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GREEN CHEMISTRY APPROACH: SYNTHESIS OF
DIHYROPYRIMIDINES
MINOR RESEARCH PROJECTMINOR RESEARCH PROJECTMINOR RESEARCH PROJECTMINOR RESEARCH PROJECT
FUNDED BY UNIVERSITY GRAND COMMISSSIONFUNDED BY UNIVERSITY GRAND COMMISSSIONFUNDED BY UNIVERSITY GRAND COMMISSSIONFUNDED BY UNIVERSITY GRAND COMMISSSION WESTERN REGIONAL OFFICEWESTERN REGIONAL OFFICEWESTERN REGIONAL OFFICEWESTERN REGIONAL OFFICE GANESHKHIND, PUNEGANESHKHIND, PUNEGANESHKHIND, PUNEGANESHKHIND, PUNE----007007007007
PRINCIPAL INVESTIGATER
PROF.NANDKISHOR D.GAWHALE
ASSISTANT PROFESSOR, M.SC. PH.D,
NET-JRF, SET, GATE
B.B.ARTS, N.B.COMMERCE &B.P.SCIENCE COLLEGE, DIGRAS, DIST-
YAVATMAL-444203
AFFILIATED TO SGB AMRAVATI UNIVERSITY
(MAHARASHTRA)
CO-INVESTIGATER DR.MANISHA M.KODAPE
ASSISTANT PROFESSOR, M.SC.M.PHIL.PH.D NET
DEPARTMENT OF CHEMISTRY SGB AMRAVATI UNIVERSITY
(MAHARASHTRA)
YEAR-2010-2012
FILE NO-47-1546/10(WRO) DATED 18TH
OCT 2010
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CONTENTS
Sr. No. Chapter Page no.
1. Introduction 03
2. Origin of the work 08
3. Present work 12
4. Experimental 14
5. Result & Discussion 24
6. Conclusion 30
7. References 31
8. Spectra 35
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INTRODUCTION:
Five and six membered heterocyclic compounds are important
constituents that often exist in biologically active natural products and synthetic
compounds of medicinal interest1.The Biginelli DHPMs (Dihydropyrimidins)
are chemical precursors of multifunctionalised pyrimidines2.
The Biginelli reaction is a multiple-component chemical reaction that
creates 3,4-dihydropyrimidin-2(1H)-ones 4 from ethyl acetoacetate 1, an aryl
aldehyde (such as benzaldehyde 2), and urea3.3,4,5,6
. It is named for the Italian
chemist Pietro Biginelli7,8
.
O
O O
O
H2N NH2
O
NH
NH
O
O
O
1 2 3
This reaction was developed by Pietro Biginelli in 1891. The reaction can
be catalyzed by Brønsted acids and/or by Lewis acids such as boron trifluoride9.
Several solid-phase protocols utilizing different linker combinations have been
published10-11
. Dihydropyrimidinones, the products of the Biginelli reaction, are
widely used in the pharmaceutical industry as calcium channel blockers12
,
antihypertensive agents, and alpha-1-a-antagonists.
Recently, interest in the synthesis of 3,4-dihydropyrimidin-2-(1H)-ones
(Biginelli compounds) and their derivatives has increased tremendously because
of their diverse therapeutic and pharmacological properties such as antiviral,
antibacterial, antitumour and antihypertensive activities13
. Some have been
successfully used as calcium channel blockers, a-1a-antagonists and
neuropeptideY (NPY) antagonists14
. Several alkaloids which contain the
dihydropyrimidine core unit have been isolated from marine sources. Most
notable among these are the batzelladine alkaloids, which were found to be
potent HIV gp-120-CD4 inhibitors15
.The Biginelli reaction is considered as an
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important multi-component reaction for generating compounds with diverse
medicinal applications.
REACTION MECHANISM:
The reaction mechanism of the Biginelli reaction is a series of
bimolecular reactions leading to the desired dihydropyrimidinone16
. According
to a mechanism proposed by Sweet in 1973 the aldol condensation of
ethylacetoacetate 1 and the aryl aldehyde is the rate-limiting step leading to the
carbenium ion 2. The nucleophilic addition of urea gives the intermediate 4,
which quickly dehydrates to give the desired product 517
.
EtO
O
O
1
Ar H
O
EtO OH
ArO
O
H+
EtO O
ArO
OH
H
- H2O
EtO
ArO
O
EtO
ArO
O
H+H2N NH2
O
- H+
EtO NH
ArO
O
NH2
O
- H2O
NH
NH
ArO
O
5 4 2 3
This scheme begins with rate determining nucleophilic addition by the
urea to the aldehyde18-19
. The ensuing condensation step is catalyzed by the
addition of acid, resulting in the imine nitrogen. The β-ketoester then adds to the
imine bond and consequently the ring is closed by the nucleophilic attack by the
amine onto the carbonyl group. This final step ensues a second condensation
and results in the Biginelli compound. Multifunctionalised 3,4-
dihydropyrimidin-2(1H)-ones(DHPMS) obtained from the Biginelli reaction
have been used as potent calcium channel blockers, antihypertensive agents, and
neuropeptide Y antagonists20
.
Although the one pot three component Biginelli reaction has been known
for than a century21
; the Biginelli 3,4-dihydropyrimidin-2(1H)-ones (DHPMs)
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more largely ignored in the early past of the 20th century22
. In past decades, the
scope of the original cyclocondensation reaction was gradually extended by
variation of all three building blocks, allowing access to a large numberof
structurally diversified multifuctionalised DHPMs23
. These nonpolar
heterocyclic compounds have received considerable attention from the
pharmaceutical industry because of their interesting multifaceted
pharmacological profiles. Synthesis of DHPMs resulted in the discovery of
calcium modulators, a1a –adrenergic receptor antagonists, mitotic kinesin
inhibitors and hepatitis B(potent HIV gp-120 CD4 inhibitors)24
and ptilomycalin
alkaloids also contain the DHPM core25
.Thus, via the Biginelli reaction, the
synthesis of 3,4-dihydropyrimidin-2-(1H)-ones has received renewed interest
and several improved procedures have recently been reported.9-23
However, to
the best of our knowledge, there is no report on enzyme catalyzed Biginelli
reaction.
It was interesting to observe that Biginelli compounds could be
synthesized in high yields under fermenting yeast conditions. Bakers’ yeast
(200 mg) and D-glucose (300 mg) were taken in 5 ml of phosphate buffer (pH
7.0) and stirred overnight. Benzaldehyde (106 mg, 1 mmol), ethyl acetoacetate
(130 mg, 1 mmol) and urea (90 mg, 1.5 mmol) were added to the fermenting
yeast and the reaction mixture stirred for a further 24 hr. Next, the reaction was
diluted with water and extracted with ethyl acetate. The organic layer was dried
over sodium sulfate and concentrated to give a crude product. Pure 3,4-
dihydropyrimidin-2-(1H)-one derivative 4a was obtained by crystallization of
the crude product from methanol in 84% yield.
A general and practical green chemistry route to the Biginelli
cyclocondensation reaction using Ascorbic acid (lemon juice) as the catalyst is
described under one step of reaction, using different aldehydes. This method
provides an efficient and much improved modification and green approach of
original. Biginelli reaction reported in 1893, in terms of high yields, short
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reaction times, and simple work-up procedure, and it has the ability to tolerate a
wide variety of substitutions in all three components, which is lacking in
existing procedures.
Here, in this project the same Biginelli reaction is carried out in the
presence of only three drops of lemon juice. Where, ethyl aceto acetate (EAA),
aldehyde and urea/thiourea in presence of only 3 drops of lemon juice is reflux
for 1 hr. After cooling the product pour into the cold water, remove unreacted
EAA by adding 5o% ethanol solution, then filter it and dry it we get the desired
product.
GREEN APPROACH AND ITS IMPORTANCE:
Green chemistry approaches hold out significant potential not only for
reduction of byproducts, a reduction in the waste produced, and lowering of
energy costs but also in the development of new methodologies toward
previously unobtainable materials, using existing technologies.2
In recent years, dihydropyrimidinones and their derivatives occupy an
important place in the realm of natural and synthetic organic chemistry because
of their therapeutic and pharmacological properties4. Synthesizing, DHPMs
using lemon juice is also one of the application of green chemistry. And, in
future it can also used as a substitute for the H2SO4.
The green chemistry programme supports the invention of more
environmentally friendly chemical processes which reduce or even eliminate the
generation of hazardous substances. Green chemistry is a tool not only for
minimizing the negative impact of those procedures aimed at optimizing
efficiency, although clearly both impact minimization and process optimization
are legitimate and complementary objectives of the subject.
Green chemistry, however, also recognizes that are significant
consequences to the use of hazardous substances, ranging from regulatory
handling and transport, and liability issues, to name a few. To limit the
definition to deal with waste only would be to address only part of the problem.
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Green chemistry is applicable to all aspects of the product life cycle as
well. Finally, the definition of green chemistry includes the term “hazardous”. It
is important to note that green chemistry is a way of dealing with risk reduction
and pollution prevention by addressing the intrinsic hazards of the substances
rather than those circumstances and conditions of their use that might increase
their risk. Only three drops of lemon juice was used in this reaction as a reagent
to maintain the acidic condition is not at all risky, but safe to handle and to carry
out the reaction within one hour. These are the advantages of using green
chemistry approach.
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ORIGIN OF WORK:
During recent year, much attention is increasingly been given to the
synthesis of Dihydropyrimidinones end their derivatives as therapeutic and
pharmacological properties such as antiviral, antibacterial, antitumour and
antihypertensive activities. Dihydropyrimidinones have shown some evidence
of many biological activities, although they are approved for few medical uses
as pharmaceuticals. The basic structure of Dihydropyrimidinones modified, to
increase their medicinal values and potency making the Dihydropyrimidinones
useful agent for treatment of asthma, inflammation and inhibition of platelet
aggregation.
Literature survey reveals that Dihydropyrimidinones has appetite-
supprissing medicinal properties like anti-tumor, anti-hypertension, anti-
arrhythmia, anti-inflammatory, anti-osteoporosis, antiseptic, and analgesic (pain
relief). But they are synthesized by using hazardous acid condensing agents.
This promoted me to synthesize novel derivatives by using green approach.
The green chemistry programme supports the invention of more
environmentally friendly chemical processes which reduce or even eliminate the
generation of hazardous substances. Green chemistry is a tool not only for
minimizing the negative impact of those procedures aimed at optimizing
efficiency, although clearly both impact minimization and process optimization
are legitimate and complementary objectives of the subject.
Therefore, the recent efforts have been directed towards the green
synthesis of novel derivatives of Dihydropyrimidinones , that can provide the
improved medicinal and pharmaceutical properties.
In this work, I wish to describe the design, synthesis of a series of new
Dihydropyrimidinones compounds. These Dihydropyrimidinones compounds
are structurally unprecedented, having a different substituent at different
position.
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LITERATURE SURVEY:
In 1893 Italian chemist Pietro Biginelli reported on the acid-catalyzed
cyclocondensation reaction of ethyl acetoacetate (1), benzaldehyde (2) and urea
(3)27
. The reaction was carried out simply by heating a mixture of the three
components dissolved in ethanol with a catalytic amountnof HCl at reflux
temperature. The product of this novel one-pot, three-component synthesis that
precipitated on cooling of the reaction mixture was identified correctly by
Biginelli as 3,4- dihydropyrimidin-2(1H)-one 4 (Scheme 1)28
.
Scheme 1
OEt
OO
H2N NH2
O
NH
NHEtO
O
O
1 2 3
H+
EtOH, Heat
H O
The synthetic potential of this new heterocycle synthesis (now known as
Biginelli reaction) remained unexplored for quite some time. In the 1970's and
1980's interest slowly increased, and the scope of the original
cyclocondensation reaction shown in Scheme 1 was gradually extended by
variation of all three building blocks, allowing access to a large number of
multifunctionalized dihydropyrimidines of type 429
.
PEG-assisted solvent and catalyst free synthesis of 3,4-
dihydropyrimidinones under mild and neutral reaction conditions is described.
In a typical experimental procedure, a mixture containing aldehyde (2 mmol),
urea (2 mmol), b-dicarbonyl compound (2 mmol) and PEG (0.2 g) was heated at
100 uC for 45 min. After cooling at room temperature the reaction mixture was
poured into water, the solid product thus obtained was filtered and
recrystallized.12 A vareity aldehydes, b-dicarbonyl compounds and ureas were
reacted under these reaction conditions to afford Corresponding 3,4-
dihydropyrimidinones.
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To evaluate the effect of PEG, a mixture of benzaldehyde, urea and
ethylacetoacetate in molar ratio (1 : 1 : 1) was heated at 100 0C for 1 h in the
absence of PEG. It was found that reaction did not proceed, indicating PEG to
be an essential promoter for this reaction.
R'
OO
RH2N NH2
X R
NH
NHEtO
O
O
PEG-400
Solvent free
1000C
H O
R' = OMe, OEt,MeX = O, S
The microwave-expedited Biginelli reaction is based on our recent
finding that polyphosphate ester (PPE) serves as an excellent reaction mediator
in the three-component Biginelli reaction. Using THF/PPE mixtures (reflux, 24
h) instead of the traditional protic solvent/mineral acid reaction media (e.g.
EtOH/HCl), improved yields of DHPMs are obtainable. The success of this
PPE-mediated method may be due to a specific interaction of PPE with the
proposed N-acyliminium ion intermediate formed from the aldehyde and urea
component
R'
OO
H2N NH2
X
NH
NHEtO
O
O
1 2 3
PPE, MW
90 s
H O
R' = OMe, OEt,MeX = O, S
R
R
Over recent years, lanthanide salt mediated Lewis acid reactions have
attracted tremendous interest throughoutscientific communities due to their low
toxicity, ease of handling, low cost, stability, and recoverability of the reagent
from water. practical route for the Biginelli cyclocondensation reaction using
cerium(III) chloride heptahydrate as the catalyst. Three different sets of reaction
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conditions were examined: (i) traditional ethanol reflux; (ii) water reflux; and
(iii) solvent-free conditions. This is a novel, one-pot combination that not only
preserves the simplicity of Biginelli’s one-pot reaction but also consistently
produces excellent yields of the dihydropyrimidine-2(1H)-ones (Scheme 1).
In a typical general experimental procedure by using traditional conditions, a
solution of dicarbonyl compound, an aldehyde, and urea in ethanol was heated
under reflux in the presence of a catalytic amount of CeCl3â7H2O (25 mol %)
for a certain period of time required to complete the reaction (TLC), resulting in
the formation of dihydropyrimidinone. The reaction mixture was then poured
into crushed ice, and the solid product separated was filtered and recrystallized.
R'
OO
H2N NH2
X
NH
NHEtO
O
O
1 2 3
CeCl3.7H2O
EtOH or H2O
H O
R' = OMe, OEt,MeX = O, S
R
R
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PRESENT WORK:
Multi-functionalized 3,4-dihydropyrimidin-2(1H)-ones (DHPMs)
obtained from the Biginelli reaction have been used as potent calcium channel
blockers, antihypertensive agents, and neuropeptide Y antagonists. However
despite the fact that pyrimidines are found in a wide range of biologically active
molecules.
Here I report an extremely facile and environmentally friendly method for
the preparation of dihydropyrimidines (DHPMs) by the simple use of lemon
juice. In general Biginelli reaction the route is slightly synthetic, rather than a
greener one. But, this reaction is totally an example of green synthesis. Because
in general synthetic routs of reaction it is carried out in presence of conc.
H2SO4, but here I have used lemon juice. Because conc. H2SO4 which is
expensive, toxic and hazardous chemical may burn the skin and less safe. But
use of lemon juice is greener towards the synthesis of (DHPMs). Because it is
easy to handle, inexpensive, non-poisonous, non-hazardous, non-irritating safer
to handle.
Here, in this reaction, I had taken the catalytic amount of ethyl
acetoacetate (EAA), benzaldehyde, and urea in 1:1:1 proportions in a R.B. flask
and to it only 3 drops of lemon juice was added. The whole mixture was then
refluxed for 1 hrs. under constant flame of burner on water bath. The purpose of
adding drops of lemon juice is to maintain acidic condition, because it is an acid
catalyzed reaction. And its pH is also less (acidic) in comparison to the other
fruit juices. After, 1 hrs. we get a solid mass at the bottom of the R.B.
simultaneously the product was then poured into the ice cold water for the
precipitation.; it was then filter by the use of suction, then dried the product by
filter paper. The completion of the product can be determined by taking single
spotted TLC. The filtered product was then recrystallized by using 50% ethanol,
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and finally the melting point was determined; and yield was calculated, and
recorded in the project
During the reaction, I first examined the reaction of urea, aldehyde, and
EAA by using lemon juice. During the course of screening of a variety of
reaction conditions such as solvent, reaction tenmperature and the amount of
catalyst. I found that the use lemon juice carry out the reaction is very effective,
non-hazardous, non-toxic. Ethyl aceto-acetate was also used as a solvent was
essential for the cyclocondensation of the reactant urea, and benzaldehyde to
form our desired product(DHPMs). Thus, the for the confirmation of the
compound I had taken single spotted TLC, and finally IR and NMR was studied
and recored
Thus, it’s a very easy and green route for the preparation of
dihydropyrimidines.
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EXPERIMENTAL
SYNTHESIS OF DIHYDROPYRIMIDINONES:
A mixture of ethyl acetoacetate (EAA) (2ml), aldehydes (1gm) and
urea (1gm) was taken in a round bottom flask, to it 3 drops of lemon juice
(ascorbic acid) was added followed by shaking. The reaction mixture was
then reflux in water bath for minimum 1 hr. After that, the burner was
removed and immediately the content of the RB flask poured into the
beaker containing ice cold water. The mixture was stirred for 10-15
minutes and allowed for the precipitation. The separated product was
filtered under suction and washed with the cold water. It was then
recrystalized by 50% alcohol. The yield was found to be 2.84 gm.
O
O O
O
H2N NH2
O
NH
NH
O
O
O
Lemon
Juice
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SYNTHESIS OF DIHYDROPYRIDINONES (DHPMS):
EXPERIMENT NO. (A):
Synthesis of ethyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4phenyl pyrimidine-5-
carboxylate :
NH
NH
O Ph
O
EtO
A mixture of ethyl acetoacetate (2.227ml), Benzaldehyde (1.844ml) and
urea (1.00 gm) was taken in a RB flask. To it 3 drops of lemon juice was added
and after mixing it properly, reflux for 1 hrs. on a water bath on constant flame
of burner. After solidification, it was then poured into the ice cold water. The
separated product (DHPMs) was filtered under suction and washed with cold
water. It was then recrystallized by 50% ethanol. Completion of reaction is
monitored by TLC.
Colour- White
Yield- 69%
M.pt.- 2870C
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EXPERIMENT NO. (B):
Synthesis of ethyl 1,2,3,4-tetrahydro-4-methoxy-4-(4-methoxyphenyl)-6-
methyl-2-oxo- pyrimidine-5-carboxylate :
OCH3
NH
NHEtO
O
O
A mixture of ethyl acetoacetate (2.227ml), anisaldehyde (2.266ml) and urea
(2.166 gm) was taken in a RB flask. To it 3 drops of lemon juice was added and
after mixing it properly, reflux for 1 hrs. 10 min on a water bath on constant
flame of burner. After solidification, it was then poured into the ice cold water.
The separated product (DHPMs) was filtered under suction and well with cold
water. It was then recrystallized by 50% ethanol. Completion of reaction is
monitored by TLC.
Colour- White
Yield- 72%
M.pt.- 282oC
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EXPERIMENT NO.( C):
Synthesis of ethyl 1,2,3,4-tetrahydro-4-(4-hydroxyphenyl)-6-methyl-2-oxo-
pyrimidine-5-carboxylate :
OH
NH
NHEtO
O
O
A mixture of ethyl acetoacetate (2.227ml),4-hydroxybenzaldehyde
(2.033ml) and urea (1.00 gm) was taken in a RB flask. To it 3 drops of lemon
juice was added and after mixing it properly, reflux for 1 hrs. 5 min on a water
bath on constant flame of burner. After solidification, it was then poured into
the ice cold water. The separated product (DHPMs) was filtered under suction
and well with cold water. It was then recrystallized by 50% ethanol. Completion
of reaction is monitored by TLC
Colour- Turmeric yellow
Yield- 67%
M.pt.- 2580C
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Page | 18
EXPERIMENT NO.( D)
Synthesis of ethyl 1,2,3,4-tetrahydro-6-methyl-4-phenyl)-2-thioxo-
pyrimidine-5-carboxylate :
NH
NHEtO
O Ph
S
A mixture of ethyl acetoacetate (1.7576ml), Benzaldehyde (1.455ml) and
thiourea (1.00 gm) was taken in a RB flask. To it 3 drops of lemon juice was
added and after mixing it properly, reflux for 1 hrs. on a water bath on constant
flame of burner. After solidification, it was then poured into the ice cold water.
The separated product (DHPMs) was filtered under suction and well with cold
water. It was then recrystallized by 50% ethanol. Completion of reaction is
monitored by TLC.
Colour- Pale yellow
Yield- 68%
M.pt.- 2780C
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Page | 19
EXPERIMENT NO. ( E):
Synthesis of ethyl 1,2,3,4-tetrahydro-4-(2,5-dimethoxyphenyl)-6-methyl- 2-
oxopyrimidine-5-carboxylate :
NH
NH
O
OCH3
H3COOC
EtO
A mixture of ethyl acetoacetate (2.227ml) 2,5dimethoxybenzaldehyde
(2.766ml) and urea (1.00 gm) was taken in a RB flask. To it 3 drops of lemon
juice was added and after mixing it properly, reflux for 1 hrs. 15 min on a water
bath on constant flame of burner. After solidification, it was then poured into
the ice cold water. The separated product (DHPMs) was filtered under suction
and well with cold water. It was then recrystallized by 50% ethanol. Completion
of reaction is monitored by TLC.
Colour- Orange
Yield- 65%
M.pt.- 2850C
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Page | 20
EXPERIMENT NO.( F):
Synthesis of ethyl 4-(4-cloro-phenyl)-1,2,3,4-tetrahydro-6-methyl- 2-
oxopyrimidine-5-carboxylate :
NH
NH
O
EtO
O
Cl
A mixture of ethyl acetoacetate (2.227ml), 4-chlorobenzaldehyde (2.340gm)
and urea (1.00 gm) was taken in a RB flask. To it 3 drops of lemon juice was
added and after mixing it properly, reflux for 1 hr. 30 min on a water bath on
constant flame of burner. After solidification, it was then poured into the ice
cold water. The separated product (DHPMs) was filtered under suction and well
with cold water. It was then recrystallized by 50% ethanol. Completion of
reaction is monitored by TLC.
Colour- Yellow
Yield- 67%
M.pt.- 2790C
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Page | 21
EXPERIMENT NO.( G):
Synthesis of ethyl 1,2,3,4-tetrahydro-4-(4-methoxyphenyl)-6-methyl-2-
thioxopyrimidine-5-carboxylate :
OCH3
NH
NHEtO
O
S
A mixture of ethyl acetoacetate (1.7576ml), 4-methoxybenzaldehyde (1.788ml)
and thiourea (1.00 gm) was taken in a RB flask. To it 3 drops of lemon juice
was added and after mixing it properly, reflux for 1 hr. 5 min on a water bath on
constant flame of burner. After solidification, it was then poured into the ice
cold water. The separated product (DHPMs) was filtered under suction and well
with cold water. It was then recrystallized by 50% ethanol. Completion of
reaction is monitored by TLC.
Colour- Light yellow
Yield- 71%
M.pt.- 2610C
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EXPERIMENT NO.( H):
Synthesis of ethyl 1,2,3,4-tetrahydro-4-(4-hydroxyphenyl)-6-methyl-2-
thioxopyrimidine-5-carboxylate :
OH
NH
NHEtO
O
S
A mixture of ethyl acetoacetate (1.7576ml), 4-methoxybenzaldehyde (1.604gm)
and thiourea (1.00 gm) was taken in a RB flask. To it 3 drops of lemon juice
was added and after mixing it properly, reflux for 1 hr. 10 min on a water bath
on constant flame of burner. After solidification, it was then poured into the ice
cold water. The separated product (DHPMs) was filtered under suction and well
with cold water. It was then recrystallized by 50% ethanol. Completion of
reaction is monitored by TLC.
Colour- Orange
Yield- 62%
M.pt.- 2520C
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Page | 23
EXPERIMENT NO.( I):
Synthesis of ethyl 1,2,3,4-tetrahydro-6-methyl-2-oxo-4-styrylpyrimidine-5-
carboxylate :
CH
NH
NHEtO
O
O
CH Ph
A mixture of ethyl acetoacetate (1.7576ml), cinnamaldehyde (2.38ml) and
thiourea (1.00 gm) was taken in a RB flask. To it 3 drops of lemon juice was
added and after mixing it properly, reflux for 1 hr. 15 min on a water bath on
constant flame of burner. After solidification, it was then poured into the ice
cold water. The separated product (DHPMs) was filtered under suction and well
with cold water. It was then recrystallized by 50% ethanol. Completion of
reaction is monitored by TLC.
Colour- Orange
Yield- 55%
M.pt.- 2670C
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Page | 24
RESULT AND DISSCUSSION
NH
NH
O Ph
O
EtO
IR Analysis:
Sr.No. Literature value(cm-1
) Observed absorption
(cm-1
) Assignment
1 3700-3500 3649.44 -NH
2 3000-2700 2977.23 -CH3
3 1900-1650 1897.54 -COOR
4 1675-1500 1602.90 C=C
5 1300-1100 1222.43 C-N
NMR Analysis:
Sr.No. Signal position multiplicity No. of H atoms Assignment
1 8.1 S 1 Ar-NH
2 5.7 S 1 Ar-NH
3 5.2 S 1 Ar-H
4 4.1 q 2 -CH2-CH3
5 2.3 S 3 Ar-CH3
6 1.2 t 3 -CH2-CH3
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OH
NH
NHEtO
O
O
IR Analysis:
Sr.No. Literature value(cm-1
) Observed absorption
(cm-1
) Assignment
1 3700-3500 3513.45 -OH
2 3500-3300 3283.92 -NH\
3 3000-2700 2822.43 -CH3
4 1900-1650 1887.41 -COOR
5 1675-1500 1613.99 C=C
6 1300-1100 1172.28 C-N
NMR Analysis:
Sr.No. Signal position multiplicity No. of H atoms Assignment
1 8.9 S 1 Ar-NH
2 8.1 S 1 Ar-NH
3 7.0 d 1 Ar-H
4 6.6 d 1 Ar-H
5 5.1 S 1 Ar-CH
6 3.1 q 2 -CH2-CH3
7 2.2 S 3 Ar-CH3
8 1.1 t 3 -CH2-CH3
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MINOR RESEARCH PROJECT-NDG/2010-2012
Page | 26
NH
NHEtO
O Ph
S
IR Analysis:
Sr.No. Literature value(cm-1
) Observed absorption
(cm-1
) Assignment
1 3700-3500 3327.32 -NH
2 3000-2700 2987.35 -CH3
3 1900-1650 1882.59 -COOR
4 1675-1500 1577.82 C=C
5 1300-1100 1124.05 C-N
NMR Analysis:
Sr.No. Signal position multiplicity No. of H atoms Assignment
1 10.14 S 1 Ar-NH
2 9.51 S 1 Ar-NH
3 7.27 m 5 Ar-H
4 5.24 S 1 Ar-CH
5 4.04 q 2 -CH2-CH3
6 2.32 S 3 Ar-CH3
7 1.15 t 3 -CH2-CH3
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MINOR RESEARCH PROJECT-NDG/2010-2012
Page | 27 NH
NH
O
OCH3
H3COOC
EtO
IR Analysis:
Sr.No. Literature value(cm-1
) Observed absorption
(cm-1
) Assignment
1 3700-3500 3478.74 -NH
2 3000-2700 2835.94 -CH3
3 1900-1650 1840.15 -COOR
4 1675-1500 1648.23 C=C
5 1475-1300 1377.70 C-O
6 1300-1100 1101.39 C-N
NMR Analysis:
Sr.No. Signal position multiplicity No. of H atoms Assignment
1 10.37 S 1 Ar-NH
2 9.02 S 1 Ar-NH
3 7.19, 7.02 dd 2 Ar-H
4 5.53 d 1 Ar-CH
5 4.0 q 2 CH2-CH3
6 3.9, 3,7 S 3, 3 Ar-OMe
7 2.34 S 3 Ar-CH3
8 1.1 t 3 CH2-CH3
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MINOR RESEARCH PROJECT-NDG/2010-2012
Page | 28
NH
NH
O
EtO
O
Cl
IR Analysis:
Sr.No. Literature value(cm-1
) Observed absorption
(cm-1
) Assignment
1 3700-3500 3473.43 -NH
2 3000-2700 2983.01 -CH3
3 1900-1650 1907.66 -COOR
4 1300-1100 1101.39 C-N
5 700-800 758.05 C-Cl
NMR Analysis:
Sr.No. Signal position multiplicity No. of H.atoms Assignment
1 10.0 S 1 Ar-NH
2 9.1 S 1 Ar-NH
3 7.9, 7.6 dd 2 Ar-H
4 7.3, 7.2 dd 2 Ar-H
5 4.0 T 3 CH2-CH3
6 1.14 q 2 CH2-CH3
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CH
NH
NHEtO
O
O
CH Ph
IR Analysis:
Sr.No. Literature value(cm-1
) Observed absorption
(cm-1
) Assignment
1 3700-3500 3431.00 -NH
2 3000-2700 2924.18 -CH3
3 1900-1650 1749.49 -COOR
4 1675-1500 1531.50 C=C
5 1300-1100 1221.46 C-N
NMR Analysis:
Sr.No. Signal position multiplicity No. of H atoms Assignment
1 7.37 M 5 Ar-H
2 5.54 d 1 Ar-CH
3 3.39 S 3 CH2-CH3
4 2.54 S 3 Ar-CH3
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CONCLUSION:
In conclusion, the present procedure of the synthesis of
dihydropyrimidin-2(1H)-ones by three-component condensation via different
advanced methods provides an efficient and much improved modification of
Biginelli’s reaction. In addition, it is possible to apply the tenets of green
chemistry to the generation of biologically interesting Biginelli products using
aqueous medium approaches, which are less expensive and less toxic than those
with organic solvents. Moreover, this method offers several advantages
including high yields, short reaction times, and a simple work-up procedure, and
it also has the ability to tolerate a wide variety of substitutions in all three
components, which is lacking in existing procedures. Furthermore, the present
procedure is readily amenable to parallel synthesis and the generation of
combinatorial dihydropyrimidinone (DHPMs) libraries.
The green chemistry programme supports the invention of more
environmentally friendly chemical processes which reduce or even eliminate the
generation of hazardous substances.
All newly synthesized dihydropyrimidin-2(1H)-ones were characterized
by H1 NMR and IR studies and their spectra and structures are given below.
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REFERENCES:
1. T. L. Gilchrist.; Heterocyclic Chemistry, 3rd ed.; Addison-Wesley
Longman, Ltd.: England, 1998. (b) Lednicer, D. Strategies for Organic
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and 9.
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15. K. S. Atwal.; B. N. Swanson.; S. E. Unger.; D. M. Floyd .; S. Mereland.;
A. Hedberg.; B. C. O’Reilly.; J. Med. Chem.1991, 34, 806–81
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24. (a) C.O. Kappe,. Acc. Chem. Res. 2000, 33, 879. (b) J. C. Bussolari.; P.
A. McDonnell, J. Org. Chem. 2000, 65, 6777. (c) G.;Byk, H. E.
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I.B. Dzvinchuk.' T.V. Makitruk, M. O. Lozinskii, Chem. Heterocycl.
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Comput. 2003, 39, 455. (f) A. Dondoni.; A. Massi.; E. Minhini .; S.
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30. Suman L. Jain, Sweety Singhal and Bir Sain org/greenchem | Green
Chemistry 2007
31. a) A. Dandia.; M. Saha.; H. Taneja.; J. Fluorine Chem. 1998,90, 17.
b) R. Gupta.; A. K. Gupta.; S. Paul.; P. L. Kachroo, Ind. J. Chem. 1995,
34B, 151.
c) See also: R. Gupta.; S. Paul.; K. Gupta, Ind. J. Chem. Technol. 1998, 5,
340.
32. K Folkers.; H. J. Harwood.; T. B. Johnson,. J. Am. Chem. Soc. 1932, 54,
3751.
33. Kappe, C. O. J. Org. Chem. 1997, 62, 7201.
34. G. A. Molander, Chem. Rev. 1992, 92, 29. (b) Marshman, R. Aldrichim.
Acta 1995, 28, 77. (c) G. Bartoli.; M. Bosco.; E. Marcantoni.; F. Nobili.;
L. Sambri, J. Org. Chem. 1997, 62, 4183. (d) A. Cappa.; E. Marcantoni.;
E. Torregiani.; G. Bartoli.; C. M. Bellucci.; M. Bosco, L. Sambri.; J.
Org. Chem. 1999, 64, 5696.D. Blachut.; Z. Czarnocki.; K. Wojtasiewicz,
Synthesis 2006, 2855-2864.
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11 10 9 8 7 6 5 4 3 2 1 0 ppm
0.0000
1.1546
1.1846
1.2448
1.2511
1.2626
1.3569
1.4383
1.8261
1.8986
2.1122
2.2290
2.2695
2.2871
2.3690
2.4117
2.5344
2.5388
2.5434
2.5479
2.5522
3.3933
5.3534
5.4620
5.5499
5.5706
5.6022
5.6277
6.6458
6.7795
6.8376
6.8566
7.1801
7.2077
7.2236
7.2526
7.2597
7.2686
7.2755
7.2844
7.2897
7.2998
7.3082
7.3214
7.3264
7.3371
7.3424
7.3528
7.3721
7.3876
7.3908
8.1237
0.86
1.14
3.55
18.17
1.10
1.01
1.44
1.00
0.27
Current Data ParametersNAME May18-2012-AdministratorEXPNO 490PROCNO 1
F2 - Acquisition ParametersDate_ 20120518Time 21.13
INSTRUM spectPROBHD 5 mm PABBO BB-PULPROG zg30TD 65536SOLVENT DMSONS 8DS 2SWH 12019.230 HzFIDRES 0.183399 HzAQ 2.7263477 secRG 256DW 41.600 usecDE 6.00 usecTE 297.5 KD1 1.00000000 secTD0 1
======== CHANNEL f1 ========NUC1 1HP1 10.90 usecPL1 -3.00 dBSFO1 400.1324710 MHz
F2 - Processing parameters
SI 32768SF 400.1299863 MHzWDW EMSSB 0LB 0.30 HzGB 0PC 1.00
NVA-I
CH
NH
NHEtO
O
O
CH Ph
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-112 11 10 9 8 7 6 5 4 3 2 1 0 ppm
0.0000
1.1411
1.1587
1.1766
2.1250
2.3264
2.4346
2.5466
2.5511
2.5557
2.5603
2.5648
3.2978
4.0123
4.0159
4.0298
4.0336
4.0475
4.0516
4.0610
4.0653
4.0693
5.2365
5.2455
7.2252
7.2419
7.2486
7.2539
7.2579
7.2625
7.2677
7.2748
7.2791
7.2901
7.2959
7.3042
7.3075
7.3105
7.3215
7.3254
7.3287
8.0120
9.5124
10.1461
3.46
3.27
2.25
1.08
5.63
1.00
1.03
NVA-D
NH
NHEtO
O Ph
S
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13 12 11 10 9 8 7 6 5 4 3 2 1 0 ppm
0.0001
1.1101
1.1278
1.1456
1.2312
1.2428
1.2484
2.1029
2.2245
2.2407
2.2651
2.4307
2.5186
2.5229
2.5273
2.5318
2.5361
3.3369
3.9744
3.9919
4.0084
4.0262
5.1665
5.1748
5.3724
5.3997
5.6347
6.0997
6.1201
6.1404
6.1569
6.1727
6.7947
6.8152
6.8651
7.2453
7.2498
7.2666
7.3097
7.3148
7.3308
7.3374
7.3447
7.3516
7.3738
7.3855
7.4196
7.4409
7.6085
7.6294
7.6938
7.9031
7.9075
7.9197
7.9241
8.1881
9.1660
10.0025
3.71
0.39
3.61
2.84
1.71
3.73
4.17
1.87
2.17
1.42
2.59
10.47
1.55
1.13
1.44
1.00
0.61
Current Data ParametersNAME May18-2012-AdministratorEXPNO 460PROCNO 1
F2 - Acquisition ParametersDate_ 20120518Time 20.58INSTRUM spectPROBHD 5 mm PABBO BB-PULPROG zg30TD 65536SOLVENT DMSONS 8DS 2SWH 12019.230 HzFIDRES 0.183399 HzAQ 2.7263477 secRG 456DW 41.600 usecDE 6.00 usecTE 297.5 KD1 1.00000000 secTD0 1
======== CHANNEL f1 ========NUC1 1HP1 10.90 usecPL1 -3.00 dBSFO1 400.1324710 MHz
F2 - Processing parametersSI 32768SF 400.1299925 MHzWDW EMSSB 0LB 0.30 HzGB 0PC 1.00
NVA-F
NH
NH
O
EtO
O
Cl
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11 10 9 8 7 6 5 4 3 2 1 0 ppm
0.0000
1.1258
1.1436
1.1614
1.1830
1.2008
2.1111
2.2590
2.5357
2.5396
2.5437
3.3681
3.9630
3.9733
3.9910
4.0086
4.0259
4.7587
5.0962
5.1038
6.5562
6.5773
6.6681
6.6892
6.9485
6.9696
7.0463
7.0675
7.4741
8.1006
8.4783
8.9918
3.67
3.55
2.45
1.00
0.20
2.02
0.20
2.01
1.00
0.15
0.11
1.21
0.65
Current Data ParametersNAME May18-2012-AdministratorEXPNO 470PROCNO 1
F2 - Acquisition Parameters
Date_ 20120518Time 21.03INSTRUM spectPROBHD 5 mm PABBO BB-PULPROG zg30TD 65536SOLVENT DMSONS 8DS 2SWH 12019.230 HzFIDRES 0.183399 HzAQ 2.7263477 secRG 287DW 41.600 usecDE 6.00 usecTE 297.5 KD1 1.00000000 secTD0 1
======== CHANNEL f1 ========NUC1 1HP1 10.90 usecPL1 -3.00 dBSFO1 400.1324710 MHz
F2 - Processing parametersSI 32768SF 400.1299878 MHzWDW EMSSB 0LB 0.30 HzGB 0PC 1.00
NVA-C
OH
NH
NHEtO
O
S
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12 11 10 9 8 7 6 5 4 3 2 1 0 ppm
0.0000
1.0848
1.1025
1.1203
1.1543
2.1269
2.2714
2.3403
2.5489
2.5534
2.5578
2.5623
2.5666
3.3346
3.4964
3.6978
3.7168
3.7212
3.7832
3.8122
3.8310
3.8356
3.8406
3.8591
3.9039
3.9618
3.9768
3.9797
3.9944
3.9977
4.0120
4.0158
5.5317
5.5388
6.6157
6.6233
6.6939
6.7330
6.7407
6.7550
6.7627
6.8406
6.8627
7.0535
7.0759
7.1653
7.1735
7.1878
7.1959
7.2106
7.2186
8.0032
9.0230
10.3791
3.33
0.32
0.53
2.70
4.22
7.22
3.79
2.89
6.50
2.15
1.03
1.16
1.17
1.32
1.40
2.21
1.08
1.00
Current Data ParametersNAME May18-2012-AdministratorEXPNO 480
PROCNO 1
F2 - Acquisition Parameters
Date_ 20120518Time 21.08INSTRUM spect
PROBHD 5 mm PABBO BB-PULPROG zg30TD 65536
SOLVENT DMSONS 8DS 2
SWH 12019.230 HzFIDRES 0.183399 HzAQ 2.7263477 sec
RG 575DW 41.600 usecDE 6.00 usecTE 297.5 K
D1 1.00000000 secTD0 1
======== CHANNEL f1 ========NUC1 1HP1 10.90 usec
PL1 -3.00 dBSFO1 400.1324710 MHz
F2 - Processing parametersSI 32768SF 400.1299807 MHz
WDW EMSSB 0LB 0.30 Hz
GB 0PC 1.00
NVA-E
NH
NH
O
OCH3
H3COOC
EtO