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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.
Studies on Pyrido furo pyrimidine derivatives28
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
Studies on Pyrido furo pyrimidine derivatives29
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.
Studies on Pyrido furo pyrimidine derivatives30
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
Studies on Pyrido furo pyrimidine derivatives31
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
Studies on Pyrido furo pyrimidine derivatives32
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
Studies on Pyrido furo pyrimidine derivatives33
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
Studies on Pyrido furo pyrimidine derivatives34
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.
Studies on Pyrido furo pyrimidine derivatives35
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
Studies on Pyrido furo pyrimidine derivatives36
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.
Studies on Pyrido furo pyrimidine derivatives37
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.
Studies on Pyrido furo pyrimidine derivatives38
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
Studies on Pyrido furo pyrimidine derivatives39
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.
Studies on Pyrido furo pyrimidine derivatives40
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),
Studies on Pyrido furo pyrimidine derivatives41
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.
Studies on Pyrido furo pyrimidine derivatives42
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
Studies on Pyrido furo pyrimidine derivatives43
1H-NMR spectrum of compound 6b: There are total 18 protons with eight different
types of protons in the structure. The proton of –OH group appeared around 9.58 ppm as
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.
Table-2.2 Assignment of the 1H-NMR chemical shifts to the different protons of
compound 6b is given here.
Sr.No.
Chemical shift Multiplicity Proton assignment No. of protons
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
Studies on Pyrido furo pyrimidine derivatives44
1H-NMR spectrum of compound 6c: There are total 18 protons with nine different
types of protons in the structure. The proton of –OH group appeared around 9.47 ppm as
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.
Table-2.3 Assignment of the 1H-NMR chemical shifts to the different protons of
compound 6c is given here.
Sr.No.
Chemical shift Multiplicity Proton assignment No. of protons
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
Studies on Pyrido furo pyrimidine derivatives45
1H-NMR spectrum of compound 6d: There are total 13 protons with nine different
types of protons in the structure. The proton of –OH group appeared around 9.64 ppm as
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.
Table-2.4 Assignment of the 1H-NMR chemical shifts to the different protons of
compound 6d is given here.
Sr.No.
Chemical shift Multiplicity Proton assignment No. of protons
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
Studies on Pyrido furo pyrimidine derivatives46
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.
Table-2.5 Assignment of the 1H-NMR chemical shifts to the different protons of
compound 6e is given here.
Sr.No.
Chemical shift Multiplicity Proton assignment No. of protons
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
Studies on Pyrido furo pyrimidine derivatives47
1H-NMR spectrum of compound 6f: There are total 16 protons with eight different
types of protons in the structure. The proton of –OH group appeared around 9.58 ppm as
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.
Figure-2.6 1H-NMR of the compound 1-[2-(3-hydroxyphenyl)pyrido[3’,2’:4,5]furo[3,2-
d] pyrimidin-4-yl]piperidin- 4-one (6f) is shown here.
Table-2.6 Assignment of the 1H-NMR chemical shifts to the different protons of
compound 6f is given here.
Sr.No.
Chemical shift Multiplicity Proton assignment No. of protons
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
Studies on Pyrido furo pyrimidine derivatives48
1H-NMR spectrum of compound 6g: There are total 16 protons with eight different
types of protons in the structure. The proton of –OH group appeared around 9.50 ppm as
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.
Table-2.7 Assignment of the 1H-NMR chemical shifts to the different protons of
compound 6g is given here.
Sr.No.
Chemical shift Multiplicity Proton assignment No. of protons
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
Studies on Pyrido furo pyrimidine derivatives49
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
Studies on Pyrido furo pyrimidine derivatives50
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.
Figure-2.9 1H-NMR of the compound 4-[2-(3-hydroxyphenyl)pyrido[3’,2’:4,5]furo[3,2-
d] pyrimidin-4-yl]piperazin- 2-one (6h) is shown here.
Table-2.9 Assignment of the 1H-NMR chemical shifts to the different protons of
compound 6h is given here.
Sr.No.
Chemical shift Multiplicity Proton assignment No. of protons
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
Studies on Pyrido furo pyrimidine derivatives51
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.
Table-2.10 Assignment of the 1H-NMR chemical shifts to the different protons of
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
Studies on Pyrido furo pyrimidine derivatives52
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