Multicomponent synthesis of diphenyl-1,3-thiazole-barbituric acid hybrids and their fluorescence property studies

Article abstract of DOI:10.1039/d0nj00406e

A series of novel diphenyl-1,3-thiazole linked barbituric acid hybrids (4) were prepared by two catalyst-free methods from readily available starting materials. The reaction of arylglyoxal, barbituric acid and aryl thioamides in the presence of 3-4 drops of water and liquid assisted grinding (LAG) provides the corresponding trisubstituted thiazoles tethered with a barbituric acid moiety within 30 minutes. Alternatively, a sequential two-step one-pot process involving aryl nitriles, ammonium sulphide, arylglyoxal and barbituric acid in water medium was developed. In this second method, in situ thioamides were prepared at room temperature from the reaction of alkyl/aryl nitriles and ammonium sulphide in aqueous medium. Arylglyoxal and barbituric acid were added to the in situ thioamides after neutralizing the reaction medium to provide trisubstituted thiazoles linked with barbituric acid derivatives. Some of our synthesized molecules showed fluorescent properties with very good quantum yields in DMSO medium. We also observed that fluorescent quantum yields of these thiazole derivatives depend on the type of electron donating/withdrawing character of R¹ and R³. R² has a very small effect on tuning the fluorescent properties. The salient features of this work are catalyst-free reactions, wide substrate scope, green reaction conditions (liquid assisted grinding and room temperature reactions in water medium) as well as the presence of more than one pharmaceutically important heterocyclic moiety with fluorescent properties.

Full text of DOI:10.1039/d0nj00406e

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Multicomponent synthesis of diphenyl 1, 3-thiazole-
barbituric acid hybrids and their fluorescence
property studies
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a
a
a
b
Alok Mahata, Prabhas Bhaumick, Anoop Kumar Panday, Rahul Yadav,
b*
a
Tasneem Parvin and Lokman H. Choudhury *
aDepartment of Chemistry, Indian Institute of Technology Patna, Bihta, Patna-801106
bDepartment of Chemistry, National Institute of Technology Patna, Ashok Rajpath, Patna-
800 005
OH
O
R3
O
OH
R2
O
R2
O
S
3-4 drops H2O
N
N
R1
+
+
Method
Liquid assisted
grinding (LAG)
NH2
R1
I
1
2
3
N
S
R3
2
5-30 min
HO
N
R2
O
N
O
R2
4
II
(
i) H O, rt
2
Method
CN
+
(NH ) S
4 2
R3
(ii) Add HCl + 1 + 2
rt
6
5
Two steps one-pot MCR
A series of novel diphenyl-1,3-thiazole linked barbituric acid hybrids (4) were prepared by two
catalyst-free methods from the readily available starting materials. The reaction of arylglyoxal,
barbituric acid and aryl thioamides in the presence of 3-4 drops of water and liquid assisted
grinding (LAG) provides corresponding trisubstituted thiazoles tethered with barbituric acid
moiety within 30 minutes. Alternatively, a sequential two-step one-pot process involving
aryl nitriles, ammonium sulphide, arylglyoxal and barbituric acids in water medium was
developed. In this second method, in situ thioamides were prepared at room temperature
from the reaction of alkyl/aryl nitriles and ammonium sulphide in aqueous medium.
Arylglyoxal and barbituric acid were added to the in situ thioamides after neutralizing the
reaction medium to provide trisubstituted thiazoles linked with barbituric acid derivatives.
Some of our synthesized molecules showed fluorescent properties with very good quantum
1

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DOI: 10.1039/D0NJ00406E
yields in DMSO medium. We also observed that fluorescent quantum yields of these thiazole
1
3
2
derivatives depend on the types of electron donating/withdrawing characters of R and R . R
has very less effect in tuning the fluorescent properties. The salient features of this work are:
catalyst-free reaction, wide substrate scope, green reaction conditions (liquid assisted grinding
and room temperature reactions in water medium) as well as presence of more than one
pharmaceutically important heterocyclic moiety with fluorescent properties.
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Introduction
Design and development of eco-friendly and cost-effective methodologies for the synthesis of
substituted heterocycles has remained an important topic in both medicinal and organic
1
chemistry. Thiazole is an important sulphur and nitrogen containing five membered
2
3
heterocycle found in numerous pharmaceuticals, and natural products. Specially thiazoles
4
5
tethered with aryl substituents exhibit interesting optical and electronic properties.
6
Substituted thiazoles are also used in liquid crystals. Apart from these, compounds having
thiazole in the core of the structures are found in many drugs used in our day to day life. A few
representative examples of substituted thiazoles with their useful properties are shown in
Figure 1.
Cl
H2NO2S
N
NC
N
HOOC
S
OH
O
S
S
O
S
N
N
O
F
CF3
S
A
O
OH
C
B
Sodeglitazar
Febuxostat
D
Cyclooxygenase-2 inhibitor
Fentiazac
S
S
N
S
S
N
EtO
N
N
N
N
Ph N
N
2
S
N
O
COOH
HO
HO
F
H
E
G
Figure 1. Representative examples of some useful substituted thiazole derivatives.
Sodelglitazar (A), also known as GW677954 is an inhibitor of peroxisome proliferator-
7
activated receptor delta (PPARδ). Trisubstituted thiazole derivative B having two aryl and one
8
methyl substituent is a cyclooxygenase-2 inhibitor. Similarly, febuxostat (C) is a urate
9
lowering drug. and fentiazac (D) is a non-steroidal anti-inflammatory agent, used for joint and
1
0
muscular pain. Disubstituted thiazole derivatives E and F are fluorescent chemo sensors of
zinc11 and aluminium12 ions respectively. Likewise, compound G is a thiazole derivative
2

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having high luminescence quantum yields. Recently, thiazole derivative H has been reported
1
4
as photostable voltage-sensitive dye with very high fluorescence quantum yield. Apart from
these, thiazole derivatives are also used as fluorescent intercalator to determine DNA binding
affinity,15 modulators of cellular development16 fluorescent sensor for detecting bisulfite
1
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anions, as well as in detection of organophosphate nerve agent etc. Considering widespread
applications of substituted thiazoles, design and development of new methods for the synthesis
of novel thiazole derivatives has remained an important topic in organic synthesis.
Similar to thiazoles, barbituric acid and its derivatives also have many applications such as
1
9
hypnotic, sedative, as well as an adjunct in anaesthesia. Recently, design and synthesis of
hybrid molecules having more than one pharmacophore has gained considerable interest in
20
drug design and medicinal chemistry. Considering the medicinal importance of hybrid
molecules, thiazoles as well as barbituric acid moiety, we were motivated to develop an
efficient method for the preparation of thiazole linked barbituric acid conjugate hybrid
molecules. One-pot multi-component assembly is an important approach for the biosynthesis
21
of various natural products by enzyme-catalysed reactions. In recent times, multicomponent
reactions have gained substantial attention in organic synthesis due to their virtues such as
2
2
atom, pot and step economic process along with good to excellent yields. Due to all these
advantages, MCRs are considered as green method in organic synthesis.23 The green
parameters of an organic synthesis can be further improved by incorporating eco-friendly
solvent or performing reactions under solvent-free conditions and introducing
mechanochemcial grinding/pasting techniques in multicomponent reactions. Grinding is a
popular mechanochemical approach for organic synthesis under solvent-free conditions.24
Considering the green chemistry aspects, grinding and ball milling has become a very popular
method for different organic transformations. 24a, 25 Solvent Drop Grinding (SDG) or Liquid
2
6
Assisted Grinding (LAG) is another well-known approach of mechanochemistry. In recent
times organic reactions performed in water medium has gained significant attention because
of economic advantage of using water as solvent as well as from the green chemistry point of
2
7
view. Considering all these, we aimed to develop a new methodology for the synthesis of tri-
substituted thiazole derivatives by a mechanochemical Liquid Assisted Grinding (LAG)
approach and a catalyst-free multicomponent reaction from the readily available starting
materials in aqueous medium.
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Conventionally, thiazoles are prepared by Hantzsch method from the reaction of α-haloketones
2
8
and thioamides where byproduct is halo acids. On the other hand, trisubstituted thiazoles are
prepared either by functionalizing pre-existing thiazole moiety or by assembly of two or more
reactants. Considering widespread applications of substituted thiazoles, development of new
methods with different substituents has remained an important topic. Recently, Zhan et al.
reported a two component reaction of thioamide with propargylic alcohol in the presence of
AgOTf as catalyst for the synthesis of substituted thiazoles in chlorobenzene medium under
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reflux conditions. Likewise, Kshiragar et al. reported a two component reaction of thioamide
and styrene system, using NBS-water under heating conditions for the synthesis of
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trisubstituted thiazoles. Togo et al. prepared -haloarylketones in situ by Friedel craft’s
acylation of arenes in dichloromethane medium and subsequently this in situ generated -
haloarylketones were treated with thioamides in dichloromethane medium in the presence of a
31
base for the preparation of disubstituted thiazoles. Murakami et al. reported a reaction of
terminal alkynes, sulfonyl azides and thionoesters using Cu(I) and Rh(II) catalysts in a
3
2
multicomponent approach for the synthesis of 2,5-disubstituted thiazoles. Yan et al. reported
a two component reaction of elemental sulfur and enaminone in the presence of ferric chloride
o
as catalyst in DMSO medium at high temperature (140 C) for the synthesis of thiazole
3
3
derivatives. Another interesting three-component reaction using elemental sulphur, primary
amine and aldehyde was reported by Jiao et al. in the presence of Cu(II) catalyst, DBU base
34
and molecular oxygen. Similarly, Deng et al. synthesized trisubstituted thiazole from the
reaction of ketone, aldehyde, ammonium halide and elemental sulfur (S ) by a four component
8
o
reaction in the presence of pyridine and water medium at high temperature (150 C ) and long
reaction time (20 h).35 We also reported a three-component reaction of arylglyoxal, 1,3-
o
36
dicarbonyls and thioamides by On-water chemistry and MW heating at 130 C. Apart from
these, recently synthesis of trisubstituted thiazoles have been reported by arylglyoxal-based
3
7
38
multicomponent reactions in the presence of acetic acid, Et N as well as under catalyst free
3
conditions.39 Although all these methods are useful for the synthesis of diverse thiazole
derivatives, but they have one or the other serious drawbacks from the green chemistry point
of view, such as involvement of metal catalysts or use of high temperature with long reaction
time or use of chlorinated solvents etc. To the best of our knowledge, there is no available
reported method in the literature for the synthesis of substituted thiazoles linked with aryl and
barbituric acid moiety. Thus, we wanted to develop a direct and one-pot practical method for
the preparation of hybrid molecules having substituted thiazole linked with barbituric acid
4

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moiety from the readily available starting materials under eco-friendly conditions. Herein we
report two room temperature methods for the synthesis of tri-substituted thiazole derivatives
linked with barbituric acid moiety (Scheme 1).
OH
OH
O
1
1
1
1
1
1
1
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1
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R2
O
O
R2
O
N
N
S
R3
R1
2
NH2
R1
N
S
1
3
3
-4 drops H O
(i). (NH4)2S, H2O, rt
ii) HCl, 1 and 2, rt
Two steps one-pot MCR
2
HO
N
R3
R3 CN
Liquid assisted
grinding (LAG)
(
R2
6
O
25-30 min
N
O
R2
4
Scheme 1. Two synthetic methods for the synthesis of trisubstituted thiazoles.
Results and discussion
In continuation of our work on multicomponent reactions for the synthesis of hybrid molecules
4
0
having more than one bioactive heterocycles, at the outset the reaction of phenylglyoxal
monohydrate (1a), 1,3-dimethylbarbituric acid (2a) and thiobenzamide (3a) was considered as
model reaction. Our first attempt using three starting materials (1:1:1) in dichloromethane
medium provided only trace amount of the desired three-component product 4a even after 12
hours stirring at room temperature (Table 1, entry 1).
Table 1. Optimization of reaction conditions for the synthesis of tri-substituted thiazole
derivatives using thioamide derivatives.a,b
O
N
O
O
OH
S
N
OH
N
Reaction
S
NH2
+
+
OH
Conditions
O
O
N
O
N
1a
2a
3a
4a
Entry
Solvent
Reaction conditionsa
Reaction
Time
Yieldb
1
2
3
4
5
Dichloromethane Room Temperature Stirring
12 h
Trace
28 %
32 %
74 %
76 %
Acetonitrile
Ethanol
Room Temperature Stirring
Room Temperature Stirring
Room Temperature Stirring
Room Temperature Stirring
24 h
24 h
24 h
24 h
Acetic acid
Water
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6
---------------
Room Temperature Grinding
45 min
55%
7
---------------
Room temperature grinding with 3
drops of water (LAG)
25 min
83%
aReaction conditions: Phenylglyoxal monohydrate (0.5 mmol), 1,3-dimethyl barbitutaric acid
b
(
0.5 mmol), thiobenzamide (0.5 mmol). Isolated yield. For entries 1-5, 3.0 mL solvent was
0
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used.
Interestingly, in acetonitrile medium and in absence of any catalyst, this model reaction
provided only 28 % yield of our desired three-component product 4a (Table 1, entry 2) within
2
4 h room temperature stirring. This three-component product 4a was then fully characterized
1
13
1
13
by using IR, H NMR, C NMR as well as by HRMS. From the H and C NMR we realized
that compound 4a, exist as a mixture of enol and amide tautomers in solution phase. After
confirming the structure, we focused on the optimization of the reaction conditions by
performing same reaction in different solvents. Protic solvent ethanol did not provide any
significant advantage and we ended with only 32% yield of 4a (Table 1, entry 3). However,
the same reaction provided significant yield improvement while performed in acetic acid
medium at room temperature.
Interestingly, when this reaction was tried in water as reaction medium, corresponding
trisubstituted thiazole was obtained in very good yield (Table 1, entry 5, 76% yield). To make
this protocol further benign we tried this reaction in solid state by grinding the mixture of the
three components using a mortar and pestle. After grinding for 45 minutes, corresponding
product 4a was obtained in moderate yield (Table 1, entry 6). To our surprise, when this
reaction was tried again by grinding and pasting in the presence of 3 drops of water, very
encouraging yield (83%) was observed within 25 minutes (Table 1, entry 7). Addition of few
drops (3-4) of water at the time of grinding resulted better yield with shorter reaction time.
Thus, we considered this mechanochemical liquid assisted grinding (LAG) or solvent drop
grinding (SDG) for 25 min as optimized reaction conditions for the three component reaction
of arylglyoxal, barbituric acid and thioamides.
Having this optimized reaction conditions, next we prepared a series of trisubstituted thiazole
derivatives (4b-4h) using this methodology by varying thioamide derivatives (Table 2).
Thioamide derivatives having variety of substituents such as R = C H , 4-Cl-C H , 4-F-C H ,
3
6
5
6
4
6
4
4-NO -C H 4-OMe-C H , 4-Me-C H C H N and Me, were tested in this three-component
2
6
4
6
4
6
4,
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reactions and we observed moderate to good yields of the corresponding products. Hetro aryl
thioamide and aliphatic thioamide provided relatively less yields (4i, 71% and 4j, 65%).
Table 2. Substrate scope for the three-component synthesis of tri-substituted thiazoles (4).a,b
R2
O
N
1
1
1
1
1
1
1
1
1
1
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2
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O
O
OH
OH
R2
O
S
3-4 drops H O
N
2
R2
R1
N
S
+
+
Grinding by mortar
and pestle for 25 min
OH
R3
NH2
O
R3
O
N
R1
N
R2
1
2
3
4
H
N
Me
N
H
N
Me
O
H
OH
O
OH
O
H
OH
O
N
OH
N
S
N
S
N
N
S
S
Cl
Me
Me
Cl
O
O
O
O
N
N
N
N
4a, 83%
4c, 83%
4d, 81%
4b, 81%
Me
Me
N
Me
Me
N
O
N
OH
O
OH
S
O
N
OH
O
OH
S
N
S
Me
F
N
N
S
OMe
N
Me
O
Me
NO2
Me
Me
N
O
O
N
O
N
N
4e, 78%
4f, 72%
4g, 80%
4h, 81%
Me
Me
H
Me
N
O
N
OH
O
N
OH
S
O
H
N
OH
O
OH
N
S
N
N
S
N
S
Me
N
Me
Me
Me
O
O
O
O
N
N
N
N
4i, 71%
4j, 65%
4k, 77%
4l, 76%
Br
F
Me
N
H
N
Me
N
Me
O
OH
O
H
OH
O
OH
O
N
OH
N
S
N
S
Me
N
S
N
S
Me
OMe Me
CF3
O
O
N
N
O
O
N
N
4m, 75%
4n, 74%
4o, 86%
4p, 87%
F3C
O2N
O2N
MeO
Me
Me
N
Me
N
O
N
OH
O
OH
S
O
OH
N
O
S
N
N
N
S
N
Me
CF3
Me
OMe
Me
Cl
O
O
O
N
4q, 85 %
4s, 75%
4r, 69%
MeO
O
OMe
aReaction conditions: arylglyoxal monohydrate derivatives (0.5 mmol), barbituric acid
derivatives (0.5 mmol), thioamide derivatives (0.5 mmol) in a mortar and grinding for 25-30
b
minutes with 3-4 drops of water. isolated yield.
7

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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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4
4
4
4
4
4
4
4
4
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5
5
5
5
5
5
5
5
5
6
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DOI: 10.1039/D0NJ00406E
Similar to thioamides, we also varied arylglyoxals. Phenylglyoxal and their derivatives having
either electron donating groups in different positions such as 4-OMe, 3-OMe, 3,4-methylene
dioxy, or electron withdrawing substituents such as 4-Br, 4-F, 4-CF and 4-NO were found
3
2
suitable for this one-pot reaction and in all these cases corresponding trisubstituted thiazoles
were observed in moderate to good yields. Both barbituric acid and 1,3-dimethylbarbituric acid
were found suitable for this methodology. In this methodology, arylglyoxals having electron
withdrawing group and thiobenzamide bearing electron-donating groups provided better
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
13
yields. All the products were fully characterized by recording, IR, H & C NMR as well as
by recording HRMS. In addition to these, we also recorded a single crystal XRD of compound
4c to unambiguously determine the structure of these compounds (Figure 2).
Figure 2. X-ray structure of 3c with 50 % ellipsoidal probability (CCDC 1979332)
After successful development of this methodology, next we wanted to develop an alternative
method for the synthesis of substituted thiazoles using alkyl or aryl nitriles as the starting
material instead of thioamide by developing a one-pot multi-component reaction. For this
initially, the reaction of phenylglyoxal (0.5 mmol), 1,3-dimethylbarbituric acid (0.5 mmol),
benzonitrile (0.5 mmol) and (NH ) S solution (0.5 mmol) in methanol was tried at room
4
2
temperature. However, this reaction failed and we did not find any desired thiazole product
Table 3, entry 1). We presumed that it may be due to the presence of ammonia which keeps
(
the reaction medium basic. Next, we tried this reaction in sequential manner. To generate
thiobenzamide in situ, firstly we did the reaction of benzonitrile and ammonium sulfide
solution at room temperature stirring for 12 hours in methanol. Then the reaction medium was
neutralized using 1.0 N HCl. In the same pot, phenylglyoxal monohydrate and 1,3-dimethyl
barbituric acid were added and stirred for another 8 hours. This reaction provided only trace
amount of desired product 4a (Table 3, entry 2). Then we shifted our attention to optimize the
8

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reaction conditions to achieve better yields by screening various solvents. When we performed
the reaction in acetonitrile medium following the same sequence, only 6% yield of desired
product 4a was obtained. Reactions in solvents like dichloromethane or toluene provided only
trace amount of product (Table 3, entries 4 and 5). Interestingly, when the first step of the
reaction was performed in water medium very good yield of benzothioamide was observed
within 12 h room temperature stirring. Then after neutralization by 1.0 N HCl and subsequent
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Table 3. Optimization of reaction conditions for the synthesis of 4a from benzonitrile.a
O
N
O
O
OH
OH
+
Solvent
N
N
CN + (NH ) S
S
+
4 2
OH
reaction conditions
O
O
N
O
5a
6
N
1a
2a
4a
Entry
1
Solvent
Reaction
sequence
and Additive
Reaction % Yield of
reaction time
condition 4a
MeOH
MeOH
at a time/ 12 h
-------------- rt
Nil
2
3
4
5
6
.
5a and 6 / 12 h followed by HCl
addition of 1a and 2a / 8 h
rt
rt
rt
rt
rt
trace
CH CN
5a and 6 / 12 h followed by HCl
addition of 1a and 2a / 8 h
6
3
CH Cl
5a and 6 / 12 h followed by HCl
addition of 1a and 2a / 8 h
trace
trace
5
2
2
Toluene
THF
5a and 6 / 12 h followed by HCl
addition of 1a and 2a / 8 h
5a and 6 / 12 h followed by HCl
addition of 1a and 2a / 8 h
7
H O
2
At a time 12 h
HCl
rt
25
8
H O
2
5a and 6 / 12 h followed by HCl
addition of 1a and 2a / 8 h
rt
84
9
H O
2
5a and 6 / 1 h followed by HCl
addition of 1a and 2a / 6 h
reflux
75
9

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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
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5
5
5
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5
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1
0
3
drops At a time grinding for 30 min HCl
rt
trace
DOI: 10.1039/D0NJ00406E
H O
2
a
Reaction conditions: benzonitrile (0.5 mmol) and (NH ) S (0.5 mmol, 40 wt% in H O),
4 2
2
followed by addition of HCl and arylglyoxal (0.5 mmol) and barbituric acid (0.5 mmol).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
addition of phenylglyoxal and 1,3-dimethylbarbituric acid to the same pot, very good yield of
a was obtained within 8 h at room temperature stirring (Table 3, entry 8). We also tried this
4
reaction under reflux conditions in water medium. Under reflux conditions, reaction time of
the first step could be reduced to 1.0 hour. Sequential two step one-pot reaction in water
medium and reflux conditions provided corresponding product 4a in 75 % yield within shorter
time (Table 3, entry 9). We also tried this reaction in a mechanochemical grinding way, but
because of the volatility of (NH ) S, the reaction failed in the first step and provided only trace
4
2
amount of the three-component product.
Table 4. Substrate scope for the synthesis of tri-substituted thiazoles by sequential two-step
one-pot reaction starting from aryl/alkylnitrile.a,b
R3
O
N
OH
N
R3
1
. H O, rt ,12h
2
CN
S
+
(NH ) S
4 2
R2
O
2. HCl, 1 & 2 .
R2
rt, stirring 8h
N
5
6
R1
4
OMe
Br
O2N
N
N
N
S
N
O
O
N
O
O
Me
O
Me
O
Me
N
Me
O
N
S
S
N
S
N
N
OH
4v, 71%
OH
O
N
OH
N
OH
4t, 71%
Me
Me
Me
4u, 85%
Me
4
a, 82%
Br
HO
N
S
N
N
S
N
S
O
O
O
O
Me
O
Me
O
Me
O
Me
N
N
S
N
N
OH
N
OH
N
OH
N
OH
O
N
OH
Me
4h, 75%
Me
4y, 75%
Me
Me
4
w, 74%
4x, 60%
N
S
N
Cl
O
O
O
N
N
S
N
Me
O
NH
O
H
N
N
S
Me
O
N
N
OH
O
N
H
OH
4bb, 49%
OH
Me
4aa, 67%
Me 4z, 81%
1
0

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a
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Reaction conditions: alkyl/aryl nitrile (0.5 mmol) and (NH ) S (0.5 mmol, 40 wt% in H O) in
DOI: 10.1 02 39/D0NJ00406E
4
2
3.0 mL water 12 hrs rt stirring, arylglyoxal (0.5 mmol) and barbituric acid (0.5 mmol) added,
b
another rt stirring for 8 hrs. Isolated yield.
Considering all these, the room temperature reaction of alkyl/aryl nitrile with ammonium
sulphide in water medium to generate in situ thioamide followed by neutralization of the
medium by 1.0 N HCl, and consecutive addition of other two substrates i.e, phenylglyoxal
monohydrate and 1,3-dimethyl barbituric acid in the same pot and stirring at room temperature
for another 8.0 hours was considered as optimum reaction conditions. Using this optimized
reaction conditions, we explored the substrate scope to synthesize another library of tri-
substituted thiazole derivatives using this sequential two-step one-pot methodology. The
results are summarized in Table 4.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Various nitriles, including benzonitrile and its derivatives having substituents such as 2-Br, 2-
OH, 4-Me, 4-CH OH were tested and we observed moderate to good yields of the products
2
(
4w, 4x, 4h and 4y). Heterocyclic nitrile such as 2-chloro-4-pyridinecarbonitrile was also used
and we observed 81% yields of the product (4z). In case of amide-protected nitrile, we observed
moderate yields of the product (4aa, 67%). Aliphatic nitrile such as acetonitrile was also found
suitable for this reaction with relatively less yield of the product (4bb, 49%). Variability of
arylglyoxals were also checked. Arylglyoxal and their derivatives having variety of
substituents such as 3-OMe, 4-NO , 4-Br were found suitable for this one-pot two-step
2
sequential reaction and provided good yields of the corresponding four component products.
After preparing these novel trisubstituted thiazoles having two-phenyl rings A and B in C-2
and C-4 position of thiazole ring with baribituric acids moiety at C-5 , we observed that some
of the products showed intense fluorescence properties under UV light whereas some other
products did not show any fluorescence properties even though they have similar basic
skeletons. To see the effect of substituent in the fluorescence properties of our substituted
thiazoles, first we recorded the absorption and steady state fluorescence spectra of compound
4
a having only two phenyl group in C-2 and C-4 position of thiazole along with dimethyl
barbituric acid moiety in C-5 position in DMSO medium. Quantum yield of 4a was determined
using quinine sulphate dihydrate in 0.1 M H SO (Φstd =0.54), as fluorescence standard. The
2
4
calculated quantum yield (Φ) of 4a was found to be 0.583. Absorption and fluorescence spectra
of compound 4a are shown in figure 3. Similarly, fluorescence quantum yield for other
thiazoles having different R , R or R were also determined and the results are summarized in
1
2
3
1
1

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2
2
2
2
2
2
2
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Table 5. Compound 4b having R = R = R = H showed slightly better quantum yield than
DOI: 10.1039/D0NJ00406E
1
2
3
4a, which may be due to the possibility of ring C attaining aromatic character by amide-iminol
tautomerization and which give extended conjugation to the thiazole ring. Compound 4d and
4
e having electron withdrawing group in ring A showed slightly lower quantum yields (Table
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
, entries 3 and 4). It is noteworthy to mention that compounds having nitro group either in
ring A (compound 4f) or in ring B (4n and 4o) did not show any fluorescence properties (Table
, entries 5, 12 and 13). In the literature it is known that incorporation of nitro group directly
5
in the fluorophore usually reduce the fluorescence of the compound due to the ability of nitro
group to elongate the path for internal conversion immediately after intersystem crossing.41
Next we recorded fluorescence quantum yield of compounds 4g and 4h having electron
donating groups OMe and Me respectively. Compound 4h showed slightly more quantum yield
that 4a whereas 4g showed reduced quantum yield. This may be due to the inductive effect of
oxygen in –OMe. It is noteworthy to mention that replacing ring A by a pyridine ring, showed
significant loss of quantum yield (Table 5, entry 8). Again, replacing benzene ring A by an
aliphatic methyl group showed only 0.08 quantum yield. Compound 4l having fluoro
substituent in the ring B showed maximum quantum yield among all the screened thiazole
derivatives (Table 5, entry 10). On the other hand thiazole derivative 4m having electron
withdrawing group CF in ring B showed very poor quantum yield (Table 4, entry 11). Next,
3
we measured quantum yield of compound 4p having EDG, 4-OMe in ring B and Electron
withdrawing 4-CF in Ring A and observed quantum yield was 0.523. Likewise 4q having
3
similar donor and acceptor groups provided 0.529 quantum yield. Thiazole derivative 4r and
4
s also showed lesser quantum yields than 4a. Thus, from these screening we realized that two
benzene rings attached with the thiazole moiety is necessary for the effective fluorescence
property of these molecules.
Table. 5 Photophysical data of some trisubstituted thiazoles in DMSO medium.a
R1
B
3
4
N
O
2
5
A
R2
O
N
S
R3
C
1
N
OH
R2
S.No
Compound
4a
R
1
R
2
R
3
 max
nm)
abs
ex
em
Stokes’
shift (nm)
Quantum
yield (Φ)
(
(nm) (nm)
1
H
Me
H
376
376
513
137
0.583
1
2

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DOI: 10.1039/D0NJ00406E
2
3
4b
4d
H
H
H
H
H
4-Cl
379
320,
379
390
514
530
135
140
0.586
0.462
3
90
4
5
4e
4f
H
H
Me
Me
4-F
379
379
484, No
358
508
129
---
0.534
NF
4-NO2 484,
58
3
emiss
ion
495
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
4g
H
Me
4-
broad
365
130
0.392
OMe
4-Me
Ring
A =
Pyridi
ne
Replac 337
e ring
A by
7
8
4h
4i
H
H
Me
Me
375
410
375
410
500
560
125
150
0.588
0.279
9
4j
H
Me
337
459
122
0.08
Me
1
1
1
0
1
2
4l
4m
4n
4-F
4-CF3 Me
4-NO2
Me
H
H
H
382
392
372,
463
382
392
463, No
372 emiss
ion
465, No
366
408
408
509
502
127
110
-
0.660
0.117
NF
H
13
4o
4-NO2 Me
4-
OMe
366,
465
-
NF
emiss
ion
562
1
1
4
5
4p
4q
4-
Me
Me
4-CF3 332,
408
4-CF3 408
154
153
0.523
0.529
OMe
3,4-
methyl
ene
dioxy
3-
OMe
4-
OMe
561
1
1
6
7
4r
4s
Me
Me
4-Cl
384
325
384
325
525
502
141
177
0.446
0.400
4-
OMe
a
-5
All spectra were recorded in DMSO solution (c= 10 M) at room temperature.
4
a
4
a
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1
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2
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2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
-5
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DOI: 10.1039/D0NJ00406E
Figure 3: (a) Absorption spectrum of 4a in DMSO (1x10 molar) (b) Fluorescence spectrum
-5
of 4a in DMSO medium (1x10 molar).
Absorption and florescence spectra of all other molecules of Table 4 are shown in supporting
information.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
The proposed reaction mechanism of our developed two methods for the synthesis of novel
trisubstituted thiazoles is shown in Scheme 2. We believe that the method I i.e, the three-
component mechanochemical LAG reaction goes via a Knoevenagel type condensation
reaction followed by a Michael addition and then intramolecular cyclization. Firstly,
arylglyoxal and barbituric acid undergo Knoevenagel type condensation reaction to form
intermediate A. Next, 1,4 Michael addition of thioamide with A will provide the intermediate
CN
4
R3
(
NH ) S
4 2
OH
2
NH3
R2
O
N
R2
N
R2
N
S
O
O
O
O
N
O
O
O
R3
NH2
OH
OH
R2
2
N
R1
R3
S
R2
N
3
R2
OH
H O
2
NH
R1
1
-2H O
2
O
O
A
H
B
R1
O
H
R2
R2
N
R2
N
HO
N
O
HO
O
HO
O
N
H
S
N
R2
S
N
S
R3
R2
R2
R3
O
R3
O
O
N
O
H
-H O
2
HN
HO
N
H
-H O
2
R1
R1
R1
O
H
4
D
C
Tautomerization
R2
O
N
O
S
N
R2
R3
O
N
R1
4
Scheme 2. Proposed reaction pathway for the catalyst-free synthesis of tri-substituted thiazoles
1
4

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DOI: 10.1039/D0NJ00406E
S
Me
Me
O
N
O
N
O
N
O
NH2
OH
O
O
Me
O
3b
N
OH
Me
N
N
Cl
S
+
Me
OH
Grinding
Gringing
O
O
O
Cl
N
Me
Intermediate A
Isolated and characterized by
NMR and HRMS
1
a
2b
4c, 83%
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 3. Stepwise reaction for the synthesis of 4c.
B. Finally, intramolecular cyclization of the intermediate B, followed by condensation,
provide our desired trisubstituted thiazole product. To confirm the formation of the
intermediate A, we have done a reaction in a stepwise manner. Firstly, we isolated the
intermediate A, from the reaction of phenylglyoxal monohydrate and 1,3-dimethylbarbituric
acid and characterized using NMR as well HRMS analysis. On addition of the third component
i.e, thioamide in A under our standard reaction conditions corresponding three-component
product was obtained in good yield (Scheme 3). Similarly, we believe that our Method II goes
through the formation of in situ thioamide from the reaction of nitriles and (NH ) S and the
4
2
other steps remain same as mentioned in Scheme 2.
After successful synthesis of tri-substituted thiazoles, we wanted to explore this methodology
to benzamide for the preparation of trisubstituted oxazoles. Interestingly, our attempt using
the reaction of phenylglyoxal monohydrate (1a), dimethyl barbituric acid (2b) and benzamide
(7a) under the same liquid assisted grinding method for 25 min. provided an acyclic three
component product 8a instead of our desired trisubstituted oxazole 9a (Scheme 4).
O
O
O
O
N
O
O
N
O
O
OH
N
N
Liquid Assisted Grinding
25 min.
N
N
+
N
NH2
H
+
+
OH
O
OH
O
N
O
O
O
8
a, 66 %
formed
9a,
1a
2b
7a
trace
Scheme 4. Three component reaction of phenylglyoxal monohydrate, 1,3-dimethylbarbituric
acid and benzamide using LAG.
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New Journal of Chemistry
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1
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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DOI: 10.1039/D0NJ00406E
0
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9
0
1
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9
0
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1
2
3
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
O
N
O
O
O
N
NH
O
Figure 4. X-ray structure of 8a with 50 % ellipsoidal probability (CCDC 1951758)
This tri-substituted methane derivative 8a containing benzoyl, barbituric acid and benzamide
1
13
moiety was fully characterized by H, C NMR and HRMS. Structure of this acyclic molecule
was further characterized by single crystal XRD also (Figure 4).
o
Interestingly, using acetic acid as reaction medium and MW heating at 130 C for 30 min.
trisubstituted oxazole derivative 9a was prepared in 69% yield. (Scheme 5).
O
O
O
N
O
O
N
OH
N
AcOH, MW
N
N
NH2
+
+
OH
130 oC, 30 min
O
O
O
OH
9
a, 69%
1a
2b
7a
Scheme 5. Reaction of phenylglyoxal monohydrate, 1,3-dimethylbarbituric acid and
benzamide under MW heating in acetic acid medium.
Conclusion
In conclusion, we have successfully developed two novel methods for the synthesis of tri-
substituted thiazole derivatives containing burbituric acid moiety by mechanochemical liquid
assisted grinding (LAG) approach and a catalyst-free water mediated multicomponent reaction
from the readily available starting materials. Environment friendly reaction conditions, wide
substrate scope, good to moderate yields of the products, easy purification process are the
notable features of both the methodologies Our products thiazole-barbituric acid molecules
are hybrid molecules having more than one pharmacophore and expected to show useful
bioactivities. We also have studied photophysical properties of some of our synthesised hybrid
molecules and observed notable fluorescence properties ranging quantum yield from (0.117 to
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.660). The fluorescence quantum yields of these molecules can be tuned by varying the
DOI: 10.1039/D0NJ00406E
different substituents present in ring A and ring B of the compounds. Compound 4l, having 4-
F substituent in ring B showed highest quantum yield of 0.660. Compounds having nitro group
either in ring A or ring B did not show any fluorescence property in DMSO medium.
Considering their prominent fluorescence properties these molecules may find applications as
chemosensors.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Author information
Corresponding Authors
*E-mail: lokman.iitp@gmail.com, lokman@iitp.ac.in (L.H.Coudhury)
*
E-mail: tasneem@nitp.ac.in (T. Parvin)
Notes
The authors declare no competing financial interest.
Acknowledgments
Authors are grateful to SERB, DST Govt of India for the financial support with sanction no
(
EMR/2016/003706) for this research work. We are also thankful to IIT Patna for providing
general research facilities and SAIF IIT Patna for providing HRMS and single crystal XRD
data.
Experimental section:
General Information: Starting materials were commercially available and used without any
further purification. Bruker 400 MHz or JEOL 500 MHz NMR spectrometer were used for
1
13
recording H NMR and C NMR spectra in DMSO-d or CDCl . Tetramethylsilane was used
6
3
as reference and the chemical shifts were calculated in δ values in ppm downfield from it.
Perkin Elmer FTIR spectrometer was used for recording infrared spectrum. HRMS analysis
was carried out using BRUKER Impact HD mass spectrometer (Impact HD UHR-TOF, ESI
with positive mode). Melting points were recorded using SRS EZ-Melt automated melting
point apparatus by capillary methods and uncorrected. Single-crystal XRD data were recorded
with a BRUKER AXS (D8 Quest System) X-ray diffractometer. UV-visible absorption spectra
were recorded by a Shimadzu UV-2550 UV-visible spectrophotometer and a Horiba Jobin Yuon
Fluoromax-4 spectrofluorimeter was used for recording fluorescence spectra of studied molecules.
General procedure for the synthesis of thiazole-barbituric acid conjugates (4):
Method I: A mixture of arylglyoxal monohydrate 1 (0.5 mmol), barbituric acid derivative 2
(0.5 mmol) and thioamide 3 (0.5 mmol) was taken in a mortar. The mixture was grinded
1
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
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5
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DOI: 10.1039/D0NJ00406E
thoroughly with a grinder for 5 minutes. To this mixture, 3-4 drops of water were added and
again grinding was continued for 15-20 minutes. TLC monitored the progress of the reaction,
and after completion of the reaction, 10.0 mL distilled water was added to the reaction mixture
and the precipitate was filtered off. The obtained crude product was further purified by
recrystallization in methanol.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Method II: A solution of aryl/alkyl nitrile (0.5 mmol) and (NH ) S (0.5 mmol, 40 wt.% in
4 2
H O) in 3.0 mL distilled water was taken in a 10.0 mL round bottom flask. The reaction mixture
2
was stirred at room temperature for 12 hours. The reaction was monitored by TLC and after
completion, a few drops of dilute HCl were added to neutralize the reaction medium (monitored
by pH paper). After neutralization, to the reaction mixture arylglyoxal monohydrate (0.5 mmol)
and barbituric acid (0.5 mmol) were added. Then the reaction mixture was stirred for another
8
hours at room temperature. The progress of the reaction was monitored by TLC and after
completion of the reaction; the precipitate obtained was filtered off. The crude product was
purified by recrystallization in methanol.
General procedure for the synthesis of 8a:
A mixture of phenylglyoxal monohydrate (0.5 mmol), 1,3-dimethylbarbituric acid (0.5 mmol),
and benzamide (0.5 mmol) was taken was taken in a mortar. The mixture was grinded
thoroughly with a grinder for 5 minutes. To this mixture, 3-4 drops of water were added and
again grinding was continued for 15-20 minutes. After completion of the reaction, 10.0 mL-
distilled water was added to the reaction mixture and the precipitate was filtered off. The
obtained crude product was further purified by recrystallization in methanol.
General procedure for the synthesis of 9a:
A solution of phenylglyoxal monohydrate (0.5 mmol), 1, 3-dimethylbarbituric acid (0.5 mmol),
and benzamide (0.5 mmol) was taken in 3.0 mL acetic acid in a 5 mL microwave vial. The
o
reaction mixture was irradiated at130 C under microwave heating conditions for 30 minutes.
After completion of the reaction, the solution was poured into 10 mL distilled water and the
resultant precipitate was filtered off. The crude product was further purified by recrystallization
in methanol.
6
-hydroxy-1,3-dimethyl-5-(2,4-diphenylthiazol-5-yl)-pyrimidine-2,4(1H,3H)-dione (4a):
o
(
Mixture of tautomers) Yield 160 mg (82%); light yellow solid, mp. 265-267 C; IR (ATR)
-1 1
3483, 3052, 1689, 1676, 1561, 1481, 1419, 1382, 1245, 1138, 1017, 770 cm . H NMR (400
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DOI: 10.1039/D0NJ00406E
MHz, DMSO-d ) δ = 7.97 (d, J = 8.0 Hz, 2H, ArH), 7.76 (d, J = 8.0 Hz, 2H, ArH), 7.56-7.48
6
(m, 3H, ArH), 7.37 (t, J = 8.0 Hz, 2H, ArH), 7.28 (t, J = 8.0 Hz, 1H, ArH), 4.68 (bs, OH), 4.38
1
3
(
bs, CH), 3.17 (s, 6H, NCH ), C NMR (100 MHz, DMSO-d ) δ = 165.0, 160.4, 152.0, 151.2,
3
6
1
35.2, 133.1, 130.2, 129.3, 128.3, 128.2, 127.5, 125.9, 81.6, 28.2 ppm. HRMS (ESI-TOF)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
calculated for C H N O S [M + H ] 392.1063, found 392.1065.
2
1
18
3
3
6
-hydroxy-5-(2,4-diphenylthiazol-5-yl)-pyrimidine-2,4(1H,3H)-dione (4b): Yield 148 mg
o
(
81%); yellow solid; mp. 325-327 C; IR (ATR): 3165, 3030, 1685, 1661, 1573, 1494, 1448,
-1
1
1
427, 1361, 1207, 921, 818, 761, 688 cm ; H NMR (400 MHz, DMSO-d ) δ 11.01 (s, 2H,
6
NH), 7.99 (d, J = 8.0 Hz, 2H, ArH), 7.75 (d, J = 4.0 Hz, 2H, ArH), 7.55 – 7.48 (m, 3H, ArH),
1
3
7
.41 (t, J = 8.0 Hz, 2H, ArH), 7.32 (t, J = 8.0 Hz, 1H, ArH), 4.21 (1H, OH). C NMR (100
MHz, DMSO-d ) δ 165.7, 161.9, 153.3, 150.0, 135.1, 133.3, 130.2, 129.3, 128.3, 127.7, 127.4,
6
+
1
25.9, 123.3, 82.0 ppm. HRMS (EI): m/z [M+H] calculated for C H N O S, 364.0750;
1
9
14
3
3
found 364.0752.
5
3
-(2-(4-chlorophenyl)-4-phenylthiazol-5-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4 (1H,
H)-dione (4c): Yield 176 mg (83%); white solid; mp. 260-262 ºC; IR (ATR): 3101, 1705,
-1 1
1601, 1500, 1188, 1089, 996, 836,763,702 cm ; H NMR (400 MHz, DMSO-d ) δ 7.97 (d, J
6
=
8.0 Hz, 2H, ArH), 7.74 (d, J = 8.0 Hz, 2H, ArH), 7.58 (d, J = 8.0 Hz, 2H, ArH), 7.36 (t, J =
13
8
.0 Hz, 2H, ArH), 7.28 (t, J = 8.0 Hz, 1H, ArH), 4.01 (1H, OH), 3.15 (s, 6H, NCH ); C NMR
3
(100 MHz, DMSO-d ) δ 163.5, 160.4, 152.4, 151.2, 135.2, 134.6, 132.1, 129.3, 128.2, 127.5,
6
+
1
4
27.4, 126.5, 81.5, 28.2 ppm. HRMS (EI): m/z [M+H] calculated for C H ClO N S,
21 17
3
3
26.0674; found 426.0695.
5-(2-(4-chlorophenyl)-4-phenylthiazol-5-yl)-6-hydroxypyrimidine-2,4(1H,3H)-dione
(
4d): (Mixture of tautomer) Yield 160 mg (81%); orange solid; mp. 328-330 ºC; IR (ATR):
-1 1
3
055, 1693, 1566, 1511, 1455, 1397, 1093, 828, 776, 766, 688 cm ; H NMR (400 MHz,
DMSO-d ) δ 11.02 (s, 2H, NH), 8.01 (d, J = 8.0 Hz, 2H, ArH), 7.73 (d, J = 8.0 Hz, 2H, ArH),
6
7.59 (d, J = 8.0 Hz, 2H, ArH), 7.40 (d, J = 4.0 Hz, 2H, ArH), 7.33 (d, J = 8.0 Hz, 1H, ArH),
1
3
4
1
.02 (bs, OH), 3.17 (s, 1H, CH). C NMR (100 MHz, DMSO-d ) δ 164.3, 161.9, 153.4, 150.0,
6
34.9, 134.7, 132.1, 129.4, 128.3, 127.8, 127.6, 127.4, 123.8, 81.8, ppm. HRMS (EI): m/z
+
[
M+H] calculated for C H ClO N S, 398.0361; found 398.0366.
1
9
13
3
3
5
3
1
-(2-(4-fluorophenyl)-4-phenylthiazol-5-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,
o
H)-dione (4e): Yield 160 mg (78%); white solid, mp. 247-249 C; I.R. (A.T.R.) 3057, 2959,
708, 1601, 1579, 1512, 1503, 1486, 1444, 1408, 1383, 1349, 1298, 1276, 1234, 1195, 1161,
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
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141, 1088, 1029, 998, 984, 956, 923, 866, 838, 799 cm . H NMR (500 MHz, DMSO-d ) δ
DOI: 10.1039 /6D 0NJ00406E
= 8.01-7.98 (d, J = 10.0 Hz, 2H, ArH), 7.74 (d, J = 10.0 Hz, 2H, ArH), 7.37-7.33 (m, 4H, ArH),
1
3
7
1
1
.28 (d, J = 5.0 Hz, 1H, ArH), 3.14 (s, 6H, NCH ); C NMR (125 MHz, DMSO-d ) δ = 164.6,
3 6
63.3 (d, JC-F = 235.0 Hz), 162.6, 161.1, 152.3, 151.9, 135.8, 130.4, 129.2, 128.6, 127.9, 127.4,
16.8 (d, JC-F = 22.5Hz), 81.6, 28.5 ppm. HRMS (ESI-TOF) calculated for C H FN O S [M
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
21
17
3
3
+
+ H ] 410.0969, found 410.0960.
6
3
-hydroxy-1,3-dimethyl-5-(2-(4-nitrophenyl)-4-phenylthiazol-5-yl)pyrimidine-2,4(1H,
o
H)-dione (4f): Yield 157 mg (72%); pale yellow solid, mp. 232-234 C; I.R. (ATR.) 2951,
1706, 1596, 1554, 1523, 1504, 1459, 1358, 1313, 1276, 1254, 1181, 1139, 1086, 1030, 996,
-1 1
9
48, 853, 802, 763 cm . H NMR (500 MHz, DMSO-d ) δ = 8.36 (d, J = 10.0 Hz, 2H, ArH),
6
8
.21 (d, J = 10.0 Hz, 2H, ArH), 7.77 (d, J = 10.0Hz, 2H, ArH), 7.38-7.35 (m, 2H, ArH), 7.29
13
(
d, J = 10.0 Hz, 1H, ArH), 4.02 (bs, OH), 3.13 (s, 6H, NCH ); C NMR (125 MHz, DMSO-
3
d6) δ = 161.5, 160.5, 152.9, 151.4, 147.7, 139.0, 135.4, 129.9, 128.1, 127.5, 127.4, 126.7, 124.7,
+
8
4
1.2, 28.0 ppm. HRMS (ESI-TOF) calculated for C H N O S [M + H ] 437.0914, found
2
1
17
4
5
37.0906.
6-hydroxy-5-(2-(4-methoxyphenyl)-4-phenylthiazol-5-yl)-1,3-dimethylpyrimidine-2,4(1
o
H,3H)-dione (4g):Yield 168 mg (80%); yellow solid, mp. 259-261 C; IR (ATR) 2970, 1738,
-1
1
1
673, 1600, 1521, 1454, 1373, 1252, 1176, 1024, 913 cm . H NMR (400 MHz, DMSO-d ) δ
6
= 7.92 (d, J = 8.0 Hz, 2H, ArH), 7.73 (d, J = 4.0 Hz, 2H, ArH), 7.36 (t, J = 8.0 Hz, 2H, ArH),
7
3
1
.30 (d, J = 4.0 Hz, 1H, ArH), 7.09 (d, J = 8.0 Hz, 2H, ArH), 4.46 (bs, OH), 3.84 (s, 3H, OCH3)
1
3
.16 (s, 6H, NCH ); C NMR (100 MHz, DMSO-d ) δ = 164.8, 160.9, 160.3, 151.2, 150.8,
3
6
34.9, 128.1, 127.7, 127.5, 125.5, 125.3, 114.6, 81.4, 55.4, 28.1 ppm. HRMS (ESI-TOF)
+
calculated for C H N O S [M + H ] 422.1169, found 422.1168.
2
2
20
3
4
6
-hydroxy-1,3-dimethyl-5-(4-phenyl-2-(p-tolyl)thiazol-5-yl)pyrimidine-2,4(1H,3H)-dione
o
(
4h): Yield 164 mg (81%); white solid, mp. 270-272 C; IR (ATR) 2950, 1706, 1606, 1488,
-1 1
1186, 1089, 998, 816 cm . H NMR (400 MHz, DMSO-d ) δ = 7.87 (d, J = 8.0 Hz, 2H, ArH),
6
7
.74 (d, J = 8.0 Hz, 2H, ArH), 7.39-7.28 (m, 5H, ArH), 3.17 (s, 6H, NCH ), 2.38 (s, 3H, CH );
3 3
1
3
C NMR (100 MHz, DMSO-d ) δ = 165.2, 160.3, 151.6, 151.0, 140.1, 134.9, 130.3, 129.8,
6
1
28.1, 127.53, 127.46, 125.9, 125.0, 81.7, 28.2, 20.9 ppm. HRMS (ESI-TOF) calculated for
+
C H N O S [M + H ] 406.1219, found 406.1202.
2
2
20
3
3
6
-hydroxy-1,3-dimethyl-5-(4-phenyl-2-(pyridin-4-yl)thiazol-5-yl)pyrimidine-2,4(1H,3H)-
o
dione (4i). Yield 140 mg (71%); red solid, mp. 325-327 C; IR (ATR) 3070, 3033, 1684, 1608,
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547, 1481, 1433, 1411, 1084, 972 cm . H NMR (400 MHz, DMSO-d ) δ = 8.79 (d, J = 4.0
6
DOI: 10.1039/D0NJ00406E
Hz, 2H, ArH), 8.30 (d, J = 4.0, 2H, ArH), 7.75 (d, J = 8.0 Hz, 2H, ArH), 7.31 (t, J = 8.0 Hz,
1
3
2
H, ArH), 7.22 (t, J = 8.0 Hz, 1H, ArH), 3.80 (bs, OH), 3.10 (s, 6H, NCH ); C NMR (100
3
MHz, DMSO-d ) δ =160.5, 154.1, 152.3, 151.9, 147.3, 143.0, 139.5, 136.9, 127.6, 127.1,
6
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
1
26.8, 121.1, 81.6, 27.3 ppm. HRMS (ESI-TOF) calculated for C H N O S [M + H ]
2
0
17
4
3
393.1015, found 393.1002.
6
-hydroxy-1,3-dimethyl-5-(2-methyl-4-phenylthiazol-5-yl)pyrimidine-2,4(1H,3H)-dione
o
(
4j): Yield 108 mg (65%); white solid, mp. 314-316 C; IR (ATR) 2947, 1740, 1679, 1611,
-1 1
1554, 1449, 1425, 1386, 1236, 1141, 992, 849 cm . H NMR (400 MHz, DMSO-d ) δ = 7.52
6
(
d, J = 8.0 Hz, 2H, ArH), 7.37 (t, J = 8.0 Hz, 2H, ArH), 7.31 (t, J = 8.0 Hz, 1H, ArH), 3.09 (s,
1
3
6
1
H, NCH ), 2.80 (s, 3H, CH ); C NMR (100 MHz, DMSO-d ) δ = 165.2, 160.3, 160.2, 151.8,
3 3 6
32.8, 128.0, 127.8, 127.1, 80.0, 27.5, 16.6 ppm. HRMS (ESI-TOF) calculated for
+
C H N O S [M + H ] 330.0907, found 330.0905.
1
6
16
3
3
5
:
-(4-(4-bromophenyl)-2-phenylthiazol-5-yl)-6-hydroxypyrimidine-2,4(1H,3H)-dione (4k)
o
Yield 170 mg (77%); light yellow solid, mp. 338-340 C; IR (ATR) 3119, 2973, 2789, 1674,
-1 1
1573, 1485, 1421, 1404, 1385, 1212, 1077, 756 cm . H NMR (400 MHz, DMSO-d ) δ =10.97
6
(
s, 2H, NH), 7.98 (d, J = 8.0 Hz, 2H, ArH), 7.69 (d, J = 12.0 Hz, 2H, ArH), 7.61 (d, J = 8.0 Hz,
13
2
H, ArH), 7.55-7.50 (m, 3H, ArH), 4.14 (bs, OH),; C NMR (100 MHz, DMSO-d ) δ = 165.7,
6
161.8, 151.7, 150.0, 134.4, 133.1, 131.2, 130.2, 129.4, 129.3, 125.9, 124.3, 120.8, 81.7 ppm.
+
HRMS (ESI-TOF) calculated for C H N O BrS [M + H ] 441.9856, found 441.9844.
19 13
3
3
5
-(4-(4-fluorophenyl)-2-phenylthiazol-5-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4 (1H,
o
3H)-dione (4l): Yield 156 mg (76%); white solid, mp. 275-278 C; IR (ATR) 3066, 1708,
1
9
604, 1590, 1489, 1408, 1385, 1346, 1282, 1222, 1198, 1155, 1141, 1088, 1071, 1012, 998,
-1 1
82, 953, 872, 847, 796 cm . H NMR (500 MHz, DMSO-d ) δ = 7.95 (d, J = 5.0 Hz, 2H,
6
ArH), 7.78 (m, 2H, ArH), 7.53-7.48 (m, 3H, ArH), 7.19-7.16 (m, 2H, ArH), 3.14 (s, 6H,
1
3
NCH ); C NMR (125 MHz, DMSO-d ) δ = 163.5 (d, J = 262.5 Hz) , 160.6, 151.6, 150.7,
3
6
C-F
1
33.3, 130.1, 129.6, 129.5, 129.4, 129.3, 127.2, 126.0, 114.9 (d, JC-F = 21.3 Hz), 81.0, 28.1
+
ppm. HRMS (ESI-TOF) calculated for C H FN O S [M + H ] 410.0969, found 410.0961.
2
1
17
3
3
6-hydroxy-1,3-dimethyl-5-(2-phenyl-4-(4-(trifluoromethyl)phenyl)thiazol-5-yl)pyrimid
o
ine-2,4 (1H,3H)-dione (4m): Yield 173 mg (75%); white solid, mp. 274-276 C; I.R. (A.T.R.)
1
7
691, 1607, 1512, 1439, 1321, 1259, 1240, 1167, 1116, 1066, 1015, 984, 950, 928, 864, 802,
-1 1
66 cm . H NMR (500 MHz, DMSO-d ) δ = 7.98 (d, J = 5.0 Hz, 4H, ArH), 7.72 (d, J = 10.0
6
2
1

New Journal of Chemistry
Page 22 of 29
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1
1
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
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5
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DOI: 10.1039/D0NJ00406E
Hz, 2H, ArH), 7.55-7.50 (m, 3H, ArH), 5.12 (bs, 1H, OH), 3.16 (s, 6H, NCH ); C NMR (125
3
MHz, DMSO-d ) δ = 165.0, 160.4, 151.2, 150.0, 139.4, 133.1, 130.2, 129.3, 128.7, 127.9,
6
1
27.7, 127.4 (q, JC-F = 33.0 Hz), 125.9, 125.1, 124.4 (q, JC-F = 271.0 Hz) 81.4, 28.1 ppm.
+
HRMS (ESI-TOF) calculated for C H F N O S [M + H ] 460.0937, found 460.0936.
2
2
17
3
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6
-hydroxy-5-(4-(4-nitrophenyl)-2-phenylthiazol-5-yl)pyrimidine-2,4(1H, 3H)-dione (4n):
o
Yield 150 mg (74%); yellow solid, mp. 300-302 C; IR (ATR) 3426, 2947, 2787, 1737, 1654,
-1 1
1
571, 1516, 1482, 1385, 1334, 1216, 1106, 1065, 851 cm . H NMR (400 MHz, DMSO-d ) δ
6
=
10.92 (s, 2H, NH), 8.28 (d, J = 8.0Hz, 2H, ArH), 8.01 (t, J = 8.0Hz, 4H, ArH), 7.52 (d, J =
1
3
8
.0 Hz, 3H, ArH), 4.81 (bs, OH),; C NMR (100 MHz, DMSO-d ) δ = 165.7, 161.8, 150.14,
6
150.07, 146.2, 141.8, 133.0, 130.3, 129.3, 128.3, 127.8, 125.9, 123.6, 81.7 ppm. HRMS (ESI-
+
TOF) calculated for C H N O S [M + H ] 409.0601, found 409.0599.
1
9
13
4
5
6
-hydroxy-5-(2-(4-methoxyphenyl)-4-(4-nitrophenyl)thiazol-5-yl)-1,3-dimethylpyrimid
o
ine-2,4(1H,3H)-dione (4o): Yield 200 mg (86%); yellow solid, mp. 309-311 C; IR (ATR)
-1 1
2
970, 1737, 1663, 1594, 1571, 1519, 1503, 1424, 1345, 1264, 1192, 1014, 843 cm . H NMR
(
400 MHz, DMSO-d ) δ = 8.20 (d, J = 8.0 Hz, 2H, ArH), 8.01 (d, J = 8.0 Hz, 2H, ArH), 7.91
6
(d, J = 8.0 Hz, 2H, ArH), 7.08 (d, J = 8.0, 2H, ArH), 4.90 (bs, OH), 3.84 (s, 3H, OCH ), 3.15
3
1
3
(
s, 6H, NCH ); C NMR (100 MHz, DMSO-d ) δ = 164.8, 160.9, 160.3, 151.3, 148.1, 145.9,
3
6
1
42.1, 129.8, 128.2, 127.6, 125.6, 123.4, 114.6, 81.6, 55.4, 28.0 ppm. HRMS (ESI-TOF)
+
calculated for C H N O S [M + H ] 467.1020, found 467.1015.
2
2
19
4
6
6
-hydroxy-5-(4-(4-methoxyphenyl)-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)-1,3-dime-
o
thylpyrimidine-2,4(1H,3H)-dione (4p): Yield 213 mg (87%); orange solid, mp. 240-243 C;
I.R. (A.T.R.) 3500, 3067, 1694, 1596, 1573, 1509, 1475, 1430, 1324, 1242, 1167, 1122, 1071,
-1 1
1026, 838, 774, 754, 721, 664 cm . H NMR (500 MHz, DMSO-d ) δ = 8.16 (d, J = 5.0 Hz,
6
2
2
1
H, ArH), 7.87 (d, J = 10.0 Hz, 2H, ArH), 7.71 (d, J = 10.0 Hz, 2H, ArH), 6.93 (d, J = 5.0 Hz,
1
3
H, ArH), 3.76 (s, 3H, OCH ), 3.15 (s, 6H, NCH ) ; C NMR (125 MHz, DMSO-d ) δ = 162.5,
3
3
6
60.5, 158.7, 152.7, 152.6, 151.3, 137.0, 129.6 (q, JC-F = 33.0 Hz), 128.8, 127.9, 126.4, 126.2,
124.1(q, JC-F = 270.0 Hz ) 113.6, 81.3, 55.1, 28.1 ppm. HRMS (ESI-TOF) calculated for
+
C H F N O S [M + H ] 490.1043, found 490.1045.
2
3
19
3
3
4
5
-(4-(benzo[d][1,3]dioxol-5-yl)-2-(4-(trifluoromethyl)phenyl)thiazol-5-yl)-6-hydroxy-1,3-
dimethylpyrimidine-2,4(1H,3H)-dione (4q): Yield 214 mg (85%); orange solid, mp. 238-240
oC; I.R. (A.T.R.) 3655, 3464, 3077, 2912, 1742, 1691, 1669, 1593, 1571, 1478, 1442, 1405,
-1
1
1
386, 1324, 1231, 1169, 1125, 1069, 1035, 1004, 937, 914, 850, 822, 808, 774 cm . H NMR
2
2

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DOI: 10.1039/D0NJ00406E
(
500 MHz, DMSO-d ) δ = 8.15 (d, J = 10.0 Hz, 2H, ArH), 7.87 (d, J = 5.0 Hz, 2H, ArH), 7.27
6
1
3
(s, 2H, ArH), 6.90 (d, J = 10.0 Hz, 1H, ArH), 6.02 (s, 2H, OCH ) 3.15 (s, 6H, NCH ) ; C
2
3
NMR (125 MHz, DMSO-d ) δ = 162.4, 160.5, 152.4, 151.3, 147.0, 146.6, 136.9, 129.6 (q, J
6
C-
=
33.0 Hz), 129.4, 129.3, 126.9, 126.4, 126.23, 126.21, 124.1(q, JC-F = 270.0 Hz), 121.4,
F
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
08.1, 107.8, 101.0, 81.1, 28.1 ppm. HRMS (ESI-TOF) calculated for C H F N O S [M +
2
3
17
3
3
5
+
H ] 504.0836, found 504.0834.
5
-(2-(4-chlorophenyl)-4-(3-methoxyphenyl)thiazol-5-yl)-6-hydroxy-1,3-dimethylpyrimi
o
dine-2,4(1H,3H)-dione (4r): Yield 158 mg (69%); white solid, mp. 278-280 C; IR (ATR)
-1 1
2957, 1709, 1601, 1576, 1499, 1477, 1230, 1195, 1089, 1047, 1001, 763, cm . H NMR (400
MHz, DMSO-d ) δ = 7.98 (d, J = 8.0 Hz, 2H, ArH), 7.59 (d, J = 4.0 Hz, 2H, ArH), 7.33-7.25
6
(
m, 3H, ArH), 6.86 (d, J = 8.0 Hz, 1H, ArH), 4.34 (bs, OH), 3.71 (s, 3H, OCH ), 3.15 (s, 6H,
3
13
NCH ); C NMR (100 MHz, DMSO-d ) δ = 163.2, 160.8, 159.0, 151.6, 136.7, 134.6, 132.3,
3
6
129.5, 129.4, 129.2, 127.6, 120.1, 113.3, 112.9, 81.0, 54.9, 28.1 ppm. HRMS (ESI-TOF)
+
calculated for C H N O SCl [M + H ] 456.0779, found 456.0771.
2
2
19
3
4
5
-(2,4-bis(4-methoxyphenyl)thiazol-5-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)
o
-dione (4s): Yield 170 mg (75%); yellow solid, mp. 256-258 C; IR (ATR) 2947, 2834, 1685,
-1 1
1
600, 1567, 1506, 1442, 1246, 1185, 1029, 833 cm . H NMR (400 MHz, DMSO-d ) δ = 7.91
6
(
d, J = 8.0 Hz, 2H, ArH), 7.67 (d, J = 8.0 Hz, 2H, ArH), 7.09 (d, J = 8.0 Hz, 2H, ArH), 6.93
(d, J = 8.0, 2H, ArH), 5.06 (bs, OH), 3.84 (s, 3H, OCH ), 3.77 (s, 3H, OCH ), 3.17 (s, 6H,
3
3
1
3
NCH ); C NMR (100 MHz, DMSO-d ) δ = 164.5, 160.8, 160.3, 158.6, 151.3, 150.5, 128.8,
3
6
1
28.7, 127.5, 125.5, 114.5, 113.4, 81.2, 55.3, 54.9, 27.9 ppm. HRMS (ESI-TOF) calculated for
+
C H N O S [M + H ] 452.1274, found 452.1260.
2
3
22
3
5
6
-hydroxy-5-(4-(3-methoxyphenyl)-2-phenylthiazol-5-yl)-1,3-dimethylpyrimidine-2,4
o
(
1H,3H)-dione (4t): Yield 150 mg (71%); white solid, mp. 254-256 C; IR (ATR) 3397, 2970,
-1 1
1
702, 1606, 1500, 1280, 1214, 1191, 1046, 1024, 995, 881 cm . H NMR (400 MHz, DMSO-
d6) δ = 7.96 (d, J = 4.0 Hz, 2H, ArH), 7.54-7.46 (m, 3H, ArH), 7.35 (bs, 2H, ArH), 7.26 (t, J =
1
3
8
.0Hz, 1H, ArH), 6.84 (d, J = 8.0 Hz, 1H, ArH), 3.71 (s, 3H, OCH ), 3.15 (s, 6H, NCH ); C
3 3
NMR (100 MHz, DMSO-d ) δ = 166.7, 160.6, 158.9, 151.6, 136.8, 133.4, 129.9, 129.2, 129.0,
6
1
25.8, 119.9, 113.1, 112.8, 80.7, 54.8, 27.8 ppm. HRMS (ESI-TOF) calculated for
+
C H N O S [M + H ] 422.1169, found 422.1172.
2
2
20
3
4
6
3
-hydroxy-1,3-dimethyl-5-(4-(4-nitrophenyl)-2-phenylthiazol-5-yl)pyrimidine-2,4(1H,
o
H)-dione (4u): Yield 186 mg (85%); orange solid, mp. 303-305 C; IR (ATR) 3077, 1737,
2
3

New Journal of Chemistry
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2
2
2
2
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3
3
3
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3
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5
5
5
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6
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683, 1607, 1562, 1515, 1500, 1435, 1345, 1239, 1144, 868 cm . H NMR (400 MHz, DMSO-
DOI: 10.1039/D0NJ00406E
d6) δ = 8.20 (d, J = 8.0 Hz, 2H, ArH), 8.03 (d, J = 8.0 Hz, 2H, ArH), 7.97 (d, J = 8.0Hz, 2H,
1
3
ArH), 7.55-7.49 (m, 3H, ArH), 5.24 (bs, OH), 3.15 (s, 6H, NCH ); C NMR (100 MHz,
3
DMSO-d ) δ = 168.5, 163.9, 160.3, 151.6, 145.7, 142.7, 133.2, 132.2, 129.9, 129.2, 128.1,
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
1
25.8, 123.2, 81.4, 27.8 ppm. HRMS (ESI-TOF) calculated for C H N O S [M + H ]
2
1
17
4
5
437.0914, found 437.0903.
5
-(4-(4-bromophenyl)-2-phenylthiazol-5-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,
o
3
H)-dione (4v): Yield 166 mg (71%); light yellow solid, mp. 257-259 C; IR (ATR) 3089,
-1 1
3055, 1687, 1609, 1520, 1485, 1439, 1238, 1008, 853 cm . H NMR (400 MHz, DMSO-d ) δ
6
=
7.96 (d, J = 4.0 Hz, 2H, ArH), 7.71 (d, J = 8.0 Hz, 2H, ArH), 7.56-7.47 (m, 5H, ArH), 4.07
1
3
(
bs, OH), 3.16 (s, 6H, NCH ); C NMR (100 MHz, DMSO-d ) δ = 164.6, 160.3, 151.3, 150.3,
3
6
1
34.7, 133.1, 130.9, 130.0, 129.4, 129.2, 127.4, 125.8, 120.5, 81.2, 28.0 ppm. HRMS (ESI-
+
TOF) calculated for C H BrN O S [M + H ] 470.0169, found 470.0163.
2
1
17
3
3
5
3
-(2-(2-bromophenyl)-4-phenylthiazol-5-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,
o
H)-dione (4w): Yield 174 mg (74%); white solid, mp. 219-221 C; IR (ATR) 2970, 1738,
-1 1
1709, 1594, 1484, 1379, 1217, 1191, 1146, 1084, 998 cm . H NMR (400 MHz, DMSO-d ) δ
6
=
8.19 (dd, J = 8.0 Hz, 2Hz, 1H, ArH), 7.83-7.78 (m, 3H, ArH), 7.56 (t, J = 8.0 Hz, 1H, ArH),
7
.41(t, J = 8.0 Hz, 1H, ArH), 7.35 (t, J = 8.0 Hz, 2H, ArH), 7.26 (t, J = 8.0 Hz, 1H, ArH), 3.15
1
3
(s, 6H, NCH ); C NMR (100 MHz, DMSO-d ) δ = 168.5, 162.1, 161.5, 153.3, 150.8, 136.4,
3
6
1
34.8, 134.3, 131.8, 131.6, 129.3, 128.8, 128.7, 128.1, 127.9, 121.1, 80.6, 28.3 ppm. HRMS
+
(
ESI-TOF) calculated for C H N O SBr [M + H ] 470.0169, found 470.0162.
2
1
17
3
3
6-hydroxy-5-(2-(2-hydroxyphenyl)-4-phenylthiazol-5-yl)-1,3-dimethylpyrimidine-2,4
o
(
1H,3H)-dione (4x): Yield 132 mg (60%); yellow solid, mp. 270-272 C; IR (ATR ) 2973,
-1 1
2
941, 1740, 1693, 1589, 1558, 1519, 1456, 1379, 1270, 1246, 1001, 748 cm . H NMR (400
MHz, DMSO-d ) δ = 7.97 (d, J = 8.0 Hz, 1H, ArH), 7.71 (d, J = 8.0 Hz, 2H, ArH), 7.39-7.27
6
(m, 4H, ArH), 7.04 (d, J = 8.0Hz, 1H, ArH), 6.98 (t, J = 8.0Hz, 1H, ArH), 4.17 (bs, OH), 3.16
1
3
(
s, 6H, NCH ); C NMR (100 MHz, DMSO-d ) δ = 162.9, 160.5, 155.5, 152.9, 151.4, 148.8,
3
6
1
34.7, 131.3, 128.2, 127.6, 127.3, 127.2, 119.6, 117.9, 116.8, 80.9, 28.0 ppm. HRMS (ESI-
+
TOF) calculated for C H N O S [M + H ] 408.1013, found 408.1015.
2
1
18
3
4
6
-hydroxy-5-(2-(4-(hydroxymethyl)phenyl)-4-phenylthiazol-5-yl)-1,3-dimethylpyrimid
o
ine-2,4(1H,3H)-dione (4y) : Yield 158 mg (75%); white solid, mp. 210-212 C; IR (ATR)
-1 1
3
441, 3055, 1670, 1603, 1574, 1489, 1447, 1420, 1383, 1242, 1140, 1002, 827 cm . H NMR
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DOI: 10.1039/D0NJ00406E
(
400 MHz, DMSO-d ) δ = 7.94 (d, J = 8.0 Hz, 2H, ArH), 7.75 (d, J = 8.0 Hz, 2H, ArH), 7.47
6
(d, J = 8.0 Hz, 2H, ArH), 7.36 (t, J = 8.0 Hz, 2H, ArH), 7.28 (t, J = 8.0 Hz, 1H, ArH), 4.57 (s,
1
3
2
1
H, CH ), 4.72 (bs, OH), 3.17 (s, 6H, NCH ); C NMR (100 MHz, DMSO-d ) δ = 164.8,
2 3 6
60.3, 151.5, 151.3, 144.8, 135.2, 131.5, 128.1, 127.4, 127.1, 125.7, 81.3, 62.5, 28.1 ppm.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
HRMS (ESI-TOF) calculated for C H N O S [M + H ] 422.1169, found 422.1153.
2
2
20
3
4
5
-(2-(2-chloropyridin-3-yl)-4-phenylthiazol-5-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4
o
(
1H,3H)-dione (4z): Yield 172 mg (81%); orange solid, mp. 260-262 C; IR (ATR) 2928,
-1
1
1
705, 1601, 1486, 1372, 1287, 1187, 1087, 998, 803 cm . H NMR (400 MHz, DMSO-d ) δ
6
= 8.76 (dd, J = 8.0, 2.0 Hz, 1H, ArH), 8.52 (dd, J = 4.0, 2.0 Hz, 1H, ArH), 7.80 (d, J = 8.0
Hz, 2H, ArH), 7.65-7.62 (m, 1H, ArH), 7.36 (t, J = 8.0 Hz, 2H, ArH), 7.27 (t, J = 8.0 Hz, 1H,
1
3
ArH), 4.56 (bs, OH), 3.15 (s, 6H, NCH ); C NMR (100 MHz, DMSO-d ) δ = 160.8, 160.7,
3
6
1
57.6, 151.7, 149.9, 146.8, 138.8, 135.5, 128.8, 128.6, 128.5, 128.2, 127.5, 123.8, 80.6, 27.9
+
ppm. HRMS (ESI-TOF) calculated for C H N ClO S [M + H ] 427.0626, found 427.0623.
2
0
16
4
3
N-(4-(5-(6-hydroxy-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-4-phenyl
o
thiazol-2-yl)phenyl)benzamide (4aa): Yield: 170 mg (67%); yellow solid, mp. 322-324 C;
IR (ATR) 3454, 3239, 3030, 2970, 1737, 1689, 1590, 1558, 1526, 1499, 1432, 1259, 1192, 839
-1 1
cm . H NMR (400 MHz, DMSO-d ) δ = 10.47 (s, 1H, NH), 7.93-7.86 (m, 6H, ArH), 7.71(d,
6
J = 8.0 Hz, 2H, ArH), 7.59 (t, J = 8.0 Hz, 1H, ArH), 7.52 (t, J = 8.0 Hz, 2H, ArH), 7.32 (t, J =
1
3
8.0 Hz, 2H, ArH), 7.24 (t, J = 8.0 Hz, 1H, ArH), 3.09 (s, 6H, NCH ); C NMR (100 MHz,
3
DMSO-d ) δ = 184.7, 168.4, 166.6, 161.7, 152.6, 151.2, 141.0, 135.8, 135.0, 132.4, 129.0,
6
1
28.8, 128.5, 128.1, 127.9, 127.8, 126.9, 121.2, 83.4, 28.2 ppm. HRMS (ESI-TOF) calculated
+
for C H N O S [M + H ] 511.1435, found 511.1432.
2
8
23
4
4
6
7
1
-hydroxy-5-(2-methyl-4-phenylthiazol-5-yl)pyrimidine-2,4(1H,3H)-dione (4bb): Yield
o
4 mg (49%); white solid, mp. 333-335 C; IR (ATR) 2950, 2787, 1681, 1564, 1465, 1389,
-1
1
208, 894 cm . H NMR (400 MHz, DMSO-d ) δ = 10.71 (s, 2H, NH), 7.61 (d, J = 8.0 Hz,
6
1
3
2H, ArH), 7.36 (t, J = 8.0 Hz, 2H, ArH), 7.27 (t, J = 8.0 Hz, 1H, ArH), 2.69 (s, 3H, CH ); C
3
NMR (100 MHz, DMSO-d ) δ = 164.6, 161.8, 150.2, 134.7, 128.7, 128.6, 128.1, 127.4, 127.2,
6
+
8
3
1.7, 18.5 ppm. HRMS (ESI-TOF) calculated for C H N O S [M + H ] 302.0594, found
1
4
12
3
3
02.0589.
N-(1-(1,3-dimethyl-2,4,6-trioxohexahydropyrimidin-5-yl)-2-oxophenylethyl)benzamide
o
(
8a): Yield 130 mg (66%); white solid, mp. 156-158 C; IR (ATR) 3460, 2926, 2853, 1738,
-1 1
1
440, 1364, 1215, 1063, 900 cm . H NMR (400 MHz, CDCl ) δ = 8.19 (d, J = 12.0 Hz, 1H,
3
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
4
4
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5
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5
5
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DOI: 10.1039/D0NJ00406E
NH), 8.04 (d, J = 8.0 Hz, 2H, ArH), 7.80 (d, J = 4.0 Hz, 2H, ArH), 7.57 (t, J = 8.0 Hz, 1H,
ArH), 7.51 (d, J = 8.0 Hz, 1H, ArH), 7.46-7.41 (m, 4H, ArH), 6.88-6.91 (m, 1H, CH), 3.69 (d,
1
3
J = 8.0 Hz, 1H, CH), 3.40 (s, 3H, NCH ), 3.32 (s, 3H, NCH ); C NMR (100 MHz, CDCl ) δ
3
3
3
=
196.9, 169.7, 166.2, 165.4, 151.5, 134.5, 133.5, 133.3, 132.4, 129.4, 128.98, 128.92, 127.4,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
5
6.1, 49.2, 28.9, 28.8 ppm. HRMS (ESI-TOF) calculated for C H N O Na [M + Na ]
2
1
19
3
5
416.1216, found 416.1200.
5
-(2,5-diphenyloxazol-4-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (9a):
o
Yield 130 mg (69%); white solid, mp. 335-337 C; IR (ATR) 2971, 1738, 1665, 1558, 1448,
-1 1
1412, 1365, 1230, 1058, 813 cm . H NMR (400 MHz, DMSO-d ) δ = 14.22 (s, 1H, OH), 7.93
6
(
d, J = 4.0 Hz, 4H, ArH), 7.77 (t, J = 8.0 Hz, 1H, ArH), 7.66 (t, J = 8.0 Hz, 2H, ArH), 7.61 (d,
J = 4.0 Hz, 1H, ArH), 7.51 (t, J = 8.0 Hz, 2H, ArH), 3.30 (s, 3H, NCH ), 3.02 (s, 3H, NCH );
3
3
13
C NMR (100 MHz, DMSO-d ) δ = 188.3, 165.5, 163.4, 161.1, 160.4, 150.3, 135.5, 134.4,
6
132.9, 130.4, 129.5, 128.6, 128.0, 127.3, 99.3, 28.0, 27.8 ppm. HRMS (ESI-TOF) calculated
+
for C H N O [M + H ] 376.1291, found 376.1287.
2
1
18
3
4
1
,3-dimethyl-5-(2-oxo-2-phenylethylidene)pyrimidine-2,4,6(1H,3H,5H)-trione
(Inter
o
mediate A) : Yield 98 mg (72%); white solid, mp. 207-209 C; IR (ATR) 3008, 1667, 1449,
-1 1
1
415, 1379, 1317, 1306, 1246, 1161, 1099, 753 cm . H NMR (400 MHz, DMSO-d ) δ = 8.14
6
(
s, 1H, CH), 7.89 (d, J = 8.0 Hz, 2H, ArH), 7.67 (t, J = 8.0 Hz, 1H, ArH), 7.54 (t, J = 8.0 Hz,
1
3
2H, ArH), 3.24 (s, 3H, NCH ), 3.05 (s, 3H, NCH ); C NMR (100 MHz, DMSO-d ) δ = 193.9,
3
3
6
1
60.2, 159.8, 151.3, 151.1, 134.7, 133.9, 128.8, 128.3, 124.6, 28.4, 27.9 ppm. HRMS (ESI-
+
TOF) calculated for C H N O [M + H ] 273.0870, found 273.0865.
1
4
13
2
4
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