4.1. Introduction 4.2. Pharmacological aspects of...

Synthesis of Novel Coumarinyldihydropyrimidinones and their N-Acylates

1

4.1. Introduction

Heterocyclic compounds are widely distributed in nature and are essential to life; they

play a vital role in the metabolism of all living cells. Compounds classified as

heterocyclic probably constitute the largest and most varied family of organic

compounds. Even if we restrict our consideration to oxygen, nitrogen and sulfur (the

most common heterocyclic elements), the permutations and combinations of such a

replacement are numerous.

4.2. Pharmacological aspects of coumarins

The fusion of a pyrone ring with a benzene nucleus gives rise to a class of heterocyclic

compounds known as benzopyrones, of which two distinct types are recognized: benzo-

α-pyrone (1), commonly called coumarin, and benzo-γ-pyrone (2), called chromone, the

two differing only in the position of the carbonyl group in the heterocyclic ring (Figure

1)

Figure1

Representatives of these groups of compounds are found to occur widely in the plant

kingdom, either in the free or in the combined state. These are present in notable amounts

in several species of Umbelliferae, Rutaceae and Compositae. The study of coumarins

began more than 200 years ago. R. D. Murray has written an excellent book that provides

a comprehensive overview of naturally occurring coumarins.1

The name coumarin

derived from Coumarounaodorata Aube (Dipteryxodorata), from which benzo-α-pyron

was isolated for the first time. Coumarin is a widely occurring secondary metabolite that

occurs naturally in several plant families and essential oils, and has been used as a

fragrance in food and cosmetic industry. The coumarins have long been recognized to

possess anti-inflammatory2

, anti-oxidant3

, anti-allergic4

, hepatoprotective5

, anti-


2

thrombotic6, anti-viral

7 and anti-carcinogenic

8 activities. The hydroxycoumarins are

typical phenolic compounds and, therefore act as potent metal chelators and free radical

scavengers. They are powerful chain-breaking anti-oxidants. Coumarins are extremely

variable in structure, due to the various types of substitutions in their basic structure

which can influence their biological activity. Several synthetic coumarins with a variety

of pharmacophoric groups at C-3, C-4 and C-7 positions have been intensively screened

for anti-microbial, anti-HIV, anti-cancer, lipid-lowering, anti-oxidant and anti-coagulant

activities. Specifically, coumarin-3-sulfonamides and carboxamides were reported to

exhibit selective cytotoxicity against mammalian cancer cell lines. Some recent literature

reports on various pharmacological properties of substituted coumarin derivatives have

been summarized in Table 1.

Table 1: Biologically activecoumarins

S. No. Structure Pharmacologic

al

Activity

References

1.

Anti-microbial Hishmat et al.9

2.

Anti-leucemic Kotali et al.10

3.

Anti-

inflammatory

Kontogiorgis &

Hadjipavlou11

4.

Anti-viral Hwu et al.12


3

5.

Anti-HIV Huang et al.13

6.

Anti-coagulant Abdelhafez et al.14

7.

Lipid-lowering

Activity

Madhavan et al.15

8.

Anti-oxidant

and Cytotoxic

Manojkumar et

al.16

4.2.1. Synthesis of coumarins

Coumarins can be classically synthesized by the Perkin, Pechmann or Knoevenagel

reactions. Though recently, the Wittig, the Kostanecki–Robinson and Reformatsky

reactions have also been conveniently applied to the synthesis of this type of

heterocycles. However, it is important to note that all the methods reported have some

disadvantages, since they lack generality and efficiency, thus making the development of

new reliable high-yielding methods for the synthesis of coumarin is an important subject.

4.2.1.1. Perkin Reaction

The Perkin reaction17,18

for the synthesis of coumarins involves aldol condensation of

aromatic ortho-hydroxy benzaldehyde and an acid anhydride, in the presence of an alkali

salt of the acid (Scheme1).19-21


4

Scheme 1

4.2.1.2. Pechmann Reaction

A very valuable method for the synthesis of coumarins is the Pechmann reaction. In

general, coumarins can be obtained by condensation of phenols with β-ketoesters, in the

presence of acid catalysts (Scheme2). The reaction is often referred to as Pechmann-

Duisberg Condensation,22

when aceto acetic esters and derivatives are used. The course

of the reaction is influenced by many different factors, viz. the nature of the phenol, the

nature of the β-keto ester and the condensing agent.

Scheme 2

4.2.1.3. Knoevenagel Reaction

Condensation of ortho-hydroxy aromatic aldehyde with active methylene compounds in

the presence of ammonia or amines is known as Knoevenagel reaction.23

Moreover, when

malonic acid and pyridine, with or without traces of piperidine, are used the reaction is

often named as Doebner modification (Scheme3)


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Scheme 3

4.3. 3,4-dihydropyrimidin-2-(1H)-ones (DHPMs)

A class of heterocyclic compounds known as 3,4-dihydropyrimidin-2-(1H)-ones

(DHPMs) and related compounds are well known for their pharmacological properties

such as anti-viral, anti-tumor, anti-hypertensive and anti-bacterial effects. Over 100 years

ago, in 1893 Italian chemist Pietro Biginelli discovered a multi-component reaction that

produced 4-aryl-3,4-dihydropyrimidin-2(1H)-one (DHPM, 3).24

He reported an acid

catalyzed cyclocondensation reaction of ethyl acetoacetate, benzaldehyde and urea by

simply heating the three components in ethanol with catalytic amount of HCl. The

product of this novel one pot synthesis was obtained as 3,4-dihydropyrimidin-2(1H)-one

(Scheme 4).

Scheme 4: The Biginelli dihyropyrimidinone synthesis

4.3.1. Biological importance of dihydropyrimidinones

Though the synthetic potential of Biginelli reaction remained unexplored for quite some

time, interest slowly increased during 1970’s and 1980’s. Since 1980’s a tremendous

interest in its activity was observed as indicated by the growing number of publications

and patents. This is attributed due to the fact that the multi-functionalised


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dihydropyrimidinone scaffold 3, “Biginelli compound” represents a heterocyclic system

of remarkable pharmacological efficiency. In the past decades, a broad range of

biological activities has been ascribed to these derivatives.25

The cardiovascular activity

of DHPMs was first recognized by Khanina, et al.26

in 1978, who reported that β-amino

ethyl esters of type 4 exhibit moderate hypotensive activity and coronary dilatory

properties (Figure 2). During mid-1980’s, interest originally focused on alkyl 4-aryl-1,4-

dihydrpyrimidine-5-carboxylate calcium channel blockers which closely mimic the

dihydropyridine (DHP) scaffold, e.g. 5.27

These analogs were shown to be potent calcium

channel blockers, but most of them did not show significant anti-hypertensive activity in

vivo. The structural modifications on dihydropyrimidine ring led to DHPMs bearing an

ester group at N-3. Thus, DHPM 628

displayed not only more potent and long lasting vaso

dilative action but also hypotensive activity with slow on set as compared to DHPs.

Further modification of the substituents at N-3 finally led to the development of orally

active long-lasting anti-hypertensive agents, such as DHPMs 7 (SQ 32926)29

and 8 (SQ

32547).30

More recently, appropriately functionalized DHPMs have emerged as orally

active anti-hypertensive agents, e.g. compounds 931

or α1a adrenoceptor-selective

antagonist compound 10.32

A very recent highlight in this context has been the

identification of the structurally rather simple DHPM monastrol (11) as a mitotic kinesin

Eg5 motor protein inhibitor and potential new lead for the development of anti-cancer

drugs.33

Figure 2


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Detailed pharmacological studies by Rovnyak, et. al.31

with a large set of DHPM analogs

have led to a general structure-activity relationship for N-3-functionalized DHPM

calcium channel blockers of type 12-15 (Figure 3). Thus ortho and / or meta aromatic

substitution, essential for optimal activity in vitro, was proposed. Similarly, the C-5 ester

alkyl group was found to be major determinant of potency. Moreover, a substituent on N-

3 of the dihydropyrimidine ring was found to be a strict requirement for activity and the

order of potency for the 2-hetero atom was S>O>N (Figure 4).

Figure 3

Figure 4

4.3.2. Synthesis of 4-aryl-3,4-dihydropyrimidin-2-(1H)-ones (DHPMs)

Two different approaches have been employed in recent years to synthesize DHPM

derivatives.

4.3.2.1. The first method relies on the traditional Biginelli three-component protocol and


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involves the acid-catalyzed cyclocondensation of 1,3-dicarbonyl component with an

aromatic aldehyde and urea or thiourea derivative (Scheme 5). A major drawback of the

original Biginelli protocol, using ethanol and catalytic HCl as reaction medium, has been

the low yield which was frequently encountered during the use of sterically more

demanding aldehydes or thiourea. In recent years, these problems have been largely

overcome by the development of improved and more robust reaction conditions,

involving Lewis-acid catalysts and solvent-free procedures or microwave-enhanced-

protocols.

Scheme 5: Acid-catalyzed Biginelli dihydropyrimidinone synthesis

A variety of process for the improved one-pot synthesis of Biginelli DHPM has been

reported time to time by using different lewis acid catalysts such as using lanthanum

triflate, ferric chloride hexahydrate or nickel chloride hexahydrate, lanthanum chloride

heptahydrate, lithium perchlorate or lithium triflate, ceric ammonium nitrate, boron

trifluorideetherate, copper (I) chloride and glacial acetic acid in THF, indium (III)

chloride, indium (III) bromide, zirconium tetrachloride, n-butyl-N,N-dimethyl-α-

phenylethylammonium bromide, polyphosphate ester, bismuth triflate, lithium bromide,

copper (II) triflate, bismuth chloride, manganese acetate, ammonium chloride, Tonsil

Actisil FF (TAFF), commercial Mexican betinitic clay, zinc trifluromethanesulfonate,

cerium (III) chloride, CBr4, p-toluenesulphonic acid, vanadium (III) chloride, in-situ

generated iodotrimethylsilane and boric acid as the catalyst in glacial acetic acid.34

4.3.2.2. The second procedure that has been used frequently is the so-called

“Atwal modification” of the Biginelli reaction (Scheme 6). Here, an enone of the type 16

is first condensed with a suitable protected urea or thiourea derivative 17a-b under mild


9

basic conditions. Deprotection of the resulting 1,4-dihydropyrimidinone 18 leads to the

desired DHPMs 19.35

Although this method requires prior synthesis of enone 16, its

reliability and broad applicability makes it an attractive alternative to the traditional one-

step Biginelli condensation. In addition, 1,4-dihydropyrimidines 18 can be alkylated or

acylated regiospecifically at N-3 by various electrophiles, thereby making the

pharmacologically interesting DHPM analogues of type 20 readily accessible.36

A

majority of DHPM analogues which have been reported in the literature so far have been

prepared by either of the two protocols discusses.

Scheme 6: The Biginelli dihydropyrimidinone synthesis (Atwal Modifications)


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4.4. PRESENT WORK

In the design of new drugs, the development of hybrid molecules through the

combination of different pharmacophores may lead to the compounds with interesting

biological profiles. Heterocyclic compounds, viz. coumarin constitute an important class

of natural/synthetic polyphenolic compounds that shows diverse biological properties like

anti-coagulant, anti-fungal, anti-biotics, anti-microbial, anti-viral, anti-oxidant, anti-

cancer, anti-inflammatory, etc. These pharmacological properties of coumarins attracted

attention of organic chemists to synthesize libraries of several new compounds featuring

different heterocyclic rings attached to the coumarin moiety with an aim to obtain more

potent pharmacological active compounds. In addition, 3,4-dihydropyrimidinone

(DHPM) class of compounds are excellent starting synthons which show many

interesting properties including calcium channel modulators, α1a-adrenergic receptor

antagonists, mitotic-kinesin inhibitors and anti-platelate activity. Encouraged by these

results shown by coumarin and dihydropyrimidinones, we have synthesized

coumarinyldihydropyrimidinones (CDHPMs) and their N-acylates which have both

coumarin and dihydropyrimidinone moieties in the same molecule. These hybrid

molecules are expected to give a synergistic effect.

A series of novel coumarinyldihydropyrimidinones alkyl4-(7',8'/7'/5',7'-di/

monomethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate 37a-s,

ethyl 4-(7',8'-dimethoxycoumarin-4-yl)-N-3-alkanoyl-6-methyl-3,4-dihydropyrimidin-2-

one-5-carboxylates 39a-f, 40a-f and 41a-f have been synthesized (Scheme 8 and 9). The

syntheses of compounds 37a-s have been achieved starting from the synthesis of 4-

methylcoumarins 25-27, following the well-known Pechmann condensation reaction.

Pyrogallol (21), resorcinol (22) and phloroglucinol (23) were condensed with ethyl

aetoacetate (24) in the presence of sulphuric acid to give 4-methylcoumarins 25-27 in 77

- 80 % yields. The coumarins so obtained had free hydroxyl which was then methylated

using dimethylsulphate (28) in acetone in the presence of potassium carbonate to yield

7,8-dimethoxy-4-methylcoumarin 29, 7-methoxy-4-methylcoumarin 30 and 5,7-

dimethoxy-4-methylcoumarin 31. Selenium dioxide (32) was then used to convert the


11

active methyl group present at C-4 position in coumarins 29, 30 and 31 to coumarin

aldehydes 33, 34 and 35 (Scheme 7).37,38

Scheme 7

The well-known Biginelli cyclocondensation reaction39,40,41

was followed to synthesize

coumarinyldihydropyrimidinones using condensation of 7,8-dimethoxy-4-

formylcoumarin (33), 7-methoxy-4-formylcoumarin (34) and 5,7-dimethoxy-4-

formylcoumarin (35) with urea and appropriate β-keto ester 36a-g in absolute ethanol in

the presence of conc. sulphuric acid as catalyst to afforded compounds 37a-s in 50-55%

yields (Scheme 8). It is worthy to mention here that the Biginelli cyclocondensation

reaction remained incomplete even after 40 hrs of refluxing in ethanol when 1 molar

equivalent of β-keto ester and urea with respect to coumarinyl aldehyde were used. The

same reaction was completed within 24 hrs of refluxing in ethanol with 50-55 % yield

when molar equivalents of β-keto ester and urea were increased upto 3 equivalents with

respect to coumarinyl aldehyde.


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Scheme 8: Synthesis of Coumarinyl DHPMs


13

The synthesis of CDHPMs having variation at the C-6 and at the ester linkage of the

DHPM ring and C-5, C-7 and C-8 positions of coumarin have been achieved (Scheme 8).

The 7,8-dimethoxycoumarin-DHPM 37a, 37b and 37f were acylated at N-3 position with

acid anhydride (acetic, propanoic, butanoic, pentanoic, hexanoic and benzoic anhydride)

38a-f (2 molar equiv.) in DCM at room temperature using 4-N,N-dimethylaminopyridine

(DMAP) (0.5 equiv.) as a catalyst to afford N-acylated derivatives, i.e. 39a-f, 40a-f and

41a-f in 61-70 % yield (Scheme 9).

Scheme 9: Synthesis of N-acylatedcoumarinyl DHPMs

Hence, a series of thirty seven different coumarinyldihydropyrimidinones and their N-

acylates were synthesized having different ester chain and acyloxy chain. The structures

of all synthesized thirty seven compounds 36a-s, 39a-f, 40a-f and 41a-f were

unambiguously established on the basis of their spectral data (1H,

13C NMR, IR and

HRMS) analysis. The structure of known compounds, i.e. 25-27, 29-31 and 33-35 were

established by comparison of their physical and spectroscopic data with their reported in


14

the literature. Copies of the 1H- and

13C NMR spectrum of compounds are given in the

Results and Discussion section.

4.5. RESULTS AND DISCUSSIONS

4.5.1. Methyl 4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-

one-5-carboxylate (37a)

The compound 37a was synthesized by multi-component

Biginelli reaction of 7,8-dimethoxy-4-formylcoumarin 33 with

urea and methyl acetoacetate 36a in ethanol & obtained as a pale

yellow solid (M.P. 240-242 oC) in 53 % yield as shown in

Scheme 8. The structure of compound 37a was established on

the basis of its spectral data analysis. Its high resolution mass

spectrum showed [M+H]+ peak at m/z 375.1183, which confirmed its molecular formula

to be C18H18N2O7. The peaks in its IR spectrum at 3375 and 3281 cm-1

were assigned to

NH, whereas peaks at 1762, 1710 and 1670 cm-1

were assigned to CO groups present in

the molecule. The characteristic peaks of C-6CH3, 2 x OCH3, C-4H and C-3'H protons in

its 1H NMR spectrum appeared at δ 2.34 (3H, s), 3.82(3H, s), 3.94 (3H, s), 5.62 (1H, s)

and 6.02 (1H, s), respectively (Figure 5). Similarly, in its 13

C NMR spectrum, the

characteristic peaks for C-6CH3, C-4, 2 x OCH3 and C-5 appeared at δ17.88, 56.46,

59.43, 60.77 and 108.93, respectively (Figure 6). The peaks of all other protons and

carbons of the molecule were also present in the 1H and

13C NMR spectra of the

compound. Based on the spectral data analysis, the structure of the compound was

unambiguously established as methyl 4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-

dihydropyrimidin-2-one-5-carboxylate (37a).

4.5.2. Ethyl 4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-

5-dicarboxylate (37b)


15

The compound 37b was synthesized by the multi-component

Biginelli reaction of 7,8-dimethoxy-4-formylcoumarin 33

with urea and ethyl acetoacetate 36b in ethanol & obtained as

a pale yellow solid (M.P. 232-238 oC) in 54 % yield as

shown in Scheme 8. The structure of compound 37b was

established on the basis of its spectral data analysis. Its high

resolution mass spectrum showed [M+H] + peak at m/z 389.1331, which confirmed its

molecular formula to be C19H20N2O7. The peaks in its IR spectrum at 3347 and 3218 cm-1

were assigned to NH, whereas peaks at 1769, 1729 and 1692 cm-1

were assigned to CO

groups present in the molecule. The characteristic peaks of C-6CH3, 2 x OCH3, C-4H and

C-3'H protons in its 1H NMR spectrum appeared at δ 2.32 (3H, s), 3.80 (3H, s), 3.90 (3H,

s), 5.61 (1H, s) and 6.02 (1H, s), respectively (Figure 7). Similarly, in its 13

C NMR

spectrum, the characteristic peaks for C-6CH3, C-4, 2 x OCH3 and C-5 appeared at δ

18.55, 50.12, 56.38, 60.28 and 97.02, respectively (Figure 8). The peaks of all other

protons and carbons of the molecule were also present in the 1H and

13C NMR spectra of

the compound. Based on the spectral data analysis, the structure of the compound was

unambiguously established as ethyl 4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-

dihydropyrimidin-5-carboxylate (37b).


16

Figure 5:1H NMR spectrum of compound 37a (400 MHz, DMSO)

Figure 6:13

C NMR spectrum of compound 37a (100.6 MHz, DMSO)


17

Figure 7:1H NMR spectrum of compound 37b (400 MHz, DMSO)

Figure 8:13

C NMR spectrum of compound 37b (100.6 MHz, DMSO)


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4.5.3. Propyl 4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-

one-5-carboxylate (37c)

The compound 37c was synthesized by the multi-

component Biginelli reaction of 7,8-dimethoxy-4-

formylcoumarin 33 with urea and propyl acetoacetate 36c

in ethanol & obtained as a pale yellow solid (M.P. 240-245

oC) in 50 % yield as shown in Scheme 8. The structure of

compound 37c was established on the basis of its spectral

data analysis. Its high resolution mass spectrum showed [M+H] + peak at m/z 403.1492,

which confirmed its molecular formula to be C20H22N2O7. The peaks in its IR spectrum at

3318 and 3223 cm-1


were assigned to CO groups present in the molecule. The characteristic peaks of C-6CH3,

2 x OCH3, C-4H and C-3'H protons in its 1H NMR spectrum appeared at δ 2.35 (3H, s),

3.82 (3H, s), 3.91 (3H, s), 5.62 (1H, s) and 6.03 (1H, s), respectively (Figure 9).

Similarly, in its 13

C NMR spectrum, the characteristic peaks for C-6CH3, C-4, 2 x OCH3

and C-5 appeared at δ 17.77, 49.60, 56.46, 60.75 and 96.01, respectively (Figure 10).

The peaks of all other protons and carbons of the molecule were also present in the 1H

and 13

C NMR spectra of the compound. Based on the spectral data analysis, the structure

of the compound was unambiguously established as propyl 4-(7',8'-dimethoxycoumarin-

4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (37c).


19

Figure 9:1H NMR spectrum of compound 37c (400 MHz, DMSO)

Figure 10:13

C NMR spectrum of compound 37c (100.6 MHz, DMSO)


20

4.5.4. Isopropyl4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-

one-5-carboxylate (37d)

The compound 37d was synthesized by the multi-component


with urea and iso-propyl acetoacetate 36d in ethanol &

obtained as a pale yellow solid (M.P. 246-248 oC) in 51 %

yield as shown in Scheme 8.The structure of compound 37d

was established on the basis of its spectral data analysis. Its

high resolution mass spectrum showed [M+H] + peak at m/z 403.1456, which confirmed

its molecular formula to be C20H22N2O7. The peaks in its IR spectrum at 3279 and 3228

cm-1


were assigned to

CO (carbonyl) groups present in the molecule. The characteristic peaks of C-6CH3, 2 x

OCH3, C-4H and C-3'H protons in its 1H NMR spectrum appeared at δ 2.31 (3H, s), 3.80

(3H, s), 3.92 (3H, s), 5.60 (1H, s) and 6.04 (1H, s), respectively (Figure 11). Similarly, in

its 13

C NMR spectrum, the characteristic peaks for C-6CH3, C-4, 2 x OCH3 and C-5

appeared at δ 17.73, 56.46, 59.47, 60.82 and 96.47, respectively (Figure 12). The peaks

of all other protons and carbons of the molecule were also present in the 1H and

13C NMR

spectra of the compound. Based on the spectral data analysis, the structure of the

compound was unambiguously established as isopropyl 4-(7',8'-dimethoxycoumarin-4-

yl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (37d).

4.5.5. Allyl4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-

5-carboxylate (37e)

The compound 37e was synthesized by the multi-component


urea and allyl acetoacetate 36e in ethanol & obtained as a pale

yellow solid (M.P. 248-252 oC) in 53 % yield as shown in

Scheme 8. The structure of compound 37e was established on

the basis of its spectral data analysis. Its high resolution mass spectrum showed [M+H]


21

+peak at m/z 401.1344, which confirmed its molecular formula to be C20H20N2O7. The

peaks in its IR spectrum at 3373 and 3216 cm-1

were assigned to NH, whereas peaks at

1756, 1701 and 1637 cm-1

were assigned to CO groups present in the molecule. The

characteristic peaks of C-6CH3, 2 x OCH3, C-4H and C-3'H protons in its 1H NMR

spectrum appeared at δ 2.31 (3H, s), 3.77 (3H, s), 3.90 (3H, s), 4.97 (1H, s) and 6.00 (1H,

s), respectively (Figure 13). Similarly, in its 13

C NMR spectrum, the characteristic peaks

for C-6CH3, C-4, 2 x OCH3 and C-5 appeared at δ 17.96, 56.48, 59.50, 60.82 and 108.95,

respectively (Figure 14). The peaks of all other protons and carbons of the molecule

were also present in the 1H and

13C NMR spectra of the compound. Based on the spectral

data analysis, the structure of the compound was unambiguously established as allyl 4-

(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate

(37e).

4.5.6. Ethyl 4-(7',8'-dimethoxycoumarin-4-yl)-6-propyl-3,4-dihydropyrimidin-2one-

5-carboxylate (37f)

The compound 37f was synthesized by the multi-component


with urea and ethyl butarylacetate 36f in ethanol & obtained

as a pale yellow solid (M.P. 232-238 oC) in 50 % yield as

shown in Scheme 8. The structure of compound 37f was


resolution mass spectrum showed [M+H] + peak at m/z 417.1656, which confirmed its



were assigned to CO

groups present in the molecule. The characteristic peaks of 2 x OCH3, C-4H and C-3'H

protons in its 1H NMR spectrum appeared at δ 3.82 (3H, s), 3.95 (3H, s), 5.64 (1H, s) and

6.02 (1H, s), respectively (Figure 15). Similarly, in its 13

C NMR spectrum, the

characteristic peaks for C-4, 2 x OCH3 and C-5 appeared at δ 49.63, 56.36 and 59.44 and

95.93, respectively (Figure 16). The peaks of all other protons and carbons of the

molecule were also present in the 1H and

13C NMR spectra of the compound. Based on


22

the spectral data analysis, the structure of the compound was unambiguously established

as ethyl 4-(7',8'-dimethoxycoumarin-4-yl)-6-propyl-3,4-dihydropyrimidin-2-one-5-

carboxylate (37f).

Figure 11:1H NMR spectrum of compound 37d (400 MHz, DMSO)

Figure 12:13

C NMR spectrum of compound 37d (100.6 MHz, DMSO)


23

Figure 13:1H NMR spectrum of compound 37e (400 MHz, DMSO)

Figure 14:13

C NMR spectrum of compound 37e (100.6 MHz, DMSO)


24

Figure 15:1H NMR spectrum of compound 37f (400 MHz, DMSO)

Figure 16:13

C NMR spectrum of compound 37f (100.6 MHz, DMSO)


25

4.5.7. Ethyl 6-(4-chlorophenyl)-4-(7',8'-dimethoxycoumarin-4-yl)-3,4-dihydro-

pyrimidin-2-one-5-carboxylate (37g)

The compound 37g was synthesized by the multi-component


urea and ethyl 3-(4-chlorophenyl)-3-oxopropanoate 36g in

ethanol & obtained as a pale yellow solid (M.P. 240-243 oC)

in 51 % yield as shown in Scheme 8. The structure of

compound 37g was established on the basis of its spectral data

analysis. Its high resolution mass spectrum showed [M+H]+ peak at m/z 485.1110, which

confirmed its molecular formula to be C24H21ClN2O7. The peaks in its IR spectrum at

3315 and 3107 cm-1


were assigned to CO groups present in the molecule. The characteristic peaks of 2 x

OCH3, C-4H and C-3'H protons in its 1H NMR spectrum appeared at (3H, s), 3.96

(3H, s), 5.74 (1H, s) and 6.24 (1H, s), respectively (Figure 17). Similarly, in its 13

C NMR

spectrum, the characteristic peaks for C-4, 2 x OCH3 and C-5 appeared at δ 50.15, 56.49,

59.56 and 97.85, respectively (Figure 18). The peaks of all other protons and carbons of

the molecule were also present in the 1H and

13C NMR spectra of the compound. Based

on the spectral data analysis, the structure of the compound was unambiguously

established as ethyl 6-(4-chlorophenyl)-4-(7',8'-dimethoxycoumarin-4-yl)-3,4-

dihydropyrimidin-2-one-5-carboxylate (37g).


26

Figure 17:

1H NMR spectrum of compound 37g (400 MHz, DMSO)

Figure 18:

13C NMR spectrum of compound 37g (100.6 MHz, DMSO)


27

4.5.8. Methyl 4-(7'-methoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-5-

carboxylate (37h)

The compound 37h was synthesized by the multi-component

Biginelli reaction of 7-methoxy-4-formylcoumarin 34 with

urea and methyl acetoacetate 36a in ethanol & obtained as a

pale yellow solid (M.P. 226-230 oC) in 52 % yield as shown in

Scheme 8. The structure of compound 37h was established on


spectrum showed [M+H]+ peak at m/z 345.1042, which confirmed its molecular formula

to be C17H16N2O6. The peaks in its IR spectrum at 3375 and 3281 cm-1

were assigned to

NH, whereas peaks at 1752, 1710 and 1652 cm-1

were assigned to CO groups present in

the molecule. The characteristic peaks of C-6CH3, COOCH3 and OCH3, C-4H and C-3′H

protons in its 1H NMR spectrum appeared at 2.34 (3H, s), 3.88 (6H, m), 5.62 (1H, s)

and 6.01 (1H, s), respectively (Figure 19). Similarly, in its 13

C NMR spectrum, the

characteristic peaks for C-6CH3, C-4, COOCH3, OCH3 and C-5 appeared at δ 17.88,

49.35, 51.05, 56.02 and 101.12, respectively (Figure 20). The peaks of all other protons

and carbons of the molecule were also present in the 1H and



unambiguously established as methyl 4-(7'-methoxycoumarin-4-yl)-6-methyl-3,4-

dihydropyrimidin-2-one-5-carboxylate (37h).

4.5.9. Ethyl 4-(7'-methoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-5-

carboxylate (37i)

The compound 37i was synthesized by the multi-

component Biginelli reaction of 7-methoxy-4-

formylcoumarin 34 with urea and ethyl acetoacetate 36b in

ethanol & obtained as a pale yellow solid (M.P. 233-239


compound 37i was established on the basis of its spectral

data analysis. Its high resolution mass spectrum showed [M+H]+ peak at m/z 359.1198,



28

3347 and 3218 cm-1



OCH3, C-4H and C-3'H protons in its 1H NMR spectrum appeared at (3H, s), 3.87

(3H, m), 5.64 (1H, s) and 6.04 (1H, s), respectively (Figure 21). Similarly, in its 13

C

NMR spectrum, the characteristic peaks for C-6CH3, C-4, OCH3 and C-5 appeared at δ





unambiguously established as ethyl 4-(7'-methoxycoumarin-4-yl)-6-methyl-3,4-

dihydropyrimidin-2-one-5-carboxylate (37i).

4.5.10. Isopropyl 4-(7'-methoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-

one-5-carboxylate (37j)

The compound 37j was synthesized by the multi-


formylcoumarin 34 with urea and iso-propyl acetoacetate

36d in ethanol & obtained as a pale yellow solid (M.P.

231-235 oC) in 52 % yield as shown in Scheme 8. The

structure of compound 37j was established on the basis of

its spectral data analysis. Its high resolution mass spectrum showed [M+H]+ peak at m/z

373.1355, which confirmed its molecular formula to be C19H20N2O6. The peaks in its IR

spectrum at 3279 and 3228 cm-1

were assigned to NH, whereas peaks at 1759, 1700 and

1653 cm-1

were assigned to CO groups present in the molecule. The characteristic peaks

of C-6CH3, OCH3, C-4H and C-3′H protons in its 1H NMR spectrum appeared at 2.32


its 13

C NMR spectrum, the characteristic peaks for C-6CH3, C-4, OCH3 and C-5 appeared

at δ 17.70, 56.02, 59.46 and 101.03, respectively (Figure 24). The peaks of all other


13C NMR spectra of



29

unambiguously established as isopropyl 4-(7'-methoxycoumarin-4-yl)-6-methyl-3,4-

dihydropyrimidin-2-one-5-carboxylate (37j).

Figure 19:

1H NMR spectrum of compound 37h (400 MHz, DMSO)


30

Figure 20:13

C NMR spectrum of compound 37h (100.6 MHz, DMSO)

Figure 21:1H NMR spectrum of compound 37i (400 MHz, DMSO)


31

Figure 22:13

C NMR spectrum of compound 37i (100.6 MHz, DMSO)

Figure 23:

1H NMR spectrum of compound 37j (400 MHz, DMSO)


32

Figure 24: 13

C NMR spectrum of compound 37j (100.6 MHz, DMSO)

4.5.11. Allyl 4-(7'-methoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-5-

carboxylate (37k)

The compound 37k was synthesized by the multi-


formylcoumarin 34 with urea and allyl acetoacetate 36e

in ethanol & obtained as a pale yellow solid (M.P. 261-

267 oC) in 53 % yield as shown in Scheme 8. The

structure of compound 37k was established on the basis

of its spectral data analysis. Its high resolution mass spectrum showed [M+H]+ peak at

m/z 371.1198, which confirmed its molecular formula to be C19H18N2O6. The peaks in its

IR spectrum at 3343 and 3216 cm-1

were assigned to NH, whereas peaks at 1748, 1691

and 1637 cm-1

were assigned to CO groups present in the molecule. The characteristic

peaks of C-6CH3, OCH3, C-4H and C-3′H protons in its 1H NMR spectrum appeared at



33


C NMR spectrum, the characteristic peaks for C-6CH3, C-4, OCH3 and

C-5 appeared at δ 17.97, 56.48, 60.83 and 108.96, respectively (Figure 26). The peaks of

all other protons and carbons of the molecule were also present in the 1H and

13C NMR


compound was unambiguously established as allyl 4-(7'-methoxycoumarin-4-yl)-6-

methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (37k).

4.5.12. Ethyl 4-(7'-methoxycoumarin-4-yl)-6-propyl-3,4-dihydropyrimidin-2-one-5-

carboxylate (37l)

The compound 37l was synthesized by the multi-component

Biginelli reaction of 7-methoxy-4-formylcoumarin 33 with

urea and ethyl butryl acetoacetate 36f in ethanol & obtained


shown in Scheme 8. The structure of compound 37l was


resolution mass spectrum showed [M+H]+ peak at m/z 387.1511, which confirmed its



were assigned to CO

groups present in the molecule. The characteristic peaks of OCH3, C-4H and C-3′H

protons in its 1H NMR spectrum were appeared at 3.88 (3H, s), 5.65 (1H, s) and 6.01

(1H, s), respectively (Figure 27). Similarly, in its 13

C NMR spectrum, the characteristic

peaks for C-4, OCH3 and C-5 appeared at δ 49.62, 56.05 and 101.10, respectively (Figure

28). The peaks of all other protons and carbons of the molecule were also present in the 1H and

13C spectra of the compound. Based on the spectral data analysis, the structure of

the compound was unambiguously established as ethyl 4-(7'-methoxycoumarin-4-yl)-6-

propyl-3,4-dihydropyrimidin-2-one-5-carboxylate (37l).

4.5.13. Ethyl 6-(4-chlorophenyl)-4-(7'-methoxycoumarin-4-yl)-3,4-

dihydropyrimidin-2-one-5-carboxylate (37m)


34

The compound 37m was synthesized by the multi-


formylcoumarin 34 with urea and ethyl 3-(4-chlorophenyl)-

3-oxopropanoate 36g in ethanol & obtained as a pale yellow

solid (M.P. 250-256 oC) in 54 % yield as shown in Scheme

8. The structure of compound 37m was established on the

basis of its spectral data analysis. Its high resolution mass spectrum showed [M+H]+ peak

at m/z 456.0902, which confirmed its molecular formula to be C23H19ClN2O6. The peaks

in its IR spectrum at 3315 and 3107 cm-1

were assigned to NH, whereas peaks at 1753,

1692 and 1642 cm-1


characteristic peaks of OCH3, C-4H and C-3′H protons in its 1H NMR spectrum appeared

at 3.87 (3H, s), 5.74 (1H, s) and 6.21 (1H, s), respectively (Figure 29). Similarly, in its

13C NMR spectrum, the characteristic peaks for C-4, OCH3 and C-5 appeared at δ 48.72,



13C spectra of the compound. Based on the

spectral data analysis, the structure of the compound was unambiguously established as

ethyl 6-(4-chlorophenyl)-4-(7'-methoxycoumarin-4-yl)-3,4-dihydropyrimidin-2-one-5-

carboxylate (37m).


35

Figure 25:1H NMR spectrum of compound 37k (400 MHz, DMSO)

Figure 26:13

C NMR spectrum of compound 37k (100.6 MHz, DMSO)


36

Figure 27:1H NMR spectrum of compound 37l (400 MHz, DMSO)

Figure 28:13

C NMR spectrum of compound 37l (100.6 MHz, DMSO)


37

Figure 29:1H NMR spectrum of compound 37m (400 MHz, DMSO)

Figure 30:13

C NMR spectrum of compound 37m (100.6 MHz, DMSO)


38

4.5.14. Methyl 4-(5',7'-dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-

one-5-carboxylate (37n)

The compound 37n was synthesized by the multi-component


with urea and methyl acetoacetate 36a in ethanol & obtained


shown in Scheme 8.The structure of compound 37n was


resolution mass spectrum showed [M+H]+ peak at m/z 375.1148, which confirmed its

molecular formula to be C18H18N2O7.The peaks in its IR spectrum at 3375 and 3281 cm-1


were assigned to CO

groups present in the molecule. The characteristic peaks of C-6CH3, 2 x OCH3, C-4H and

C-3′H protons in its 1H NMR spectrum appeared at (3H, s), (3H, s), 3.91 (3H,

s), 5.87 (1H, s) and 6.15 (1H, s), respectively (Figure 31). Similarly, in its 13

C NMR

spectrum, the characteristic peaks for C-6CH3, C-4, 2 x OCH3 and C-5 appeared at δ



13C NMR spectra of


unambiguously established as methyl 4-(5',7'-dimethoxycoumarin-4-yl)-6-methyl-3,4-

dihydropyrimidin-2-one-5-carboxylate (37n).

4.5.15. Ethyl 4-(5',7'-dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-

one-5-carboxylate (37o)

The compound 37o was synthesized by the multi-


formylcoumarin 35 with urea and ethyl acetoacetate 36b in

ethanol & obtained as a pale yellow solid (M.P. 210-214


compound 37o was established on the basis of its spectral


39



3347 and 3218 cm-1



2 x OCH3, C-4H and C-3'H protons in its 1H NMR spectrum appeared at 2.35 (3H, s),



C NMR spectrum, the characteristic peaks for C-6CH3, 2 x OCH3, C-4

and C-5 appeared at 17.84, 56.03, 56.83 and 101.59, respectively (Figure 34). The peaks


13C NMR


compound was unambiguously established as ethyl 4-(5',7'-dimethoxycoumarin-4-yl)-6-

methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (37o).

4.5.16. Isopropyl 4-(5',7'-dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-

2-one-5-carboxylate (37p)

The compound 37p was synthesized by the multi-


formylcoumarin 35 with urea and iso-propyl acetoacetate

36d in ethanol & obtained as a pale yellow solid (M.P.

260-265 oC) in 52 % yield as shown in Scheme 8. The

structure of compound 37p was established on the basis of

its spectral data analysis. Its high resolution mass spectrum showed [M+H]+ peak at m/z

403.1461, which confirmed its molecular formula to be C20H22N2O7. The peaks in its IR

spectrum at 3279 and 3228 cm-1

were assigned to NH, whereas peaks at 1759, 1693 and

1643 cm-1

were assigned to CO groups present in the molecule. The characteristic peaks

of C-6CH3, 2 x OCH3, C-4H and C-3′H protons in its 1H NMR spectrum appeared at

2.33 (3H, s), 3.86 (3H, s), 3.91 (3H, s), 5.88 (1H, s) and 6.18 (1H, s), respectively

(Figure 35). Similarly, in its 13

C NMR spectrum, the characteristic peaks for C-6CH3, 2 x

OCH3, C-4 and C-5 appeared at δ 13.99, 56.01, 56.76 and 101.73, respectively (Figure

36). The peaks of all other protons and carbons of the molecule were also present in the


40

1H and

13C NMR spectra of the compound. Based on the spectral data analysis, the

structure of the compound was unambiguously established as isopropyl 4-(5',7'-

dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (37p).

Figure 31:1H NMR spectrum of compound 31n (400 MHz, DMSO)


41

Figure 32:13

C NMR spectrum of compound 37n (100.6 MHz, DMSO)

Figure 33:1H NMR spectrum of compound 37o (400 MHz, DMSO)


42

Figure 34:13

C NMR spectrum of compound 37o (100.6 MHz, DMSO)

Figure 35:1H NMR spectrum of compound 37p (400 MHz, DMSO)


43

Figure 36:13

C NMR spectrum of compound 37p (100.6 MHz, DMSO)

4.5.17. Allyl 4-(5',7'-dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-

one-5-carboxylate (37q)

The compound 37q was synthesized by the multi-


formylcoumarin 35 with urea and allyl acetoacetate 36e

in ethanol & obtained as a pale yellow solid (M.P. 255-

260 oC) in 50 % yield as shown in Scheme 8. The

structure of compound 37q was established on the basis

of its spectral data analysis. Its high resolution mass spectrum showed [M+H]+ peak at

m/z 401.1304, which confirmed its molecular formula to be C20H20N2O7. The peaks in its

IR spectrum at 3343 and 3216 cm-1

were assigned to NH, whereas peaks at 1748, 1701

and 1639 cm-1

were assigned to CO groups present in the molecule. The characteristic


44

peaks of C-6CH3, 2 x OCH3, C-4H and C-3′H protons in its 1H NMR spectrum appeared

at 2.37 (3H, s), 3.85 (3H, s), 3.90 (3H, s), 5.06 (1H, s) and 6.19 (1H, s), respectively


C NMR spectrum, the characteristic peaks for C-6CH3, C-

4, 2 x OCH3 and C-5 appeared at δ 17.82, 56.02, 56.76 and 101.49, respectively (Figure

38). The peaks of all other protons and carbons of the molecule were also present in the

1H and


structure of the compound was unambiguously established as allyl 4-(5',7'-

dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (37q).

4.5.18. Ethyl 4-(5',7'-dimethoxycoumarin-4-yl)-6-propyl-3,4-dihydropyrimidin-2-

one-5-carboxylate (37r)

The compound 37r was synthesized by the multi-


formylcoumarin 35 with urea and ethyl butryl acetoacetate

36f in ethanol & obtained as a pale yellow solid (M.P. 258-

260 oC) in 53 % yield as shown in Scheme 8.The structure

of compound 37r was established on the basis of its spectral


which confirmed its molecular formula to be C21H24N2O7.The peaks in its IR spectrum at

3347 and 3225 cm-1



OCH3, C-4H and C-3′H protons in its 1H NMR spectrum appeared at 3.85-3.97 (6H,

m), 5.03 (1H, s) and 6.18 (1H, s), respectively (Figure 39). Similarly, in its 13

C NMR






established as ethyl 4-(5',7'-dimethoxycoumarin-4-yl)-6-propyl-3,4-dihydropyrimidin-2-

one-5-carboxylate (37r).


45

4.5.19. Ethyl 6-(4-chlorophenyl)-4-(5',7'-dimethoxycoumarin-4-yl)-3,4-

dihydropyrimidin-2-one-5-carboxylate (37s)

The compound 37s was synthesized by the multi-


formylcoumarin 35 with urea and ethyl 3-(4-chlorophenyl)-

3-oxopropanoate 36g in ethanol & obtained as a pale yellow

solid (M.P. 271-277 oC) in 51 % yield as shown in Scheme

8. The structure of compound 37s was established on the

basis of its spectral data analysis. Its high resolution mass spectrum showed [M+H]+ peak

at m/z 486.1008, which confirmed its molecular formula to be C24H21ClN2O7. The peaks

in its IR spectrum at 3315 and 3107 cm-1

were assigned to NH, whereas peaks at 1753,

1692 and 1649 cm-1


characteristic peaks of 2 x OCH3, C-4H and C-3′H protons in its 1H NMR spectrum

appeared at 3.83 (3H, s), 3.96 (3H, s), 5.74 (1H, s) and 6.24 (1H, s), respectively


C NMR spectrum, the characteristic peaks for 2 x OCH3,

C-4 and C-5 appeared at δ 50.19, 56.49, 59.56 and 109.71, respectively (Figure 42). The

peaks of all other protons and carbons of the molecule were also present in the 1H and

13C

NMR spectra of the compound. Based on the spectral data analysis, the structure of the

compound was unambiguously established as ethyl 6-(4-chlorophenyl)-4-(5',7'-

dimethoxycoumarin-4-yl)-3,4-dihydropyrimidin-2-one-5-carboxylate (37s).


46

Figure 37:

1H NMR spectrum of compound 37q (400 MHz, DMSO)

Figure 38:

13C NMR spectrum of compound 37q (100.6 MHz, DMSO)


47

Figure 39:1H NMR spectrum of compound 37r (400 MHz, DMSO)

Figure 40:13

C NMR spectrum of compound 37r (100.6 MHz, DMSO)


48

Figure 41:1H NMR spectrum of compound 37s (400 MHz, DMSO)

Figure 42:13

C NMR spectrum of compound 37s (100.6 MHz, DMSO)


49

4.5.20. Methyl 3-N-acetyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-

dihydropyrimidin-2-one-5-carboxylate (39a)

The compound 39a was obtained by the acetylation of

compound 37a as awhite solid (M.P. 184-187 oC) in 68 % yield

as shown in Scheme 9. The structure of compound 39a was


resolution mass spectrum showed [M+H]+ peak at m/z 417.1299,

which confirmed its molecular formula to be C20H20N2O8. The

peak in its IR spectrum at 3342 cm-1

was assigned to NH, whereas peaks at 1761, 1699,

1660 and 1622 cm-1


characteristic peaks of C-6CH3, NCOCH3, 2 x OCH3, C-3'H and C-4H protons in its 1H

NMR spectrum appeared at δ 2.45 (3H, s), 2.55 (3H, s), 3.95 (3H, s), 3.98 (3H, s), 6.36

(1H, s) and 6.89 (1H, s), respectively (Figure 43). Similarly, in its 13

C NMR spectrum,

the characteristic peaks for C-6CH3, NCOCH3, C-4, 2 x OCH3 and C-5 appeared at δ

17.99, 26.42, 49.02, 56.27, 61.38 and 108.12, respectively (Figure 44). The peaks of all

other protons and carbons of the molecule were also present in the 1H and

13C NMR


compound was unambiguously established as methyl 3-N-acetyl-4-(7',8'-

dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (39a).

4.5.21. Methyl 3-N-propanoyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-

dihydropyrimidin-2-one-5-carboxylate (39b)

The compound 39b was obtained by the propanoylation of

compound 37a using propanoic anhydride, DMAP in DCM &

obtained as a white solid (M.P. 220-225 oC) in 63 % yield as




which confirmed its molecular formula to be C21H22N2O8. The peak in its IR spectrum at

3335 cm-1

was assigned to NH, whereas peaks at 1757, 1690, 1663 and 1620 cm-1

were


50

assigned to CO groups present in the molecule. The characteristic peaks of NCOCH2CH3,

C-6CH3, 2 x OCH3, C-3'H and C-4H protons in its 1H NMR spectrum appeared at

(3H, t, J = 7.32 Hz), 2.44 (3H, s), 3.96 (3H, s), 3.98 (3H, s), 6.37 (1H, s) and 6.90 (1H, s),

respectively (Figure 45). Similarly, in its 13

C NMR spectrum, the characteristic peaks for

NCOCH2CH3, C-6CH3, C-4, 2 x OCH3 and C-5 appeared at δ 8.98, 17.95, 49.13, 56.25,





established as methyl 3-N-propanoyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-

dihydropyrimidin-2-one-5-carboxylate (39b).

4.5.22. Methyl 3-N-butyryl-4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-

dihydropyrimidin-2-one-5-carboxylate (39c)

The compound 39c was obtained by the butanoylation of

compound 37a using butanoic anhydride, DMAP in DCM &


shown in Scheme 9. The structure of compound 39c was



which confirmed its molecular formula to be C22H24N2O8. The peak in its IR spectrum at

3334 cm-1


were

assigned to CO groups present in the molecule. The characteristic peaks of

NCO(CH2)2CH3, C-6CH3, 2 x OCH3, C-3'H and C-4H protons in its 1H NMR spectrum

appeared at 0.94 (3H, t, J = 7.68 Hz), 2.44 (3H, s), 3.96 (3H, s), 3.98 (3H, s), 6.37 (1H,

s) and 6.89 (1H, s), respectively (Figure 47). Similarly, in its 13

C NMR spectrum, the

characteristic peaks for NCO(CH2)2CH3, C-6CH3, C-4, 2 x OCH3 and C-5 appeared at δ



13C NMR



51

compound was unambiguously established as methyl 3-N-butyryl-4-(7',8'-

dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (39c).

Figure 43:1H NMR spectrum of compound 39a (400 MHz, CDCl3)


52

Figure 44:13

C NMR spectrum of compound 39a (100.6 MHz, CDCl3)

Figure 45:1H NMR spectrum of compound 39b (400 MHz, CDCl3)


53

Figure 46:13

C NMR spectrum of compound 39b (100.6 MHz, CDCl3)

Figure 47:1H NMR spectrum of compound 39c (400 MHz, CDCl3)


54

Figure 48:13

C NMR spectrum of compound 39c (100.6 MHz, CDCl3)

4.5.23. Methyl 3-N-pentanoyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-

dihydropyrimidin-2-one-5-carboxylate (39d)

The compound 39d was obtained by the pentanoylation of

compound 37a using valeric anhydride, DMAP in DCM &


shown in Scheme 9. The structure of compound 39d was


resolution mass spectrum showed [M+H]+ peak at m/z

459.1756, which confirmed its molecular formula to be C23H26N2O8. The peak in its IR

spectrum at 3336 cm-1

was assigned to NH, whereas peaks at 1763, 1675, 1664 and 1610

cm-1

were assigned to CO groups present in the molecule. The characteristic peaks of




55


C NMR spectrum, the




13C NMR


compound was unambiguously established as methyl 3-N-pentanoyl-4-(7',8'-

dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (39d).

4.5.24. Methyl 3-N-hexanoyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-

dihydropyrimidin-2-one-5-carboxylate (39e)

The compound 39e was obtained by the hexanoylation of

compound 37a using hexanoic anhydride in, DMAP in DCM

& obtained as awhite solid (M.P. 184-187 oC) in 66 % yield

as shown in Scheme 8. The structure of compound 39e was






cm-1





C NMR spectrum, the




13C NMR


compound was unambiguously established as methyl 3-N-hexanoyl-4-(7',8'-

dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (39e).


56

4.5.25. Methyl 3-N-benzoyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-

dihydropyrimidin-2-one-5-carboxylate (39f)

The compound 39f was obtained by the benzoylation of

compound 37a using benzoic anhydride, DMAP in DCMas

awhite solid (M.P. 230-232 oC) in 70 % yield as shown in

Scheme 9. The structure of compound 39f was established on


spectrum showed [M+H]+ peak at m/z 479.1449, which

confirmed its molecular formula to be C25H22N2O8. The peak in its IR spectrum at 3322

cm-1


were

assigned to CO groups present in the molecule. The characteristic peaks of C-6CH3, 2 x

OCH3, C-3'H and C-4H protons in its 1H NMR spectrum appeared at 2.34 (3H, s), 3.97


its 13

C NMR spectrum, the characteristic peaks for C-6CH3, C-4, 2 x OCH3 and C-5

appeared at δ 17.98, 51.74, 56.27, 61.40 and 108.07, respectively (Figure 54). The peaks


13C NMR


compound was unambiguously established as methyl 3-N-benzoyl-4-(7',8'-

dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (39f).


57

Figure 49:1H NMR spectrum of compound 39d (400 MHz, CDCl3)

Figure 50:13

C NMR spectrum of compound 39d (100.6 MHz, CDCl3)


58

Figure 51:1H NMR spectrum of compound 39e (400 MHz, CDCl3)

Figure 52:13

C NMR spectrum of compound 39e (100.6 MHz, CDCl3)


59

Figure 53:1H NMR spectrum of compound 39f (400 MHz, CDCl3)

Figure 54:13

C NMR spectrum of compound 39f (100.6 MHz, CDCl3)


60

4.5.26. Ethyl 3-N-acetyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-



compound 37b as a white solid (M.P. 208-210 oC) in 65 %

yield as shown in Scheme 9. The structure of compound 40a


high resolution mass spectrum showed [M+H]+ peak at m/z

431.1445, which confirmed its molecular formula to be

C21H22N2O8. The peak in its IR spectrum at 3347 cm-1

was assigned to NH, whereas

peaks at 1759, 1692, 1648 and 1610 cm-1

were assigned to CO groups present in the

molecule. The characteristic peaks of C-6CH3, NCOCH3, 2 x OCH3, C-3'H and C-4H

protons in its 1H NMR spectrum appeared at (3H, s), 2.55 (3H, s), 3.95 (3H, s),

3.98 (3H, s), 6.36 (1H, s) and 6.89 (1H, s), respectively (Figure 55). Similarly, in its 13

C

NMR spectrum, the characteristic peaks for C-6CH3, -NOCH3, C-4, 2 x OCH3 and C-5

appeared at δ 18.05, 26.51, 49.03, 56.29, 60.92 and 104.07, respectively (Figure 56). The

peaks of all other protons and carbons of the molecule were also present in the 1H and

13C

NMR spectra of the compound. Based on the spectral data analysis, the structure of the

compound was unambiguously established as ethyl 3-N-acetyl-4-(7',8'-dimethoxy

coumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (40a).

4.5.27. Ethyl 3-N-propanoyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-



compound 37b using propanoic anhydride, DMAP in DCM &







61



cm-1


NCOCH2CH3, C-6CH3, 2 x OCH3, C-3'H and C-4H protons in its 1H NMR spectrum



C NMR spectrum, the

characteristic peaks for NCOCH2CH3, C-6CH3, C-4, 2 x OCH3 and C-5 appeared at δ



13C NMR


compound was unambiguously established as ethyl 3-N-propanoyl-4-(7',8'-

dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (40b).

4.5.28. Ethyl 3-N-butyryl-4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-



compound 37b using butanoic anhydride, DMAP in DCM &


shown in Scheme 9. The structure of compound 40c was






cm-1


NCOCH2CH2CH3, C-6CH3, 2 x OCH3, C-3'H and C-4H protons in its 1H NMR spectrum



C NMR spectrum, the

characteristic peaks for NCOCH2CH2CH3, C-4, 2 x OCH3 and C-5 appeared at δ 13.62,






62

unambiguously established as ethyl 3-N-butyryl-4-(7',8'-dimethoxycoumarin-4-yl)-6-

methyl-3,4-tetrahydropyrimidin-2-one-5-carboxylate (40c).


Figure 56:13



63

Figure57:1H NMR spectrum of compound 40b (400 MHz, CDCl3)

Figure 58:13



64


Figure 60:13



65

4.5.29. Ethyl 3-N-pentanoyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-



compound 37b using valeric anhydride, DMAP in DCM &




resolution mass spectrum showed [M+Na]+ peak at m/z




cm-1


NCO(CH2)3CH3,C-6CH3, 2 x OCH3, C-3'H and C-4H protons in its 1H NMR spectrum



C NMR spectrum, the

characteristic peaks for NCO(CH2)3CH3, C-6CH3, C-4, 2 x OCH3 and C-5appeared at δ



13C NMR


compound was unambiguously established as ethyl 3-N-pentanoyl-4-(7',8'-

dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (40d).

4.5.30. Ethyl 3-N-hexanoyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-



66


compound 37b using hexanoic anhydride, DMAP in DCM

& obtained as a white solid (M.P. 207-210 oC) in 70 %

yield as shown in Scheme 9. The structure of compound

40e was established on the basis of its spectral data

analysis. Its high resolution mass spectrum showed

[M+H]+ peak at m/z 487.2070, which confirmed its molecular formula to be C25H30N2O8.

The peak in its IR spectrum at 3340 cm-1

was assigned to NH, whereas peaks at 1758,

1707, 1641 and 1609 cm-1


characteristic peaks of NCOCH2(CH2)2CH3, C-6CH3, 2 x OCH3, C-3'H and C-4H protons

in its 1H NMR spectrum appeared at 0.87 (3H, t, J = 6.60 Hz), 2.44 (3H, s), 3.96 (3H,

s), 3.98 (3H, s), 6.35 (1H, s) and 6.89 (1H, s), respectively (Figure 63). Similarly, in its

13C NMR spectrum, the characteristic peaks for NCOCH2(CH2)2CH3, C-6CH3, C-4, 2 x

OCH3 and C-5 appeared at δ 13.88, 18.00, 49.07, 56.27, 60.89 and 104.06, respectively

(Figure 64). The peaks of all other protons and carbons of the molecule were also present

in the 1H and


structure of the compound was unambiguously established as ethyl 3-N-hexanoyl-4-(7',8'-

dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (40e).

4.5.31. Ethyl 3-N-benzoyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-methyl-3,4-



compound 37b using benzoic anhydride, DMAP in DCM &








cm-1

were assigned to CO groups present in the molecule. The characteristic peaks of C-

6CH3, 2 x OCH3, C-3'H and C-4H protons in its 1H NMR spectrum appeared at 2.18


67

(3H, s), 3.97(3H, s), 3.98 (3H, s), 6.39 (1H, s) and 6.59 (1H, s), respectively (Figure 65).


C NMR spectrum, the characteristic peaks for C-6CH3, C-4, 2 x OCH3

and C-5 appeared at δ 17.92, 51.08, 56.27, 60.92 and 104.09, respectively (Figure 66).

The peaks of all other protons and carbons of the molecule were also present in the 1H

and 13

C NMR spectra of the compound. Based on the spectral data analysis, the structure

of the compound was unambiguously established as ethyl 3-N-benzoyl-4-(7',8'-

dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-one-5-carboxylate (40f).



68

Figure 62:13




69

Figure 64:13




70

Figure 66:13


4.5.32. Ethyl 3-N-acetyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-propyl-3,4-



compound 37f as a white solid (M.P. 185-188 oC) in 65 %

yield as shown in Scheme 9. The structure of compound 41a


high resolution mass spectrum showed [M+H]+ peak at m/z

459.1758, which confirmed its molecular formula to be

C23H26N2O8. The peak in its IR spectrum at 3371 cm-1

was assigned to NH, whereas

peaks at 1749, 1692, 1650 and 1611 cm-1

were assigned to CO groups present in the

molecule. The characteristic peaks of NCOCH3, 2 x OCH3, C-3'H and C-4H protons in its

1H NMR spectrum appeared at 2.56 (3H, s), 3.96 (3H, s), 3.98 (3H, s), 6.36 (1H, s) and

6.89 (1H, s), respectively (Figure 67). Similarly, in its 13

C NMR spectrum, the

characteristic peaks for NOCH3, C-4, 2 x OCH3 and C-5 appeared at δ 26.46, 48.86,

56.14, 60.88 and 103.81, respectively (Figure 68). The peaks of all other protons and


71

carbons of the molecule were also present in the 1H and



unambiguously established as ethyl 3-N-acetyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-

propyl-3,4-dihydropyrimidin-2-one-5-carboxylate (41a).

4.5.33. Ethyl 3-N-propanoyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-propyl-3,4-



compound 37f using propanoic anhydride, DMAP in DCM &








cm-1


NCOCH2CH3, 2 x OCH3, C-3'H and C-4H protons in its 1H NMR spectrum appeared at

1.01 (3H, t, J = 7.32 Hz), 3.95 (3H, s), 3.98 (3H, s), 6.35 (1H, s) and 6.89 (1H, s),



NCOCH2CH3, C-4, 2 x OCH3 and C-5 appeared at δ 13.61, 49.09, 56.26, 60.88 and





as ethyl 3-N-propanoyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-propyl-3,4-

dihydropyrimidin-2-one-5-carboxylate (41b).


72

4.5.34. Ethyl 3-N-butyryl-4-(7',8'-dimethoxycoumarin-4-yl)-6-propyl-3,4-



compound 37f using butanoic anhydride, DMAP in DCM &


shown in Scheme9. The structure of compound 41c was






cm-1


NCOCH2CH2CH3, 2 x OCH3, C-3'H and C-4H protons in its 1H NMR spectrum appeared

at 0.89 (3H, t, J = 7.32 Hz), 3.91 (3H, s), 3.93 (3H, s), 6.29 (1H, s) and 6.85 (1H, s),

respectively (Figure71). Similarly, in its 13


NCOCH2CH2CH3, C-4, 2 x OCH3 and C-5 appeared at δ 13.61, 49.09, 56.26, 60.88 and

103.88, respectively (Figure72). The peaks of all other protons and carbons of the




as Ethyl 3-N-butyryl-4-(7',8'-dimethoxycoumarin-4-yl)-6-propyl-3,4-dihydropyrimidin-2-

one-5-carboxylate (41c).


73


Figure 68:13



74

Figure 69:1H NMR spectrum of compound 41b (400 MHz, CDCl3)

Figure 70:13



75


Figure 72:13



76

4.5.35. Ethyl 3-N-pentanoyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-propyl-3,4-



compound 37f using valeric anhydride, DMAP in DCM &








cm-1


NCO(CH2)3CH3, 2 x OCH3, C-3'H and C-4H protons in its 1H NMR spectrum appeared

at 0.90 (1H, t, J = 7.32 Hz), 3.95 (3H, s), 3.98 (3H, s), 6.35 (1H, s) and 6.89 (1H, s),



NCO(CH2)3CH3, C-4, 2 x OCH3 and C-5 appeared at δ 13.83, 49.14, 56.27, 60.89 and





as ethyl 3-N-pentanoyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-propyl-3,4-dihydropyrimidin-

2-one-5-carboxylate (41d).

4.5.36. Ethyl 3-N-hexanoyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-propyl-3,4-



77


compound 37f using hexanoic anhydride, DMAP in DCM

& obtained as a white solid (M.P. 158-160 oC) in 62 %

yield as shown in Scheme 9. The structure of compound

41e was established on the basis of its spectral data

analysis. Its high resolution mass spectrum showed

[M+H]+ peak at m/z 515.2382, which confirmed its molecular formula to be C27H34N2O8.

The peak in its IR spectrum at 3340 cm-1

was assigned to NH, whereas peaks at 1758,

1699, 1648 and 1612 cm-1


characteristic peaks of NCOCH2(CH2)2CH3, 2 x OCH3, C-3'H and C-4H protons in its 1H

NMR spectrum appeared at 0.90 (3H, t, J = 6.60 Hz), 3.95 (3H, s), 3.98 (3H, s), 6.35

(1H, s) and 6.89 (1H, s), respectively (Figure 75). Similarly, in its 13

C NMR spectrum,

the characteristic peaks for NCOCH2(CH2)2CH3, C-4, 2 x OCH3 and C-5 appeared at δ



13C NMR spectra of


unambiguously established as ethyl 3-N-hexanoyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-

propyl-3,4-dihydropyrimidin-2-one-5-carboxylate (41e).

4.5.37. Ethyl 3-N-benzoyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-propyl-3,4-



compound 37f using benzoic anhydride, DMAP in DCM &








cm-1


OCH3, C-3'H and C-4H protons in its 1H NMR spectrum appeared at 3.97 (6H, m),


78

6.41(1H, s) and 6.61 (1H, s), respectively (Figure 77). Similarly, in its 13

C NMR






established as ethyl 3-N-benzoyl-4-(7',8'-dimethoxycoumarin-4-yl)-6-propyl-3,4-

dihydropyrimidin-2-one-5-carboxylate (41f).



79

Figure 74:13




80

Figure 76:13




81

Figure 78:13



82

4.6. Conclusions

A simple and efficient one pot methodology was developed for the synthesis of

novel alkyl 4-(mono/dimethoxycoumarin-4-yl)-6-methyl-3,4-dihydropyrimidin-2-

one-5-carboxylates 37a-s.

A total of thirty

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