1H, ArH), 6.01 (s, 2H, OCH O); C NMR
33.6, 132.3, 128.8, 127.7, 124.1, 121.3, 119.0, 116.9, 116.4, (100 MHz, DMSO-d ) d 168.3, 164.0, 163.2, 161.9, 160.7, 153.2,
12.1, 110.8, 108.6, 104.8, 97.1, 56.0, 55.8; HRMS (ESI) calcd 149.0, 148.5, 141.9, 133.5, 132.5, 129.6, 129.6, 124.7, 124.5, 122.7,
6
+
+
for C H N O S[M + H] : 500.1280, found: 500.1292 [M + H] .
116.9, 116.4, 115.7, 115.5, 110.7, 109.0, 105.1, 102.0, 97.3; HRMS
2
7
21 3 5
+
(
E)-4-Hydroxy-3-(2-(2-(1-(4-nitrophenyl)ethylidene)hydrazinyl)-4- (ESI) calcd for C26
phenylthiazol-5-yl)-2H-chromen-2-one (5m). Yellow solid; m.p. [M + H] .
14–216 1C; IR (nmax cm ) (neat): 3186, 1670, 1568, 1333, 1277,
54, 689; H NMR (400 MHz, DMSO-d
ArH), 7.95 (d, J = 8.9 Hz, 2H, ArH), 7.85 (d, J = 7.4 Hz, 1H, ArH), Off white solid; m.p. 265–266 1C; IR (nmax cm ) (neat): 1618,
.66–7.53 (m, 3H, ArH), 7.41–7.22 (m, 4H, ArH), 7.19 (t, J = 1595, 1448, 1254, 1028, 826, 752; H NMR (400 MHz, DMSO-d )
.2 Hz, 1H, ArH), 2.34 (s, 3H, CH3); C NMR (100 MHz, DMSO-d ) d d 7.93 (s, 1H, CH imine), 7.86 (d, J = 7.8 Hz, 1H, ArH), 7.71–7.59
H
16FN
3
O
5
S [M + H] : 502.0873, found: 502.0875
+
À1
2
7
(E)-3-(2-(2-(Benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-4-(4-
1
6
) d 8.17 (d, J = 8.9 Hz, 2H, methoxyphenyl)thiazol-5-yl)-4-hydroxy-2H-chromen-2-one (5r).
À1
1
7
7
6
13
6
1
1
1
72.7, 169.4, 164.1, 161.9, 153.2, 149.3, 147.4, 144.8, 144.5, (m, 1H, ArH), 7.48 (d, J = 8.8 Hz, 2H, ArH), 7.43–7.29 (m, 2H,
35.6, 133.5, 128.8, 127.6, 127.0, 124.7, 124.4, 124.2, 116.9, ArH), 7.17 (s, 1H, ArH), 7.05 (d, J = 8.1 Hz, 1H, ArH), 6.90
16.3, 111.8, 97.3, 21.5; HRMS (ESI) calcd for C26
H
18
N
4
O
5
S
(d, J = 8.0 Hz, 1H, ArH), 6.82 (d, J = 8.8 Hz, 2H, ArH), 6.01 (s, 2H,
OCH O), 3.66 (s, 3H, OCH ); C NMR (100 MHz, DMSO-d ) d
2 3 6
+
+
13
[M + H] : 499.1076, found: 499.1072 [M + H] .
(E)-3-(2-(2-(1-(4-Bromophenyl)ethylidene)hydrazinyl)-4-phenyl- 168.1, 164.1, 162.0, 159.1, 153.2, 149.0, 148.5, 141.8, 133.4,
thiazol-5-yl)-4-hydroxy-2H-chromen-2-one (5n). White solid; m.p. 129.4, 128.9, 128.5, 124.7, 122.7, 116.9, 116.4, 114.1, 109.0,
À1
2
7
39–240 1C; IR (n
cm ) (neat): 3252, 1663, 1603, 1489, 1082, 105.0, 102.0, 97.5, 55.5; HRMS (ESI) calcd for C H N O S
max
27 19 3 6
1
+
+
54, 700; H NMR (400 MHz, DMSO-d ) d 7.85 (d, J = 7.8 Hz, 1H, [M + H] : 514.1073, found: 514.1094 [M + H] .
6
ArH), 7.72–7.59 (m, 3H, ArH), 7.55 (t, J = 6.0 Hz, 4H, ArH),
4-Hydroxy-3-(4-phenyl-2-(phenylamino)thiazol-5-yl)-2H-chromen-
À1
7
.42–7.29 (m, 2H, ArH), 7.22 (m, 3H, ArH), 2.28 (s, 3H, CH
3
); 2-one (5s). Off white solid; m.p. 224–226 1C; IR (nmax cm ) (neat):
1
3
1
C NMR (100 MHz, DMSO-d
6
) d 169.6, 164.0, 161.9, 153.2, 3323, 3262, 1724, 1682, 1601, 1491, 745, 685; H NMR (400 MHz,
1
1
C
46.1, 137.6, 135.8, 133.5, 131.9, 128.7, 128.2, 127.6, 124.8, 124.4, DMSO-d
6
) d 10.31 (s, 1H, NH), 7.89 (d, J = 8.2 Hz, 1H, ArH), 7.72
22.6, 116.9, 116.3, 111.2, 97.5, 14.3; HRMS (ESI) calcd for (d, J = 8.2 Hz, 2H, ArH), 7.63 (d, J = 7.8 Hz, 2H, ArH), 7.44–7.28
+
+
26
H
18BrN
3
O
3
S [M + H] : 532.0330, found: 532.0361 [M + H]
(m, 7H, ArH), 7.23 (t, J = 7.1 Hz, 1H, ArH), 6.96 (t, J = 7.3 Hz, 1H,
ArH); C NMR (100 MHz, DMSO-d ) d 164.3, 163.2, 161.9, 153.2,
+
13
and 534.0341 [M + H + 2] .
6
3-(2-(2-(9H-Fluoren-9-ylidene)hydrazinyl)-4-phenylthiazol-5-yl)- 149.4, 141.7, 135.8, 133.6, 129.6, 128.8, 127.7, 124.8, 124.5,
4
-hydroxy-2H-chromen-2-one (5o). Yellow solid; m.p. 261–262 1C; 121.9, 117.5, 116.9, 116.3, 97.1; HRMS (ESI) calcd for
À1
+
+
IR (nmax cm ) (neat): 3227, 1695, 1605, 1532, 1179, 1076, 756;
24 16 2 3
C H N O S [M + H] : 413.0960, found: 413.0959 [M + H] .
1
H NMR (400 MHz, DMSO-d
6
) d 8.74 (d, J = 7.0 Hz, 1H, ArH), 7.82
4-Hydroxy-3-(4-phenyl-2-(p-tolylamino)thiazol-5-yl)-2H-chromen-
À1
(d, J = 8.2 Hz, 2H, ArH), 7.76 (d, J = 8.3 Hz, 2H, ArH), 7.68–7.58 (m, 2-one (5t). Off white solid; m.p. 210–212 1C; IR (nmax cm ) (neat):
1
1
H, ArH), 7.54–7.46 (m, 2H, ArH), 7.45–7.22 (m, 9H, ArH); 3264, 1676, 1605, 1524, 1092, 822, 696; H NMR (400 MHz,
1
3
6 6
C NMR (100 MHz, DMSO-d ) d 164.5, 161.9, 153.2, 140.7, DMSO-d ) d 10.19 (s, 1H, NH), 7.88 (d, J = 8.2 Hz, 1H, ArH),
1
1
39.3, 137.5, 133.7, 131.5, 130.3, 129.4, 129.0, 128.3, 127.9, 7.73–7.51 (m, 5H, ArH), 7.44–7.18 (m, 5H, ArH), 7.14 (d, J = 8.2 Hz,
13
24.8, 124.5, 121.3, 120.7, 117.0, 116.2, 96.7; HRMS (ESI) 2H, ArH), 2.25 (s, 3H, ArCH3); C NMR (100 MHz, DMSO-d ) d
6
+
calcd for C H N O S [M + H] : 514.1225, found: 514.1226 164.2, 163.5, 161.9, 153.2, 149.3, 139.2, 135.9, 133.5, 130.8, 130.0,
3
1
19 3 3
+
[M + H] .
128.8, 128.0, 127.7, 124.7, 124.4, 117.7, 116.9, 116.3, 109.9, 97.1,
+
(
E)-3-(2-(5-(4-Hydroxy-2-oxo-2H-chromen-3-yl)-4-phenylthiazol- 20.9; HRMS (ESI) calcd for C25H N O S [M + H] : 427.1116, found:
18 2 3
+
2-yl)hydrazono)indolin-2-one (5p). Red solid; m.p. 280–284 1C; IR 427.1112 [M + H] .
À1
(
n
max cm ) (neat): 3068, 1705, 1676, 1612, 1545, 1153, 754;
1
H NMR (400 MHz, DMSO-d
6
) d 13.32 (s, 1H, OH), 11.24 (s, 1H,
Conflicts of interest
NH), 7.84 (m, 2H, ArH), 7.67–7.60 (m, 1H, ArH), 7.58 (d, J =
8
7
6
1
1
1
.5 Hz, 1H, ArH), 7.50–7.45 (m, 2H, ArH), 7.40–7.27 (m, 4H, ArH),
There are no conflicts to declare.
.22 (d, J = 7.3 Hz, 1H, ArH), 7.04 (t, J = 7.6 Hz, 1H, ArH),
1
3
6
.96–6.90 (m, 1H, ArH); C NMR (100 MHz, DMSO-d ) d 165.9,
64.4, 163.7, 161.9, 153.2, 150.3, 141.8, 135.3, 133.7, 132.7, Acknowledgements
31.0, 128.9, 127.7, 124.8, 124.5, 123.0, 120.3, 117.0, 116.3,
MS thanks CSIR, New Delhi, India for the grant of a SPM Fellow-
ship. The authors also acknowledge University of Delhi, Delhi, India
for providing a Research grant and a DU-DST Purse grant.
14.7, 111.6, 96.7; HRMS (ESI) calcd for
26 16 4 4
C H N O S
+
+
[M + H] : 481.0971, found: 481.0971 [M + H] .
(E)-3-(2-(2-(Benzo[d][1,3]dioxol-5-ylmethylene)hydrazinyl)-5-(4-
fluorophenyl)thiazol-4-yl)-4-hydroxy-2H-chromen-2-one (5q). Off
À1
white solid; m.p. 262–264 1C; IR (n
1
cm ) (neat): 3176, 1672,
max
References
1
603, 1497, 1227, 837, 750; H NMR (400 MHz, DMSO-d
6
) d 12.09
(
7
bs, 1H, OH), 7.94 (s, 1H, CH imine), 7.86 (d, J = 7.8 Hz, 1H, ArH),
.67–7.60 (m, 1H, ArH), 7.60–7.51 (m, 2H, ArH), 7.41–7.28
1 P. D. Stein, J. T. Hunt, D. M. Floyd, S. Moreland, K. E. J.
Dickinson, C. Mitchell, E. C. K. Liu, M. L. W. N. Murugesan,
New J. Chem.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2019

View Article Online
NJC
Paper
J. Dickey, D. McMullen, R. Zhang, V. G. Lee, R. Serdino, 14 S. Karamthulla, S. Pal, M. N. Khan and L. H. Choudhury,
C. Delaney, T. R. Schaeffer and M. Kozlowski, J. Med. Chem.,
994, 37, 329–331.
C. Borelli, M. Schaller, M. Niewerth, K. Nocker, B. Baasner,
RSC Adv., 2014, 4, 37889–37899.
15 I. Yavari, A. Amirahmadi and M. R. Halvagar, Synlett, 2017,
1
2
2629.
D. Berg, R. Tiemann, K. Tietje, N. B. Fugmann, S. Lang- 16 L. Liu, C. Tan, R. Fan, Z. Wang, H. Du, K. Xu and J. Tan, Org.
Fugmann and H. C. Korting, Chemotherapy, 2008, 54,
45–259.
Ø. Rist, M. Grimstrup, J. M. Receveur, T. M. Frimurer,
T. Ulven, E. Kostenis and T. H o¨ gberg, Bioorg. Med. Chem. 18 W. Zhou, S. Ni, H. Mei, J. Han and Y. Pan, Tetrahedron Lett.,
Lett., 2010, 20, 1177–1180. 2015, 56, 4128–4130.
(a) P. Karegoudar, M. S. Karthikeyan, D. J. Prasad, M. Mahalinga, 19 L. Luo, L. Meng, Q. Sun, Z. Ge and R. Li, Tetrahedron Lett.,
B. S. Holla and N. S. Kumari, Eur. J. Med. Chem., 2008, 43, 2014, 55, 259–263.
Biomol. Chem., 2019, 17, 252–256.
17 A. Mishra, M. Srivastava, P. Rai, S. Yadav, B. P. Tripathi and
J. Singh, RSC Adv., 2016, 6, 49164.
2
3
4
261–267; (b) B. Sridevi, Y. Tangella, K. Babu, J. B. Nanubolu, 20 (a) S. Balalaiea, M. Soleiman-Beigia and F. Rominger, J. Iran.
R. S. Rani, C. G. Kumar, H. M. Meshram and A. Kamala, New
J. Chem., 2017, 41, 3745–3749; (c) K. M. Fock, N. Talley, R. Hunt,
R. Fass, S. Nandurkar, S. K. Lam, K. L. Goh and J. Sollano,
J. Gastroenterol. Hepatol., 2004, 19, 357.
Chem. Soc., 2005, 2, 319–329; (b) N. N. Kolos, L. L. Zamigaylo
and V. I. Musatov, Chem. Heterocycl. Compd., 2009, 45, 970;
(c) V. A. Peshkov, A. A. Peshkov, O. P. Pereshivko, K. V.
Hecke, L. L. Zamigaylo, E. V. V. D. Eycken and N. Y.
Gorobets, ACS Comb. Sci., 2014, 16, 535.
5
6
7
B. K. Sarojini, B. G. Krishna, C. G. Darshanraj, B. R. Bharath
and H. Manjunatha, Eur. J. Med. Chem., 2010, 45, 3490–3496. 21 (a) H. G. O. Alvim, J. R. Correa, J. A. F. Assumpç ˜a o, W. A. da
M. Wang, L. F. Wang, Y. Z. Li, Q. X. Li, Z. D. Xu and
D. M. Qu, Trans. Met. Chem., 2001, 26, 307–310.
Silva, M. O. Rodrigues, J. L. de Macedo, M. Fioramonte,
F. C. Gozzo, C. C. Gatto and B. A. D. Neto, J. Org. Chem., 2018,
83, 4044; (b) O. S. Ojo, O. Miranda, K. C. Baumgardnera and
A. Bugarin, Org. Biomol. Chem., 2018, 16, 9354; (c) L. Zeng,
B. Huang, Y. Shen and S. Cui, Org. Lett., 2018, 20, 3460;
(d) H. Hosseini and M. Bayat, RSC Adv., 2018, 8, 27131;
(e) R. Mishra, A. Jana, A. K. Panday and L. H. Choudhury,
Org. Biomol. Chem., 2018, 16, 3289–3302; ( f ) G. Mari,
M. Verboni, L. De Crescentini, G. Favi and S. Santeusanio,
Org. Chem. Front., 2018, 5, 2108–2114; (g) W. Fan, Y. Queneau
and F. Popowycz, Green Chem., 2018, 20, 485–492.
(a) S. K. Bharti, G. Nath, R. Tilak and S. K. Singh, Eur. J. Med.
Chem., 2010, 45, 651–660; (b) C. I. Lino, I. G. Souza,
B. M. Borelli, T. T. S. Matos, I. N. S. Teixeira, J. P. Ramos,
E. M. S. Fagundes, P. O. Fernandes, V. G. Maltarollo, S. Johann
and R. B. Oliveira, Eur. J. Med. Chem., 2018, 151, 248–260.
B. S. Holla, K. V. Malini, B. S. Rao, B. K. Sarojinin and
N. S. Kumari, Eur. J. Med. Chem., 2003, 38, 313–318.
G. A. Hampannavar, R. Karpoormath, M. B. Palkar, M. S. Shaikh
and B. Chandrasekaran, ACS Med. Chem. Lett., 2016, 7, 686–691.
8
9
10 T. I. Santanaa, M. O. Barbosab, P. A. T. M. Gomes, A. C. N. 22 (a) G. Khanna, K. Aggarwal and J. M. Khurana, RSC Adv., 2015, 5,
Cruza, T. G. Silva and A. C. L. Leite, Eur. J. Med. Chem., 2018,
44, 874–886.
1 P. Wipf and S. Venkatraman, J. Org. Chem., 1996, 61, 8004–8005.
2 E. Aguilar and A. I. Meyers, Tetrahedron Lett., 1994, 35,
46448–46454; (b) M. Saroha, G. Khanna and J. M. Khurana,
ChemistrySelect, 2017, 2, 7263; (c) M. Saroha, K. Meena and
J. M. Khurana, ChemistrySelect, 2018, 3, 5905–5909;
(d) M. Saroha, G. Khanna and J. M. Khurana, ChemistrySelect,
2018, 3, 12560.
1
1
1
2473–2476.
13 K. M. Weiß, S. Wei and S. B. Tsogoeva, Org. Biomol. Chem., 23 M. Xiabing, K. Ablajan, M. Obul, M. Seydimemet, R. Ruzi
2011, 9, 3457–3461. and L. Wenbo, Tetrahedron, 2016, 72, 2349–2353.
This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2019
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