green chemistry approach: synthesis of … · file no-47-1546/10(wro) dated 18 th oct 2010 . minor...

MINOR RESEARCH PROJECT-NDG/2010-2012

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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.



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

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

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,


Page | 13

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-oxopyrimidine-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


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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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


monitored by TLC.

Colour- Pale yellow

Yield- 68%

M.pt.- 2780C


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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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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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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





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




Colour- Orange

Yield- 62%

M.pt.- 2520C


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





Colour- Orange

Yield- 55%

M.pt.- 2670C


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


Page | 25

OH

NH

NHEtO

O

O

IR Analysis:



(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:


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


Page | 26

NH

NHEtO

O Ph

S

IR Analysis:



(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:


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


Page | 27 NH

NH

O

OCH3

H3COOC

EtO

IR Analysis:



(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:


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


Page | 28

NH

NH

O

EtO

O

Cl

IR Analysis:



(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


Page | 29

CH

NH

NHEtO

O

O

CH Ph

IR Analysis:



(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:


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


Page | 30

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.



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.


Page | 31

REFERENCES:

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3751-3758.

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Page | 34

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.

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c) See also: R. Gupta.; S. Paul.; K. Gupta, Ind. J. Chem. Technol. 1998, 5,

340.

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3751.

33. Kappe, C. O. J. Org. Chem. 1997, 62, 7201.

34. G. A. Molander, Chem. Rev. 1992, 92, 29. (b) Marshman, R. Aldrichim.

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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.

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Synthesis 2006, 2855-2864.


Page | 35

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

[email protected]

CH

NH

NHEtO

O

O

CH Ph


Page | 36

-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


Page | 37

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


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


F2 - Processing parametersSI 32768SF 400.1299925 MHzWDW EMSSB 0LB 0.30 HzGB 0PC 1.00

NVA-F

[email protected]

NH

NH

O

EtO

O

Cl


Page | 38

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


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


F2 - Processing parametersSI 32768SF 400.1299878 MHzWDW EMSSB 0LB 0.30 HzGB 0PC 1.00

NVA-C

OH

NH

NHEtO

O

S


Page | 39

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

green chemistry approach: synthesis of … · file no-47-1546/10(wro) dated 18 th oct 2010 . minor...

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