Chapter – IIshodhganga.inflibnet.ac.in/bitstream/10603/9155/7/07_chapter 2.pdf · The formation...

Chapter – II

Studies of Substituted

Pyrido[3’,2’:4,5]furo[2,3-

d]pyrimidine

Studies on Pyrido furo pyrimidine derivatives27

Introduction

The formation of novel fused heterocyclic rings is an important task for heterocyclic

chemists from various points of view. Furthermore, many condensed heterocyclic system

especially linked to a pyrimidine ring.

Pyrimidines are the most important six membered heterocyclic ring containing two

nitrogen atoms as shown below.

N

N

Pyrimidines are present among the three isomeric diazines. Several (mainly uracil,

thymine and cytosine) pyrimidines have been isolated from the nucleic acid hydrolyses.

The nucleic acids are essential constituents of all cell and thus, of all living matter

cytosine is found in both types of nucleic acids i.e. ribonucleic acid (RNA) and

deoxyribonucleic acid (DNA), while uracil present only in RNA and thymine only in

DNA [1]. The structure of cytosine, uracil and thymine are shown below.

In addition to this, pyrimidines are also found in vitamin B1, barbituric acid (2, 4, 6-

trihydroxy pyrimidine) and their several derivatives e.g. (veranal), which is used as

hypnotics [2]. The structure of barbituric acid and veranal are shown here.


Numerous reports have been appeared in the literature that highlights chemistry and uses

of pyrimidines.

Pyrimidines, being an integral part of DNA and RNA, exhibit diverse pharmacological

properties[3] as effective bactericide, fungicide, vericide, insecticide & medicine [4-5].

Certain pyrimidines and annulated pyrimidine derivatives are also known to display

anticancer, antimalarial, anti anthelmintic and antifilarial activities [6-10]. Some furans are

useful for the inhibition of thrombin formation [11]. Furans have also been extensively

investigated for their pharmacological uses. Some heterocyclic systems constructed on

furan, possess antihypertensive, antiallergic and antidepressant activities[12-14]. Recently,

furopyrimidine has been discovered as potent dual inhibitor of Tie-2 and VEGFR2

receptor tyrosine kinases [15]. The biodynamic properties of these ring systems prompted

us to design a system, which combines these biolabile components in ring together to

give compact structures for screening their antimicrobial activities.

In addition, the furo [2,3-d]pyrimidine ring system is of biological interest due to the

formal isoelectronic relationship between this ring and purine[16-19]. This observation led

us to attempt the synthesis of some new furo pyrimidine products with expected

biological activity.

Biological activities of pyrimidines

Padamshali et. al.[20] prepared naptho[2,1-b]furo[3,2-d]pyrimidine, which were useful in

the preparation of pharmacologically active compound like anti-inflammatory, anti-

anthelmintic and antimicrobial agents. Carrageen induced rat paw edema method was

employed for evaluating the anti-inflammatory activity. The compounds were given at a

dose of 80 mg/kg body weight in albino rats weighing between 150 and 200 gm. The


edema was produced by injecting carrageenan solution at the left hind paw. The structure

of said compound is shown here.

Synthesis of 1,2,3,4-tetrahydro-4-oxo-2-thiobenzofuro[3,2-d] pyrimidine was reported by

Basavaraja et. al.[21] and examined for their activity against S. Aureus and E. Coli. and its

proposed structure is shown below.

Naptho[2,3-b]furo[3,2-d]pyrimidines were prepared by Vaidya et. al.[22]. The

antimicrobial activity of the selected synthesized compounds was determined by cup

plate method. The in-vitro antimicrobial activity was carried against 24 hr cell culture of

two bacteria and two fungi. The bacterial strains used were S. Aureus and P. Aerugenosa

and the fungi used were A. Niger and C. Albicans.


Preparation of pyrimidines: Synthetic strategies of pyrimidines have involved four

main routes based on the condensation of two fragments as illustrated in scheme 2.1 all

four strategies that illustrated

by 1 i.e. the condensation of

three carbon unit with an N-C-

N fragment appears to most

widely used, called the

common synthesis because of

its general applicability to the

synthesis of a whole range of

pyrimidine derivatives. The

great versatility in this

synthesis rests with the fact

that one or both of the group of

Scheme-2.1

three carbon atom fragments may be present as an aldehydes, ketone, ester or nitrile, β-

dialdehyde, β-ketoaldehydes, β-keto esters, malonic ester, β-aldehydo or β-keto nitrile

and much other combination of these groups or their masked derivatives may be used.

The nitrogen containing fragment may be an amidine, urea, thiourea or guanidine and

acetyl acetone serves as an excellent illustrative example in that, it readily under goes

reaction with formamidine[23], guaidine[24], urea[25] or thiourea[26] to produce 4,6-dimethyl

pyrimidines.

Synthesis of furopyrimidines

Gibson et. al.[27] have reported the synthesis of several furo[2, 3-d]pyrimidines as

potential inhibitors of GTP-cyclohydrolase. The reaction of 2,6-diaminopyrimidin-4(3H)-

one with 3-bromo-1,1,1-trifluropropanone afforded exclusively, the dihydrofuro[2,3-

d]pyrimidine in 67% yield. The dihydrofuro[2,3-d]pyrimidine could be dehydrated to the

corresponding furo[2,3-d]pyrimidine by treatment with concentrated sulfuric acid.

Similarly, condensation of ethyl bromopyruvate with pyrimidinones yielded the furo[2,3-

d]pyrimidines directly as illustrated in scheme-2.2.

C

C

C

N

N

C

C

C

N

N

C

C

C

C

N

N

CC

C

CN

C

N

1 2

3 4


HN

NH2N NHR1

O

3-bromo-1,1,1-trif luoropropane

DMF 60 0C

N

N

O OH

CF3

NH2H2N

N

N

O

NHR1H2N

R2

DMF 60 0C

ethyl bromopyruvate

H 2SO

4

Scheme-2.2

Recently, Blewett et. al.[28-32] have synthesized bicyclic furo pyrimidine nucleosides as

potent and selective Varicella Zoster Virus inhibitors. The synthetic route for the target

compounds involved Pd catalyzed coupling of 5-iodo-2’-deoxyuridine with the

corresponding terminal alkyne to give intermediate 5-(2-alkoxyphenyl)ethyl-2’-

deoxyuridines. These intermediates were cyclized in-situ using Cu(I) catalysis as shown

in scheme 2.3.

Scheme-2.3


Bhuiyan et. al.[33] have reported the synthesis of several furopyrimidines from ethyl 2-

amino-4,5 diphenylfuran 3-carboxylate. Ethyl-2-amino-4,5-diphenylfuran-3-carboxylate

Scheme-2.4

was prepared from ethyl cyanoacetate by using standard protocol reported elsewhere [34].

Treatment of amino carboxylate with formamide under reflux afforded 5,6-

diphenylfuro[2,3-d]pyrimidin-4(3H)-one in good yield. 5,6-Diphenylfuro[2,3-

d]pyrimidin-4(3H)-one was then chlorinated by SOCl2 to afford 4-chloro-5,6-

diphenylfuro[2,3-d]pyrimidine. A nucleophilic substitution reaction of the chloro

compound with hydrazine hydrate in dioxane under reflux afforded 4-hydrazino-5,6-

diphenylfuro[2,3-d]pyrimidine. The hydrazino compound was then treated with

acetylacetone under reflux to give 4-(3,5-dimethylpyrazolyl)-5,6-diphenylfuro[2,3-

d]pyrimidine as shown in scheme-2.4.

Bhuiyan et. al.[35] have reported the synthesis of several furo imidazo pyrimidines as

follows. Refluxing an equimolar mixture of 2-amino-4,5-diphenylfuran-3-carbonitrile

and the annelating reagent, N-[bis(methylthio)methylene]glycine ethyl ester in dry acetic

acid allows one pot annelation yielded in a remarkably easy way and efficient double


cyclized product 5-methylthio-8,9-diphenylfuro[3,2-e]imidazo[1,2-c]pyrimidin-2(3H)-

one as shown in scheme-2.5.

Scheme-2.5

Kim et. al.[36] have synthesise furo[2,3-d]pyrimidines as Akt1 Kinase inhibitors.

Hydroxyketone were treated with malononitrile in dimethylformamide in the presence of

diethylamine to give 1-amino-2-cyano-3,4-disubstituted furan. Ring closure by treatment

of 1-amino-2-cyano-3, 4-disubstituted furan with acetic anhydride in formamide followed

by bromination of the resulting 4-aminofuro [2,3-d]pyrimidine with isoamyl nitrile in

methylene bromide provided 4-bromofuro[2,3-d]pyrimidine. Finally, the amination of 4-

bromofuro [2,3-d]pyrimidine was achieved by treatment with aliphatic and aromatic

amines in ethanol to give the desired compound as illustrated in Scheme-2.6.

Scheme-2.6


Mazaahir Kidwai et. al.[37] prepared 2-amino-3-ethylcarboxylate-4,5-diphenylfuran

efficiently by the condensation of cyanoethyl acetate and benzoin under microwave

irradiation over basic alumina. Further, 2-amino-3-ethylcarboxylate-4,5-diphenylfuran

was reacted with monosubstituted thioureas to obtain furopyrimidines under microwave

condition as illustrated in scheme 2.7.

Scheme-2.7

Nasser A Hassan[38] prepared 2-amino-4,5-di-(2-furyl)furan-3-carbonitrile according to a

modified Gewald method[39]. Refluxing of 2-amino-4,5-di-(2-furyl)furan-3-carbonitrile

with neat triethyl orthoacetate afford the corresponding 2-ethoxyimine derivative.

Treatment of 2-ethoxyimine derivative with p-fluorobenzylamine led to the formation of

3-p-fluorobenzyl-5,6-di-(2-furyl)-3H-2-methylfuro[2,3-d]pyrimidin-4-imine as shown

below.


Sh. A. Abdel-Mohsen et. al.[40] prepared the 5-amino-4-methyl-2-phenyl-6-substituted

furo[2,3-d]pyrimidines from the sodium 5-cyano-6-methyl-2-phenylpyrimidin-4-olate.

The amino group of 5-amino-4-methyl-2-phenyl-6-substitutedfuro[2,3-d]pyrimidines

was converted into the 1-pyrrolyl moiety via the interaction with 2,5-

dimethoxytetrahydrofuran in boiling acetic acid to afford the corresponding pyrrolyl

ketones as shown above.

Raafat M. Shaker[41] prepared furo pyrimidine by treatment of substituted furan with

Scheme-2.8


triethylorthoformate or triethylorthoacetate in acetic anhydride with refluxed, yielding the

corresponding imidates. Hydrazinolysis of imidates compound in ethanol yielded the 3-

amino-5,6-di-(4-methoxyphenyl)-4-imino-3H,4H-furo[2,3-d]pyrimidine as illustrated in

scheme-2.8. The structure of compound was determined on the basic of elemental

analysis and spectral data.

Present work

The strategy adopted for the synthesis of these new condensed tricyclic hetero

compounds involved successive building up of furan and pyrimidine ring on substituted

pyridine. The key starting material 2-chloro-3-cyano pyridine was condensed with

ethylglycolate in 3-methyl-1-butanol and anhydrous sodium carbonate yields

transesterified compound 1, which upon reaction with m-anisoyl chloride in pyridine

gave corresponding amide 2. Alkaline hydrolysis of compound 2 and the reaction of

obtained acid with thionyl chloride followed by ammonium hydroxide yield

corresponding bisamide 3, which undergone cyclization in methanolic KOH to produce

2-(3-methoxy phenyl)pyrido [3',2':4,5]furo[3,2-d]pyrimidin-4(3H)-one that is compound

4. Compound 4 was refluxed with phosphorus oxychloride and obtained cyclic

iminochloride upon condensation with various functionalised aliphatic and cyclic amine

yielded novel substituted pyrido[3',2':4,5]furo[2,3-d]pyrimidine and derivatives,

compound 5a-5i. Compounds 5a-5i were demethylated using AlCl3/Ethanethiol in

dichloromethane resulting in corresponding hydroxy compounds 6a-6i, useful toggle for

the further pharmacological tweaking of these compounds. The proposed reaction

scheme-2.9 is illustrated here, which show preparation of new pyrido furo pyrimidine

derivatives.


N Cl

CN EtOOH

O

3-Methyl-1-butanolref lux N O

O

O

1

NH2

N O

O

O

2

NH

O

OMe

m-Anisoylchloride

Pyridinert, 18hr

1: NaOH, MeOH

2: SOCl2, NH4OH

N O

HN

O

NH2

O

OMe3

KOH, MeOH

N O

N

NH

O

OMe4

N O

N

N

R

OMe5a-5i

1: POCl3

2: Amine

N O

N

N

R

OH6a-6i

AlCl3,Ethanethiol

MDC, ref lux

Reaction scheme 2.9

1) Compound 5a, R = Dimethylamine.

2) Compound 5b, R = Diethylamine.

3) Compound 5c, R = Piperidine.

4) Compound 5d, R = 3-Cyano azetidine.

5) Compound 5e, R = 3-Methoxy pyrrolidine.

6) Compound 5f, R = 4-piperidone.

7) Compound 5g, R = Morpholine.

8) Compound 5h, R = Piperazin-2-one.

9) Compound 5i, R = Thiomorpholine.


Experimental section

Synthesis of isopentyl 3-aminofuro[2,3-b]pyridine-2-carboxylate compound 1

The suspension of 2-chloro-3-cyanopyridine (10.0gm, 72.2mmol), ethyl glycolate

(10.51gm, 101mmol) and sodium carbonate (22.95gm, 216.6mmol) in 3-methyl-1-

butanol (80ml) were refluxed for 72hrs. The solvent was evaporated and water (100ml)

was added to the residue, solid obtained was dissolved in ethyl acetate (200ml). The

organic layer was washed with brine (3x25ml), dried over sodium sulfate, filtered and

concentrated to give off white solid, which upon column chromatography over silica gel

yielded compound 1 (3.2gm, 21.5%, m.p. 112-114oC) as white solid. The product

obtained was taken for the next step. The primary characterization of compound 1 was

done by 1H NMR and data were summarized here.

1H NMR (CDCl3, 300MHz): 0.97(d, J=6.5Hz, 6H), 1.73(m, 2H), 1.84(m, 1H),

4.40(t, J=6.8Hz, 2H), 5.03(bs, 2H), 7.25(m, 1H), 7.94(d, J=7.8Hz, 1H), 8.49(d, J=7.6Hz,

1H) ppm.

Synthesis of isopentyl 3-(3-methoxybenzamido)furo[2,3-b]pyridine-2-carboxylate

compound 2

Dimethylamino pyridine (0.35gm, 0.1mmol) and m-anisoyl chloride (7.94gm,

46.56mmol) were added to the solution of compound 1 (6.4gm, 31.04mmol) in pyridine

(40ml). The reaction mixture was stirred at room temperature for 18hrs and then

concentrated. The residue was dissolved in chloroform (200ml), washed with 1N HCl.

The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to

give residue, which upon purification by column chromatography over silica gel gave

compound 2 (4.8gm, 45.5%) as yellow solid. The product obtained was taken for the next

step.

Synthesis of 3-(3-methoxybenzamido)furo[2,3-b]pyridine-2-carboxamide compound

3

To a solution of compound 2 (4.8gm, 14.1mmol) in methanol (50ml) was added 1M

NaOH (7.9gm in 50ml H2O). The reaction mixture was stirred at room temperature for 2

hrs and then 1M HCl was added to maintain resultant pH 6. The precipitated solid was

filtered to give the desired acid. To this solid, thionyl chloride (16.7gm, 140mmol) was

added; the reaction mixture was refluxed for 2hrs, cooled to the room temperature


followed by concentrated the product. The residue was dissolved in DMF (25ml) and

followed by drop wise addition of aq. ammonia (50ml), the reaction mixture was stirred

at room temperature for 2hrs. The water (100ml) was added to the reaction mixture and

resultant mixture was extracted with chloroform (3x25ml). The organic layer was dried

over anhydrous sodium sulfate, filtered and concentrated to give compound 3 (3.1gm,

70.5%) as light brown solid. The 1H-NMR data for compound 3 was summarized here.

1H NMR (DMSO, 300MHz) : 3.85(s, 3H), 7.23(d, J=7.3Hz, 1H), 7.45-7.53(m, 4H),

8.07(bs, 1H), 8.45(bs, 1H), 8.50(d, J=4.1Hz, 1H), 8.78(d, J=7.9Hz, 1H), 11.2(s, 1H)

ppm.

Synthesis of 2-(3-methoxyphenyl)pyrido [3',2':4,5]furo[3,2-d]pyrimidin-4(3H)-one

compound 4

compound 3 (3.1gm, 9.96mmol) was dissolved in methanol (25ml) and 2M KOH was

added and the reaction mixture was stirred at 100 oC over water bath for 5hrs. The

reaction mixture was cooled down to the room temperature and conc. HCl was added till

solid product was obtained. The solid obtained was dissolved in the ethyl acetate (50ml),

washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give

residue, which upon purification by column chromatography yielded compound 4

(2.7gm, 93%) as white solid and its primary characterization was done by 1H-NMR and

data were briefly shown here.

1H NMR (DMSO, 300MHz) : 3.85(s, 3H), 7.13(dd, J1=8.2Hz, J2=2.3Hz, 1H), 7.45(t,

J=7.6Hz,1H),7.59(m, 1H), 7.74(m, 2H), 8.62(m, 2H) ppm.

General procedure for the synthesis of compound 5a-5i

Phosphorus oxychloride (10ml) was added to the compound 4 (1mmol) and the reaction

mixture was refluxed for 30min. The reaction mixture was concentrated and

azeotropically dried with toluene. Corresponding amine (2mmol) was added to the

obtained residue and was refluxed for 30min. The reaction mixture was concentrated

under reduced pressure, the residue was dissolved in chloroform (50ml), washed with

brine (2x25ml), dried over sodium sulfate, filtered and concentrated to give residues. The

obtained residues were purified by the column chromatography over silica gel to yield

purified compund 5a-5i and their primary characterization were done by 1-HNMR and

summarized in brief given here.


Compound 5a: R= Dimethylamine, yield 56% m.p.122-125oC 1H NMR (CDCl3, 300

MHz) 2.32(s, 6H); 3.87(s, 3H); 6.71-6.96(m, 2H); 7.12-7.28(m, 3H);

7.68(m, 1H); 8.49(d, , 1H), 8.59(d, J=3.4Hz, 1H)ppm.

Compound 5b: R=Diethylamine, yield 64% m.p.128-129oC 1H NMR (CDCl3, 300

MHz) 1.02(t, J=7.3Hz, 6H); 3.05(q, J=7.4Hz, 4H); 3.69(s, 3H); 6.82-

6.94(m, 2H); 7.02-7.21(m, 2H); 7.27(m, 1H); 7.68(m, 1H); 8.63(d,

J=3.4Hz, 1H)ppm.

Compound 5c: R= Piperidine, yield 59% m.p.120-122oC 1H NMR (CDCl3, 300

MHz) 1.53(m, 6H); 2.73(m, 4H); 3.89(s, 3H); 6.76-6.89(m, 2H);

7.07-7.16 (m, 2H); 7.31(m, 1H); 7.71(m, 1H); 8.59(d, J=3.4Hz,

1H)ppm.

Compound 5d: R= 3-Cyano azetidine, yield 64% m.p.169-171oC 1H NMR (DMSO,

300 MHz) 3.91(s, 3H), 4.17(m, 1H), 4.69-4.86(m, 4H), 7.14(d,

J=7.9Hz, 1H), 7.50(t, J=7.9Hz, 1H), 7.69(m, 1H), 8.03-8.09(m, 3H),

8.72-8.86(m, 1H)ppm.

Compound 5e: R= 3-Methoxy pyrrolidone, yield 56% m.p.156-158oC 1H NMR

(DMSO, 300 MHz) 2.16(m, 2H) 3.32(s, 3H), 3.84(s, 3H), 4.02-

4.08(m, 4H), 4.17 (bs, 1H), 7.03(dd, J1=7.9Hz, J2=2.4Hz, 1H), 7.41

(t, , J=7.9Hz, 1H), 7.58(dd, J1=7.1Hz, J2=2.5Hz, 1H), 7.96(bs, 1H),

8.02(d, J=7.8Hz, 1H),8.60(d, J=1.1Hz, 1H ); 8.62(s, 1H)ppm.

Compound 5f: R= 4-Pyridone, yield 57% m.p.163-165oC 1HNMR (DMSO, 300

MHz) 2.65(t, J=5.8Hz 4H); 3.34(s, 3H), 4.41(t, J=4.58Hz, 4H),

7.09(m, 1H) 7.45 (m, 1H), 7.64(m, 1H), 7.99(bs, 1H), 8.06(d,

J=7.9Hz, 1H), 8.67-8.71 (m, 2H)ppm.

Compound 5g: R= Morpholine, yield 61% m.p.158-159oC 1H NMR (CDCl3, 300

MHz) 3.90(t, J=4.6Hz 4H); 3.92(s, 3H), 4.20(t, J=4.6Hz, 4H);

7.03(m, 1H); 7.38-7.50(m, 2H); 8.01-8.10(m, 2H); 8.58(s, 1H),

8.59(s, 1H)ppm.

Compound 5h: R=Piperazin-2-one, yield 67% m.p.181-182oC 1H NMR (DMSO,

300 MHz) 3.46(s, 2H) 3.85(s, 3H), 4.27(bs, 2H), 4.58(bs, 2H),


7.08(d, J=7.4Hz, 1H), 7.43 (t, J=7.7Hz, 1H), 7.62(t, J=5.9Hz, 1H),

7.96(bs, 1H), 8.02(d, J=7.5Hz, 1H), 8.28(bs, 1H ); 8.66(m, 2H)ppm.

Compound 5i: R=Thiomorpholine, yield 71% m.p.151-152oC 1H NMR (CDCl3, 300

MHz) 2.83(t, J=4.9Hz 4H); 3.94(s, 3H), 4.52(t, J=4.9Hz, 4H),

7.03(dd, J1=8.1Hz, J2=2.3Hz, 1H) 7.41 (t, J=7.9Hz, 1H), 7.47(dd,

J1=7.3Hz, J2=5.2Hz, 1H), 7.89(bs, 1H), 8.06(d, J=7.8Hz, 1H),

8.60(bs, 1H ); 8.62(d, J=3.1Hz,1H) ppm.

General procedure for the synthesis of compounds 6a-6i

The solution of compound 5a-5i (0.5 mmol) was dissolved in dichloromethane (MDC)

(15 ml) and 6 mmol ammonium chloride and 6 mmol ethanethiol were added under cold

condition with stirring.The reaction mixture was allowed to cool to room temperature and

was stirred further for 2hrs. The reaction mixture was poured into water, acidified with

dilute HCl, and extracted with dichloromethane. The organic layer was washed with brine

(3x15ml), dried over sodium sulfate, filtered and concentrated to give crude material,

which was purified by column chromatography over silica gel to yield compounds 6a-6i.

(Characterization of the synthesized compounds 6a-i using NMR spectroscopy, the NMR

spectra and its assignments are shown in Figure 2.1-2.10 and Table 2.1-2.10

respectively.)

Characterization of the synthesized compounds 6a-6i using NMR spectroscopy1H-NMR spectrum of final product were carried out in CDCl3or DMSO-d6 solvent

against TMS as reference on Bruker Avance-300MHz instrument and the respective data

were summarize accordingly.


1H-NMR spectrum of compound 6a: There are total 14 protons with seven different

types of protons in the structure. The proton of –OH group appeared around 9.64 ppm as

singlet and a singlet of N-dimethyl is appeared arround 2.79 with 6 protons. This data is

of suggestive that a basic skeleton of 3-[4-(dimethylamino)pyrido[3’,2’:4,5]furo[3,2-d]

pyrimidin-2-yl]phenol is present.

Figure-2.1 1H-NMR of the compound 3-[4-(dimethylamino)pyrido[3’,2’:4,5]furo[3,2-d]

pyrimidin-2-yl]phenol (6a) is shown here.

Table-2.1 Assignment of the 1H-NMR chemical shifts to the different protons of

compound 6a is given here.

Sr.No.

Chemical shift Multiplicity Proton assignment No. of protons

1 2.79 Singlet N-methyl 62 6.85 Doublet Proton of phenol ring 13 7.30 Triplet Proton of pyridine ring 14 7.65 Multiplet Proton of phenol ring 15 7.90 Multiplet Proton of phenol & pyridine 26 8.66 Multiplet Proton of phenol & pyridine 27 9.64 Singlet -OH 1

N O

NN

N

OH

6a


1H-NMR spectrum of compound 6b: There are total 18 protons with eight different


singlet and protons of N-diethyl is appeared around 2.98 ppm as quartet and 0.98 ppm

as triplet with 4 proton and 6 protons respectively. This data is of suggestive that a basic

skeleton of 3-[4-(diethylamino)pyrido[3’,2’:4,5]furo[3,2- d]pyrimidin-2-yl]phenol is

present.

Figure-2.2 1H-NMR of the compound 3-[4-(diethylamino)pyrido[3’,2’:4,5]furo[3,2-

d]pyrimidin-2-yl]phenol (6b) is shown here.


compound 6b is given here.

Sr.No.


1 0.98 Triplet N-CH2CH3 62 2.98 Quartet N-CH2CH3 43 6.89 Doublet Proton of phenol ring 14 7.28 Triplet Proton of pyridine ring 15 7.69 Multiplet Proton of phenol 16 8.20 Multiplet Proton of phenol & pyridine 27 8.72 Multiplet Proton of phenol & pyridine 28 9.58 Singlet -OH 1

N O

NN

N

OH

6b


1H-NMR spectrum of compound 6c: There are total 18 protons with nine different


singlet and a protons of piperidine are appeared around 2.75 ppm as multiplet, 1.49

ppm as multiplate and 1.25 ppm as multiplate with 2, 2 and 1 protons respectively.

This data is of suggestive that a basic skeleton of 3-(4-piperidin-1-

ylpyrido[3’,2’:4,5]furo[3,2-d]pyrimidin-4-yl)phenol is present.

Figure-2.3 1H-NMR of the compound 3-(4-piperidin-1-ylpyrido[3’,2’:4,5]furo[3,2-

d]pyrimidin-4-yl)phenol (6c) is shown here.


compound 6c is given here.

Sr.No.


1 1.25 Multiplet Proton of piperidine 22 1.49 Multiplet Proton of piperidine 43 2.75 Multiplet Proton of piperidine 44 6.89 Doublet Proton of phenol ring 15 7.30 Triplet Proton of pyridine 16 7.63 Multiplet Proton of phenol 17 7.88 Multiplet Proton of phenol & pyridine 28 8.68 Multiplet Proton of phenol & pyridine 29 9.47 Singlet -OH 1

N O

NN

N

OH

6c


1H-NMR spectrum of compound 6d: There are total 13 protons with nine different


singlet and protons of azitidine are appeared around 4.77 ppm as multiplet, 4.65 ppm

as multiplet and 4.13ppm as multiplet with 4, 4 and 2 protons respectively. This data is

of suggestive that a basic skeleton of 1-[2-(3-hydroxyphenyl)pyrido[3’,2’:4,5]furo[3,2-

d]pyrimidin-4-yl]azetidine- 3-carbonitrile is present.

Figure-2.4 1H-NMR of the compound 1-[2-(3-hydroxyphenyl)pyrido[3’,2’:4,5]furo[3,2-

d]pyrimidin-4-yl]azetidine- 3-carbonitrile (6d) is shown here.


compound 6d is given here.

Sr.No.


1 4.13 Multiplet Proton of azitidine 12 4.65 Multiplet Proton of azitidine 23 4.77 Multiplet Proton of azitidine 24 6.88 Doublet Proton of phenol ring 15 7.30 Triplet Proton of pyridine 16 7.64 Multiplet Proton of phenol 17 7.87 Multiplet Proton of phenol & pyridine 28 8.66 Multiplet Proton of phenol & pyridine 29 9.64 Singlet -OH 1

N O

NN

N

OH

6d

CN


1H-NMR spectrum of compound 6e: There are total 18 protons with 10 different types

of protons in the structure. The proton of –OH group appeared around 9.53 ppm as

singlet and protons of pyrrolidine are appeared around 4.16 ppm as multiplet, 4.01 ppm

as multiplet and 2.15 ppm as multiplet with 1, 4 and 2 protonsrespectively. This data is

of suggestive that a basic skeleton of 3-[4-(3-methoxypyrrolidin-1-yl)pyrido[3’,2’:4,5]

furo[3,2-d]pyrimidin-2- yl]phenol is present.

Figure-2.5 1H-NMR of the compound 3-[4-(3-methoxypyrrolidin-1-yl)pyrido[3’,2’:4,5]

furo[3,2-d]pyrimidin-2- yl]phenol (6e) is shown here.


compound 6e is given here.

Sr.No.


1 2.15 Multiplet Proton of pyrrolidine 22 3.33 Singlet Proton of –OMe 33 4.01 Multiplet Proton of pyrrolidine 44 4.16 Multiplet Proton of pyrrolidine 15 6.87 Doublet Proton of phenol ring 16 7.29 Triplet Proton of pyridine 17 7.57 Multiplet Proton of phenol 18 7.88 Multiplet Proton of phenol & pyridine 29 8.58 Multiplet Proton of phenol & pyridine 210 9.53 Singlet -OH 1

N O

NN

N

OH

6e

OMe


1H-NMR spectrum of compound 6f: There are total 16 protons with eight different


singlet and protons of piperidine are appeared around 4.41 ppm as singlet and 2.65

ppm as singlet with 4 and 4 protons respectively. This data is of suggestive that a basic

skeleton of 1-[2-(3-hydroxyphenyl)pyrido[3’,2’:4,5]furo[3,2-d] pyrimidin-4-yl]piperidin-

4-one is present.


d] pyrimidin-4-yl]piperidin- 4-one (6f) is shown here.


compound 6f is given here.

Sr.No.


1 2.65 Singlet(bs) Proton of piperidine 42 4.41 Singlet(bs) Proton of piperidine 43 6.88 Doublet Proton of phenol ring 14 7.31 Triplet Proton of pyridine 15 7.63 Multiplet Proton of phenol 16 7.90 Multiplet Proton of phenol & pyridine 27 8.65 Multiplet Proton of phenol & pyridine 28 9.58 Singlet -OH 1

N O

NN

N

OH

6f

O


1H-NMR spectrum of compound 6g: There are total 16 protons with eight different


singlet and protons of morpholine are appeared around 4.09 ppm as multiplet and 3.82

ppm as multiplet with 4 and 4 protons respectively. This data is of suggestive that a

basic skeleton of 3-(4-morpholin-4-ylpyrido[3’,2’:4,5]furo[3,2-d] pyrimidin-2-yl)phenol

is present.

Figure-2.7 1H-NMR of the compound 3-(4-morpholin-4-ylpyrido[3’,2’:4,5]furo[3,2-d]

pyrimidin-2-yl)phenol (6g) is shown here.


compound 6g is given here.

Sr.No.


1 3.82 Multiplet Proton of morpholin 42 4.09 Multiplet Proton of morpholin 43 6.85 Doublet Proton of phenol ring 14 7.27 Triplet Proton of pyridine 15 7.60 Multiplet Proton of phenol 16 7.85 Multiplet Proton of phenol & pyridine 27 8.63 Multiplet Proton of phenol & pyridine 28 9.50 Singlet -OH 1

N O

NN

N

OH

6g

O


Figure-2.8 13C-NMR of the compound 3-(4-morpholin-4-ylpyrido[3’,2’:4,5]furo[3,2-d]

pyrimidin-2-yl)phenol (6g) is shown here.

Table-2.8 Assignment of the 13C-NMR chemical shifts to the different Carbons of

compound 6g is given here.

Sr.No.

Chemical shift Carbon assignment No. of Carbons

1 55.3 Carbon of morphonilne ring 22 55.9 Carbon of morphonilne ring 23 109.9 Carbon of pyridofuro ring 14 111.3 Carbon of phenol ring 15 114.3 Carbon of phenol ring 16 119.8 Carbon of phenol ring 17 122.0 Carbon of pyridine ring 18 130.3 Carbon of phenol ring 19 131.1 Carbon of pyridine ring 1

10 131.7 Carbon of phenol ring 111 141.9 Carbon of furopyrimidine ring 112 143.0 Carbon of furopyrimidine ring 113 148.1 Carbon of pyridine ring 114 161.2 Carbon of phenol ring 115 162.1 Carbon of pyridofuro ring 116 163.4 Carbon of pyrimidine ring 117 168.9 Carbon of pyrimidine ring 1

N O

NN

N

OH

6g

O


1H-NMR spectrum of compound 6h: There are total 15 protons with 10 different types

of protons in the structure. The proton of –OH group appeared around 9.66 ppm as

singlet and a NH proton of piperazine-2-one are appeared around 8.29 ppm as singlet

with 1 proton respectively. This data is of suggestive that a basic skeleton of 4-[2-(3-

hydroxyphenyl)pyrido[3’,2’:4,5]furo[3,2-d] pyrimidin-4-yl]piperazin- 2-one is present.


d] pyrimidin-4-yl]piperazin- 2-one (6h) is shown here.


compound 6h is given here.

Sr.No.


1 3.47 Singlet(bs) Proton of piperazine-2-one 22 4.30 Singlet(bs) Proton of piperazine-2-one 23 4.69 Singlet Proton of piperazine-2-one 24 6.88 Doublet Proton of phenol ring 15 7.31 Triplet Proton of pyridine 16 7.64 Multiplet Proton of phenol 17 7.98 Multiplet Proton of phenol & pyridine 28 8.29 Singlet -NH of piperazine-2-one 19 8.67 Multiplet Proton of phenol & pyridine 210 9.66 Singlet -OH 1

N O

NN

N

OH

6h

NH

O


1H-NMR spectrum of compound 6i: There are total 16 protons with 8 different types of

protons in the structure. The proton of –OH group appeared around 9.60 ppm as singlet

and a protons of thiomorpholine are appeared around 4.40 ppm as singlet and 2.85 ppm

as singlet with 4 and 4 protons respectively. This data is of suggestive that a basic

skeleton of 3-(4-thiomorpholin-4-ylpyrido[3’,2’:4,5]furo[3,2-d]pyrimidin-2-yl)phenol is

present.

Figure-2.10 1H-NMR of the compound 3-(4-thiomorpholin-4-yl pyrido [3’,2’:4,5] furo

[3,2-d]pyrimidin-2-yl)phenol (6i) is shown here.


compound 6i is given here.

Sr.No.

Chemical shift Multiplicity Proton assignment No. of proton

1 2.85 Singlet(bs) Proton of thiomorpholine 42 4.40 Singlet(bs) Proton of thiomorpholine 43 6.88 Doublet Proton of phenol ring 14 7.30 Triplet Proton of pyridine 15 7.62 Multiplet Proton of phenol 16 7.87 Multiplet Proton of phenol & pyridine 27 8.65 Multiplet Proton of phenol & pyridine 28 9.64 Singlet -OH 1

N O

NN

N

OH

6i

S


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