; 4,5 ]FURO[2,3- D][PYRIMIDINES] · Journal of Humanities and Applied Science (J HAS) Issue No. (2 9) December 2016-123 - 1. INTRDUCTION Literature survey has revealed the diversified

Journal of Humanities and Applied Science (JHAS) Issue No. (29) December 2016

- 122 -

SYNYHESIS AND REACTION MECHANISMOF SOME COMPOUNDS RELATED TO

FURO[2,3-D][PYRIMIDINES ANDPYRIMIDO[4\,5\ ; 4,5 ]FURO[2,3-

D][PYRIMIDINES] .

Suliman M. Mussa

Department of Chemistry, Faculty of science, Misurata University, Misurata, Libya .Email : [email protected]

ABSTRACTEthyl 5-amino-4-methyl-2-phenylfuro[2,3-d]pyrimidine–6-carboxylate (1) was used asprecursor for the synthesis of pyrimidofuroppyrimidines 2 , 3 and furopyrimidinederivative4 by reaction withphenyl isothiocyanate , formamide and hydrazine hydraterespectively .AlsoSaponification of compound 1 followed by treatment withorthophosphoric acid afforded compound6 which underwent condensation with 4-methoxybenzaldehyde to give 6-arylidene-4-methyl-2-phenylfuro[2,3-d]pyrimidin-5-one(7) . On the other handrefluxing of compound 5 with acetic anhydride gave 5-(N,N-diacetylamino)-4-methyl-2-phenylfuro[2,3-d]pyrimidine (9), which on treatment withhydrazine hydrate afforded N-acetylamino derivative 10 .Chlorination of compound 3 withphosphorus oxychloride gave 8-Chloro-4-methyl-2-phenylpyrimido[4\,5\:4,5]furo[2,3-d]pyrimidine (11),which up on treatment with hydrazine hydrate gave the correspondinghydrazine derivatives 12. Condensation of compound 4 with 4-nitrobenzaldehydes gave 5-Amino-6-(4-nitrobenzylidene)-4-methyl-2-phenylfuro[2,3-d]pyrimidine-6-carbohydrazone(13).On the other hand refluxing of carbohydrazide 4 with formic acid and aceticanhydride led to the formation of compounds 14 and 15 respectively. Also 3,5-dimethylparazolyl derivative 16 was prepared from the reaction of compound 4 with acetyl acetone. Treatment of compound1with 2,5-dimethoxytetrahydrofuran produced thecompound17,which reacted with hydrazine hydrate to give carbohydrazide derivative18.The reaction of 18 with CS2followed by methyl iodide gave the 6-(2-methylthio-1,3,4-oxadiazol-5-yl)-4-methyl-5-(1-pyrrolyl)-2-phenylfuro[2,3-d]pyrimidine ( 20 ). On the otherhandcompounds21 and 22 were obtained by the condensation of compound 20 withmorpholine and 1,2,3,4-tetrahydroquinoline respectively .

Keywords:Synthesis , reaction mechanism , furo[2,3-d]pyrimidine ,pyrimido[4\,5\:4,5]furo[2,3-d]pyrimidine , Spectral characteristics;


- 123 -

1. INTRDUCTIONLiterature survey has revealed the diversified biological and

pharmacological significance of several nitrogen , oxygen and sulphur

heterocycles. This aspect has been drawing the attention of many

researchers towards exploiting the biological importance of various

heterocyclic compounds and to establish the relationship between their

biological, pharmacological potency and structural features. A rapid

progress in the work on fused furopyrimidines and thienopyrimidines has

given rise to a number of compounds exhibiting potent pharmacological

actions. Furopyrimidines attract considerable attention because of their great

practical significance through exerting various pharmacological potential as

antimicrobial[1], antitumor[2-4], antivirus[5-6] and anti-cancer[7]. The

presence of a pyrimidine base in cytosine, uracil and thymine, which are the

essential building blocks of nucleic acids (DNA and RNA) is one of the

possible reasons for their activities [8]. These observation and as

continuation of our previous work on fused pyrimidine ring [9-11] led us to

attempt the synthesis of some furopyrimidines with expected biological

activity.

2. RESULTS AND DISCUSSIONEthyl 5-amino-4-methyl-2-phenylfuro[2,3-d]pyrimidine–6-carboxylate (1),

which previously prepared [9] was used as precursor for synthesizing other

furopyrimidines as well as pyrimidofuroppyrimidines. Thus the reaction of

compound 1 with an equimolar quantity of phenyl isothiocyanate in

pyridinegave4-Methyl-8-oxo-5,6,7,8-tetrahydro-2,7-diphenylpyrimido[4\,5\:


- 124 -

4,5]furo[2,3-d]pyrimidin-6-thione (2). Heating of 1 in formamide leads to

the formation of 4-Methyl-2-phenylpyrimido[4\,5\:4,5]furo[2,3-

d]pyrimidin-8(7H)-one (3) and refluxing of the amino ester 1 with

hydrazine hydrate in ethanol afforded the corresponding carbohydrazide

derivative 4 . Scheme 1.

O

N

N

NH2

CO2C2H5

CH3

PhO

N

N

CH3

PhNPh

NH

S

O

O

N

N

NH2

CONHNH2

CH3

Ph

O

N

N

CH3

PhNH

N

O

PhNCS HCONH2

NH2NH2.H2O

(1)(2)

(4)

(3)

Scheme 1

The possible mechanism for formation of compounds 2 can be explained by

the reaction pathway depicted in scheme 2. [12-14]

O

N

N

NHCH3

Ph

O

O

CH2CH3

H

O

N

N

CH3

PhNPh

NH

S

O

S

NPh

- ( C2H5OH )

(1) (2)Scheme 2

The structural formulae of the synthesized compounds 1 - 4 were confirmed

by elemental and spectral analysis table 1,2. Thus the mass spectrum of

compound 1 showed a molecular ion peak at m/z = 297.09 (100%) which is

in agreement with its molecular formula (C16H15N3O3) . Fig. 1 .


- 125 -

The IR spectrum of compound 2 showed the disappearance of NH2

vibration band and appearance of characteristic absorption bands at 3300

cm-1 for (NH) group .Fig. 2

Also the 1HNMR spectrum of compound 4 in DMSO-d6 (90 MHz) showed

a singlet at 9.8 (1H, NH) . Fig.3

Fig. 1

Fig. 2


- 126 -

Saponification of o-aminoester 1 with an ethanolic sodium hydroxide

solution followed by treatment with orthophosphoric acid resulted in

decarboxylation followed by hydrolysis of the imino group to give the 4-

methyl-2-phenylfuro[2,3-d]pyrimidin-5(6H)-one (6) which underwent

condensation with 4-methoxybenzaldehyde to give 6-arylidene-4-methyl-2-

phenylfuro[2,3-d]pyrimidin-5-ones (7) . Scheme 3 .

O

N

N

N H 2

C O 2 C 2H 5

C H 3

Ph

O

N

N

N H 2

C H 3

P h C O 2N a

O

N

N

N H 2

C H 3

P h

O

N

N

N H

C H 3

Ph

N aO Ho rtho p ho s ph o ric a cid

O

N

N

O

C H 3

Ph

O

N

N

O

C H 3

Ph CH

O M e

M eO C H O

(1 )

(5 )

S c h e m e 3

(7 )

(6 )

Fig. 3


- 127 -

The possible mechanism for formation of compound 7 can be explained by

the reaction pathway depicted in scheme 4. [12-14]

O

N

N

O

CH3

Ph

O

N

N

O

CH3

Ph CH

OMe

O

HOMe

O

N

N

O

CH3

PhOHH

OMe

- (H2O )

Scheme 4

(7)

(6)

The structural formulae of the synthesized compounds 5 , 6 were confirmed

by elemental and spectral analysis table 1,2. Thus the 1HNMR of compound

6 in CDCl3 (90 MHz) showed a singlet signal at 4.8 for (2H, CH2) . The

presence of CH2 was confirmed by the appearance of its signal on

deuteration (Fig. 4).

Fig. 4


- 128 -

Refluxing of compound 5 with an excess amount of acetic anhydride didn’t

give the expected oxazine derivative 8 and instead of 5-(N,N-

diacetylamino)-4-methyl-2-phenylfuro[2,3-d]pyrimidine (9) was obtained.

Also treatment of the latter compound with hydrazine hydrate (99%) in

ethanol gave N-acetylamino derivative 10 . Scheme 5.

O

N

N

NH2

CH3

Ph COONa

O

N

N

CH3

PhO

N CH3

O

O

N

N

N

CH3

Ph

COCH3

COCH3

Ac2O

O

N

N

N

CH3

Ph

COCH3

H

NH2NH2.H2O

(5)

(8)

(9)

Scheme 5

(10)

The possible mechanism for formation of compounds 9 and 10 can be

explained by the reaction pathway depicted in Scheme 7. [12-14]

O

N

N

N

CH3

Ph

H

O

O Na

H

O

N

N

N

CH3

Ph

H3COC

CH3

O

CH3

O

O

O

CH3O

N

N

N

CH3

Ph

COCH3

H

- (CH3COONa )

- (CO2 )O

H3COC

O

- ( CH3COOH )

O

N

N

NH

CH3

Ph

COCH3

N NH2H

H

NH2NH2.H2O

(5)

(9)

+

Scheme 7

(10)


- 129 -

The structural formulae of the compounds 9 , 10 were confirmed by

elemental and spectral analysis table 1,2. Thus the 1HNMR spectrum of

compound 9 in CDCl3 (90 MHz) showed a singlet at 2.5 for (6H,

2COCH3) . Whilst The 1HNMR spectrum of compound 10 in CDCl3 (90

MHz) showed a singlet at 2.3 for (3H, COCH3) , which confirmed the

total acetylation of NH2 group for compound 5 and deacetylation of

compound 9 (Fig. 5, 6).

( XXIX )

N

ON

CH3

Ph

NHCOCH3

( XXVIII )

N

ON

CH3

Ph

N(COCH3)2

Fig. 5

Fig. 6


- 130 -

The chlorination of compound 3 with an excess amount of phosphorus

oxychloride gave 8-Chloro-4-methyl-2-phenylpyrimido[4\,5\:4,5]furo[2,3-

d]pyrimidine (11), and on treatment of the latter compound with hydrazine

hydrate (99%) in ethanol gave the corresponding hydrazino compound 12

(Scheme 8).

O

N

N

CH3

PhNH

N

OO

N

N

CH3

PhN

N

Cl

POCl3

O

N

N

CH3

PhN

N

NHNH2

NH2NH2.H2O

(3) (11)

(12)Scheme 8

The possible mechanism for formation of compounds 11 and 12 can be

explained by the reaction pathway depicted in scheme 9. [12-14]

O

N

N

CH3

PhN

N

O

H

O

N

N

CH3

PhN

N

ClO

N

N

CH3

PhN

N

NHNH2

P

Cl

Cl Cl

O O

N

N

CH3

PhN

N

O

P OCl

Cl

H

Cl

N NH2H

H

(3)

(11)

(12)Scheme 9

+

- (HCl)


- 131 -

The mass spectrum of compound 11 showedM and M+2 peaks m/z =

296.68 (100%) and at 298.68 (35.4%) which are in agreement with its

molecular formula (C15H9ClN4O). (Fig. 7).

Condensation of 5-Amino-4-methyl-2-phenylfuro[2,3-d]pyrimidine-6-

carbohydrazide (4) with 4 -nitrobenzaldehydes gave 5-Amino-6-(4-

nitrobenzylidene)-4-methyl-2-phenylfuro[2,3-d]pyrimidine-6-

carbohydrazone (13) (Scheme 10).

O

N

N

NH2

CONHNH2

CH3

Ph

O2N CHO

O

N

N

NH2

CH3

Ph CO NH

N CH

NO2

(4) Scheme 10(13)

The possible mechanism for formation of compounds 13 can be explained

by the reaction pathway depicted in scheme 11. [12-14]

( XXX )

N

ON

CH3

Ph

N

N

ClFig. 7


- 132 -

O

N

N

NH2

CH3

Ph

O

NH

N H

H

ArO

N

N

NH2

CH3

Ph CO NH

N CH

ArO

N

N

NH2

CH3

Ph

O

NH

N

OHH

H

Ar

O

H

(4)

Scheme 11

(13)

- (H2O)

Heating of carbohydrazide 4 with formic acid and acetic anhydride at reflux

temperature led to the formation of 7-N-Formylamino-4-methyl-2-

phenylpyrimido[4\,5\:4,5]furo[2,3-d]pyrimidin-8( 7H )-one (14) and 7-

(N,N-Diacetylamino)-4,6-dimethyl-2-phenylpyrimido[4\,5\:4,5]furo[2,3-

d]pyrimidin -8(7H)-one (15) respectively. Also 3,5-dimethyl parazolyl

derivative 16 was prepared from the reaction of 4 with acetyl acetone

(Scheme12).

O

N

N

NH2

CONHNH2

CH3

Ph O

N

N

CH3

PhN

N

O

N(COCH3)2

CH3

O

N

N

CH3

PhN

N

O

NHCHO

HCOOH

Ac2O

Ac2CH2 NNO

N

N

NH2

CH3

Ph

CH3

CH3

O

(4)

Scheme 12

(15)

(14)

(16)


- 133 -

The possible mechanism for formation of compounds 16 can be explained

by the reaction pathway depicted in Scheme 13. [12-14]

O

N

N

NH2

CO

CH3

PhN N

H H

H

NNO

N

N

NH2

CH3

Ph

CH3

CH3

O

O O

N

N

O

N

N

NH2

CO

CH3

PhOH

OH

H

H

H

- (H2O)

(4)

Scheme 13

(16)

(4)

The 1HNMR spectrum of compound 15 in CDCl3 (400 MHz) showed a

singlet at 2.52 for (3H, CH3, pyrimidinone) and a singlet at 2.46 for (6H,

2 COCH3) and revealed the disappearance of any absorption bands due to

NH or NH2 groups which confirmed the cyclization . (Fig. 8).

( XXXIV )O

N

ON

CH3

PhN N(COCH3)2

N CH3

Fig. 8


- 134 -

The structural formulae of the compound 16 was confirmed by elemental

and spectral analysis table 1,2. Thus the 1HNMR spectrum of compound 16

in DMSO-d6 (90 MHz) showed a singlet at 6.2 (1H, CH, pyrazole) and a

double singlet at 2.3, 2.5 (6H, 2CH3, pyrazole) (Fig. 9).

Reaction of compound 1 with dimethyltetrahydrofuran afforded pyrrolyl

derivatives 17 followed by its hydrazinolysis to give carbohydrazide 18

which was cyclized by CS2\pyridine to afford compound 19 , the latter

compound was treated by iodomethane in the presence of sodium methoxide

to yield the 6-(2-methylthio-1,3,4-oxadiazol-5-yl)-4-methyl-5-(1-pyrrolyl)-

2-phenylfuro[2,3-d]pyrimidine 20 Scheme 14.

O

N

N

NH2

CH3

PhO

N N

CH3CH3

Fig. 9


- 135 -

O

N

N

NH2

CO2C2H5

CH3

Ph

N

O

N

N CO2C2H5

CH3

Ph

N

O

N

N CONHNH2

CH3

Ph

NH2NH2.H2O

N NH

O

N

O

N

N

CH3

PhS

CS2

Pyridine

N N

O

N

O

N

N

CH3

PhSCH3

CH3I

CH3ONa

(1)

Scheme 14

(17)

DMTF

(18)(19)

(20)

The structural formulae of the compounds 17 - 20 were established on the

basis of their elemental analysis and spectral data table 1,2.

On the other hand, some novel 6-(2-substituted-1,3,4-oxadi-azol-5-yl)-4-

methyl-5-(1-pyrrolyl)-2-phenylfuro[2,3-d]pyrimidine derivatives 21 and 22

were also obtained by the condensation reaction of compound 20 with

morpholine and 1,2,3,4-tetrahydroquinoline respectively . Nevertheless,

under the same reaction conditions, reaction of carbohydrazide 18 with N,N-

diphenylamine did not produce the desired compound 23, but led only to the

recovery of starting material. Scheme 15


- 136 -

N N

O

N

O

N

N

CH3

PhSCH3

N N

O

N

O

N

N

CH3

Ph N

Ph

Ph

NO

N N

O

N

O

N

N

CH3

Ph

PhNHPh

N N

O

N

O

N

N

CH3

Ph N

Scheme 15

(20) (21)

(23)

Morpholine

1,2,3,4-tetrahydroguinoline

(22)

structural formulae of the compounds 21 and 22 were established on the

basis of their elemental analysis and spectral data table 1,2. Thus the mass

spectrum of compound 21 showed a molecular ion peak at m/z = 428

(100%) which is in agreement with its molecular formula (C23H20N6O3).

The proposed mass fragmentation pathway of compound 21 is shown in

Scheme 16.


- 137 -

N

N

O

O

N

N

N N

O

CH3

N

NO

O

N

N

N N

O

CH2

NO

N N

O

N

ON

N

N

CH2

N N

O

N

ON

N

N N

O

N

ON

NN

ON

N

N

N

ON

NN

ON

+

m\z = 428 (100%)m\z = 427

+

++

m\z = 371 ( 3% )

+

m\z = 342 ( 37% )

+

m\z = 273 ( 13% )

+

m\z = 300 ( 15 % )

+

m\z = 246 ( 2 % )


- 138 -

3. EXPERIMENTAL PROCEDURESAll melting points are uncorrected and measured on a Gallan-Kamp

apparatus. IR spectra were recorded on a Shimadzu-470 IR-

spectrophotometer (KBr; υmax in cm-1). 1HNMR spectra were measured

on a Varian EM-390, 90 MHz spectrometer or on a Jeol LA 400 MHz FT-

NMR spectrometer with TMS as internal standard ( in ppm); MS on a Jeol

JMS-600 mass spectrometer. Elemental analyses were determined on a

Perkin-Elmer 240C elemental analyzer or on an Elemental Analyses system

GmbH VARIOEL V2,3 CHNS Mode (Egypt).

Ethyl 5-amino-4-methyl-2-phenylfuro[2,3-d]pyrimidine-6-carboxylate (1):

This compound is perversely prepared as yellow crystals in 83% yield [9]

4-Methyl-8-oxo-5,6,7,8-tetrahydro-2,7-diphenylpyrimido[4\,5\:45]furo[2,3-

d]pyrimidin-6-thione (2) :

A mixture of 1 (1.5 gm, 0.005 mol.) and phenylisothiocyanate (0.005 mol.)

in pyridine (30 ml) was refluxed on an oil bath for 10 hrs, then allowed to

cool. The solid product was filtered off and recrystallized from DMF as

yellow crystals .

4-Methyl-2-phenylpyrimido[4\,5\:4,5]furo[2,3-d]pyrimidin-8(7H)-one (3):

A sample of compound 2 (1.18 gm, .004 mol.) in formamide (10 ml) was

refluxed for 3 hrs. The solid product which separated from the hot mixture

was filtered off and recrystallized from acetic acid as yellowish brown

crystals .

5-Amino-4-methyl-2-phenylfuro[2,3-d]pyrimidine-6-carbohydrazide (4):


- 139 -

A mixture of 2 (2.97, 0.01 mol.) and hydrazine hydrate 99% (3 ml) was

refluxed in ethanol (20 ml) for 3 hrs. The solid product which formed in the

hot mixture was filtered off and recrystallized from dioxan as pale yellow

crystals .

Sodium 5-amino-4-methyl-2-phenylfuro[2,3-d]pyrimidine-6-carboxylate

(5):

A mixture of 1 (1.5 gm, 0.005 mol.) and sodium hydroxide (0.005 mol) in

ethanol (20 ml) was refluxed for 5 hrs, then allowed to cool. The solid

product was filtered off, washed with ethanol and air dried to give

yellowish white solid in 80% yield. Compound 5 was subjected to the next

step without further purification.

4-Methyl-2-phenylfuro[2,3-d]pyrimidin-5(6H)-one (6):

A sample of 5 (l.45 gm, 0.005 mol.), orthophosphoric acid (10 ml) was

stirred at room temperature for 3 hrs, then cooled and neutralized with

ammonium hydroxide. The white precipitate was collected and

recrystallized from ethanol as white crystals .

6-(4-Methoxybenzylidene)-4-methyl-2-phenylfuro[2,3-d]pyrimidin–5-one

(7):

A mixture of 6 (0.01 mol.) and 4-methoxybenzaldehyde (0.01 mol.) in

ethanol/acetic acid mixture (30 ml) was refluxed for 3 hrs. The solid

product, which formed after cooling, was filtered off and recrystallized from

ethanol as yellow crystals.

5-(N,N-Diacetylamino)-4-methyl-2-phenylfuro[2,3-d]pyrimidine (9):


- 140 -

A sample of 5 (1.45 gm, 0.005 mol.) in acetic anhydride (30 mol) was

refluxed for 3 hrs, then allowed to cool, poured into ice-water/mixture. The

solid product was filtered off and recrystallized from ethanol as pale yellow

crystals .

N-(4-methyl-2-phenylfuro[2,3-d]pyrimidin-5-yl)acetamide (10):

A mixture of 9 (1.55 gm, 0.005 mol.) and hydrazine hydrate 99% (3 ml) in

ethanol (30 ml) was refluxed for 4 hrs, and then allowed to cool. The solid

product was filtered off and recrystallized from ethanol as pale yellow

crystals.

8-Chloro-4-methyl-2-phenylpyrimido[4\,5\:4,5]furo[2,3-d]pyrimidine (11):

A sample of compound 3 (1.11 gm, 0.004 mol.) in phosphorus oxychloride

(15 ml) was heated under reflux for 4 hrs, then allowed to cool and poured

into ice/water mixture with stirring. The solid product was collected and

recrystallized from ethanol as orange crystals.

8-Hydarzino-4-methyl-2-phenylpyrimido[4\,5\:4,5]furo[2,3-d]pyrimidine

(12):

A mixture of 11 (1.18 gm 0.004 mol.) and hydrazine hydrate 99% (3ml) in

ethanol (15 ml) was refluxed for 4 hrs, then allowed to cool. The solid

product was collected and recrystallized from ethanol as orange crystals.

5-Amino-6-(4-nitrobenzylidene)-4-methyl-2-phenylfuro[2,3-d]pyrimidine-

6-carbohydrazone (13):

A mixture of the hydrazide derivative 4 (0.01 mol) and 4-nitrobenzaldehyde

(0.01 mol.) in ethanol/acetic acid mixture (30 ml) was refluxed for 4 hrs,


- 141 -

then allowed to cool. The solid product was collected and recrystallized

from acetic acid as reddish yellow crystals.

7-N-Formylamino-4-methyl-2-phenylpyrimido[4\,5\:4,5]furo[2,3-

d]pyrimidin-8(7H)-one (14):

A sample of compound 3 (0.5 gm, 0.002 mol.) in formic acid (10 ml) was

refluxed for 5 hrs, then allowed to cool. The solid product was collected and

recrystallized from dioxan as pale yellow crystals.

7-(N,N-Diacetylamino)-4,6-dimethyl-2-phenylpyrimido[4\,5\:4,5]furo[2,3-

d]pyrimidin-8(7H)-one (15):

A sample of compound 3 (0.5 gm, 0.002 mol.) in acetic anhydride (10 ml)

was refluxed for 2 hrs, then allowed to cool and poured into cold water. The

solid product was collected and recrystallized from dioxan as pale yellow

crystals.

5-Amino-4-methyl-2-phenyl-6-(3\,5\-dimethylpyrazol-1-

ylcarbonly)furo[2,3-d]pyrimidine (16):

A mixture of carbohydrazide 3 (2.83gm, 0.01mol.) and acetylacetone

(0.012 mol) in ethanol (40 ml) was refluxed for 3 hrs, then allowed to cool.

The solid product was collected and recrystallized from ethanol as yellow

needles.

Ethyl 5-(1-pyrrolyl)-4-methyl-2-phenylfuro[2,3-d]pyrimidine-6-carboxylate

(17)

A mixture of compound 1 (1.5 g, 0.005 mol) and 2,5-

dimethoxytetrahydrofuran (0.63 g, 0.005 mol) in glacial acetic acid (20 mL)

was refluxed for 12 hr. After cooling, the resultant solid product was


- 142 -

collected by filtration and washed with water, and the crude product

recrystallized from ethanol/glacial acetic acid as gray white needles .

4-Methyl-5-(1-pyrrolyl)-2-phenylfuro[2,3-d]pyrimidine carbohydrazide (18)

A mixture of compound 17 (0.01mol) and hydrazine hydrate (10 mL, 85%

solution) was refluxed in absolute ethanol (20 mL) for 24 hr. After cooling,

the solid product was collected by filtration and washed with water, and

recrystallized from ethanol as gray white needles.

6-(2,3-Dihydro-2-mercapto-1,3,4-oxadiazol-5-yl)-4-methyl-5-(1-pyrrolyl)-

2-phenylfuro[2,3-d]pyrimidine (19).

A mixture of compound 19 (0.01mol) and carbondisulphide (5 mL) in

pyridine (10 mL) was refluxed on a steam bath for 6 h. After cooling, the

solid product was collected by filtration, washed with water and

recrystallized from ethanol as greenish yellow crystals.

6-(2-Methylthio-1,3,4-oxadiazol-5-yl)-4-methyl-5-(1-pyrrolyl)-2-

phenylfuro[2,3-d]pyrimidine (20)

To a mixture of compound 20 (1 mmol) in methanol (10 mL) and sodium

methoxide (1.5 mmol), iodomethane (1.2 mmol) was added. After stirring at

room temperature for 24 hr, the solid product was collected, washed with

water and recrystallized from THF as pale yellow crystals .

6-(2-Morpholinyl-1,3,4-oxadiazol-5-yl)-4-methyl-5-(1-pyrrolyl)-2-


A mixture of compound 20 (1 mmol) and an excess amount of morpholine,

was refluxed for 10 hr. and then poured into ice-water, the precipitated

product was collected, washed with water, and recrystallized from

chloroform/THF as pale yellow crystals .


- 143 -

6-(2-Quinolizinyl-1,3,4-oxadiazol-5-yl)-4-methyl-5-(1-pyrrolyl)-2-


A mixture of compound 20 (1 mmol) and an excess amount of 1,2,3,4-

tetrahydroquinoline was refluxed for 10 hr. and then poured into ice-water,

and the precipitated product was collected, washed with water, and

recrystallized from chloroform/THF as pale yellow crystals .

ANALYTICAL DATA

Table 1 physical properties and analytical data for compounds( 2-22 )

No m.poC Yield %

colour

Formula /

mol.wt

Calculated% / Found%

C H N Other

2 >350 56

yellow

C21H14N4O2S386.43

65.27

65.14

3.65

3.60

14.50

14.45

S : 8.30

8.38

3 >310 76

yellowish

C15H10N4O2

278.27

64.74

64.63

3.62

3.71

20.13

20.10

4 265-266

85

pale yellow

C14H13N5O2

283.29

59.36

59.22

4.63

4.62

24.72

24.75

6 150-151

71

white

C13H10N2O2

226.23

69.02

68.88

4.46

4.52

12.38

12.35

7230-231

78

yellow

C21H16N2O3

344.36

73.24

73.18

4.68

4.71

8.13

7.97

9 140-141

74

pale yellow

C17H15N3O3

309.32

66.01

65.93

4.89

4.90

13.58

13.46

10 209-210

70

pale yellow

C15H13N3O2

267.28

67.40

67.30

4.90

4.84

15.72

15.83


- 144 -

11 210-211

68

orange

C15H9 ClN4O296.71

60.72

60.64

3.06

2.97

18.88

19.01

Cl;11.95

11.78

12 218 -220

71

orange

C15H12N6O

292.30

61.64

61.57

4.14

4.21

28.75

28.85

13 308-309

81

yellow

C21H16N6O4

416.39

60.57

60.65

3.87

4.0

20.18

20.03

14 290-291

80

pale yellow

C16H11N5O3

321.29

59.81

59.72

3.45

3.50

21.80

21.74

15 219-220

82

pale yellow

C20H17N5O4

391.38

61.38

61.29

4.38

4.48

17.89

17.90

16 199-200

76

yellow

C19H17N5O2

347, 37

65.69

65.61

4.93

4.83

20.16

20.25

17 166-167

80

Grayyellow

C20H17N3O3

347.38

69.15

69.20

4.93

5.01

12.01

12.05

18 232-233

90

Grayyellow

C18H15N5O2

333.35

64.86

64.93

4.54

4.57

21.01

21.07

19 270-271

85

yellow

C19H13N5O2S

375.41

60.79

60.84

3.49

3..47

18.66

18.60

S: 8.54

8.50

20 210-211

70

Pale yellow

C20H15N5O2S

389.44

61.68

61.70

3.88

3.80

17.98

17.90

S: 8.23

8.30

21 281-282

75

Pale yellow

C23H20N6O3

428.45

64.48

64.51

4.71

4.70

19.61

19.58

22 184-185

60

Pale yellow

C28H22N6O2

474.53

70.87

70.91

4.67

4.69

17.71

17.70


- 145 -

Table 2 : Spectroscopic Data of Compounds (2-22)2 IR: υ = 3300 cm-1 (NH) and at 1700 cm-1 (C=O).

1HNMR (TFA \ 90 MHz) : = 3.8 ( s,3H, CH3 , pyrimidine ) and 8.2-7.6 ( m, 10H,

Ar-H ) .

3

IR: υ = 3150 cm-1( NH) and 1670 cm-1 (C=O) .1HNMR (Cf3COOD \ 90 MHz) : = 3.5 ( s,3H, CH3 , pyrimidine ), 7.6-7.9 (m,

3H, aromatic) 8.4-8.6 (m, 2H, aromatic) and 8.9 (s, 1H, N=CH) .

4

IR: υ = IR: υ = 3450, 3350, 3250 cm-1 (NH2), (NHNH2) and 1620 cm-1 (C=O).1HNMR( DMSO-d6\90 MHz): = 2.9 (s, 3H, CH3, pyrimidine), 4.5 (s, 2H, NH2),

6.1 (s, 2H, NH2), 7.5-7.7 ( m, 3H, Ar-H ), 8.5-8.7 ( m, 2H, Ar-H) and 9.8 (s, 1H,

NH ) .

MS : m/z 283( M+, 99.5% ) .

6

IR: υ = 1710 cm-1 ( C=O ).1HNMR(CDCl3\ 90 MHz ): = 2.8 ( s,3H, CH3, pyrimidine ), 4.8 (s, 2H, CH2) ,

7.4-7.6 ( m, 3H, Ar-H ) and 8.4-8.6 ( m, 2H, Ar-H) .

MS : m/z 226.41( M+, 100% ) .

7

IR: υ = 1690 cm-1 ( C=O ).1HNMR(CDCl3\ 400 MHz) : = 2.8 ( s,3H, CH3, pyrimidine ), 3.8 (s, 3H, OCH3),

7.3 (s, 1H, CH), 6.9-7.1( m, 3H, Ar-H ), 7.45-7.65 ( m, 2H, Ar-H) , 7.94-7.96 ( d,

2H, Ar-H) and 8.58-8.60 ( d, 2H, Ar-H)

9

IR: υ = 1720, 1700 cm-1 (2C=O, acetyl).1HNMR(CDCl3\ 90 MHz ): = 2.3 (s, 3H, COCH3), 2.9 ( s, 3H, CH3, pyrimidine

), 7.4-7.6 ( m, 3H, Ar-H) , 8.1 (s, 1H, CH), and 8.3-8.5 ( m, 2H, Ar-H ) .

10

IR: υ = 3400 cm-1( NH) and 1650 cm-1 ( C=O ).1HNMR(CDCl3\ 90 MHz ): = 2.5 (s, 6H, 2COCH3), 2.8 ( s, 3H, CH3, pyrimidine

), 7.4-7.6 ( m, 3H, Ar-H) , 7.7 (s, 1H, CH), 8.4-8.6( m, 2H, Ar-H ), and 9.1 (s,

1H, NH) .

MS : m/z 267 ( M+, 100% ) .


- 146 -

11

1HNMR(CDCl3\ 400 MHz) : = 3.11 ( s,3H, CH3, pyrimidine ), 7.46 ( m, 3H, Ar-

H ), 8.51 ( m, 2H, Ar-H) and 8.99 (s, 1H, CH),

MS : m/z M = 296.68 (100%) and M+2 at 298.68 (35.4%).

12

IR: υ = 3450 , 3300 cm-1( NHNH2 ).1HNMR( DMSO-d6): = 3.0 (s,3H, CH3, pyrimidine), 3.55 (s, 2H, NH2), 7.56-

7.57 ( m, 3H, Ar-H ), 7.81 (s, 1H, NH ), 8.47-8.50 ( m, 2H, Ar-H ) and 8.57 (s, 1H,

CH),.

13

IR: υ = 3450 , 3300 cm-1( NHNH2 ), 1640 cm-1 ( C=O ) and 1590 cm-1 for (C=N).1HNMR (TFA \ 90 MHz) : = 3.3 ( s,3H, CH3 , pyrimidine ) and 7.6-8.5 ( m, 9H,

Ar-H+ 1H CH=N) .

14

IR: υ = 3170 cm-1 (NH) , 1720 ( CO Aldehyde) and 1680 cm-1 (C=O,

pyrimidinone).1HNMR( DMSO-d6\90 MHz): = 2.9 (s, 3H, CH3, pyrimidine), 7.4-7.6 ( m, 3H,

Ar-H ), 8.4-8.5 ( m, 2H, Ar-H +1H, CH, pyrimidine ), 8.6 (1H, CHO), and 9.4 (

br.s, 1H, NH ) .

15 IR: υ = 1730 ( 2CO Acetyl) and 1700 cm-1 (C=O, pyrimidinone).1HNMR(CDCl3\ 400 MHz) : = 2.46 ( s, 6H, 2 COCH3), 3.0 ( s,3H, CH3,

pyrimidine ), 7.51-7.53 ( m, 3H, Ar-H ), 8.57-8.60 ( m, 2H, Ar-H) .

16

IR: υ = 3450, 3350 cm-1( NH) and 1620 cm-1 ( C=O ).1HNMR( DMSO-d6\90 MHz): = 2.3, 2.5 (a double singlet , 6H, 2CH3, pyrazole)

2.9 (s, 3H, CH3, pyrimidine), 6.2 ( s, 1H, CH, pyrazole), 7.3 ( s, 2H, NH2), 7.4-

7.6 ( m, 3H, Ar-H ) and 8.4-8.4-8.6 ( m, 2H, Ar-H ) .

17 IR: υ = 1700 cm-1 ( C=O ).1HNMR(CDCl3\ 400 MHz) : = 1.20 ( t, 3H, CH3 ester ), 2.81 ( s,3H, CH3,

pyrimidine ), 4.28 (q, 2H, ester) , 6.40 ( m, 2H, pyrrolyl ) , 6.75 ( m. 2H, pyrrolyl ),

7.4-7.6 ( m, 3H, Ar-H ), 8.48-8.54 ( m, 2H, Ar-H) .

MS : m/z M = 347 (85%) , 328(82%) and 300 (100%).


- 147 -

18

IR: υ = 3450 , 3300 cm-1( NHNH2 ) and 1640 cm-1 ( C=O ) .1HNMR(CDCl3\ 400 MHz) : = 2.80 ( s,3H, CH3, pyrimidine ), 6.45 ( m, 2H,

pyrrolyl ), 6.6 ( br.s, 2H, NH2), 6.8 ( m. 2H, pyrrolyl ), 7.4-7.6 ( m, 3H, Ar-H ),

8.51-8.56 ( m, 2H, Ar-H), and 9.8 (br.s, 1H, NH) .

19 IR: υ = 1182 cm-1( C=S ) , MS : m/z M = 375 (100%).

20

1HNMR (Cf3COOD \ 90 MHz) : = 2.90 ( s,3H, SCH3 ), 3.0 ( s,3H, CH3 ,

pyrimidine ), 6.20 ( m, 2H, pyrrolyl ), 7.0 ( m. 2H, pyrrolyl ), 7.6-7.9 (m, 3H, Ar-

H) and 8.4-8.6 (m, 2H, Ar-H).

MS : m/z M = 389 (100%) , 215(38%) , 288 (53%).

21

1HNMR(CDCl3\ 400 MHz) : = 2.6 ( s,3H, CH3, pyrimidine ),3.85 (d, 4H.2,6-H,

morpholinyl ), 6.78 ( m, 2H, pyrrolyl ), 7.0 ( m. 2H, pyrrolyl ), 7.4-7.7 ( m, 3H,

Ar-H ) and 8.4 -8.6 ( m, 2H, Ar-H).

22 1HNMR(CDCl3\ 400 MHz) : = 2.01-1.98 (m, 2H, 3-H of quinolizinyl), 2.24 (s,

3H, CH3, pyrimidine), 2.81 (t, 2H, J = 1.28 Hz, 4H of quinolizinyl), 3.72 (t, 2H, J=

1.25 Hz, 2-H of quinolizinyl), 6.45 ( m, 2H, 3,4-H of pyrrolyl), 6.84 (m, 2H, 2,5-H

of pyrrolyl), 7.01-6.98 (m, 1H, 6-H of quinolizinyl), 7.08 (d , 1H, 5-H of

quinolizinyl), 7.19-7.16 (m, 1H, 7-H of quinolizinyl), 7.41-7.55 ( m, 3H, Ar-H )

,7.64 (d, 1H, J= 1.0 Hz, 8-H of quinolizinyl), and 8.4-8.6 ( m, 2H, Ar-H).

MS : m/z M = 474 (100%) , 422(5%) , 389 (44%), 342(18%) , 315 (41%)

,299(12%) , 286 (60%), 117(78%) .

REFERENCES[1] Sambaverkar, P. P., Aitawade, M. M., Kolekar, G. B., Deshmuka, M. B. and Anbhnle,

P. V. " Uncatalized Synthesis of furo[2,3-d]pyrimidine -2,4-(1H,3H)-diones in waterand their anti-microbial activity ″. Indian Journal of Chemistry. (2014), 53B, p.p.1454.

[2] Xin , Zhang et al "Synthesis and biological evalution of Conformationally restricted 4-substituted -2,6-dimethylfuro[2,3-d]pyrtimidine as multitargeted receptor tyrosinekinase and microtubule inhibitors as potential antitumor agents ″ Biorg. Med. Chem.(2015), 23, pp 2408.


- 148 -

[3] Devambatla R. K. et al "Design, Synthesis preclinical evaluation of 4-substituted -5-methylfuro[2,3-d]pyrimidines as microtubule targeting agent that are effective againstmultidrug resistant cancer cells ″ J. Med. Chem. (2016) doi : 1021/acs. Jmedchem.6b00237.

[4] Gangjee, A., Yu, J., Mcguire, J. J., Cody, V., C., Galitsky, N., Kisliuk, R. L. andQueener, S. F. 2000 "Design, Synthesis and X-ray Crystal Structure of an Potent DualInhibitors of Thymidylate Synthase and Dihydrofolate Reductase as an AntitumorAgent″ J. Med. Chem. (2000), 43(21) , p.p. 3837-3851.

[5] Rochdi, A., Taourirte, M., Lazrek, H. B., BarascutJ. L. and Imbach, J. L. "Synthesis ofNew Bis-Alkylated Phosphono Alkenyl Acylonucleosides : (Z) and (E)-Diethyl –2-(3-alkyl Pyrimidin-1-Yl Phosphonate. ″ Molecules., (2000), 3(5) p.p. 1139-1145.

[6] Goebel, R. J., Adams, A. D., McKernan, P. A., Murray, B. K.,Robins, R. K., Revankar,G. R. and Canonico, P. G. "Synthesis and Antiviral Activity of CertainCarbamoylpyrrolopyrimidine and Pyrazolopyrimidine Nucleosides″ J. Med. Chem.(1982), 25(11), p.p. 1334-1338.

[7] Marwa, A. Aziz, Rabah, A. T. Serya. Deena, S. Lasheen and Kahled, A. Abouzid. "furo[2,3-d]pyrimidine based derivatives as kinase inhibitors and anticancer agents.″future J. pharm. Sci. (2016), 2, pp 1-8. ( http// dx.doi.org/10.1016/j.fips2015 ) .

[8] Rakesh S. and Anuja C. "An over view of biological importance of pyrimidines ″World J. pharm. Pharm. Sci. (2014) 3 , (12), P.p.574-597 .

[9] Kamal El-Dean, Adel M. "Synthesis of Some Pyrimidothienopyrimidine Derivatives″Monatshefte für Chemie, 129, Faculty of Science, Assiut University, Egypt, (1998)523-533.

[10] Mussa S. M. "Synthesis of Some New Fused Pyrimidothienopyrimidines Derivatives″Al-Satil, Jouranal, Misurata University, 2007, 1, pp 53.

[11] Mussa S. M, Salem El-T. Ashoor and Lamia A. Albahi "Synthesis and ComputionalStudies of Some Pyrimido[4\,5\:4,5] thieno[2,3-d]pyrimidine Compounds″ Ind. J. Het.Chem. 2016 , 25, (3&4) p.p. 251-261

[12] J. A. Joule and G. F. Smith, Heterocyclic Chemistry, Second edition (1978).[ 13] W. Mc Crae, Basic organic reactions book,. Translated by Dr. K. M. Dwod (1984) .[14 ] Peter Sykes , A guide book to mechanism in organic chemistry . Fourth edition.

Documents

; 4,5 ]FURO[2,3- D][PYRIMIDINES] · Journal of Humanities and Applied Science (J HAS) Issue No. (2 9) December 2016-123 - 1. INTRDUCTION Literature survey has revealed the diversified