6.1 Introduction - INFLIBNETshodhganga.inflibnet.ac.in/bitstream/10603/20742/14/13... · 2018. 7. 9. · nucleosides and nucleotides were subject of extensive research and their

Synthesis of purine derivatives containing coumarin scaffold Chapter 6

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6.1 Introduction

Purine was named by the German chemist Emil Fischer in 1884. He

synthesized it in 1898. Fischer showed that purines were part of a single

chemical family.1 The adenine and guanine are the two important derivatives of

purine moiety comprising nucleic acids and the structures are given below.

Purine Adenine Guanine

The quantity of naturally occurring purines produced on earth is huge.

Fifty percent of the bases in nucleic acids, adenine and guanine are purine

derivatives. In DNA, these bases form hydrogen bonds with their pyridines

thymine and cytosine, respectively. This is called as complementary base

pairing of molecules. In RNA, the complement of adenine is uracil instead of

thymine2. Other notable purine derivatives are hypoxanthine, xanthine,

theobromine, caffeine, uric acid, and isoguanine and are given below.

Xanthine Hypoxanthine Theobromine

HN

NH

NH

HN

O

OO

Caffeine Uric acid Isoguanine


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Purine derivatives play a crucial role in the most of biological processes.

Purine bases are constituents of nucleic acids as two letters of genetic alphabet

forming Watson-Crick pairs with complementary pyrimidine bases. Number of

enzymes of nucleotide and/or nucleic acids metabolism use purine bases,

nucleosides and nucleotides as substrates. Furthermore, purines are also

constituents of several cofactors (e.g. NADH, FAD, AcetylCoA, SAM, ATP

etc.) used by many important classes of enzymes (oxidoreductases,

transferases, ligases etc.). Therefore, most enzymes of nucleic acid metabolism

and enzymes using nucleotide cofactors contain a purine (usually adenine)

binding site. Moreover, purines and Purine nucleosides and nucleotides

participate in the signal transduction and regulation of many biological

processes in cells and tissues as ligands of receptors (purinoceptors, adenosine

receptors) and as second messengers (c-AMP). Therefore, purine bases,

nucleosides and nucleotides were subject of extensive research and their

structural modifications lead to discovery of thousands of biologically active

compounds including many clinically used drugs. Furthermore, many modified

purine derivatives were used in chemical biology for the study and modulation

of biological processes at molecular level.3

Purine is a heterocyclic aromatic organic compound, consisting of a

pyrimidine ring fused to an imidazole ring. Purine derivatives are included

substituted purine and its tautomers, which are of most widely distributed a

kind of nitrogen-containing heterocyclic compounds present in nature. Purines

and pyrimidines make up the two groups of nitrogen bases, including the two


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group of nitrogen bases. More broadly, the general term purine is also used in

reference to derived, substituted purines and their structurally related tautomers

i.e., organic compounds that are inter-convertible by a chemical reaction.4

Purines are also found in high concentration in meat and meat products,

especially in internal organs such as liver and kidney. Plants based diets are

generally low in purines. An example of high source purine includes

sweetbreads, brain, beef kidneys, liver, meat extracts, herring, mackerel,

scallops etc. A moderate amount of purine is also present in poultry, fish, sea

food, asparagus, cauliflower, spinach, green peas, wheat bran, dried peas, oat

meal, wheat germ and hawthorn.5

They are of great importance to chemists as they have been found in a

large variety of naturally occurring compounds and also in clinically useful

molecules having diverse biological activities.6 Purine bases modified in the 6-

position and their derivatives and analogues possess a wide range of biological

properties such as antitubercular, fungicidal, antiallergic, antimicrobial,

antitumor, antihistamic, myocardium inhibiting agent, etc.7-14

Xanthine (3,7-dihydro-purine-2,6-dione) is a purine base found in most

human body tissues and fluids. There are three main xanthine derivatives i.e.,

caffine, theophyline and theobromine. Theophyline is used as a bronchodilator

in astamatic disease treatment, but it has strong stimulant effect to the central

nervous system (CNS). Theobromine is one of the xanthine derivatives that has

a weak stimulant effect to the CNS, but still has bronchodilatation activity

although not as strong as theophyline.15


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The poly-substituted xanthines, collectively known as xanthenes, are a

group of alkaloids commonly used for their effects as mild stimulants and as

bronchodilators, notably in treating the symptoms of asthma. Active

compounds of the xanthines type at the level of the central nervous,16,17 of the

cardio–vascular18,19 and the broncho–pulmonary systems20 are known.

Recently, actions of xanthenes were evidenced at the level of the endocrine

glands, the reproduction apparatus or at the gastro–intestinal tract.21 The

pharmacological activity of xanthene derivatives depends on both the

substitution site and the chemical structure of the substituent. Thus, substitution

at the 8-position of the purine ring has shown to dramatically increase the

binding affinity to the human adenosine receptors subtypes.22,23 The 1,3-

substituted xanthines are used as stimulants, phosphodiesterase inhibitors,24 as

anti-asthmatic drugs25 or adenosine receptors antagonists.26 One of the most

prominent members of this class is theophylline (1,3-dimethylxanthine) whose

bronchodilator action has been used in treating the acute and chronic

asthma25,26 and the vascular diseases27 and it behaves as a very efficient

immunomodulatory28 and anti-inflammatory drug.29 However, there are

adverse effects associated with theophylline’s use, such as tachycardia,

agitation and occasionally seizures,30 as well as the central nervous system

stimulation and gastric acid hyper secretion.31

On the other hand, coumarin derivatives have also been reported to

possess a significant range of biological properties such as antitumor,32 anti-

inflammatory,33 antibacterial,34 antioxidant,35 analgesic,36 antimutagenic, anti-


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HIV37 and mild adrenergic38 activities. 3-Pyridyl coumarins have been reported

to function as CNS depressant,39 antimicrobial agents,40 fish toxin and

bactericidal agents41 So far, some coumarins, e.g., warfarin, acenocoumarol,

armillarisin A, hymecromone, and carbochromene have been approved for

therapeutic purpose in clinic. More importantly, an increasing number of

coumarin compounds have displayed great potency in the treatment of various

types of diseases.42-46

Despite of numerous attempts in search for more effective drugs,

coumarin still remains as one of the most versatile class of compound and are

an important component among the molecules in drug discovery. Most of

hybrid molecules have been reported where both coumarin and purine moieties

were attached as shown in Figure 1(A, B).47,48 Still, rare examples are known

for coumarin–purine hybrids.

(A) (B)

Figure–1. Chemical Structure of Coumarin-purine hybrids known in the literature.

Based on all above, it was planned for finding novel, efficient lead

compounds with potent biological activity, the design of xanthine–coumarin

hybrids of 3,7-dimethyl-1H-purine-2,6(3H,7H)-dione with substituted 4-

(bromomethyl)-2H-chromen-2-one and X-ray crystal structure is carried out in

this research work.

N

NNH

N

S

OO


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6.2 Methods for the synthesis of Purine and coumarin derivatives

K. Lin49 and others have reported synthesized a series of xanthine

derivatives in which a methylene was inserted at position 8 of xanthine

scaffold.

A. Drabczynska50 and others have reported N-cycloalkyl-substituted

imidazo-, pyrimido- and 1,3-diazepino[2,1-f]purinediones. These derivatives

were synthesized by cyclization of 7-halogenoalkyl-8-bromo-1,3-

dimethylxanthine derivatives with aminocycloalkanes.


184

A. Zagorska51 and others have reported synthesis of 1,3-dimethyl-

(1H,8H)-imidazo[2,1-f]purine-2,4-dione and amide derivatives of 1,3-

dimethyl-6,7-dihydroimidazo[2,1-f]purine-2,4-(1H,3H)-dione-7-carboxylic

acid.

M.A. Zajac52 and others have reported an inexpensive and novel method

of caffeine synthesis starting from uracil in six simple steps is described. Uracil

1 is first converted to I, 3-dimethyluracil 2, followed by nitration, reduction,

and cyclization to theophylline and finally methylation of theophylline forms

caffeine.

J.C. Burbiel53 and others have reported the application of microwaves in

the syntheses of the 8-styrylxanthine derivative istradefylline and in the

preparation of 2-substituted pyrimido [1,2,3-cd]purines.


185

Y.L. Hu54 and others have reported synthesized a series of 6-substituted

purines from commercially available 2-amino-6-chloropurine with appropriate

reagents, and nine new compounds have been discovered.

E. Y. Sutcliffe55 and R. K. Robins have reported the synthesis of 2,6,8-

trichloro-9-(tetrahydro-2-pyranyl)purine by the reaction of 2,6,8-trichloro

purine with 2,3-dihydropyran in ethyl acetate in the presence of p-

toluenesulfonic acid.

M.A. Carvalho56 and others have reported two different approaches for

the synthesis of 6-enaminopurines from 5-amino-4-

cyanoformimidoylimidazoles.


186

N. Kode57 and others have reported a series of ortho-, meta- and para-

bis-N9-(methylphenylmethyl)purine derivatives 4-15 were obtained by two-

step synthesis from various substituted chloropurines with dichloroxylenes.

Jalal Albadi58 and others have reported synthesis of coumarin

derivatives by the Pechmann reaction using Poly(4-vinylpyridine)-supported

copper iodide as a green, efficient and recyclable catalyst for the under solvent-

free conditions.


187

O

C2H5O

H3C NH2

CN

RO

+OO

HOOC PFPATSolvent-free

80oCO

C2H5O

H3C

RO

N

O

OO

A.T. Khan59 and others have reported synthesis of substituted

pyrido[2,3-c] coumarin derivatives from 3-aminocoumarins, aromatic

aldehydes, and alkynes in the presence of 10 mol % molecular iodine in

acetonitrile through one-pot Povarov reactions.

L.C.C. Vieira60 and others have reported synthesis of coumarin

derivatives was successfully accomplished via Suzuki coupling by using PEG-

400 as a solvent under microwave irradiation.

M. Ghashang61 and others have reported a new, simple thermally

efficient and solvent-free condensation of 2-amino-3-cyano-6-methyl-4-

phenyl-4H-pyran-5-ethylcarboxylate derivatives with coumarin-3-carboxylic

acid using pentafluorophenylammonium triflate as an organocatalyst to give

coumarin derivatives.


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6.3 Biologically active Purine and coumarin derivatives

Purines and condensed derivatives of purines have received much

attention over the years for their interesting pharmacological properties as

antineoplastic,62 antileukemic,63 anti-HIV-1,64 antiviral65 and antimicrobial66

agents. A brief review of the literature available on the chemical structure of

purine and derivatives of purines, the biological activity are given below-

A. Drabczynska50 and others have reported N-cycloalkyl-substituted

imidazo-, pyrimido- and 1,3-diazepino[2,1-f]purinediones. Most of them

showed anticonvulsant activity in chemically induced seizures; among them

compounds (1) and (2) showed best protection in both tests on short time

symptoms, without signs of neurotoxicity.

(1) (2)

F.A. Ashour67 and others have reported some new triazino and

triazolo[4,3-e]purine derivatives. Compounds (3) and (4) displayed improved

antineoplastic, anti-HIV-1 and antimicrobial activities.

(3) (4)


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R. Thomas68 and others have reported the design, synthesis and

optimization of a new series of xanthine derivatives. Compound (5) displays

adenosine A2A receptor antagonists.

(5)

M. Krecmerova69 and others have reported synthesis of purine N9-[2-

hydroxy-3-o-phosphono methoxy)propyl] derivatives and their side-chain

modified analogs. Compound (6) displayed potential antimalarial activity.

(6)

R = NO2

F.G. Braga70 and others have reported synthesis and in-vitro

antileishmanial evaluation of a series of 6-substituted purines. Most of the

purine derivatives showed good to moderate antileishmanial activity and

compounds (7) and (8) were most active against Leishmania amazonensis.

(7) (8)


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Maruti71 and others have synthesized N-9substituted 6-chloropurine

derivatives and evaluated these compounds for their cytotoxic activities against

Hep-2 cell lines by SRBS assay. Some of the tested compounds showed

moderate anticancer activity and compounds (9) showed potent activity.

(9)

S. Abdel-Sattar72 and others have reported a series of novel purine and

pyrimidine derivatives and evaluated for their in vitro anti-CDK2/cyclin A3

and antitumor activities in Ehrlich ascites carcinoma (EAC) cell based assay.

The novel purine derivatives (10) and (11) demonstrated potent inhibitor

activities with IC50 values of 14 ± 9 and 13 ± 9 lM, respectively.

(10) (11)

R.A. Hartz73 and others have reported a series of novel purine-dione

derivatives was synthesized and evaluated as factor-1 (CRF1) receptor

antagonists. Compounds within this series, represented by compounds (12),

(13) and (14) were found to be highly potent CRF1 receptor antagonists.


191

N

N N

NN

N

N

N

N

N

N

N

N

N

N

NHO

Cl

Cl

O

(12) (13) (14)

V. Mik74 and others have reported a series of N6-[(3-methylbut-2-en-1-

yl)amino]purine derivatives Biological activity of prepared compounds (15)

and (16) was assessed in three in vitro cytokinin bioassays. The majority of

derivatives were significantly active in both Amaranthus as well as in tobacco

callus bioassay and almost inactive in detached wheat leaf senescence assay.

(15) (16)

N. Kode75 and others have reported a series of bis-N9-

(methylphenylmethyl)purine derivatives and evaluated for the primary

cytotoxic activity against cancer cell lines. In particular, compounds exhibited

high sensitivity in leukemia cell lines, while other compounds (17) and (18)

exhibited consistent high sensitivity in many breast cancer cell lines.

(17) (18)


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J. Mitkov76 and others have reported reported some aliphatic and

arylaliphatic amides of caffeine-8-thioglycolic acid and compound (19)

exhibited brain antihypoxic activity against haemic and circulatory hypoxia,

respectively.

(19)

Xiao-Qin Wu77 and others have reported synthesis a series of coumarin-

dihydropyrazole thio-ethanone derivatives and screened for anticancer activity.

Compound (20) suppress cell proliferation through inducing cell showed potent

activity

(20)

K. Paul78 and others have reported synthesis of novel coumarin–

benzimidazole hybrids, were screened for in vitro antitumor activity.

Compound (21) displayed appreciable anticancer activities against leukemia,

colon cancer and breast cancer cell lines.

(21)


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W. Shen79 and others have reported synthesis of resveratrol–coumarin

hybrid compounds and were evaluated for their antitumor activities. Among

them, compounds (22) and (23) showed varying degrees of growth inhibition

on cell lines.

O O

OCH3

H3CO

OCH3

(22) (23)

Y. Shi80 and C.H. Zhou have reported a series of new coumarin-based

1,2,4-triazole derivatives and evaluated for their antimicrobial activity/

Compounds (24) and (25) exhibited stronger antibacterial and antifungal

efficiency

B. Sandhya81 and others have reported synthesis of coumarin derivatives

and tested the target compound for its analgesic, anti-inflammatory,

antimicrobial activities. Compound () showed significant anti-inflammatory,

analgesic and antimicrobial activities.


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6.4 Present work

HN

N N

N

O

Br

O

O O

N N

O

O NN

O

O

+R

R

Activated K2CO3

Dry Ethanol

Where R= a) 6-CH3, b) 6-Cl, c) 6-OCH3, d) 5,6-Benzo, e) 7-CH3,

f) 7-Cl, g) 7-OCH3, h) 7,8-Benzo, i) 5,7-CH3 ; and j) 7,8-CH3

In the present study, it has been explored the possibility of synthesizing

purine derivatives (Scheme-5) containing coumarin moiety, which involves

reaction between substituted 4-(bromomethyl)-2H-chromen-2-one and 3,7-

dimethyl-1H-purine-2,6(3H,7H)-dione in ethanol using K2CO3 to facilitate the

synthesis of drugs from commercially available building blocks. All the

reactions involved are highly efficient to give the desired compounds in high

yield and high purity. And also, this adopted procedure is simple and eco-

friendly due to easy experimental procedures. The versatility of this

methodology can be extended to develop a stream-lined approach to other

drugs.

Scheme – 5.

In summary, it is developed and reported that a series of novel purine

derivatives have been synthesized in the presence activated K2CO3 using

ethanol as a solvent. The product is obtained in excellent yield with high purity

after simple filtration. This method developed is very simple, environmental

friendly and easy to work-up which makes this as a valid contribution to the

existing protocols.


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6.5 Experimental procedure

6.6 Results and discussion

A series of novel coumarin–purine derivatives (5a-5j) were synthesized

by stirring the reaction mixture of 3,7-dimethyl-1H-purine-2,6(3H,7H)-dione

(0.01mol) and powdered anhydrous K2CO3 (0.03mol) with various 4-

bromomethyl coumarins (0.01mol) in absolute ethanol (10ml) at room

temperature. After completion of reaction, the reaction mixture was quenched

in crushed ice; the solid product was filtered and given water wash. Lastly the

product was recrystallized from ethanol.

The synthesis was started from 4-(bromomethyl)-2H-chromen-2-ones,

which is a very important intermediate in the synthesis of 3,7-dimethyl-1-{(2-

oxo-2H-chromen-4-yl)methyl}-1H-purine-2,6(3H,7H)-dione derivatives.

Synthesis of various 4-(bromomethyl)-2H-chromen-2-ones82 was brought about

by the Pechman cyclization of substituted phenols with 4-

bromoethylacetoacetate. The resulting 4-(bromomethyl)-2H-chromen-2-ones

was treated with 3,7-dimethyl-1H-purine-2,6(3H,7H)-dione using activated

K2CO3 in absolute alcohol at room temperature to give 3,7-dimethyl-1-{(2-oxo-

2H-chromen-4-yl)methyl}-1H-purine-2,6(3H,7H)-dione derivatives in good

yields. A notable feature of this procedure is the straightforward product

isolation without formation of any side-products. The results shown in Table-1

clearly indicate the scope and generality of the reaction with respect to various

4-(bromomethyl)-2H-chromen-2-ones.


196

Table – 1. Synthesis of xanthine-coumarin derivatives

Entry

Product Time in hrs a

Yield (%)b

Melting point

5a

4

76

195–166oC

5b

2

91

179–181oC

5c

3

75

204–205oC

5d

4

80

218–219oC

5e

4

72

186–188oC

5f

2

93

182–184oC

5g

4

78

211–212oC

5h

3

75

215–217oC

5i

4

68

233–235oC

5j

4

65

226–227oC

a Time to finish the reaction monitored by TLC. bYield refer to isolated products.


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6.7 X-ray Crystal Studies

The structure of newly synthesized compounds was elucidated by

spectroscopic measurements (IR, Mass, 1H NMR, 13C NMR, and Mass). Thin

layer chromatography (TLC) was used throughout to optimize the reaction for

purity and completion along with physical and elemental analyses data for

titled compounds. The IR spectra of these compounds exhibited an absorption

at about 2800-3070 cm-1, characteristic of the CH stretching mode, in addition

to a strong absorption around 1600-1700 cm-1 assigned to the C=O stretching

of xanthine and coumarin moiety. The 1H-NMR and 13C-NMR spectra were

consistent with the assigned structures and the assignment of the remaining

carbon and proton signals in each case were straightforward. Mass Spectra

showed accurate molecular ion peak with respect to the targeted compounds.

Single crystal X-ray studies of compound 5a provided a conclusive evidence

for the assigned structures (Figure-2). Compound (5a) 3,7-dimethyl-1-[(6-

methyl-2-oxo-2H-chromen-4-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione was

purified by recrystallization. The chemical structure was confirmed on the basis

of its NMR (1H, 13C) spectroscopic data, as well as mass spectrometry, and the

crystal structure was determined by single-crystal X-ray diffraction.

Specifically, presence of a xanthine linking the coumarin moiety in Scheme-1.

X – Ray Crystallographic Structure Analysis of 3,7-dimethyl-1-[(6-methyl-2-oxo-2H-chromen-4-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione

Crystals of 3,7-dimethyl-1-[(6-methyl-2-oxo-2H-chromen-4-yl)methyl]-

3,7-dihydro-1H-purine-2,6-dione was crystallized using dry DMF (solvent) by

slow evaporation at room temperature and crystalline state is characterized by a


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long range, well defined three dimensional orders. The asymmetric unit

contains only on independent molecule is depicted in Figure-3. The 2 H-

chromene ring systems is nearly planar, with a maximum deviation of

0.01964(25) Å for atom C12. The dihedral angle between the 2H-chromene

ring and the purine ring is 79.35(9)°. Bond lengths and angles are within the

normal ranges. The crystal structure contains weak intramolecular C---H...N

and C---H...O and intermolecularC---H…O hydrogen bonds.

Table-2, 3, 4 and 5 presents crystallographic data and X-ray structure

parameters. Measurements were made using Bruker SMART CCD area-

detector diffractometer with monochromatic Mo Kα radiation at room

temperature. The crystalline state of a crystal is characterized by a long range,

well defined three dimensional orders.

Data collection: SMART (Bruker, 2001) [R]; cell refinement: SAINT

(Bruker, 2001)[R]; data reduction: SAINT[R]; program(s) used to solve

structure: SHELXS97 [R]; molecular graphics: ORTEP-3 [R]; software used to

prepare material for publication: SHELXL97[R]. E-map provided positions for

all non H-atoms. The full-matrix least-squares refinement was carried out on F2

using anisotropic temperature factors for all non H-atoms. The H-atoms were

located from DF-maps, and then their positions were refined using a riding

model with isotropic thermal parameters taken as 1.2and 1.5 times temperature

factors for their parent-atoms. The ORTEPs of these isomers were obtained by

the PLATON [R] program. Coordinates were deposited in the Cambridge

Crystallographic Data Centre vide no. CCDC-964289


199

Figure-2. Ortep diagram of compound (5a) 3,7-dimethyl-1-[(6-methyl-2-oxo-2H-chromen-4-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione

Figure-3. Packing diagram of compound (5a) 3,7-dimethyl-1-[(6-methyl-2-oxo-2H-chromen-4-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione


200

Table – 2. Crystal data and structure refinement for compound 5a.

Empirical formula C18 H16 N4 O4 Formula weight 352.35 Temperature 296(2) K Wavelength 0.71073 A Crystal system, space group Triclinic P-1 Unit cell dimensions a = 7.8995(4) A b = 9.1925(5) A c = 12.0821(7) A α = 99.622(3)°, β= 93.284(4) °

γ = 108.126(3)° Volume 816.48(8) Å 3 Z 2 Calculated density 1.433mg/m3 Crystal size 0.22 × 0.15 × 0.12 mm Absorption coefficient 0.104 mm-1 F(000) 368 Crystal form Prism, pale yellow Radiation source fine-focus sealed tube Radiation type Mo Kα Radiation monochromator graphite Criterion for observed reflection I > 2σ(I) Data collection Diffractometer Bruker SMART CCD area-detector Data collection method ω- χ scans Absorption correction multi-scan Theta range for data collection 2.38 to 25.00° Limiting indices -9<=h<=9, -10<=k<=10, -14<=l<=14 Reflections collected / unique 10906 / 2853 [R(int) = 0.0224] Completeness to theta 99.2 % Max. and min. transmission Tmax = 1.000, Tmin = 0.790 Refinement Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 2853 / 0 / 235 Goodness-of-fit on F2 1.052 Final R indices [I>2σ(I)] R1 = 0.0609, wR2 = 0.1803 R indices (all data) R1 = 0.0758, wR2 = 0.1894 Weighting scheme

Where (Δ/σ)max < 0.001 Largest diff. peak and hole 0.550 and -0.211 e. Ǻ-3


201

Table–3. Atomic coordinates (x 10^4) and equivalent isotropic displacement parameters (A^2 x 10^3) for compound 5a. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ______________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ O(1) 12320(2) 11297(2) 3843(2) 54(1) O(2) 13516(3) 9809(3) 2760(2) 71(1) O(3) 7640(3) 8917(3) 219(2) 72(1) O(4) 6314(3) 5402(2) 2569(2) 67(1) N(5) 7049(3) 7161(2) 1392(2) 49(1) N(6) 7754(3) 6508(3) -464(2) 61(1) N(7) 6915(4) 3097(3) 605(2) 62(1) N(8) 7754(4) 3849(3) -1006(3) 72(1) C(9) 6471(5) 12937(4) 5472(3) 80(1) C(10) 7996(4) 12479(3) 5017(2) 55(1) C(11) 7697(4) 11200(3) 4153(2) 49(1) C(12) 9107(3) 10754(3) 3729(2) 41(1) C(13) 10838(3) 11645(3) 4205(2) 44(1) C(14) 11180(4) 12921(3) 5063(2) 56(1) C(15) 9755(4) 13320(3) 5463(3) 59(1) C(16) 8892(3) 9407(3) 2845(2) 44(1) C(17) 10365(3) 9075(3) 2551(2) 49(1) C(18) 12147(4) 10026(3) 3031(2) 51(1) C(19) 7026(4) 8408(3) 2312(3) 53(1) C(20) 6740(3) 5672(3) 1651(2) 48(1) C(21) 7003(4) 4622(3) 720(3) 53(1) C(22) 7518(4) 5050(4) -265(3) 55(1) C(23) 7486(4) 7616(4) 364(2) 54(1) C(24) 7354(5) 2709(4) -447(3) 73(1) C(25) 6420(6) 2128(4) 1433(3) 81(1) C(26) 8285(6) 6917(5) -1576(3) 84(1) ________________________________________________________________ Table–4. Bond lengths [A] and angles [deg] for compound 5a. _____________________________________________________________ O(1)-C(18) 1.359(3) O(1)-C(13) 1.382(3) O(2)-C(18) 1.212(3) O(3)-C(23) 1.207(4) O(4)-C(20) 1.220(3) N(5)-C(23) 1.405(4) N(5)-C(20) 1.405(4) N(5)-C(19) 1.463(3) N(6)-C(22) 1.359(4) N(6)-C(23) 1.378(4) N(6)-C(26) 1.502(4) N(7)-C(24) 1.356(4) N(7)-C(21) 1.365(4)


202

N(7)-C(25) 1.439(4) N(8)-C(24) 1.308(5) N(8)-C(22) 1.368(4) C(9)-C(10) 1.498(4) C(9)-H(9A) 0.9600 C(9)-H(9B) 0.9600 C(9)-H(9C) 0.9600 C(10)-C(11) 1.384(4) C(10)-C(15) 1.387(4) C(11)-C(12) 1.397(4) C(11)-H(11) 0.9300 C(12)-C(13) 1.388(4) C(12)-C(16) 1.452(4) C(13)-C(14) 1.374(4) C(14)-C(15) 1.377(4) C(14)-H(14) 0.9300 C(15)-H(15) 0.9300 C(16)-C(17) 1.344(4) C(16)-C(19) 1.511(4) C(17)-C(18) 1.433(4) C(17)-H(17) 0.9300 C(19)-H(19A) 0.9700 C(19)-H(19B) 0.9700 C(20)-C(21) 1.424(4) C(21)-C(22) 1.360(4) C(25)-H(25A) 0.9600 C(25)-H(25B) 0.9600 C(25)-H(25C) 0.9600 C(26)-H(26A) 0.9600 C(26)-H(26B) 0.9600 C(26)-H(26C) 0.9600 C(18)-O(1)-C(13) 121.5(2) C(23)-N(5)-C(20) 127.3(2) C(23)-N(5)-C(19) 115.7(2) C(20)-N(5)-C(19) 116.9(2) C(22)-N(6)-C(23) 119.3(3) C(22)-N(6)-C(26) 120.8(3) C(23)-N(6)-C(26) 119.9(3) C(24)-N(7)-C(21) 105.3(3) C(24)-N(7)-C(25) 128.4(3) C(21)-N(7)-C(25) 126.3(3) C(24)-N(8)-C(22) 102.6(3) C(10)-C(9)-H(9A) 109.5 C(10)-C(9)-H(9B) 109.5 H(9A)-C(9)-H(9B) 109.5 C(10)-C(9)-H(9C) 109.5 H(9A)-C(9)-H(9C) 109.5 H(9B)-C(9)-H(9C) 109.5 C(11)-C(10)-C(15) 118.1(3)


203

C(11)-C(10)-C(9) 121.3(3) C(15)-C(10)-C(9) 120.7(3) C(10)-C(11)-C(12) 121.8(3) C(10)-C(11)-H(11) 119.1 C(12)-C(11)-H(11) 119.1 C(13)-C(12)-C(11) 117.5(2) C(13)-C(12)-C(16) 117.7(2) C(11)-C(12)-C(16) 124.8(2) C(14)-C(13)-O(1) 116.1(2) C(14)-C(13)-C(12) 122.1(2) O(1)-C(13)-C(12) 121.8(2) C(13)-C(14)-C(15) 118.7(3) C(13)-C(14)-H(14) 120.6 C(15)-C(14)-H(14) 120.6 C(14)-C(15)-C(10) 121.8(3) C(14)-C(15)-H(15) 119.1 C(10)-C(15)-H(15) 119.1 C(17)-C(16)-C(12) 118.5(2) C(17)-C(16)-C(19) 122.4(2) C(12)-C(16)-C(19) 119.1(2) C(16)-C(17)-C(18) 123.2(3) C(16)-C(17)-H(17) 118.4 C(18)-C(17)-H(17) 118.4 O(2)-C(18)-O(1) 117.2(3) O(2)-C(18)-C(17) 125.5(3) O(1)-C(18)-C(17) 117.3(2) N(5)-C(19)-C(16) 112.2(2) N(5)-C(19)-H(19A) 109.2 C(16)-C(19)-H(19A) 109.2 N(5)-C(19)-H(19B) 109.2 C(16)-C(19)-H(19B) 109.2 H(19A)-C(19)-H(19B) 107.9 O(4)-C(20)-N(5) 121.4(2) O(4)-C(20)-C(21) 127.8(3) N(5)-C(20)-C(21) 110.7(3) C(22)-C(21)-N(7) 105.7(3) C(22)-C(21)-C(20) 123.3(3) N(7)-C(21)-C(20) 131.0(3) N(6)-C(22)-C(21) 122.7(3) N(6)-C(22)-N(8) 125.3(3) C(21)-C(22)-N(8) 112.0(3) O(3)-C(23)-N(6) 121.9(3) O(3)-C(23)-N(5) 121.6(3) N(6)-C(23)-N(5) 116.6(3) N(8)-C(24)-N(7) 114.5(3) N(7)-C(25)-H(25A) 109.5 N(7)-C(25)-H(25B) 109.5 H(25A)-C(25)-H(25B) 109.5 N(7)-C(25)-H(25C) 109.5 H(25A)-C(25)-H(25C) 109.5


204

H(25B)-C(25)-H(25C) 109.5 N(6)-C(26)-H(26A) 109.5 N(6)-C(26)-H(26B) 109.5 H(26A)-C(26)-H(26B) 109.5 N(6)-C(26)-H(26C) 109.5 H(26A)-C(26)-H(26C) 109.5 H(26B)-C(26)-H(26C) 109.5 _____________________________________________________________ Table -5. Anisotropic displacement parameters (A^2 x 10^3) for compound 5a. The anisotropic displacement factor exponent takes the form: -2 pi^2 [ h^2 a*^2 U11 + ... + 2 h k a* b* U12 ] ____________________________________________________________________ U11 U22 U33 U23 U13 U12 ____________________________________________________________________ O(1) 40(1) 58(1) 57(1) 1(1) 2(1) 11(1) O(2) 39(1) 85(2) 82(2) -5(1) 9(1) 20(1) O(3) 81(2) 54(1) 86(2) 18(1) 12(1) 24(1) O(4) 78(2) 58(1) 58(1) 1(1) 10(1) 17(1) N(5) 41(1) 41(1) 58(1) -4(1) 5(1) 11(1) N(6) 59(2) 61(2) 59(2) 9(1) 10(1) 17(1) N(7) 64(2) 50(2) 72(2) 10(1) 13(1) 20(1) N(8) 72(2) 61(2) 76(2) -13(2) 20(2) 21(1) C(9) 68(2) 74(2) 94(3) -10(2) 23(2) 26(2) C(10) 60(2) 50(2) 54(2) 3(1) 8(1) 20(1) C(11) 44(2) 45(2) 54(2) 5(1) 7(1) 12(1) C(12) 42(1) 39(1) 42(1) 9(1) 6(1) 12(1) C(13) 44(1) 47(2) 42(1) 10(1) 5(1) 15(1) C(14) 53(2) 53(2) 52(2) 0(1) -5(1) 11(1) C(15) 68(2) 51(2) 52(2) -3(1) 2(1) 18(1) C(16) 40(1) 41(1) 48(2) 8(1) 8(1) 11(1) C(17) 43(2) 47(2) 52(2) 2(1) 8(1) 13(1) C(18) 45(2) 54(2) 51(2) 7(1) 6(1) 15(1) C(19) 42(2) 44(2) 65(2) -6(1) 9(1) 12(1) C(20) 38(1) 50(2) 49(2) -1(1) 3(1) 10(1) C(21) 43(2) 41(2) 69(2) -2(1) 0(1) 13(1) C(22) 44(2) 60(2) 53(2) -1(1) 9(1) 10(1) C(23) 42(2) 59(2) 54(2) 2(1) 3(1) 12(1) C(24) 77(2) 66(2) 73(2) -5(2) 22(2) 26(2) C(25) 102(3) 67(2) 83(3) 24(2) 20(2) 34(2) C(26) 94(3) 88(3) 73(2) 27(2) 27(2) 23(2) _____________________________________________________________________


205

3,7-dimethyl-1-{(6-methyl-2-oxo-2H-chromen-4-yl)methyl}-1H-purine-2,6(3H,7H)-dione (5a) : Pale yellow powder; IR (KBr) (vmax/cm-1): 3052, 2966,

2924, 1709, 1661 cm-1; 1H NMR (300 MHz, DMSO) δ

ppm: 2.45 (s, 3H, Ar–CH3), 3.51 (s, 3H, N–CH3), 3.94

(s, 3H, N–CH3), 5.25 (s, 2H, CH2), 6.10 (s, 1H, Ar-H), 7.36 (d, 2H, Ar-H), 7.51

(d, 1H, Ar-H), 7.8 (s, 1H, Ar-H), 8.1 (s, 1H, Ar-H); 13C NMR (100 MHz,

CDCl3) δ ppm: 22.0, 31.2, 38.1, 51.3, 112.3, 117.7, 119.1, 120.47, 123.36,

125.4, 127.39, 128.43, 139.49, 149.1, 151.9, 158.74, 163.01, 169.27; LC-MS:

m/z 352 (M+). Anal. Calcd for C18H16N4O4: C, 61.36; H, 4.58; N, 15.90. Found:

C, 61.41; H, 4.67; N, 15.82.

1-{(6-chloro-2-oxo-2H-chromen-4-yl)methyl}-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione (5b) :

Orange powder; IR (KBr) (vmax/cm-1): 3029, 2928,

1715, 1635, cm-1; 1H NMR (300 MHz, DMSO) δ: 3.58

(s, 3H, N-CH3), 3.89 (s, 3H, N-CH3), 5.29 (s, 2H,

CH2), 5.95 (s, 1H, Ar-H), 7.46 (d, 1H, Ar-H), 7.65 (d,

1H, Ar-H), 7.85 (s, 1H, Ar-H) 8.09 (s, 1H, Ar-H); 13C NMR (100 MHz, CDCl3)

δ ppm: 32.5, 37.7, 50.9, 115.3, 118.9, 120.4, 123.4, 125.6, 126.2, 127.7, 129.1,

140.1, 148.9, 151.5, 157.6, 163.2, 169.7; LC-MS: m/z 372 (M). Anal. Calcd for

C17H13ClN4O4: C, 54.78; H, 3.52; N, 15.03. Found: C, 54.84; H, 4.71; N, 15.79.

O O

N N

O

O NN

O O

N N

O

O NN

Cl


206

1-{(6-methoxy-2-oxo-2H-chromen-4-yl)methyl}-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione (5c) :

Yellow powder; IR (KBr) (vmax/cm-1): 3035, 2925,

1708, 1641, cm-1; 1H NMR (300 MHz, DMSO) δ

ppm: 3.59 (s, 3H, N-CH3), 3.86 (s, 3H, N-CH3),

4.01 (s, 3H, O-CH3), 5.31 (s, 2H, CH2), 5.94 (s, 1H,

Ar-H), 7.41 (d, 1H, Ar-H), 7.56 (d, 1H, Ar-H), 7.82 (s, 2H, Ar-H), 8.02 (s, 1H,

Ar-H); LC-MS: m/z 368 (M). Anal. Calcd for C18H16N4O5: C, 58.69; H, 4.38;

N, 15.21. Found: C, 58.75; H, 4.29; N, 15.25.

3,7-dimethyl-1-{(3-oxo-3H-benzo[f]chromen-1-yl)methyl}-1H-purine-2,6(3H,7H)-dione (5d) :

Brown powder ; IR (KBr) (vmax/cm-1): 3047, 2922,

1710, 1645, cm-1; 1H NMR (300 MHz, DMSO) δ: 3.48

(s, 3H, N-CH3), 3.79 (s, 3H, N-CH3), 5.25 (s, 2H, CH2),

5.99 (s, 1H, Ar-H), 7.35 (d, 1H, Ar-H), 7.42 (d, 1H, Ar-

H), 7.48–7.92 (m, 4H, Ar-H), 8.05 (s, 1H, Ar-H); LC-MS: m/z 388 (M). Anal.

Calcd for C21H16N4O4: C, 64.94; H, 4.15; N, 14.43. Found: C, 69.87; H, 4.22;

N, 14.47.

O O

N N

O

O NN

H3CO

O O

N N

O

O NN


207

3,7-dimethyl-1-{(7-methyl-2-oxo-2H-chromen-4-yl)methyl}-1H-purine-2,6(3H,7H)-dione (5e) :

Yellow powder: m.p. 159–161oC; IR (KBr) (vmax/cm-1):

3065, 2923, 1714, 1635, cm-1; 1H NMR (300 MHz,

DMSO) δ ppm: 2.39 (s, 3H, Ar-CH3), 3.59 (s, 3H, N-

CH3), 3.92 (s, 3H, N-CH3), 5.31 (s, 2H, CH2), 5.94 (s,

1H, Ar-H), 7.36 (d, 1H, Ar-H), 7.55 (d, 1H, Ar-H), 7.72 (s, 1H, Ar-H), 8.1 (s,

1H, Ar-H); LC-MS: m/z 352 (M). Anal. Calcd for C18H16N4O4: C, 61.36; H,

4.58; N, 15.90. Found: C, 61.28; H, 4.55; N, 15.94.

1-{(7-chloro-2-oxo-2H-chromen-4-yl)methyl}-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione (5f) :

Dark brown Powder: m.p. 181–183oC; IR (KBr)

(vmax/cm-1): 3045, 2919, 1708, 1641, cm-1; 1H NMR

(300 MHz, DMSO) δ ppm: 3.55 (s, 3H, N-CH3), 3.78

(s, 3H, N-CH3), 5.32 (s, 2H, CH2), 6.01 (s, 1H, Ar-H),

7.35 (s, 1H, Ar-H), 7.46 (d, 1H, Ar-H), 7.75 (s, 1H, Ar-H), 7.99 (s, 1H, Ar-H);

LC-MS: m/z 372 (M). Anal. Calcd for C17H13ClN4O4: C, 54.78; H, 3.52; N,

15.03. Found: C, 54.82; H, 3.47; N, 15.07.

O O

N N

O

O NN

O O

N N

O

O NN

Cl


208

1-{(6-methoxy-2-oxo-2H-chromen-4-yl)methyl}-3,7-dimethyl-1H-purine-2,6(3H,7H)-dione (5g) :

Blue solid; IR (KBr) (vmax/cm-1): 3039, 2941, 1721,

1645, cm-1; 1H NMR (300 MHz, DMSO) δ ppm:

3.50 (s, 3H, N-CH3), 3.79 (s, 3H, N-CH3), 3.99 (s,

3H, O-CH3), 5.28 (s, 2H, CH2), 5.99 (s, 1H, Ar-H),

7.18 (s, 1H, Ar-H), 7.42 (d, 1H, Ar-H), 7.87 (s, 1H, Ar-H), 8.09 (d, 1H, Ar-H);

LC-MS: m/z 368 (M). Anal. Calcd for C18H16N4O5: C, 58.69; H, 4.38; N,

15.21. Found: C, 58.73; H, 4.35; N, 15.18.

3,7-dimethyl-1-{(2-oxo-3H-benzo[f]chromen-1-yl)methyl}-1H-purine-2,6(3H,7H)-dione (5h) :

Red powder: m.p. 168–169 oC; IR (KBr) (vmax/cm-1):

3037, 2931, 1725, 1648, cm-1; 1H NMR (300 MHz,

DMSO) δ ppm: 3.42 (s, 3H, N-CH3), 3.75 (s, 3H, N-

CH3), 5.19 (s, 2H, CH2), 6.01 (s, 1H, Ar-H), 7.32 (d,

1H, Ar-H), 7.41 (d, 1H, Ar-H), 7.50–7.77 (m, 6H, Ar-H), 8.01 (s, 1H, Ar-H);

LC-MS: m/z 388 (M). Anal. Calcd for C21H16N4O4: C, 64.94; H, 4.15; N,

14.43. Found: C, 69.89; H, 4.11; N, 14.50.

O O

N N

O

O NN

H3CO

O O

N N

O

O NN


209

1-{(5,7-dimethyl-2-oxo-2H-chromen-4-yl)methyl}-3,7-dimethyl-1H-purine-2,6(3H, 7H)-dione (5i) :

Orange powder; IR (KBr) (vmax/cm-1): 3024, 2932,

1717, 1628, cm-1; 1H NMR (300 MHz, DMSO) δ: 2.39

(s, 3H, Ar-CH3), 2.45 (s, 3H, Ar-CH3), 3.37 (s, 3H, N-

CH3), 3.88 (s, 3H, N-CH3), 5.21 (s, 2H, CH2), 5.99 (s,

1H, Ar-H), 6.89 (s, 1H, Ar-H), 7.05 (s, 1H, Ar-H), 7.98 (s, 1H, Ar-H); LC-MS:

m/z 366 (M+). Anal. Calcd for C19H18N4O4: C, 62.29; H, 4.95; N, 15.29. Found:

C, 62.35; H, 4.92; N, 15.33.

1-{(7,8-dimethyl-2-oxo-2H-chromen-4-yl)methyl}-3,7-dimethyl-1H-purine-2,6(3H, 7H)-dione (5j) :

Pale yellow powder; m.p. 185–186oC; IR (KBr)

(vmax/cm-1): 3029, 2935, 1712, 1626, cm-1; 1H NMR

(300 MHz, DMSO) δ: 2.22 (s, 3H, Ar-CH3), 2.35 (s,

3H, Ar-CH3), 3.35 (s, 3H, N-CH3), 3.92 (s, 3H, N-CH3),

5.17 (s, 2H, CH2), 5.93 (s, 1H, Ar-H), 7.12 (d, 1H, Ar-H), 7.49 (d, 1H, Ar-H),

8.0 (s, 1H, Ar-H); LC-MS: m/z 366 (M+). Anal. Calcd for C19H18N4O4: C,

62.29; H, 4.95; N, 15.29. Found: C, 62.33; H, 4.99; N, 15.25.

O O

N N

O

O NN

O O

N N

O

O NN


210

Spectrum 1: IR Spectrum of compound 5a

Spectrum 2: 1H NMR Spectrum of compound 5a in CDCl3

O O

N N

O

O NN

CH3

CH3

H3C


211

O O

N N

O

O NN

CH3

CH3

H3C

Spectrum 3: 13C NMR Spectrum of compound 5a in CDCl3

O O

N N

O

O NN

CH3

CH3

H3C

Spectrum 4: Mass Spectrum of compound 5a


212

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