Efficient and facile synthesis of heterocycles and their mechanistic consideration using kaolin

Article abstract of DOI:10.1039/c3ra40993g

A kaolin catalyzed solvent-free synthesis for new heterocyclic compounds is described. A series of heterocyclic compounds can be readily obtained using the three-component reaction of diketones, aldehydes and 2-amino benzothiazole, urea or thiourea. The m

Full text of DOI:10.1039/c3ra40993g

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Efficient and facile synthesis of heterocycles and their mechanistic
consideration using kaolin
a, b
b, c
a, b, c
Pramod Kumar Sahu,* , Praveen Kumar Sahu,* Dau Dayal Agarwal
a
School of Studies in Chemistry, Jiwaji University, Gwalior-474011, Madhya Pradesh, India
Department of Industrial Chemistry, Jiwaji University, Gwalior-474011, Madhya Pradesh, India
b
c
Jagdishprasad Jhabarmal Tibrewala University, Churu Jhunjhunu Road, Chudela, District-Jhunjhunu-333001, Rajasthan, India
*To whom correspondence should be addressed: Telephone: +91ꢀ9993932425; Email: sahu.chemistry@gmail.com,
researchdata6@gmail.com (pramod K. Sahu), praveensahu1234@gmail.com (Praveen K. Sahu)
Graphical abstract
N
H
N
S
N
N
H
S
5
Via.
No Target Product Formed
O
O
N
NH2
H C
OC
2
H
5
S
3
O
O
H
O
S
CHO
OC H
5
O
O
R
H
3
C
2
O
O
H N
2
NH
2
H N
2
NH2
H
+
4
Via.
H C
OC H
H C O
N
H
3
2
5
5
2
NH
Via. H C O
and
5
2
N
H
O
N
H
N
S
H C
3
S
H C
O
3
4
NH2
N
NH
2
3
O
OC H
2
5
R
CH3
N
S
N
1
Via.
O
O
H C
OC H
2 5
3
H
4
1

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Abstract
Kaolin catalyzed solventꢀfree synthesis for new heterocyclic compounds are described. A series
of heterocyclic compounds can be readily obtained using threeꢀcomponent reaction of diketone,
aldehydes and 2ꢀamino benzothiazole or urea or thiourea. Mechanism of three component kaolin
catalyzed biginelli (using urea and thiourea) and biginelli like (using 2ꢀamino benzothiazole)
reaction has been investigated. This is first time that we have isolated and characterized the key
1
13
intermediates using H NMR, C NMR and ESIꢀmass spectral characterization. Imine 3 and
Knoevenagel type intermediate 4 were highly suggested as key intermediates for mechanistic
study. The reaction is simple, clean and good yield is obtained within minutes.
Keywords: Mechanistic considerations, Isolation and Characterization of Key Intermediate,
Kaolin, Solvent free conditions, Heterocycles.
Introduction
1,2
Multiꢀcomponent reactions (MCRs)
are powerful tool and have attracted much
attention of synthetic organic chemists because of the building of complex molecules with
diverse range of complexity which can easily be achieved from readily available starting
material. Dihydropyrimidines (DHPMs) exhibit interesting pharmacological activities such as
3
4
5
6
7
antiꢀinflammatory, antiꢀmicrobial, antiꢀcardiiac, antileishmanial, calcium channel antagonist,
8
9
10
TRPV1 antagonists, antimycobacterial, antitubercular. DHPMs also have been reported
1
1
anticancer and anti HIV agents. Recently many catalysts have been reported to catalyzed the
1
2
13
14
15
Biginelli reaction such as metal catalysts, iodine, acid catalysts, ultrasonication promoted,
1
6
17
18
19
20
lanthanide catalyzed, ZeiglerꢀNatta catalyst, Lewis base, zeolite catalyzed, ionic liquid,
2
1
22
23
Baker’s yeast, NefionꢀH, Heteropoly acids etc. The drawbacks of these reactions are harsh
reaction conditions, long reaction time, lower yield, higher temperature etc.
2

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In recent years, environmental benign industrial chemical process has been developed. In
this sense, heterogeneous catalysts play a vital role in the development of cleaner technologies
over homogeneous catalyst. These solid catalyst act as good supporting agents, entrain by
2
4
products and ability to selectivity of product. Aluminosilicate clays are well characterized by
2
5,26
their surface acidities, which render them efficient, versatile supports, or catalysts.
There are
extremely limited number of reactions in literature in which kaolinꢀbased or kaolinꢀassisted
2
7ꢀ33
reaction are to be reported as catalysts.
Kaolin, due to its acidic nature, can be a suitable
replacement for various homogeneous catalysts. Kaolin has been used as solid catalyst in FCC
2
7
28
29
additives, fluid catalytic cracking catalysts, alkylation, protection reaction of carbonyl
3
0
31
32
33
compounds, halogenation, biodiesel production, esterification.
3
4ꢀ39
Many research groups have developed solvent free synthesis using different catalysts,
but they have some drawbacks such as poor yield, long reaction time, high temperature,
microwave and ultrasonication conditions etc. Although the ultrasonication technology has been
shown feasible on a small scale, the commercialization of sonolysis is still a challenge due to its
4
0
high energy requirement which makes ultrasonication an uneconomical technique. Shaabani et
4
1(a)
al.
have synthesized 4Hꢀpyrimido[2,1ꢀb]benzothiazole derivatives using ionic liquid at 100
o
C with poor yields. Rao et al. have also synthesized these compounds with poor yield, higher
4
1(b)
reaction time and harsh reaction conditions.
The drawback of ionic liquids is that it cannot
be removed by distillation and their limited solubility in water restricts their use. They have high
4
2
cost and also causes acute for aquatic organism and human.
In view of the importance of heterogeneous solid acids as reusable catalysts in organic
4
3
synthesis and in our continuation of ongoing research to develop heterocyclic compounds, in
the present research work, pyrimidines derivatives were synthesized using kaolin as novel solid
3

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catalyst which is rapid, easy to separate, inexpensive and highly efficient. Kaolin used as catalyst
led to formation of 82ꢀ95% yield. This paper reports this novel recyclable solid catalyst for
multiꢀcomponent reaction of diketone, aldehydes and 2ꢀamino benzothiazole or urea or thiourea.
Results and Discussion
Oneꢀpot three component condensation reaction of ethyl acetoacetate, aromatic aldehyde
and 2ꢀamino benzothiazole using different catalysts and temperature under similar conditions has
been studied to optimize the reaction conditions. Table 1 suggests that reaction took longer
o
reaction time of 48 hours at 30 C temperature without catalysts led to poor yield. Then reaction
o
o
was carried out at 70 and 90 C temperature. Hence 70 C temperature was found to be optimum
temperature. Best result was observed when kaolin as a catalyst was used (Table 1, entry 4).
Different acidic and basic catalysts have been tried but most of them gave lower yield except
acidic acid (Table 1, entry 12). Moderate yield was obtained when CeCl and Al O was used
3
2
3
(Table 1, entry 10 and 18). Significance yields (55ꢀ69 %) were observed for other metal
catalysts.
a
Table 1. Optimization of reaction conditions
o
b
Entry Catalyst (mol%)
Time (hrs) Temperature ( C) Yield% of 1a
1
2
3
4
5
6
7
8
9
1
1
1
1
1
No Catalyst
No Catalyst
No Catalyst
Kaolin
AlCl3
LiCl
48
20
15
30
70
90
70
70
70
70
70
70
70
70
70
70
70
15
30
30
85
65
68
69
65
66
70
69
69
65
65
1.0
2.0
1.1
1.3
1.4
1.4
2.0
1.5
2.0
2.0
1.3
SnCl .2H O
2
2
ZnCl2
Ni(NO3)2
CeCl2
0
1
2
3
3
CuCl2
CH COOH
3
AgNO3
MgCl2
1
1
1
4
5
6
Mg(OH)2
Al(OH)3
Ca(OH)2
4.2
3.5
4.0
70
70
70
63
69
68
1
1
7
8
MgO
Al O3
2
5.0
4.2
70
70
65
71
4

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1
2
2
9
0
1
CaO
NaHCO3
KOH
5.2
6.0
6.0
70
70
70
61
55
59
a
Condensation of benzaldehyde, ethyl acetoacetate and 2ꢀamino benzothiazole in presence of various catalysts under solvent free
conditions.
b
Isolated yield
In order to evaluate the appropriate catalyst loading, a model reaction of benzaldehyde
(0.0025 mol), ethyl acetoacetate (0.0025 mol) and 2ꢀamino benzothiazole (0.0025 mol) was
o
carried out using 10 mg, 20 mg, 50 mg, 80 mg, and 100 mg of kaolin as catalyst at 70 C. The
catalyst loading 50 mg was found to be the optimal quantity (Fig 2).
Fig 2. Optimization of kaolin as a catalyst
Catalyst was reused four times and the results show that the kaolin can be reused as such
without significant loss in its catalytic activity (Table 2). The procedure was easy to work up,
efficient and greatly reduced the role of solvent thus reducing environmental pollution.
Table 2. Recyclability of Kaolin
Product Fresh catalyst
Recycled (I) Recycled (II)
Recycled (III)
Recycled (IV)
a
a
a
a
a
1
a
85
83
83
82
81
a
Isolated yield
The methodology involves oneꢀpot three component reaction of aldehydes (0.0025 mol),
ethyl acetoacetate (0.0025 mol) and 2ꢀamino benzothiazole (0.0025 mol) using kaolin as a
o
catalyst under solvent free conditions at 70 C (Scheme 1).
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Scheme 1. Preparation of 4Hꢀpyrimido [2,1ꢀb] benzothiazole derivatives and 3,4ꢀdihydropyrimidineꢀ2
(
1H)ꢀones/2 (1H) thione
O
N
OC H
2 5
NH2
R
CH3
S
N
S
N
CHO
O
O
1
Kaolin (50 mg)
C, Solvent free
+
H C
3
R
OC H
70
o
X
2
5
O
H N
NH2
2
H C O
N
H
5
2
N
H
X= O, S
H C
3
X
2
Reaction was completed within 40ꢀ60 min with good yield (Table 3) and the structure of
1
13
4
Hꢀpyrimido[2,1ꢀb][1,3]benzothiazole derivatives has been characterized by IR, H NMR, C
NMR and Mass spectra which support the probable structure of target compounds. Using the
optimized reaction conditions, 3,4ꢀdihydropyrimidinꢀ2(1H)ꢀone or thione were synthesized using
benzaldehyde, ethyl acetoacetate and urea or thiourea (Scheme 1). A variety of electron donating
and electron withdrawing groups on phenyl ring of aldehydes have been studied and found no
significant effect of subsituents. The reaction using urea and thiourea was faster than that
observed using 2ꢀamino benzothiazole. It may be due to steric hinderance of benzothiazole
moiety, as sterically hindered substrates proceed slowly.
Table 3. Kaolin catalyzed synthesis of 4Hꢀpyrimido[2,1ꢀb]benzothiazole (1aꢀ1b) derivatives and 3, 4ꢀ
dihydropyrimidineꢀ2 (1H)ꢀones/(1H) thione (2a, 2b)
a
Entry
1
Products
aldehydes
Yield (%) Time (min)
O
CHO
85
60
OC H
2
5
CH3
N
S
N
1
a
6

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OCH3
CHO
2
88
50
O
HO
OC H5
2
OCH3
OH
CH3
N
S
N
1
b
CH
CHO
3
3
91
40
O
N
OC H
2
5
CH3
CH3
N
N
N
H C
CH3
3
S
1
c
4
5
89
83
40
45
O
NO2
O N
2
OC H5
2
N
S
CH3
N
CHO
1
d
OH
O
OH
OC H
2
5
CHO
N
S
CH3
N
1
e
6
7
88
89
55
40
HO
O
OH
OC H5
2
N
S
CH3
N
CHO
1
f
H CO
O
OCH3
3
OC H5
2
N
S
CH3
N
CHO
1
g
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8
82
45
O
Cl
OC H
2
5
Cl
Cl
CHO
Cl
N
S
CH3
N
1
h
CHO
9
1
95
93
25
25
O
N
H
O
H C O
5
2
N
H
H C
3
2
a
0
CHO
O
N
H
H C O
5
2
N
H
H C
S
3
2
b
a
Isolated yield
Mechanistic study
The mechanistic pathway of three components reaction using aldehyde, dicarbonyl and
urea could not be established so far due to non characterization of intermediates. In a Previous
report, Kappe proposed that Lewis acid or protic acidꢀmediated Biginelli reaction proceeded via
the formation of an imine ion (formed by acidꢀcatalyzed condensation of aldehyde with urea) as
a key intermediate rather than carbenium ion intermediate (derived from the acidꢀcatalyzed Aldol
4
4
45
reaction of aldehyde and ethyl acetoacetate). Shen et al. have suggested that mechanism of
Biginelli reaction proceeded in a different way using tꢀBuOK but they failed to isolate and
characterize the intermediate 6 from the reaction (currently there is no report on the successful
isolation of intermediate). Further they have synthesized the intermediate 9 (derived from the
acidꢀmediated condensation of 4ꢀchlorobenzaldehyde and 2ꢀphenyl acetophenone) and
intermediates 7 and 8 (using 4ꢀchlorobenzaldehyde and thiourea or urea respectively) under
8

Page 9 of 26
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4
6
acidic conditions by the well known method documented in literature (Fig 1) and these
intermediates further reacts with third component to give the target product. Shen et al. have
synthesized intermediate 8 in toluene solvent using acidꢀmediated conditions which gave target
product with good yield but authors have reported that target product was formed with low yield
(15%) in toluene that’s why there is minimum possibility to form this type of intermediate in situ
reaction because reaction does not proceed well in toluene solvent.
Fig 1. Possible reaction intermediates suggested by Shen et al.
Cl
H
N
O
Ph
O
NH
OH
X
NH2
Cl
HN
NH2
S
NH2
Ph
N
NH2
O
Cl
Cl
6
7
8
9
X= O, S
Intermediate 9 proposed by Shen et al. also was prepared in benzene but authors have
reported that reaction proceeds well with high yield in protic solvents only hence there is also
minimum possibility for this reaction to follow the mechanistic pathway as suggested by Shen et
al. Thus author has synthesized all intermediates under different conditions as final product was
formed. This shows that there is a need to look for mechanism and intermediates isolation. In the
present article, Synthesis was tried with kaolin which is rapid, easy to separation, inexpensive
and highly efficient. Reusability of catalyst makes very important criteria over cost and
environment pollution. The utility of kaolin as catalyst led to formation of high yield.
To prove the mechanism of this kaolinꢀmediated oneꢀpot reaction for synthesis of 3,4ꢀ
dihydropyrimidinꢀ2(1H)ꢀone/thione, each three set of reactions of two components were carried
out (Scheme 2).
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Scheme 2. Three set of reaction for preparation of 3,4ꢀdihydropyrimidineꢀ2 (1H)ꢀones/2 (1H) thione
First Set
Second Set
Third Set
CHO
CHO
O
O
O
O
O
O
OC H5
2
NH2+
3
+
+
H N
NH2
H C
H
N
H C
2
OC H5
2
3
2
O
O
O
No Intermediate Formed
N
NH2
H C
OC H5
2
3
O
H C O
NH
5
2
H C
N
H
O
3
Target Product
The intermediate formed was reacted with third component and the product formed was
characterized by mp. IR, NMR, and mass spectral studies. It was found that mechanism follow
via two different pathway, which gives the product. First pathway i.e. the reaction proceeds in
two steps: condensation of bezaldehyde and urea. Then ethyl acetoacetate was reacted with
1
13
intermediate 3 (characterized by IR, H NMR, C NMR and mass spectra) and gives the target
product with 65% yield, which is as below;
Scheme 3.
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O
O
CHO
O
O
Kaolin
H C
O C H5
NH
3
2
N
2
+
H N
NH2
Kaolin
2
3
O
O
O
O
H C O
Kaolin
Kaolin
H O
5
2
H C O
H C O
5 2
5
2
NH
NH
O
-
HN
NH2
2
H C
H C
3
3
O
N
H
O
H C
N
H
O H
3
Plausible Mechanistic pathway using intermediate 3
This is for the first time that we have isolated the intermediate 3 (prepared by
condensation of benzaldehyde and urea) and the intermediate type 4 was prepared by
1
13
condensation of ethyl acetoacetate and benzaldehyde and characterized by IR, H NMR, C
NMR and mass spectral study (Fig 3). Spectroscopic data has confirmed the proposed structure
of intermediate 3 and 4.
Fig 3. Key intermediate for mechanistic study
(
128.36)
(
152.88)
O
O
(
128.14)
O
N
H
N
(
127.70)
5
2
7
6
OC H
2 5
H C
3
S
N
4
3
8
NH2
N
H
N
H
1
(167.02)
S
(
127.10)
(127.95)
(
127.47)
3
4
5
Second pathway i.e. condensation of aldehyde with ethyl acetoacetate, then urea is
reacted with intermediate 4 (prepared by reaction of ethyl acetoacetate and benzaldehyde) and
gives target product with 95% yield. Reaction scheme is as follow;
Scheme 4.
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O
O
O
O
CHO
O
O
Kaolin
H C
OC H5
H C
OC H5
3
2
3
2
+
OH
H C
OC H5
3
2
Kaolin
4
X
Kaolin
H N
NH2
2
O
O
O
O
H C
OC
X
H
2 5
Kaolin
3
NH
Kaolin
H C O
H C O
NH
5
2
5
2
H C
N
H
X
NH
2
3
N
H
N
H
H C
X
3
OH
X= O, S
Plausible Mechanistic pathway using intermediate 4
4
7
Characterization data of intermediate 4 was matched with literature. This reveals that
first mechanism pathway of reaction gives slightly low yield as compared to second. However, it
is interesting that reaction mechanism followed these both routs using intermediates 3 and 4.
This is first time that we have isolated and characterized the intermediate (prepared by
condensation of benzaldehyde and urea) which is the key intermediate for mechanistic study (Fig
3). In case of dihydropyrimidinꢀ2(1H)ꢀthione, imine type of intermediate (prepared by
condensation of benzaldehyde and thiourea) was not isolated and characterized. Sticky material
was obtained with thiourea resultant intermediate could not be isolated and characterized. It may
be due to the larger atomic size of sulhpur than oxygen in case of dihydropyrimidinꢀ2(1H)ꢀ
thione. Reaction with thiourea (larger atomic size of sulphur) may be proceeds with slow rate
and kinetic of reaction which is not obtained under these reaction conditions. Interestingly this
intermediate is not able to form the target product. Only intermediate 4 is formed the final
product and follow the mechanistic pathway likewise to synthesis of dihydropyrimidinꢀ2ꢀ(1H)ꢀ
one using urea. It shows the different behavior of urea and thiourea. It may be due to the
12

Page 13 of 26
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difference between atomic size of oxygen and sulphur atoms. Larger atomic size of sulphur may
create hindrance in mechanism to form the target molecule resultant reaction was not proceed
further. It revealed the involvement of key intermediates which is formed in the first step and
responsible for formation of target molecule.
In the similar pattern, three set of reactions of two components each were carried out for
synthesis of 4Hꢀpyrimido[2,1ꢀb][1,3]benzothiazole. The intermediate formed was reacted with
third component and the product formed was analyzed by mp, IR, NMR and mass spectral
studies. It was found that only one set of reaction gave the product i.e. the reaction proceeds in
two steps: condensation of bezaldehyde and ethyl acetoacetate according to Knoevenagel type
reaction. Then 2ꢀamino benzothiazole is reacted with condensate 4 through Michael addition (4
characterized by IR, NMR and mass spectra) to afford the target product which is as follow:
Scheme 5.
O
O
O
O
CHO
O
O
Kaolin
H C
OC H5
H C
OC H5
2
3
2
3
+
OH
H C
OC H5
3
2
Kaolin
4
.
.
Kaolin
N
NH2
S
O
O
O
OC H5
2
OC H5
2
OC H5
Kaolin
2
R
Kaolin
CH3
R
R
CH3
N
S
CH3
N
S
O
N
OH
N
NH
NH2
S
Plausible Mechanistic pathway using intermediate 4 with 2ꢀamino benzothiazole.
We have successfully isolated the product 5 (prepared by reacting benzaldehyde and 2ꢀ
+
1
amino benzothiazole). The mass fragmentation of compound 5 show [MꢀH] ion peak at 387. H
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NMR spectra shows the triplet at 6.99 (ꢀCH), doublet at 7.19 due to two similar hydrogen of –
NH and multiplet is observed between 7.37ꢀ8.02 due to hydrogen of aromatic rings. This
intermediate failed to produce the target product, hence it involvement as intermediate can be
ruled out.
Conclusion
It can be concluded that synthesis of compounds containing 4Hꢀpyrimido[2,1ꢀ
b][1,3]benzothiazole (1a-1h) derivatives and 3,4ꢀdihydropyrimidinꢀ2(1H)ꢀone/thione 2a, 2b
have carried out using oneꢀpot three component reaction of aromatic aldehydes, 1,3ꢀdicarbonyl
and urea/thiourea/2ꢀamino benzothiazole in the presence of kaolin as catalyst under solvent free
conditions. The operational simplicity, availability of starting materials makes it a rather forward
alternative procedure than traditional one. In addition, we have isolated and characterized the
Intermediates 3 and 4. 2ꢀAmino benzothiazole and benzaldehyde has been reacted and resultant
product 5 is formed which is successfully isolated and characterized. Overall study show that
intermediate 3 and 4 are highly suggested key intermediates for reaction. We have tried the
mechanistic study with amine scaffold and observed the different mechanistic behavior due to
moiety of amine scaffold (urea/thiourea/2ꢀamino benzothiazole). It shows the dependency of
mechanistic behavior on amine scaffold which formed the intermediate in the first step of
mechanism.
Experimental section
General
1
The H NMR spectra were measured by BRUKER AVANCE II 400 NMR spectrometer with
o
1
tretramethylsilane as an internal standard at 20ꢀ25 C; data for H NMR are reported as follow:
chemical shift (ppm), integration, multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m,
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multiplet and br, broad), coupling constant (Hz). IR spectra were recorded by SHIMADZU, IR
spectrometer of sample dispersed in KBr pellet and are reported in terms of frequency of
ꢀ1
absorption (cm ). EꢀMerck preꢀcoated TLC plates, RANKEM silica gel G for preparative thinꢀ
layer chromatography were used. Melting points were determined on electrical melting point
apparatus in open capillary and were uncorrected. 2ꢀAmino benzothiazole was purchased from
Sigma Aldrich and other chemical were purchased from Himedia, Mumbai India.
One-pot three component reaction
Typical procedure. A mixture of aldehydes (0.0025 mol), dicarbonyl (0.0025 mol) and
o
urea/thiourea/2ꢀamino benzothiazole (0.0025 mol) were heated at 70 C under solvent free
conditions using kaolin (50 mg) as a catalyst. The time taken by different aldehydes in reaction
was as mentioned in tables 2. After completion of the reaction (TLC analysis), the reaction
mixture was cooled to room temperature and poured in cold water. The solid mass was filtered. It
was dissolved in ethanol and filtered. The solid kaolin got separated as solid. The filtrate having
product soluble in ethanol was concentrate to crystallize the product. Kaolin was washed with
ethanol to remove any organic impurities that may has been present and used in next run.
Recyclability of catalyst
Recycled kaolin was reused for four times as such using benzaldehyde (0.0025 mol),
o
ethyl acetoacetate (0.0025 mol) and 2ꢀamino benzothiazole (0.0025 mol) heated at 70 C under
solvent free conditions without significant lose in activity.
Synthesis of intermediate 3
o
A mixture of benzaldehyde (0.0025 mol) and urea (0.0025 mol) were heated at 70 C
under solvent free conditions using kaolin (50 mg). The reaction was monitored by TLC. After
completion of the reaction, mixture was cooled to room temperature and poured in cold water.
15

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The solid mass obtained after filtration was dissolved in ethanol and contents stirred for 5 min.
and resulting solution was filtered to separate kaolin. Crude product was recrystallized using
methanol to give intermediate 3.
Synthesis of intermediate 4
A mixture of ethyl acetoacetate (0.0025 mol) and benzaldehyde (0.0025 mol) were
o
heated at 70 C under solvent free conditions using kaolin (50 mg). After completion of the
reaction (judged by TLC analysis), the reaction mixture was cooled to room temperature and
poured in cold water. Filtered the solid mass and dissolved in ethanol to separate the kaolin.
Synthesis of compound 5
A mixture of 2ꢀamino benzothiazole (0.0025 mol) and benzaldehyde (0.0025 mol) were
o
heated at 70 C under solvent free conditions using kaolin (50 mg). After completion of the
reaction (judged by TLC analysis), the reaction mixture was cooled to room temperature and
poured in cold water. Filtered the solid mass and dissolved in ethanol to separate the kaolin.
Kaolin was washed ethanol to remove any organic impurities that may has been present.
Ethyl-2-methyl-4-(phenyl)-4H-pyrimido[2,1-b][1,3]benzothiazole-3-carboxylate (1a).
o
ꢀ1
Paleꢀyellow crystals, mp 178ꢀ180 C, R = 0.47 (DCM:Toluene; 3:2); IR (KBr) (υ , cm ): 3043
f
max
(
CꢀH ), 2968 (CꢀH in CH CH ), 1670 (C=O ), 1589 (C=N ), 1462 (C=C ), 744 (CꢀH );
str str 2 3 str str str def
1
HꢀNMR (400 MHz, CDCl ): H ppm 1.29 (3H, t, J = 7.12 Hz, CH CH ), 2.46 ( 3H, s, CH ),
3
HH
2
3
3
1
3
4
.17 (2H, m, CH CH ), 6.39 (1H, s, ꢀCH), 7.07ꢀ7.43 (9H, m, ArH); C NMR (100 MHz,
2 3
DMSO): 165.44, 162.59, 154.04, 141.26, 137.43, 128.26, 126.79, 122.22, 111.65, 102.56, 59.35,
+
5
6.82, 23.17, 13.99; ESIꢀMS: m/z Calculated for C H N O S 350.44, Found [M+H] 351.2.
20
18
2
2
Ethyl-2-methyl-4-(4-hydroxy-3-methoxy phenyl)-4H-pyrimido[2,1-b][1,3]benzothiazole-3-
carboxylate (1b).
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o
ꢀ1
Paleꢀyellow powder, mp 192ꢀ194 C, R = 0.53 (DCM:Toluene; 3:2); IR (KBr) (υ , cm ): 3059
f
max
(
CꢀH ), 2983 (CꢀH in CH CH ), 1703 (C=O ), 1597 (C=N ), 1504 (C=C ), 740 (CꢀH );
str str 2 3 str str str def
1
HꢀNMR (400 MHz, CDCl ): H ppm 1.31 (3H, t, J = 7.12 Hz, CH CH ), 2.47 (3H, s, CH ), 3.8
3
HH
2
3
3
(
3H, s, ArꢀOCH ), 4.12ꢀ4.19 (2H, m, CH CH ), 6.36 (1H, s, ꢀCH), 6.78 (1H, d, J = 5.6 Hz,
3 2 3 HH
1
3
ArH), 6.89ꢀ6.92 (2H, m, ArH), 7.13ꢀ7.31 (4H, m, ArH), 9.80 (1H, s, OH); C NMR (100 MHz,
DMSO): 165.60, 162.34, 153.51, 147.12, 146.42, 137.61, 132.52, 126.37, 122.21, 115.18,
1
11.92, 110.88, 59.28, 55.43, 23.09, 14.08; ESIꢀMS: m/z Calculated for C H N O S 396.49,
21 20 2 4
+
Found [M+H] 397.2.
Ethyl-2-methyl-4-(4-dimethylamino phenyl)-4H-pyrimido[2,1-b][1,3]benzothiazole-3-
carboxylate (1c).
o
ꢀ1
Paleꢀyellow powder, mp 175ꢀ178 C, R = 0.57 (DCM:Toluene; 3:2); IR (KBr) (υ , cm ): 3059
f
max
(
CꢀH ), 2897 (CꢀH in CH CH ), 1612 (C=O ), 1581 (C=N ), 1431 (C=C ), 815ꢀ754 (Cꢀ
str str 2 3 str str str
1
H ); HꢀNMR (400 MHz, CDCl ): H ppm 1.29 (3H, t, J = 7.12 Hz, CH CH ), 2.86 (3H, s,
def
3
HH
2
3
CH ), 3.06 (6H, s, N(CH ) ), 4.15 (2H, m, CH CH ), 6.71ꢀ7.5 (4H, m, ArH), 7.71ꢀ7.92 (4H, m,
3
3 2
2
3
1
3
ArH); C NMR (100 MHz, DMSO): 166.39, 165.44, 153.95, 152.63, 133.43, 127.71, 125.91,
1
24.45, 121.63, 120.57, 23.13, 13.60; ESIꢀMS: m/z Calculated for C H N O S 393.54, Found
2
2
23
3
2
+
[
M+H] 394.2.
Ethyl-2-methyl-4-(4-nitro phenyl)-4H-pyrimido[2,1-b][1,3]benzothiazole-3-carboxylate
1d).
Yellow powder, mp 170ꢀ172 C, R = 0.52 (DCM:Toluene; 3:2); IR (KBr) (υ , cm ): 3348 (Cꢀ
(
o
ꢀ1
f
max
H ), 2933 (CꢀH in CH CH ), 1625 (C=O ), 1510 (C=N ), 1267 (C=C ), 962ꢀ812 (CꢀH );
str
str
2
3
str
str
str
def
1
HꢀNMR (400 MHz, CDCl ): H ppm 1.31 (3H, s, CH CH ), 2.46 (3H, s, CH ), 4.15 (2H, m,
3
2
3
3
1
3
CH CH ), 6.52 (1H, s, ꢀCH), 7.03ꢀ7.63 (8H, m, ArH); C NMR (100 MHz, CDCl ): 166.25,
2
3
3
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1
63.56, 155.83, 147.95, 147.62, 137.44, 128.06, 126.88, 124.43, 124.01, 123.73, 122.47, 111.36,
02.01, 60.42, 57.03, 23.97, 14.40; ESIꢀMS: m/z Calculated for C H N O S 395.46, Found
1
2
0
17
3
4
+
[
M+H] 396.4.
Ethyl-2-methyl-4-(2-hydroxy phenyl)-4H-pyrimido[2,1-b][1,3]benzothiazole-3-carboxylate
1e).
Paleꢀyellow powder, mp 212ꢀ215 C, R = 0.53 (DCM:Toluene; 3:2); IR (KBr) (υ , cm ): 3028
(
o
ꢀ1
f
max
(
CꢀH ), 2810 (CꢀH in CH CH ), 1668 (C=O ), 1575 (C=N ), 1485 (C=C ), 837ꢀ750 (Cꢀ
str
str
2
3
str
str
str
1
H ); HꢀNMR (400 MHz, DMSO): H ppm 1.29 (3H, t, J = 4.76, CH CH ), 2.45 (3H, s, CH ),
def
HH
2
3
3
1
3
4
.1ꢀ4.19 (2H, m, CH CH ), 6.33 (1H, s, ꢀCH), 6.66ꢀ7.92 (8H, m, ArH), 8.9 (1H, s, OH); C
2 3
NMR (100 MHz, DMSO): 171.88, 165.92, 162.99, 157.23, 151.33, 133.73, 128.14, 126.08,
22.92, 116.07, 59.26, 56.23, 23.11, 14.04; ESIꢀMS: m/z Calculated for C H N O S 367.34,
1
20
18
2
3
+
Found [M] 367.2.
Ethyl-2-methyl-4-(4-hydroxy phenyl)-4H-pyrimido[2,1-b][1,3]benzothiazole-3-carboxylate
1f).
Paleꢀyellow powder, mp 210ꢀ212 C, R = 0.59 (DCM:Toluene; 3:2); IR (KBr) (υ , cm ): 3288
(
o
ꢀ1
f
max
(OH ), 3059 (CꢀH ), 2897 (CꢀH in CH CH ), 1612 (C=O ), 1581 (C=N ), 1431 and 1377
str str str 2 3 str str
1
(
C=C ), 815ꢀ754 (CꢀH ); HꢀNMR (400 MHz , CDCl ): H ppm 1.25 (3H, t, J = 4.76 Hz,
str
def
3
HH
CH CH ), 2.35 (3H, s, CH ), 4.04ꢀ4.12 (m, 2H, CH CH ), 6.30 (1H, s, ꢀCH), 6.66 (2H, d, J =
HH
3
2
3
3
2
1
3
8
.40 Hz, ArH), 7.13ꢀ7.59 (5H, m, ArH), 7.59 (1H, d, JHH = 7.76 Hz, ArH), 9.26 (1H, s, OH); C
NMR (100 MHz, DMSO): 165.55, 162.27, 157.22, 153.46, 137.56, 131.95, 128.13, 126.34,
123.57, 122.94, 122.20, 115.02, 111.80, 102.96, 59.27, 56.37, 23.09, 14.03; ESIꢀMS: m/z
+
Calculated for C H N O S 367.34, Found [M] 367.2.
2
0
18
2
3
Ethyl-2-methyl-4-(4-methoxy phenyl)-4H-pyrimido[2,1-b][1,3]benzothiazole-3-carboxylate
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(1g).
o
ꢀ1
Paleꢀyellow powder, mp 130ꢀ132 C, R = 0.53 (DCM:Toluene; 3:2); IR (KBr) (υ , cm ): 2941
f
max
1
(
CꢀH in CH CH ), 1627 (C=O ), 1508 (C=N ), 1280 (C=C ), 962ꢀ813 (CꢀH ); H NMR
str 2 3 str str str def
(
400 MHz, CDCl ): Hꢀppm 1.28 (3H, t, JHH = 4.76 Hz, CH CH ), 2.45 (3H, s, CH ), 3.71 (3H, s,
3
3
2
3
ArꢀOCH ), 4.11ꢀ4.21 (2H, m, CH CH ), 6.34 (1H, s, ꢀCH), 6.78 (2H, d, J = 8.64 Hz, ArH),
3
3
2
HH
1
3
7
1
6
.21ꢀ7.58 (6H, m, ArH); C NMR (100 MHz, DMSO): 166.67, 163.27, 159.42, 154.51, 152.07,
38.06, 133.81, 128.51, 126.57, 123.88, 123.82, 122.14, 120.89, 119.04, 113.90, 111.80, 103.24,
0.09, 57.20, 55.18, 23.73, 14.40; ESIꢀMS: m/z Calculated for C H N O S 380.47, Found
2
1
20
2
2
+
[
M+H] 381.3.
Ethyl-2-methyl-4-(2, 6-dichloro phenyl)-4H-pyrimido[2,1-b][1,3]benzothiazole-3-
carboxylate (1h).
o
ꢀ1
Paleꢀyellow powder, mp 150ꢀ152 C, R = 0.56 (DCM:Toluene; 3:2); ); IR (KBr) (υ , cm ):
f
max
3
012 (CꢀH ), 2922 (CꢀH in CH CH ), 1625 (C=O ), 1500 (C=N ), 1278 (C=C ), 960ꢀ812
str str 2 3 str str str
1
(
CꢀH ); HꢀNMR (400 MHz, DMSO): H ppm 1.09 (3H, t, J = 4.76 Hz, CH CH ), 2.47 ( 3H,
def HH 2 3
1
3
s, CH ), 4.04 (2H, m, CH CH ), 7.01ꢀ7.66 (7H, m, ArꢀH); C NMR (100 MHz, DMSO):
3
2
3
1
1
4
5
71.88, 165.92, 162.99, 151.33, 137.57, 133.73, 132.41. 129.14, 126.08, 125.57, 124.52, 122.97,
21.69, 117.66, 116.07, 59.26, 23.11, 14.04; ESIꢀMS: m/z Calculated for C H N Cl O S
2
0
16
2
2
2
+
19.41, Found [M] 419.6.
-ethoxycarbonyl-4-pheyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one, 2a
o
ꢀ1
Yellow powder, mp. 204ꢀ206 C, R = 0.53 (DCM : Toluene 3:2); IR (KBr) (υ , cm ): 3245,
f
max
1
3
118, 2987, 1725, 1701, 1649; H NMR (400 MHz, CDCl ): Hꢀppm 1.06 (3H, t, J = 6.84 Hz,
3
CH ), 2.24 (3H, s, CH ), 3.94 (2H, q, J = 6.75 Hz, CH ,), 5.13 (1H, d, J = 3.06 Hz, Hꢀ4,), 7.21ꢀ
3
3
2
7.37 (5H, m, ArꢀH), 7.73 (1H, brs, NH), 9.19 (1H, brs, NH) ESIꢀMS: m/z Calculated for
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+
C H N O 260.32 Found [M+H] 261.1.
14
16
2
3
Intermediate 3
Off white powder, mp 225ꢀ226 C, Rf = 0.69 (toluene : ethyl acetate 2:3); HꢀNMR (400 MHz,
o
1
1
3
CDCl ): H ppm 2.12 (2H, s, ꢀNH ), 2.54 (1H, s, ꢀCH), 7.19ꢀ7.62 (5H, m, ArꢀH); C NMR (100
3
2
MHz, CDCl ): 167.02, 152.88, 128.36, 128.14, 127.95, 127.70, 127.47, 127.10; ESIꢀMS: m/z
3
+
Calculated for C H ON 148.3, Found [M+H] 149.4.
8
8
2
Intermediate 4
o
1
Off white powder, mp 78ꢀ80 C, Rf = 0.72 (hexane : methanol 2:3), HꢀNMR (400 MHz,
CDCl ): H ppm 1.29 (3H, t, J = 14.24 Hz, CH CH ), 2.46 (3H, s, CH ), 4.17 (2H, m, CH CH ),
3
2
3
3
2
3
1
3
6
.39 (1H, s, =CH), 7.07ꢀ7.43 (5H, m, ArꢀH); C NMR (100 MHz, CDCl ): 200.71, 164.16,
3
140.09, 137.16, 134.65, 134.01, 132.73, 129.49, 128.75, 61.29, 29.72, 13.71; ESIꢀMS: m/z
+
Calculated for C H O 218.3, Found [M+H] 219.5.
1
3
14
3
Intermediate 5
o
1
Off white crystal, mp 117ꢀ119 C, Rf = 0.61 (Hexane : Methanol 1:1); HꢀNMR (400 MHz,
CDCl ): H ppm 6.99 (1H, t, J = 6.96 Hz, ꢀCH), 7.19 (2H, d, J = 6.72 Hz , NH), 7.37ꢀ8.02 (13H,
3
1
3
m, ArꢀH); C NMR (100 MHz, CDCl ): 132.41, 130.86, 129.35, 128.15, 125.25, 120.77,
3
+
1
20.521, 117.69; ESIꢀMS: m/z Calculated for C H N S 388.52, Found [MꢀH] 387.2.
2
1
16
4 2
Acknowledgements
We are grateful thanks to Dr. Yogesh Sharma, Parabolic Drug Ltd., Chandigarh and Punjab
University, Chandigarh for spectral analytical data.
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Efficient and facile synthesis of heterocycles and their mechanistic
consideration using kaolin
a, b
b, c
a, b, c
Pramod Kumar Sahu,* , Praveen Kumar Sahu,* Dau Dayal Agarwal
a
School of Studies in Chemistry, Jiwaji University, Gwalior-474011, Madhya Pradesh, India
Department of Industrial Chemistry, Jiwaji University, Gwalior-474011, Madhya Pradesh, India
b
c
Jagdishprasad Jhabarmal Tibrewala University, Churu Jhunjhunu Road, Chudela, District-Jhunjhunu-333001, Rajasthan, India
*To whom correspondence should be addressed: Telephone: +91-9993932425; Email: sahu.chemistry@gmail.com,
researchdata6@gmail.com (pramod K. Sahu), praveensahu1234@gmail.com (Praveen K. Sahu)
Graphical abstract
N
H
N
S
N
N
H
S
5
Via.
No Target Product Formed
O
O
N
NH2
H C
OC
2
H
5
S
3
O
O
H
O
S
CHO
OC H
5
O
O
R
H
3
C
2
O
O
H N
2
NH
2
H N
2
NH2
H
+
4
Via.
H C
OC H
H C O
N
H
3
2
5
5
2
NH
Via. H C O
and
5
2
N
H
O
N
H
N
S
H C
3
S
H C
O
3
4
NH2
N
NH
2
3
O
OC H
2
5
R
CH3
N
S
N
1
Via.
O
O
H C
OC H
2 5
3
H
4