Research ArticleBF3sdotEt2O Catalysed 4-Aryl-3-phenyl-benzopyrones Pro-SERMsand Their Characterization
Ambika Srivastava Pooja Singh and Rajesh Kumar
Department of Chemistry Centre of Advanced Study Faculty of Science Banaras Hindu University Varanasi 221005 India
Correspondence should be addressed to Rajesh Kumar rkr bhuyahoocom
Received 19 May 2015 Accepted 22 July 2015
Academic Editor Todd C Skaar
Copyright copy 2015 Ambika Srivastava et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited
We have synthesized the novel 4-(4-hydroxy-benzyl)-3-phenyl-chromen-2-one which is a precursor of SERMs with a smallernumber of steps and good yield Twomethodologies for the synthesis have beenworked out Anhydrous BF
3sdotEt2Ocatalyzed reaction
was found to be selective for product formation while anhydrous AlCl3 FeCl
3 and SnCl
4catalyzed ones were nonselective
1 Introduction
Activity of estrogen receptor can be controlled by a classof compounds which is called selective estrogen receptormodulators (SERMs) The modulators have a distinctive fea-ture in different individual tissues by which they can inhibitor stimulate or selectively suppress or excite estrogen-likebehavior in different tissuesThe structures of few biologicallyvital SERMs are shown in Figure 1 in which compoundA is a polyhydroxy phenyl benzothiophene which has lowphysiological response when combined with the receptorestrogen in gnawing uterus [1] Compound A was initiallyknown as Ly156758keoxifen and its advancement has beenstopped for improved action for treatment of breast cancer [2]due to less bioavailability than the required essential dose [3]But the concept of SERM was shown by compound A due tosustainable property of bone density [4 5] with restriction inmammary carcinogenesis in rat [6 7] Studies on compoundA reveal the reduction of risk of osteoporosis [8] and breastcancer in women after menopause [9] Compound B is anonhydroxy and typical model compound for SERM whichwas used clinically for the occupational therapy of breastcancer [10 11] with the maintained density in bone of womenaftermenopause [12]The drawback of the treatment by com-poundBwas the increased possibilities of endometrial cancer[13] Hence it is clear that there are various factors whichare responsible for estrogenic and antiestrogenic properties of
SERM complexes and could be useful in improving targetedtherapeutic agents
Coumarin and its derivatives are important compoundsdue to their presence in numerous natural products alongwith their wide ranging applications as drugs pharmaceuti-cals and SERMs Coumarin based selective estrogen recep-tor modulators (SERMs) and coumarin-estrogen conjugateshave been described as potential anti-breast-cancer agentsThus coumarin derivatives acting as SERMs either stimulateor inhibit the estrogen action thereby generating the possibil-ity of curing estrogen related problems Coumarins and theirderivatives are common in nature [14ndash18] among them the 4-substituted coumarins were identified as anticancer and anti-HIV-1 molecules [19 20]
Among the oxygen heterocycles coumarins are one ofthemwhich are present in various naturally [21 22] occurringmotifs Due to comprehensive and inexhaustible perfor-mance of coumarin in biological activities [23ndash33] such asanti-HIV [34ndash37] anticoagulation [38] antibiotic [39ndash42]anticancer [43 44] anti-inflammatory [45 46] antioxidant[47ndash49] antitumor [50ndash52] antiviral [53] antihypertensiveand antimicrobial activity its chemistry grew up widelyAmong the nuclear hormone receptor modulators namelySERMs PRMs and SARMs [54ndash58] coumarins are alsoidentified with a similar kind of properties Among thecoumarin derivatives more attention is given to 4-substitutedcoumarins but there are very few methods known for
Hindawi Publishing CorporationAdvances in Pharmacological SciencesVolume 2015 Article ID 527159 9 pageshttpdxdoiorg1011552015527159
2 Advances in Pharmacological Sciences
SOH
OH
O
O N
(A) RaloxifeneOH
ON
(C) Lasofoxifene
Cl
ON
(D) Clomifene
OO
O
N
(E) Centchroman
ON
(B) Tamoxifen
Figure 1 Examples of biologically active heterocyclic frameworks
synthesis Route 1 (Scheme 1) to coumarins incorporatesPechmann [59 60] Knoevenagel [61ndash64] Reformatsky [61ndash64] Perkin [65] and Wittig [66] condensation reactions Tomake these reactions efficacious several variations in termsof catalyst and reaction conditions have been done Howeverthe route 1 methodology suffers from laborious multistepprocedures long reaction time high reaction temperaturenonselectivity andwaste problem To overcome these a faciletwo-step synthesis of 4-aryl-3-phenyl-coumarin-2-one hasbeen reported as shown in Scheme 2 which would be helpfulin designing novel SERMs
2 Results and Discussion
Condensation reactions have been amongst the most usefulroutes for the synthesis of these compounds particularlycatalyzed by Lewis acids In Scheme 1 4-methoxy phenylacetic acid and phenol were taken as starting material Inthe first step acyl chloride of acid was prepared where theyield of phenyl acyl chloride obtained was 50 Furtheresterification led to some good yield but the yield was verypoorly shed down to 10with next step reaction that is FriesrearrangementThe reaction of ester andAlCl
3at 145∘C led to
four products of which only two (iv-a iv-b) were importantfor synthesis purpose Fries rearrangement with AlCl
3has
no selectivity and gave four products with almost 10 yieldwhich were separated chromatographically Then cyclizationwith phenyl acetyl chloride was carried out with anhydrousK2CO3in dry acetone There were some shortcomings
like low reaction yields and nonselectivity of reactionmorebyproduct formationlow atom economic reactions Hence
the nonselectivity of reactions (via Scheme 1) and low atomeconomy demanded the search for a simple short and high-yielding alternate process to synthesize substituted coumarinbased SERMs precursors
To decrease the product loss and number of stepsthe synthetic strategy was modified and Scheme 2 routewas selected in which 4-substituted phenyl acetic acid andsubstituted phenolwere used as startingmaterial and reactionwas catalyzed by BF
3sdotEt2O which was found to be a very
efficient catalyst In this report a facile and high-yieldingprotocol for diverse SERMs precursors through synthesis offunctionalized benzylic ketone and further intermolecularcyclization using substituted phenyl acetyl chloride with dryacetone and potassium carbonate under reflux conditionhas been described Further to our ongoing research onnovel synthetic methodologies for SERMs precursors syn-thesis we commenced our synthetic strategy with environ-mentally benign phenol which on coupling with differentphenyl acetyl chlorides including p-anisole acetyl chloride p-phenyl acetyl chloride and p-hydroxy phenyl acetyl chlorideafforded substituted benzylic ketones in good yields Thesubstituted benzylic ketones (ix (andashi)) on further treatmentwith substituted phenyl acetyl chloride in the presence ofK2CO3and dry acetone led to the formation of various
substituted SERMsprecursors (4-benzyl-3-phenyl coumarin)(vi (andashi)) in good yields (Scheme 2) Thus the synthesis ofsubstituted SERMs precursor (4-benzyl-3-phenyl coumarin)was achieved in two steps Acetylation was regioselective andoccurred at ortho position which was the major reactionproduct Thus in just one step phenol was esterified andthe ester readily rearranged to give 4-methoxy phenyl acetyl
Advances in Pharmacological Sciences 3
Dry benzenereflux
Phenol
O
R
O
Cl
O
(vi)
(i) (ii) (iii)
(v)
SOCl2
O
OH
R1
O
Cl
R1
O
O
R1
R2
R2
+ + +O
OH
R1
O
HO
R1
O
OH
R998400
1
O
HO
R998400
1
where R1 = OCH3 R998400
1= OH R2 = H CH3 C2H5
OCH3 R = OCH3 OH
Acetone r
eflux K 2CO 3
AlCl3
(iv (andashd))
Scheme 1 Route 1 for the synthesis of coumarin based SERMrsquos precursors
COCl
R
+R
HOO COCl
OH
(vii) (ix (andashi)) (vi (andashi))(viii)
(v)
R2
O
R
O
R2
where R = OCH3 OH R2 = H CH3 C2H5 OCH3
Dry acetonereflux Dry acetone K2CO3 reflux
BF3middotEt2O
Scheme 2 Route 2 for the synthesis of coumarin based SERMrsquos precursors
group at ortho position of phenol This stage product wasachieved by Scheme 1 after 3 steps with low atom economyand many undesirable products The intermediate ester(Scheme 2) could not be isolated since BF
3sdotEt2O readily
rearranged it to ortho substituted phenol Thus the two-stepprocess was reduced to one step the probable mechanism ofwhich has been given in Figure 2
In our early attempts to synthesize the coumarin basedSERMs precursors we were not successful in convertingthe reactants to products without the catalyst (BF
3sdotEt2O)
The anhydrous AlCl3 FeCl
3 and SnCl
4were not able to
give the desired intermediate selectively in quantitative yieldThis was possibly due to poor Lewis acid character ofAlCl3 FeCl
3 and SnCl
4compared to BF
3 The reaction
was investigated carefully and it was observed that theintermediate (benzylic ketones (ix (andashi))) formed after thecoupling of phenol with substituted phenyl acetyl chloridewas sufficiently stable and could be isolated In the secondstep intermolecular cyclization was carried out with substi-tuted phenyl acetyl chloride and a base (anhydrous K
2CO3)
The desired product (vi-e) was characterized by 1H NMR(Figure S6(a) in Supplementary Material available online at
httpdxdoiorg1011552015527159) which contains addi-tional peaks at 120575 679 and 698 due to benzylic proton and at120575 72 and 73 due to phenylic protons and one signal at 120575 715was due to proton at para position in the phenyl ringThe restof the protons were the same as in the precursor that is orthosubstituted phenol (iv-a)13C NMR (Figure S6(b)) also confirmed the formation
of 4-(4-hydroxy-benzyl)-3-phenyl-chromen-2-one peaks at11960 12640 12838 12953 13405 and 16122 show sixdifferent types of carbons which are present in 4-aryl-3-phenyl-benzopyrone in addition to the carbons alreadypresent in the starting that is 2-(4-hydroxy-phenyl)-1-(2-hydroxy phenyl)-ethanone FTIR spectrum also confirmedthe formation of lactone ring that is the cyclized productshows carbonyl absorption at a higher wavenumber that isat 1707 cmminus1 (Figure S6(c)) while it was 1633 cmminus1 in the 2-(4-hydroxy-phenyl)-1-(2-hydroxy-phenyl)-ethanone (FigureS2(a)) Mass spectroscopy shows (m + 1) peak at 343 whilethe molecular weight of (vi-e) is 342 (Figure S6(d))
Finally the single crystal diffraction studies showed thespace orientation (Figures 3(a) and 3(b)) bond lengths andbond angles regarding the crystal structure (Table 1) The
4 Advances in Pharmacological Sciences
COCl
HO
Cl
O
minusO
OCH3
O OH
OClminus
OCH3
O OH
OCH3
OH
+
OCl
BF3
OCH3
O O
H3CO
OO
BF3
H3CO
O
+
H
OCH3
Ominus
OCl
BF3
H3CO
Ominus
O
+
BF3
OCH3
Ominus
Anhy K2CO3 dry acetone
Figure 2 Probable mechanism related to Scheme 2
structure reflects that the coumarin ring is planar phenylring which is attached at position 3 is slightly out of planeand substituted benzylic group is perpendicular to the ringcoumarin (Figure 3(a)) Compound (vi-e) exhibited ldquoZ-rdquo likepacking diagram (Figure 3(b))
This new procedure allows facile introduction of sub-stituents at position 4 of the 4-(4-substituted-benzyl)-3-phenyl-chromen-2-one skeleton and gives the flexibility forthe construction of novel precursors
Various derivatives have been prepared with para sub-stituted benzyl chloride with hydroxyl methoxy acetoxymethyl and ethyl groups as shown in Table 2 All thederivatives have been prepared smoothly under the samereaction conditions The reactions are simple easy to handleand feasible and have simple workup procedures
After the establishment of the protocol for the syn-thesis of substituted SERMs precursors (4-benzyl-3-phenylcoumarins) we shifted our focus towards the role of solventslike CH
2Cl2 CHCl
3 acetone and toluene upon yield and
the reaction time The results illustrated that the reactionin toluene did not give the desired precursors whereas the
Table 1 Bond lengths and bond angles of (vi-e) have beendemonstrated
S number Atoms Bond lengths Atoms Bond angles1 O3-C20 13772(1) C20-O3-C23 117762 O3-C23 13963(1) C8-O1-C7 121713 O1-C8 13848(1) O3-C20-C21 115934 O1-C7 13722(1) O1-C8-C1 115405 C5-C6 13610(1) O3-C20-C19 124736 C6-C7 14647(1) O1-C7-C6 117787 O2-C7 12114(1) C6-C7-O2 12571
reaction in CHCl3was slow and the yield was low However
for this cyclization CH2Cl2was found to be good in terms
of yield and handling but took a slightly longer time toafford the products Eventually acetone appeared as a solventof choice for intermolecular cyclization in very good yieldIntermolecular cyclization was greatly influenced by the baseused therefore to find out the appropriate base we examinedK2CO3and triethylamine in the intermolecular cyclization
Advances in Pharmacological Sciences 5
Prob= 50
Temp = 293
Z 154 ambl-s4 Pbca R = 009 Res = 0
PLAT
ON
-Mar
2807
25
252011
- (160211
)
C23O3
C19 C20C21
C17C18
C22
C5
C9C4
C3
C2
No move forced
C1
C8
C16 C6
C10
C15C14
C11
C12
C13
C7
O1
O2
(a) (b)
Figure 3 (a) ORTEPPLATON structure of (vi-e) (b) Packing structure of (vi-e) showing Z-like packing
Table 2 Derivatives of 4-aryl-3-phenyl-coumarin-2-one and theiryield () for Scheme 2
S number Compound R R2
Time (h) Yielda ()1 (vi-a) -OH H 7 742 (vi-b) -OH -CH
37 77
3 (vi-c) -OH -OCH3
6 804 (vi-d) -OH -C
2H5
8 705 (vi-e) -OCH
3H 7 75
6 (vi-f) -OCH3
-CH3
8 797 (vi-g) -OCH
3-OCH
37 82
8 (vi-h) -OCH3
-C2H5
7 809 (vi-i) -OAc H 6 90aThe reaction yield refers to product isolated through column chromatogra-phy
reaction of (ix-a) with (v) and found that the reaction in thepresence of K
2CO3afforded the cyclized product (vi-a) in
74yield after 7 h whereas triethylamine gave this product in57 yield We believe that potassium carbonate may be moredissociated in aprotic polar solvents and consequently provedto be more reactive
3 Conclusion
In conclusion a simple efficient and novel method hasbeen developed for an easy access to synthesis of the 4-(4-hydroxy-benzyl)-3-phenyl-chromen-2-one via Scheme 2and this has been supported by 1H NMR FTIR 13C NMRmass spectroscopy and single crystal X-ray data analysisSynthetic pathway with just 2 steps proved to be the bestwith less side reactions and greater yield Thus the numberof steps has been decreased and the yield was increasedHerein we reported some precursors of coumarin basedSERMs which could be useful in designing new SERMs Thepure products were obtained by column chromatography
This methodology presents several advantages including (a)mild reaction conditions (b) simple workup procedure (c)moderately high yields of the desired products (d) theselectivity of the product and finally (e) economic availabilityof the reagents making the whole process simple and feasibleEfforts to extend the span of the procedure on SERMs areunder progress in our laboratory
4 Experimental Section
41 General Methods All the required chemicals are pur-chased since they are commercially available and used asreceived without further purification Commercially avail-able acetone and benzene were further purified and driedfollowing the known procedure Thin-layer chromatography(TLC) was performed using silica gel 60 F254 precoatedplates Column chromatography was carried out on silica gel60 (100ndash200mesh) Infrared (FTIR) spectra were recordedin KBr and wavelengths (]) have been reported in cmminus1 1Hand 13C NMR spectra were recorded on NMR spectrometersoperating at 300 and 755MHz respectively Chemical shifts(120575) were given in parts per million (ppm) using the residuesolvent peaks as reference relative to TMS 119869 values have beengiven in Hz Mass spectra were recorded using electrosprayionization (ESI) mass spectrometer The melting points weretaken in open capillary and uncorrected
411 Procedure for Scheme 1
Compound (ii) To a solution of 4-methoxy phenyl acetic acid(425 g 025mol) in dry benzene (50mL) was added thionylchloride (30mL 025mol) dropwise with syringe After thereaction was complete the reaction mixture was distilledto remove excess thionyl chloride and the solvent benzeneBrown colored liquid was obtained Yield- 50 1H NMR-(300MHz CDCl
Compound (iii) A solution of p-methoxy phenyl acetylchloride (24 g 013mol) and phenol (122mL 013mol) in drybenzene (63mL) was refluxed for 21 h till the reaction wascomplete as monitored by TLC Then the reaction mixturewas washed with 5 aqueous NaOH to remove excessunreacted phenol and then washed with water three timesand dried over anhydrous Na
Compounds (vi (a-h)) To a solution of ortho substituted phe-nol (236mg 1mmol) and K
2CO3(690mg 5mmol) in dry
acetone (25mL) was added phenyl acetyl chloride (308mg2mmol) dropwise The reaction mixture was refluxed at100∘C for 7 h After the reaction was completed (asmonitoredby TLC) the reaction mixture was cooled filtered and con-centrated The residue was chromatographed to obtain thepure compound with 20 ethyl acetate-hexane Yield- 70
412 Procedure for Scheme 2
Compound (ix-e) To a solution of 4-methoxy phenyl aceticacid (166mg 1mmol) in dry acetone (10mL) was addedBF3sdotEt2O (04mL 3mmol) at 0∘C After 30 minutes we
added phenol (01mL 1mmol) and refluxed it till the reactionwas completed as monitored by TLC Then we filtered thereaction mixture and evaporated the solvent in vacuum
White solid was obtained recrystallized from ethanol Yield-80 mp 65∘C 1H NMR- (300MHz CDCl
Compound (vi-e) Phenyl acetyl chloride (013mL 1mmol)was added to a solution of (ix-e) (242mg 1mmol) in dryacetone and K
2CO3(552mg 4mmol) and refluxed for 6 h
Then the reaction mixture was filtered and concentrated invacuumThe obtained crude was recrystallized from ethanolto obtain the pure product Yield- 75
Procedure for Compound (vi-i) Acetic anhydride (920mg1mL) was added to a solution of (vi-a) (328mg 1mmol)and pyridine (025mL 9mmol) and refluxed under nitrogenatmosphere for 6 h at 90∘C After the reaction was completed(as monitored by TLC) solvent was removed under vacuumThe residuewaswashedwith saturatedNa
2HCO3until excess
pyridine was removed and then it was washed with aqueousHCl and finally with saturated brine solution and dried andchromatographed with 20 ethyl acetate-hexane Yield 90mp 160∘C
Analytical Data for Compounds (vi (andashi))
(vi-a) 1H NMR- (300MHz CDCl3) 120575 403 (s 2H -CH
864Hz 2H Ar-H) 720 (t 119869 = 144Hz 1H Ar-H) 730 (m2H Ar-H) 743 (m 4H Ar-H) 753 (m 2H Ar-H) (FigureS7)119898119911 37012 Elemental Analysis C 7782 H 490 O 1728119898119911 370 C 8106 H 599 O 1296
Note Crystallographic information is given in the supportingfile with details of refinement and other structural parame-ters
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The authors are thankful to the Department of ChemistryBHU for proving NMR FTIR and single crystal X-ray dataFinancial assistance from CSIR (Grant no 01(2362)10EMR-II) New Delhi in the form of a project and fellowships toAmbika Srivastava and Pooja Singh andCSIR andUGCNewDelhi in the form of SRF and UGC Fellowship respectivelyis gratefully acknowledged
References
[1] L J Black C D Jones and J F Falcone ldquoAntagonism of estro-gen action with a new benzothiophene derived antiestrogenrdquoLife Sciences vol 32 no 9 pp 1031ndash1036 1983
[2] A U Buzdar CMarcus F Holmes V Hug and G HortobagyildquoPhase II evaluation of LY156758 in metastatic breast cancerrdquoOncology vol 45 no 5 pp 344ndash345 1988
[3] K R Snyder N Sparano and J M Malinowski ldquoRaloxifenehydrochloriderdquo American Journal of Health-System Pharmacyvol 57 no 18 pp 1669ndash1678 2000
[4] V C Jordan E Phelps and J U Lindgren ldquoEffects of anti-estrogens on bone in castrated and intact female ratsrdquo BreastCancer Research and Treatment vol 10 no 1 pp 31ndash35 1987
[5] L J Black M Sato E R Rowley et al ldquoRaloxifene (LY139481HCI) prevents bone loss and reduces serum cholesterol withoutcausing uterine hypertrophy in ovariectomized ratsrdquo The Jour-nal of Clinical Investigation vol 93 no 1 pp 63ndash69 1994
[6] M M Gottardis and V C Jordan ldquoAntitumor actions ofkeoxifene and tamoxifen in the N-nitrosomethylurea-inducedrat mammary carcinoma modelrdquo Cancer Research vol 47 no15 pp 4020ndash4024 1987
[7] M A Anzano C W Peer J M Smith et al ldquoChemopreventionof mammary carcinogenesis in the rat combined use of ralox-ifene and 9-cis-retinoic acidrdquo Journal of the National CancerInstitute vol 88 no 2 pp 123ndash125 1996
[8] B Ettinger D M Black B H Mitlak et al ldquoReduction of verte-bral fracture risk in postmenopausal women with osteoporosistreated with raloxifene results from a 3-year randomizedclinical trialrdquo The Journal of the American Medical Associationvol 282 no 7 pp 637ndash645 1999
[9] S R Cummings S Eckert K A Krueger et al ldquoThe effect ofraloxifene on risk of breast cancer in postmenopausal womenresults from the MORE randomized trialrdquo The Journal of theAmerican Medical Association vol 281 no 23 pp 2189ndash21971999
[10] MClarke R Collins CDavies J Godwin R Gray andR PetoldquoThe EBCTCG secretariat clinical trial service unit radcliffeinfirmary Oxford OX2 6HE UKrdquoThe Lancet vol 351 pp 1451ndash1467 1998
[11] B Fisher J P Costantino D L Wickerham et al ldquoTamoxifenfor prevention of breast cancer report of the National SurgicalAdjuvant Breast and Bowel Project P-1 Studyrdquo Journal of theNational Cancer Institute vol 90 no 18 pp 1371ndash1388 1998
[12] R R Love R BMazessH S Barden et al ldquoEffects of tamoxifenon bonemineral density in postmenopausal women with breastcancerrdquo The New England Journal of Medicine vol 326 no 13pp 852ndash856 1992
[13] V J Assikis P Neven V C Jordan and I Vergote ldquoA realisticclinical perspective of tamoxifen and endometrial carcinogene-sisrdquo European Journal of Cancer A vol 32 no 9 pp 1464ndash14761996
[14] E J Lederer ldquoChemistry and biochemistry of somemammaliansecretions and excretionsrdquo Journal of the Chemical Society pp2115ndash2125 1949
[15] G G Freeman ldquoIsolation of alternariol and alternariol mono-methyl ether from Alternaria dauci (kuhn) groves and skolkordquoPhytochemistry vol 5 no 4 pp 719ndash725 1966
[16] W T L Sidwell H Fritz and C Tamm ldquoAutumnariol undAutumnariniol zwei neue Dibenzo-120572-pyrone aus Eucomisautumnalis Graeb Nachweis einer Fernkopplung uber sechsBindungen in den magnetischen ProtonenresonanzmdashSpek-trenrdquo Helvetica Chimica Acta vol 54 no 1 pp 207ndash215 1971
[17] L Farkas F Soti M Incze and M Nogradi ldquoSynthesenaturlicher Dibenzo-120572-pyrone I Synthese des Autumnariniolsund des Autumnariniolsrdquo Chemische Berichte vol 107 no 12pp 3874ndash3877 1974
[18] S Ghosal J P Reddy and V K Lal ldquoShilajit I chemicalconstituentsrdquo Journal of Pharmaceutical Sciences vol 65 no 5pp 772ndash773 1976
8 Advances in Pharmacological Sciences
[19] B Naser-Hijazi B Stolze and K S Zanker Second Proceed-ings of the International Society of the Coumarin InvestigatorsSpringer Berlin Germany 1994
[20] R D H Murray J Mendez and S A Brown The Natu-ral Coumarin Occurrence Chemistry and Biochemistry JohnWiley Chichester UK 1982
[21] J D Hepworth C D Gabbutt and B N Heron ComprehensiveHeterocyclic Chemistry II vol 5 Pergamon Press Oxford UK1996
[22] F M Deans Naturally Occurring Oxygen Ring CompoundsButterworths London UK 1963
[23] J A Joule and K Mills Eds Heterocyclic Chemistry BlackwellScience Oxford UK 4th edition 2006
[24] R D H Murray ldquoNaturally occurring plant coumarinsrdquo Fort-schritte der Chemie Organischer Naturstoffe vol 35 pp 199ndash2491978
[25] G R Geen J M Evans and A K Vong in ComprehensiveHeterocyclic Chemistry II A R Katritzky C W Rees and EF V Scriven Eds vol 5 p 469 Pergamon Press Oxford UK1984
[26] H-X Xu and S F Lee ldquoActivity of plant flavonoids againstantibiotic-resistant bacteriardquo Phytotherapy Research vol 15 no1 pp 39ndash43 2001
[27] J M Hamilton-Miller ldquoAntimicrobial properties of tea (Camel-lia sinensis L)rdquoAntimicrobial Agents and Chemotherapy vol 39no 11 pp 2375ndash2377 1995
[28] K C Fylaktakidou D J Hadjipavlou-Litina K E Litinas andD N Nicolaides ldquoNatural and synthetic coumarin derivativeswith anti-inflammatoryantioxidant activitiesrdquo Current Phar-maceutical Design vol 10 no 30 pp 3813ndash3833 2004
[29] J R Hwu R Singha S C Hong et al ldquoSynthesis of newbenzimidazole-coumarin conjugates as anti-hepatitis C virusagentsrdquo Antiviral Research vol 77 no 2 pp 157ndash162 2008
[30] S Sardari Y Mori K Horita R G Micetich S Nishibe andMDaneshtalab ldquoSynthesis and antifungal activity of coumarinsand angular furanocoumarinsrdquo Bioorganic amp Medicinal Chem-istry vol 7 no 9 pp 1933ndash1940 1999
[31] D Egan P James D Cooke and R OrsquoKennedy ldquoStudies on thecytostatic and cytotoxic effects and mode of action of 8-nitro-7-hydroxycoumarinrdquo Cancer Letters vol 118 no 2 pp 201ndash2111997
[32] P Valenti A Rampa M Recanatini et al ldquoSynthesis cytotoxic-ity and SAR of simple geiparvarin analoguesrdquoAnti-Cancer DrugDesign vol 12 no 6 pp 443ndash451 1997
[33] C Spino M Dodier and S Sotheeswaran ldquoAnti-HIV coum-arins from calophyllum seed oilrdquo Bioorganic and MedicinalChemistry Letters vol 8 no 24 pp 3475ndash3478 1998
[34] L M Bedoya M Beltran R Sancho et al ldquo4-Phenylcoumarinsas HIV transcription inhibitorsrdquo Bioorganic ampMedicinal Chem-istry Letters vol 15 no 20 pp 4447ndash4450 2005
[35] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[36] D Yu M Suzuki L Xie S L Morris-Natschke and K-H LeeldquoRecent progress in the development of coumarin derivativesas potent anti-HIV agentsrdquoMedicinal Research Reviews vol 23no 3 pp 322ndash345 2003
[37] S Kirkiacharian D T Thuy S Sicsic R Bakhchinian RKurkjian and T Tonnaire ldquoStructurendashactivity relationshipsof some 3-substituted-4-hydroxycoumarins as HIV-1 proteaseinhibitorsrdquo Farmaco vol 57 no 9 pp 703ndash708 2002
[38] A G Kidane H Salacinski A Tiwari K R Bruckdorfer andA M Seifalian ldquoAnticoagulant and antiplatelet agents theirclinical and device application(s) together with usages to engi-neer surfacesrdquo Biomacromolecules vol 5 no 3 pp 798ndash8132004
[39] KMKhan Z S SaifyM Z Khan et al ldquoSynthesis of coumarinderivatives with cytotoxic antibacterial and antifungal activityrdquoJournal of Enzyme Inhibition and Medicinal Chemistry vol 19no 4 pp 373ndash379 2004
[40] G Appendino E Mercalli N Fuzzati et al ldquoAntimycobacterialcoumarins from the Sardinian giant fennel (Ferula communis)rdquoJournal of Natural Products vol 67 no 12 pp 2108ndash2110 2004
[41] NHamdiM Saoud andARomerosa ldquo4-Hydroxy coumarinea versatile reagent for the synthesis of heterocyclic and vanillinether coumarins with biological activitiesrdquo in Bioactive Hetero-cycles V vol 11 of Topics in Heterocyclic Chemistry pp 283ndash301Springer Berlin Germany 2007
[42] F Chimenti B Bizzarri A Bolasco et al ldquoSynthesis and in vitroselective anti-Helicobacter pylori activity of N-substituted-2-oxo-2H-1-benzopyran-3-carboxamidesrdquo European Journal ofMedicinal Chemistry vol 41 no 2 pp 208ndash212 2006
[43] C Ito M Itoigawa Y Mishina et al ldquoChemical con-stituents of Calophyllum brasiliense 2 Structure of three newcoumarins and cancer chemopreventive activity of 4-substi-tuted coumarinsrdquo Journal of Natural Products vol 66 no 3 pp368ndash371 2003
[44] I Kostova ldquoSynthetic and natural coumarins as cytotoxicagentsrdquo Current Medicinal ChemistrymdashAnti-Cancer Agents vol5 no 1 pp 29ndash46 2005
[45] GMelagraki A Afantitis O Igglessi-Markopoulou et al ldquoSyn-thesis and evaluation of the antioxidant and anti-inflammatoryactivity of novel coumarin-3-aminoamides and their alpha-lipoic acid adductsrdquo European Journal of Medicinal Chemistryvol 44 no 7 pp 3020ndash3026 2009
[46] C A Kontogiorgis and D J Hadjipavlou-Litina ldquoSynthesis andantiinflammatory activity of coumarin derivativesrdquo Journal ofMedicinal Chemistry vol 48 no 20 pp 6400ndash6408 2005
[47] S Stanchev V Hadjimitova T Traykov T Boyanov and IManolov ldquoInvestigation of the antioxidant properties of somenew 4-hydroxycoumarin derivativesrdquo European Journal ofMed-icinal Chemistry vol 44 no 7 pp 3077ndash3082 2009
[48] C A Kontogiorgis and D J Hadjipavlou-Litina ldquoSynthesis andbiological evaluation of novel coumarin derivatives with a 7-azomethine linkagerdquo Bioorganic and Medicinal Chemistry Let-ters vol 14 no 3 pp 611ndash614 2004
[49] C Xiao Z-G Song and Z-Q Liu ldquoSynthesis of methyl-substi-tuted xanthotoxol to clarify prooxidant effect of methyl onradical-induced oxidation of DNArdquo European Journal of Medic-inal Chemistry vol 45 no 6 pp 2559ndash2566 2010
[50] O M Abdel Hafez K M Amin N A Abdel-Latif T KMohamed E Y Ahmed and T Maher ldquoSynthesis and antitu-mor activity of some new xanthotoxin derivativesrdquo EuropeanJournal of Medicinal Chemistry vol 44 no 7 pp 2967ndash29742009
[51] V Reutrakul P Leewanich P Tuchinda et al ldquoCytotoxic coum-arins fromMammea harmandiirdquo Planta Medica vol 69 no 11pp 1048ndash1051 2003
[52] I Kempen D Papapostolou N Thierry et al ldquo3-Bromophenyl6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylateinhibits cancer cell invasion in vitro and tumour growth invivordquo British Journal of Cancer vol 88 no 7 pp 1111ndash1118 2003
Advances in Pharmacological Sciences 9
[53] P OrsquoKennedy and R D Thornes Eds Coumarins BiologyApplications andMode ofAction JohnWileyampSons ChichesterUK 1997
[54] L Zhi C M Tegley E A Kallel et al ldquo5-Aryl-12-dihydrochro-meno[34-f]quinolines a novel class of nonsteroidal humanprogesterone receptor agonistsrdquo Journal ofMedicinal Chemistryvol 41 no 3 pp 291ndash302 1998
[55] J M Schmidt G B Tremblay M Page et al ldquoSynthesisand evaluation of a novel nonsteroidal-specific endothelial cellproliferation inhibitorrdquo Journal of Medicinal Chemistry vol 46no 8 pp 1289ndash1292 2003
[56] K Hajela K Kapoor and R Kapil ldquoSynthesis and post-coitalcontraceptive activity of ether and ester analogues of 23-diaryl-2H-1-benzopyransrdquo Bioorganic amp Medicinal Chemistry vol 3pp 1417ndash1420 1995
[57] K Hajela and R S Kapil ldquoSynthesis and post-coital contra-ceptive activity of a new series of substituted 23-diaryl-2H-1-benzopyransrdquo European Journal of Medicinal Chemistry vol 32no 2 pp 135ndash139 1997
[58] K Hajela J Pandey A Dwivedy et al ldquoResolution molecularstructure and biological activities of the D- and L-enan-tiomers of potent anti-implantation agent DL-2-[4-(2-piperi-dinoethoxy)phenyl]-3-phenyl-2H-1-benzopyranrdquo Bioorganic ampMedicinal Chemistry vol 7 no 9 pp 2083ndash2090 1999
[59] H Pechmann and C Duisberg ldquoNeue Bildungsweise derCumarine Synthese desDaphnetins IrdquoChemische Berichte vol17 no 1 pp 929ndash936 1884
[60] J Johnson ldquoThe Perkin reaction and related reactionsrdquoOrganicReactions vol 1 pp 210ndash265 1942
[61] G Jones ldquoThe Knoevenagel condensationrdquo Organic Reactionsvol 15 pp 204ndash599 1967
[62] G Brufola F Fringuelli O Piermatti and F Pizzo ldquoSimpleand efficient one-pot preparation of 3-substituted coumarins inwaterrdquo Heterocycles vol 43 no 6 pp 1257ndash1266 1996
[63] R L Shriner ldquoThe reformatsky reactionrdquo in Organic Reactionsvol 1 pp 1ndash58 John Wiley amp Sons 1942
[64] I Yavari RHekmat-Shoar andA Zonouzi ldquoAnewand efficientroute to 4-carboxymethylcoumarins mediated by vinyltriph-enylphosphonium saltrdquo Tetrahedron Letters vol 39 no 16 pp2391ndash2392 1998
[65] J R Johnson ldquoPerkin reaction and related reactionsrdquo OrganicReactions vol 1 p 210 1942
[66] M H Elnagdi S O Abdallah K M Ghoneim E M Ebiedand K N Kassab ldquoSynthesis of some Coumarin derivatives aspotential LaserDyesrdquo Journal of Chemical Research Synopsesno 2 pp 44ndash45 1997
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Figure 1 Examples of biologically active heterocyclic frameworks
synthesis Route 1 (Scheme 1) to coumarins incorporatesPechmann [59 60] Knoevenagel [61ndash64] Reformatsky [61ndash64] Perkin [65] and Wittig [66] condensation reactions Tomake these reactions efficacious several variations in termsof catalyst and reaction conditions have been done Howeverthe route 1 methodology suffers from laborious multistepprocedures long reaction time high reaction temperaturenonselectivity andwaste problem To overcome these a faciletwo-step synthesis of 4-aryl-3-phenyl-coumarin-2-one hasbeen reported as shown in Scheme 2 which would be helpfulin designing novel SERMs
2 Results and Discussion
Condensation reactions have been amongst the most usefulroutes for the synthesis of these compounds particularlycatalyzed by Lewis acids In Scheme 1 4-methoxy phenylacetic acid and phenol were taken as starting material Inthe first step acyl chloride of acid was prepared where theyield of phenyl acyl chloride obtained was 50 Furtheresterification led to some good yield but the yield was verypoorly shed down to 10with next step reaction that is FriesrearrangementThe reaction of ester andAlCl
3at 145∘C led to
four products of which only two (iv-a iv-b) were importantfor synthesis purpose Fries rearrangement with AlCl
3has
no selectivity and gave four products with almost 10 yieldwhich were separated chromatographically Then cyclizationwith phenyl acetyl chloride was carried out with anhydrousK2CO3in dry acetone There were some shortcomings
like low reaction yields and nonselectivity of reactionmorebyproduct formationlow atom economic reactions Hence
the nonselectivity of reactions (via Scheme 1) and low atomeconomy demanded the search for a simple short and high-yielding alternate process to synthesize substituted coumarinbased SERMs precursors
To decrease the product loss and number of stepsthe synthetic strategy was modified and Scheme 2 routewas selected in which 4-substituted phenyl acetic acid andsubstituted phenolwere used as startingmaterial and reactionwas catalyzed by BF
3sdotEt2O which was found to be a very
efficient catalyst In this report a facile and high-yieldingprotocol for diverse SERMs precursors through synthesis offunctionalized benzylic ketone and further intermolecularcyclization using substituted phenyl acetyl chloride with dryacetone and potassium carbonate under reflux conditionhas been described Further to our ongoing research onnovel synthetic methodologies for SERMs precursors syn-thesis we commenced our synthetic strategy with environ-mentally benign phenol which on coupling with differentphenyl acetyl chlorides including p-anisole acetyl chloride p-phenyl acetyl chloride and p-hydroxy phenyl acetyl chlorideafforded substituted benzylic ketones in good yields Thesubstituted benzylic ketones (ix (andashi)) on further treatmentwith substituted phenyl acetyl chloride in the presence ofK2CO3and dry acetone led to the formation of various
substituted SERMsprecursors (4-benzyl-3-phenyl coumarin)(vi (andashi)) in good yields (Scheme 2) Thus the synthesis ofsubstituted SERMs precursor (4-benzyl-3-phenyl coumarin)was achieved in two steps Acetylation was regioselective andoccurred at ortho position which was the major reactionproduct Thus in just one step phenol was esterified andthe ester readily rearranged to give 4-methoxy phenyl acetyl
Advances in Pharmacological Sciences 3
Dry benzenereflux
Phenol
O
R
O
Cl
O
(vi)
(i) (ii) (iii)
(v)
SOCl2
O
OH
R1
O
Cl
R1
O
O
R1
R2
R2
+ + +O
OH
R1
O
HO
R1
O
OH
R998400
1
O
HO
R998400
1
where R1 = OCH3 R998400
1= OH R2 = H CH3 C2H5
OCH3 R = OCH3 OH
Acetone r
eflux K 2CO 3
AlCl3
(iv (andashd))
Scheme 1 Route 1 for the synthesis of coumarin based SERMrsquos precursors
COCl
R
+R
HOO COCl
OH
(vii) (ix (andashi)) (vi (andashi))(viii)
(v)
R2
O
R
O
R2
where R = OCH3 OH R2 = H CH3 C2H5 OCH3
Dry acetonereflux Dry acetone K2CO3 reflux
BF3middotEt2O
Scheme 2 Route 2 for the synthesis of coumarin based SERMrsquos precursors
group at ortho position of phenol This stage product wasachieved by Scheme 1 after 3 steps with low atom economyand many undesirable products The intermediate ester(Scheme 2) could not be isolated since BF
3sdotEt2O readily
rearranged it to ortho substituted phenol Thus the two-stepprocess was reduced to one step the probable mechanism ofwhich has been given in Figure 2
In our early attempts to synthesize the coumarin basedSERMs precursors we were not successful in convertingthe reactants to products without the catalyst (BF
3sdotEt2O)
The anhydrous AlCl3 FeCl
3 and SnCl
4were not able to
give the desired intermediate selectively in quantitative yieldThis was possibly due to poor Lewis acid character ofAlCl3 FeCl
3 and SnCl
4compared to BF
3 The reaction
was investigated carefully and it was observed that theintermediate (benzylic ketones (ix (andashi))) formed after thecoupling of phenol with substituted phenyl acetyl chloridewas sufficiently stable and could be isolated In the secondstep intermolecular cyclization was carried out with substi-tuted phenyl acetyl chloride and a base (anhydrous K
2CO3)
The desired product (vi-e) was characterized by 1H NMR(Figure S6(a) in Supplementary Material available online at
httpdxdoiorg1011552015527159) which contains addi-tional peaks at 120575 679 and 698 due to benzylic proton and at120575 72 and 73 due to phenylic protons and one signal at 120575 715was due to proton at para position in the phenyl ringThe restof the protons were the same as in the precursor that is orthosubstituted phenol (iv-a)13C NMR (Figure S6(b)) also confirmed the formation
of 4-(4-hydroxy-benzyl)-3-phenyl-chromen-2-one peaks at11960 12640 12838 12953 13405 and 16122 show sixdifferent types of carbons which are present in 4-aryl-3-phenyl-benzopyrone in addition to the carbons alreadypresent in the starting that is 2-(4-hydroxy-phenyl)-1-(2-hydroxy phenyl)-ethanone FTIR spectrum also confirmedthe formation of lactone ring that is the cyclized productshows carbonyl absorption at a higher wavenumber that isat 1707 cmminus1 (Figure S6(c)) while it was 1633 cmminus1 in the 2-(4-hydroxy-phenyl)-1-(2-hydroxy-phenyl)-ethanone (FigureS2(a)) Mass spectroscopy shows (m + 1) peak at 343 whilethe molecular weight of (vi-e) is 342 (Figure S6(d))
Finally the single crystal diffraction studies showed thespace orientation (Figures 3(a) and 3(b)) bond lengths andbond angles regarding the crystal structure (Table 1) The
4 Advances in Pharmacological Sciences
COCl
HO
Cl
O
minusO
OCH3
O OH
OClminus
OCH3
O OH
OCH3
OH
+
OCl
BF3
OCH3
O O
H3CO
OO
BF3
H3CO
O
+
H
OCH3
Ominus
OCl
BF3
H3CO
Ominus
O
+
BF3
OCH3
Ominus
Anhy K2CO3 dry acetone
Figure 2 Probable mechanism related to Scheme 2
structure reflects that the coumarin ring is planar phenylring which is attached at position 3 is slightly out of planeand substituted benzylic group is perpendicular to the ringcoumarin (Figure 3(a)) Compound (vi-e) exhibited ldquoZ-rdquo likepacking diagram (Figure 3(b))
This new procedure allows facile introduction of sub-stituents at position 4 of the 4-(4-substituted-benzyl)-3-phenyl-chromen-2-one skeleton and gives the flexibility forthe construction of novel precursors
Various derivatives have been prepared with para sub-stituted benzyl chloride with hydroxyl methoxy acetoxymethyl and ethyl groups as shown in Table 2 All thederivatives have been prepared smoothly under the samereaction conditions The reactions are simple easy to handleand feasible and have simple workup procedures
After the establishment of the protocol for the syn-thesis of substituted SERMs precursors (4-benzyl-3-phenylcoumarins) we shifted our focus towards the role of solventslike CH
2Cl2 CHCl
3 acetone and toluene upon yield and
the reaction time The results illustrated that the reactionin toluene did not give the desired precursors whereas the
Table 1 Bond lengths and bond angles of (vi-e) have beendemonstrated
S number Atoms Bond lengths Atoms Bond angles1 O3-C20 13772(1) C20-O3-C23 117762 O3-C23 13963(1) C8-O1-C7 121713 O1-C8 13848(1) O3-C20-C21 115934 O1-C7 13722(1) O1-C8-C1 115405 C5-C6 13610(1) O3-C20-C19 124736 C6-C7 14647(1) O1-C7-C6 117787 O2-C7 12114(1) C6-C7-O2 12571
reaction in CHCl3was slow and the yield was low However
for this cyclization CH2Cl2was found to be good in terms
of yield and handling but took a slightly longer time toafford the products Eventually acetone appeared as a solventof choice for intermolecular cyclization in very good yieldIntermolecular cyclization was greatly influenced by the baseused therefore to find out the appropriate base we examinedK2CO3and triethylamine in the intermolecular cyclization
Advances in Pharmacological Sciences 5
Prob= 50
Temp = 293
Z 154 ambl-s4 Pbca R = 009 Res = 0
PLAT
ON
-Mar
2807
25
252011
- (160211
)
C23O3
C19 C20C21
C17C18
C22
C5
C9C4
C3
C2
No move forced
C1
C8
C16 C6
C10
C15C14
C11
C12
C13
C7
O1
O2
(a) (b)
Figure 3 (a) ORTEPPLATON structure of (vi-e) (b) Packing structure of (vi-e) showing Z-like packing
Table 2 Derivatives of 4-aryl-3-phenyl-coumarin-2-one and theiryield () for Scheme 2
S number Compound R R2
Time (h) Yielda ()1 (vi-a) -OH H 7 742 (vi-b) -OH -CH
37 77
3 (vi-c) -OH -OCH3
6 804 (vi-d) -OH -C
2H5
8 705 (vi-e) -OCH
3H 7 75
6 (vi-f) -OCH3
-CH3
8 797 (vi-g) -OCH
3-OCH
37 82
8 (vi-h) -OCH3
-C2H5
7 809 (vi-i) -OAc H 6 90aThe reaction yield refers to product isolated through column chromatogra-phy
reaction of (ix-a) with (v) and found that the reaction in thepresence of K
2CO3afforded the cyclized product (vi-a) in
74yield after 7 h whereas triethylamine gave this product in57 yield We believe that potassium carbonate may be moredissociated in aprotic polar solvents and consequently provedto be more reactive
3 Conclusion
In conclusion a simple efficient and novel method hasbeen developed for an easy access to synthesis of the 4-(4-hydroxy-benzyl)-3-phenyl-chromen-2-one via Scheme 2and this has been supported by 1H NMR FTIR 13C NMRmass spectroscopy and single crystal X-ray data analysisSynthetic pathway with just 2 steps proved to be the bestwith less side reactions and greater yield Thus the numberof steps has been decreased and the yield was increasedHerein we reported some precursors of coumarin basedSERMs which could be useful in designing new SERMs Thepure products were obtained by column chromatography
This methodology presents several advantages including (a)mild reaction conditions (b) simple workup procedure (c)moderately high yields of the desired products (d) theselectivity of the product and finally (e) economic availabilityof the reagents making the whole process simple and feasibleEfforts to extend the span of the procedure on SERMs areunder progress in our laboratory
4 Experimental Section
41 General Methods All the required chemicals are pur-chased since they are commercially available and used asreceived without further purification Commercially avail-able acetone and benzene were further purified and driedfollowing the known procedure Thin-layer chromatography(TLC) was performed using silica gel 60 F254 precoatedplates Column chromatography was carried out on silica gel60 (100ndash200mesh) Infrared (FTIR) spectra were recordedin KBr and wavelengths (]) have been reported in cmminus1 1Hand 13C NMR spectra were recorded on NMR spectrometersoperating at 300 and 755MHz respectively Chemical shifts(120575) were given in parts per million (ppm) using the residuesolvent peaks as reference relative to TMS 119869 values have beengiven in Hz Mass spectra were recorded using electrosprayionization (ESI) mass spectrometer The melting points weretaken in open capillary and uncorrected
411 Procedure for Scheme 1
Compound (ii) To a solution of 4-methoxy phenyl acetic acid(425 g 025mol) in dry benzene (50mL) was added thionylchloride (30mL 025mol) dropwise with syringe After thereaction was complete the reaction mixture was distilledto remove excess thionyl chloride and the solvent benzeneBrown colored liquid was obtained Yield- 50 1H NMR-(300MHz CDCl
Compound (iii) A solution of p-methoxy phenyl acetylchloride (24 g 013mol) and phenol (122mL 013mol) in drybenzene (63mL) was refluxed for 21 h till the reaction wascomplete as monitored by TLC Then the reaction mixturewas washed with 5 aqueous NaOH to remove excessunreacted phenol and then washed with water three timesand dried over anhydrous Na
Compounds (vi (a-h)) To a solution of ortho substituted phe-nol (236mg 1mmol) and K
2CO3(690mg 5mmol) in dry
acetone (25mL) was added phenyl acetyl chloride (308mg2mmol) dropwise The reaction mixture was refluxed at100∘C for 7 h After the reaction was completed (asmonitoredby TLC) the reaction mixture was cooled filtered and con-centrated The residue was chromatographed to obtain thepure compound with 20 ethyl acetate-hexane Yield- 70
412 Procedure for Scheme 2
Compound (ix-e) To a solution of 4-methoxy phenyl aceticacid (166mg 1mmol) in dry acetone (10mL) was addedBF3sdotEt2O (04mL 3mmol) at 0∘C After 30 minutes we
added phenol (01mL 1mmol) and refluxed it till the reactionwas completed as monitored by TLC Then we filtered thereaction mixture and evaporated the solvent in vacuum
White solid was obtained recrystallized from ethanol Yield-80 mp 65∘C 1H NMR- (300MHz CDCl
Compound (vi-e) Phenyl acetyl chloride (013mL 1mmol)was added to a solution of (ix-e) (242mg 1mmol) in dryacetone and K
2CO3(552mg 4mmol) and refluxed for 6 h
Then the reaction mixture was filtered and concentrated invacuumThe obtained crude was recrystallized from ethanolto obtain the pure product Yield- 75
Procedure for Compound (vi-i) Acetic anhydride (920mg1mL) was added to a solution of (vi-a) (328mg 1mmol)and pyridine (025mL 9mmol) and refluxed under nitrogenatmosphere for 6 h at 90∘C After the reaction was completed(as monitored by TLC) solvent was removed under vacuumThe residuewaswashedwith saturatedNa
2HCO3until excess
pyridine was removed and then it was washed with aqueousHCl and finally with saturated brine solution and dried andchromatographed with 20 ethyl acetate-hexane Yield 90mp 160∘C
Analytical Data for Compounds (vi (andashi))
(vi-a) 1H NMR- (300MHz CDCl3) 120575 403 (s 2H -CH
864Hz 2H Ar-H) 720 (t 119869 = 144Hz 1H Ar-H) 730 (m2H Ar-H) 743 (m 4H Ar-H) 753 (m 2H Ar-H) (FigureS7)119898119911 37012 Elemental Analysis C 7782 H 490 O 1728119898119911 370 C 8106 H 599 O 1296
Note Crystallographic information is given in the supportingfile with details of refinement and other structural parame-ters
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The authors are thankful to the Department of ChemistryBHU for proving NMR FTIR and single crystal X-ray dataFinancial assistance from CSIR (Grant no 01(2362)10EMR-II) New Delhi in the form of a project and fellowships toAmbika Srivastava and Pooja Singh andCSIR andUGCNewDelhi in the form of SRF and UGC Fellowship respectivelyis gratefully acknowledged
References
[1] L J Black C D Jones and J F Falcone ldquoAntagonism of estro-gen action with a new benzothiophene derived antiestrogenrdquoLife Sciences vol 32 no 9 pp 1031ndash1036 1983
[2] A U Buzdar CMarcus F Holmes V Hug and G HortobagyildquoPhase II evaluation of LY156758 in metastatic breast cancerrdquoOncology vol 45 no 5 pp 344ndash345 1988
[3] K R Snyder N Sparano and J M Malinowski ldquoRaloxifenehydrochloriderdquo American Journal of Health-System Pharmacyvol 57 no 18 pp 1669ndash1678 2000
[4] V C Jordan E Phelps and J U Lindgren ldquoEffects of anti-estrogens on bone in castrated and intact female ratsrdquo BreastCancer Research and Treatment vol 10 no 1 pp 31ndash35 1987
[5] L J Black M Sato E R Rowley et al ldquoRaloxifene (LY139481HCI) prevents bone loss and reduces serum cholesterol withoutcausing uterine hypertrophy in ovariectomized ratsrdquo The Jour-nal of Clinical Investigation vol 93 no 1 pp 63ndash69 1994
[6] M M Gottardis and V C Jordan ldquoAntitumor actions ofkeoxifene and tamoxifen in the N-nitrosomethylurea-inducedrat mammary carcinoma modelrdquo Cancer Research vol 47 no15 pp 4020ndash4024 1987
[7] M A Anzano C W Peer J M Smith et al ldquoChemopreventionof mammary carcinogenesis in the rat combined use of ralox-ifene and 9-cis-retinoic acidrdquo Journal of the National CancerInstitute vol 88 no 2 pp 123ndash125 1996
[8] B Ettinger D M Black B H Mitlak et al ldquoReduction of verte-bral fracture risk in postmenopausal women with osteoporosistreated with raloxifene results from a 3-year randomizedclinical trialrdquo The Journal of the American Medical Associationvol 282 no 7 pp 637ndash645 1999
[9] S R Cummings S Eckert K A Krueger et al ldquoThe effect ofraloxifene on risk of breast cancer in postmenopausal womenresults from the MORE randomized trialrdquo The Journal of theAmerican Medical Association vol 281 no 23 pp 2189ndash21971999
[10] MClarke R Collins CDavies J Godwin R Gray andR PetoldquoThe EBCTCG secretariat clinical trial service unit radcliffeinfirmary Oxford OX2 6HE UKrdquoThe Lancet vol 351 pp 1451ndash1467 1998
[11] B Fisher J P Costantino D L Wickerham et al ldquoTamoxifenfor prevention of breast cancer report of the National SurgicalAdjuvant Breast and Bowel Project P-1 Studyrdquo Journal of theNational Cancer Institute vol 90 no 18 pp 1371ndash1388 1998
[12] R R Love R BMazessH S Barden et al ldquoEffects of tamoxifenon bonemineral density in postmenopausal women with breastcancerrdquo The New England Journal of Medicine vol 326 no 13pp 852ndash856 1992
[13] V J Assikis P Neven V C Jordan and I Vergote ldquoA realisticclinical perspective of tamoxifen and endometrial carcinogene-sisrdquo European Journal of Cancer A vol 32 no 9 pp 1464ndash14761996
[14] E J Lederer ldquoChemistry and biochemistry of somemammaliansecretions and excretionsrdquo Journal of the Chemical Society pp2115ndash2125 1949
[15] G G Freeman ldquoIsolation of alternariol and alternariol mono-methyl ether from Alternaria dauci (kuhn) groves and skolkordquoPhytochemistry vol 5 no 4 pp 719ndash725 1966
[16] W T L Sidwell H Fritz and C Tamm ldquoAutumnariol undAutumnariniol zwei neue Dibenzo-120572-pyrone aus Eucomisautumnalis Graeb Nachweis einer Fernkopplung uber sechsBindungen in den magnetischen ProtonenresonanzmdashSpek-trenrdquo Helvetica Chimica Acta vol 54 no 1 pp 207ndash215 1971
[17] L Farkas F Soti M Incze and M Nogradi ldquoSynthesenaturlicher Dibenzo-120572-pyrone I Synthese des Autumnariniolsund des Autumnariniolsrdquo Chemische Berichte vol 107 no 12pp 3874ndash3877 1974
[18] S Ghosal J P Reddy and V K Lal ldquoShilajit I chemicalconstituentsrdquo Journal of Pharmaceutical Sciences vol 65 no 5pp 772ndash773 1976
8 Advances in Pharmacological Sciences
[19] B Naser-Hijazi B Stolze and K S Zanker Second Proceed-ings of the International Society of the Coumarin InvestigatorsSpringer Berlin Germany 1994
[20] R D H Murray J Mendez and S A Brown The Natu-ral Coumarin Occurrence Chemistry and Biochemistry JohnWiley Chichester UK 1982
[21] J D Hepworth C D Gabbutt and B N Heron ComprehensiveHeterocyclic Chemistry II vol 5 Pergamon Press Oxford UK1996
[22] F M Deans Naturally Occurring Oxygen Ring CompoundsButterworths London UK 1963
[23] J A Joule and K Mills Eds Heterocyclic Chemistry BlackwellScience Oxford UK 4th edition 2006
[24] R D H Murray ldquoNaturally occurring plant coumarinsrdquo Fort-schritte der Chemie Organischer Naturstoffe vol 35 pp 199ndash2491978
[25] G R Geen J M Evans and A K Vong in ComprehensiveHeterocyclic Chemistry II A R Katritzky C W Rees and EF V Scriven Eds vol 5 p 469 Pergamon Press Oxford UK1984
[26] H-X Xu and S F Lee ldquoActivity of plant flavonoids againstantibiotic-resistant bacteriardquo Phytotherapy Research vol 15 no1 pp 39ndash43 2001
[27] J M Hamilton-Miller ldquoAntimicrobial properties of tea (Camel-lia sinensis L)rdquoAntimicrobial Agents and Chemotherapy vol 39no 11 pp 2375ndash2377 1995
[28] K C Fylaktakidou D J Hadjipavlou-Litina K E Litinas andD N Nicolaides ldquoNatural and synthetic coumarin derivativeswith anti-inflammatoryantioxidant activitiesrdquo Current Phar-maceutical Design vol 10 no 30 pp 3813ndash3833 2004
[29] J R Hwu R Singha S C Hong et al ldquoSynthesis of newbenzimidazole-coumarin conjugates as anti-hepatitis C virusagentsrdquo Antiviral Research vol 77 no 2 pp 157ndash162 2008
[30] S Sardari Y Mori K Horita R G Micetich S Nishibe andMDaneshtalab ldquoSynthesis and antifungal activity of coumarinsand angular furanocoumarinsrdquo Bioorganic amp Medicinal Chem-istry vol 7 no 9 pp 1933ndash1940 1999
[31] D Egan P James D Cooke and R OrsquoKennedy ldquoStudies on thecytostatic and cytotoxic effects and mode of action of 8-nitro-7-hydroxycoumarinrdquo Cancer Letters vol 118 no 2 pp 201ndash2111997
[32] P Valenti A Rampa M Recanatini et al ldquoSynthesis cytotoxic-ity and SAR of simple geiparvarin analoguesrdquoAnti-Cancer DrugDesign vol 12 no 6 pp 443ndash451 1997
[33] C Spino M Dodier and S Sotheeswaran ldquoAnti-HIV coum-arins from calophyllum seed oilrdquo Bioorganic and MedicinalChemistry Letters vol 8 no 24 pp 3475ndash3478 1998
[34] L M Bedoya M Beltran R Sancho et al ldquo4-Phenylcoumarinsas HIV transcription inhibitorsrdquo Bioorganic ampMedicinal Chem-istry Letters vol 15 no 20 pp 4447ndash4450 2005
[35] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[36] D Yu M Suzuki L Xie S L Morris-Natschke and K-H LeeldquoRecent progress in the development of coumarin derivativesas potent anti-HIV agentsrdquoMedicinal Research Reviews vol 23no 3 pp 322ndash345 2003
[37] S Kirkiacharian D T Thuy S Sicsic R Bakhchinian RKurkjian and T Tonnaire ldquoStructurendashactivity relationshipsof some 3-substituted-4-hydroxycoumarins as HIV-1 proteaseinhibitorsrdquo Farmaco vol 57 no 9 pp 703ndash708 2002
[38] A G Kidane H Salacinski A Tiwari K R Bruckdorfer andA M Seifalian ldquoAnticoagulant and antiplatelet agents theirclinical and device application(s) together with usages to engi-neer surfacesrdquo Biomacromolecules vol 5 no 3 pp 798ndash8132004
[39] KMKhan Z S SaifyM Z Khan et al ldquoSynthesis of coumarinderivatives with cytotoxic antibacterial and antifungal activityrdquoJournal of Enzyme Inhibition and Medicinal Chemistry vol 19no 4 pp 373ndash379 2004
[40] G Appendino E Mercalli N Fuzzati et al ldquoAntimycobacterialcoumarins from the Sardinian giant fennel (Ferula communis)rdquoJournal of Natural Products vol 67 no 12 pp 2108ndash2110 2004
[41] NHamdiM Saoud andARomerosa ldquo4-Hydroxy coumarinea versatile reagent for the synthesis of heterocyclic and vanillinether coumarins with biological activitiesrdquo in Bioactive Hetero-cycles V vol 11 of Topics in Heterocyclic Chemistry pp 283ndash301Springer Berlin Germany 2007
[42] F Chimenti B Bizzarri A Bolasco et al ldquoSynthesis and in vitroselective anti-Helicobacter pylori activity of N-substituted-2-oxo-2H-1-benzopyran-3-carboxamidesrdquo European Journal ofMedicinal Chemistry vol 41 no 2 pp 208ndash212 2006
[43] C Ito M Itoigawa Y Mishina et al ldquoChemical con-stituents of Calophyllum brasiliense 2 Structure of three newcoumarins and cancer chemopreventive activity of 4-substi-tuted coumarinsrdquo Journal of Natural Products vol 66 no 3 pp368ndash371 2003
[44] I Kostova ldquoSynthetic and natural coumarins as cytotoxicagentsrdquo Current Medicinal ChemistrymdashAnti-Cancer Agents vol5 no 1 pp 29ndash46 2005
[45] GMelagraki A Afantitis O Igglessi-Markopoulou et al ldquoSyn-thesis and evaluation of the antioxidant and anti-inflammatoryactivity of novel coumarin-3-aminoamides and their alpha-lipoic acid adductsrdquo European Journal of Medicinal Chemistryvol 44 no 7 pp 3020ndash3026 2009
[46] C A Kontogiorgis and D J Hadjipavlou-Litina ldquoSynthesis andantiinflammatory activity of coumarin derivativesrdquo Journal ofMedicinal Chemistry vol 48 no 20 pp 6400ndash6408 2005
[47] S Stanchev V Hadjimitova T Traykov T Boyanov and IManolov ldquoInvestigation of the antioxidant properties of somenew 4-hydroxycoumarin derivativesrdquo European Journal ofMed-icinal Chemistry vol 44 no 7 pp 3077ndash3082 2009
[48] C A Kontogiorgis and D J Hadjipavlou-Litina ldquoSynthesis andbiological evaluation of novel coumarin derivatives with a 7-azomethine linkagerdquo Bioorganic and Medicinal Chemistry Let-ters vol 14 no 3 pp 611ndash614 2004
[49] C Xiao Z-G Song and Z-Q Liu ldquoSynthesis of methyl-substi-tuted xanthotoxol to clarify prooxidant effect of methyl onradical-induced oxidation of DNArdquo European Journal of Medic-inal Chemistry vol 45 no 6 pp 2559ndash2566 2010
[50] O M Abdel Hafez K M Amin N A Abdel-Latif T KMohamed E Y Ahmed and T Maher ldquoSynthesis and antitu-mor activity of some new xanthotoxin derivativesrdquo EuropeanJournal of Medicinal Chemistry vol 44 no 7 pp 2967ndash29742009
[51] V Reutrakul P Leewanich P Tuchinda et al ldquoCytotoxic coum-arins fromMammea harmandiirdquo Planta Medica vol 69 no 11pp 1048ndash1051 2003
[52] I Kempen D Papapostolou N Thierry et al ldquo3-Bromophenyl6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylateinhibits cancer cell invasion in vitro and tumour growth invivordquo British Journal of Cancer vol 88 no 7 pp 1111ndash1118 2003
Advances in Pharmacological Sciences 9
[53] P OrsquoKennedy and R D Thornes Eds Coumarins BiologyApplications andMode ofAction JohnWileyampSons ChichesterUK 1997
[54] L Zhi C M Tegley E A Kallel et al ldquo5-Aryl-12-dihydrochro-meno[34-f]quinolines a novel class of nonsteroidal humanprogesterone receptor agonistsrdquo Journal ofMedicinal Chemistryvol 41 no 3 pp 291ndash302 1998
[55] J M Schmidt G B Tremblay M Page et al ldquoSynthesisand evaluation of a novel nonsteroidal-specific endothelial cellproliferation inhibitorrdquo Journal of Medicinal Chemistry vol 46no 8 pp 1289ndash1292 2003
[56] K Hajela K Kapoor and R Kapil ldquoSynthesis and post-coitalcontraceptive activity of ether and ester analogues of 23-diaryl-2H-1-benzopyransrdquo Bioorganic amp Medicinal Chemistry vol 3pp 1417ndash1420 1995
[57] K Hajela and R S Kapil ldquoSynthesis and post-coital contra-ceptive activity of a new series of substituted 23-diaryl-2H-1-benzopyransrdquo European Journal of Medicinal Chemistry vol 32no 2 pp 135ndash139 1997
[58] K Hajela J Pandey A Dwivedy et al ldquoResolution molecularstructure and biological activities of the D- and L-enan-tiomers of potent anti-implantation agent DL-2-[4-(2-piperi-dinoethoxy)phenyl]-3-phenyl-2H-1-benzopyranrdquo Bioorganic ampMedicinal Chemistry vol 7 no 9 pp 2083ndash2090 1999
[59] H Pechmann and C Duisberg ldquoNeue Bildungsweise derCumarine Synthese desDaphnetins IrdquoChemische Berichte vol17 no 1 pp 929ndash936 1884
[60] J Johnson ldquoThe Perkin reaction and related reactionsrdquoOrganicReactions vol 1 pp 210ndash265 1942
[61] G Jones ldquoThe Knoevenagel condensationrdquo Organic Reactionsvol 15 pp 204ndash599 1967
[62] G Brufola F Fringuelli O Piermatti and F Pizzo ldquoSimpleand efficient one-pot preparation of 3-substituted coumarins inwaterrdquo Heterocycles vol 43 no 6 pp 1257ndash1266 1996
[63] R L Shriner ldquoThe reformatsky reactionrdquo in Organic Reactionsvol 1 pp 1ndash58 John Wiley amp Sons 1942
[64] I Yavari RHekmat-Shoar andA Zonouzi ldquoAnewand efficientroute to 4-carboxymethylcoumarins mediated by vinyltriph-enylphosphonium saltrdquo Tetrahedron Letters vol 39 no 16 pp2391ndash2392 1998
[65] J R Johnson ldquoPerkin reaction and related reactionsrdquo OrganicReactions vol 1 p 210 1942
[66] M H Elnagdi S O Abdallah K M Ghoneim E M Ebiedand K N Kassab ldquoSynthesis of some Coumarin derivatives aspotential LaserDyesrdquo Journal of Chemical Research Synopsesno 2 pp 44ndash45 1997
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Scheme 1 Route 1 for the synthesis of coumarin based SERMrsquos precursors
COCl
R
+R
HOO COCl
OH
(vii) (ix (andashi)) (vi (andashi))(viii)
(v)
R2
O
R
O
R2
where R = OCH3 OH R2 = H CH3 C2H5 OCH3
Dry acetonereflux Dry acetone K2CO3 reflux
BF3middotEt2O
Scheme 2 Route 2 for the synthesis of coumarin based SERMrsquos precursors
group at ortho position of phenol This stage product wasachieved by Scheme 1 after 3 steps with low atom economyand many undesirable products The intermediate ester(Scheme 2) could not be isolated since BF
3sdotEt2O readily
rearranged it to ortho substituted phenol Thus the two-stepprocess was reduced to one step the probable mechanism ofwhich has been given in Figure 2
In our early attempts to synthesize the coumarin basedSERMs precursors we were not successful in convertingthe reactants to products without the catalyst (BF
3sdotEt2O)
The anhydrous AlCl3 FeCl
3 and SnCl
4were not able to
give the desired intermediate selectively in quantitative yieldThis was possibly due to poor Lewis acid character ofAlCl3 FeCl
3 and SnCl
4compared to BF
3 The reaction
was investigated carefully and it was observed that theintermediate (benzylic ketones (ix (andashi))) formed after thecoupling of phenol with substituted phenyl acetyl chloridewas sufficiently stable and could be isolated In the secondstep intermolecular cyclization was carried out with substi-tuted phenyl acetyl chloride and a base (anhydrous K
2CO3)
The desired product (vi-e) was characterized by 1H NMR(Figure S6(a) in Supplementary Material available online at
httpdxdoiorg1011552015527159) which contains addi-tional peaks at 120575 679 and 698 due to benzylic proton and at120575 72 and 73 due to phenylic protons and one signal at 120575 715was due to proton at para position in the phenyl ringThe restof the protons were the same as in the precursor that is orthosubstituted phenol (iv-a)13C NMR (Figure S6(b)) also confirmed the formation
of 4-(4-hydroxy-benzyl)-3-phenyl-chromen-2-one peaks at11960 12640 12838 12953 13405 and 16122 show sixdifferent types of carbons which are present in 4-aryl-3-phenyl-benzopyrone in addition to the carbons alreadypresent in the starting that is 2-(4-hydroxy-phenyl)-1-(2-hydroxy phenyl)-ethanone FTIR spectrum also confirmedthe formation of lactone ring that is the cyclized productshows carbonyl absorption at a higher wavenumber that isat 1707 cmminus1 (Figure S6(c)) while it was 1633 cmminus1 in the 2-(4-hydroxy-phenyl)-1-(2-hydroxy-phenyl)-ethanone (FigureS2(a)) Mass spectroscopy shows (m + 1) peak at 343 whilethe molecular weight of (vi-e) is 342 (Figure S6(d))
Finally the single crystal diffraction studies showed thespace orientation (Figures 3(a) and 3(b)) bond lengths andbond angles regarding the crystal structure (Table 1) The
4 Advances in Pharmacological Sciences
COCl
HO
Cl
O
minusO
OCH3
O OH
OClminus
OCH3
O OH
OCH3
OH
+
OCl
BF3
OCH3
O O
H3CO
OO
BF3
H3CO
O
+
H
OCH3
Ominus
OCl
BF3
H3CO
Ominus
O
+
BF3
OCH3
Ominus
Anhy K2CO3 dry acetone
Figure 2 Probable mechanism related to Scheme 2
structure reflects that the coumarin ring is planar phenylring which is attached at position 3 is slightly out of planeand substituted benzylic group is perpendicular to the ringcoumarin (Figure 3(a)) Compound (vi-e) exhibited ldquoZ-rdquo likepacking diagram (Figure 3(b))
This new procedure allows facile introduction of sub-stituents at position 4 of the 4-(4-substituted-benzyl)-3-phenyl-chromen-2-one skeleton and gives the flexibility forthe construction of novel precursors
Various derivatives have been prepared with para sub-stituted benzyl chloride with hydroxyl methoxy acetoxymethyl and ethyl groups as shown in Table 2 All thederivatives have been prepared smoothly under the samereaction conditions The reactions are simple easy to handleand feasible and have simple workup procedures
After the establishment of the protocol for the syn-thesis of substituted SERMs precursors (4-benzyl-3-phenylcoumarins) we shifted our focus towards the role of solventslike CH
2Cl2 CHCl
3 acetone and toluene upon yield and
the reaction time The results illustrated that the reactionin toluene did not give the desired precursors whereas the
Table 1 Bond lengths and bond angles of (vi-e) have beendemonstrated
S number Atoms Bond lengths Atoms Bond angles1 O3-C20 13772(1) C20-O3-C23 117762 O3-C23 13963(1) C8-O1-C7 121713 O1-C8 13848(1) O3-C20-C21 115934 O1-C7 13722(1) O1-C8-C1 115405 C5-C6 13610(1) O3-C20-C19 124736 C6-C7 14647(1) O1-C7-C6 117787 O2-C7 12114(1) C6-C7-O2 12571
reaction in CHCl3was slow and the yield was low However
for this cyclization CH2Cl2was found to be good in terms
of yield and handling but took a slightly longer time toafford the products Eventually acetone appeared as a solventof choice for intermolecular cyclization in very good yieldIntermolecular cyclization was greatly influenced by the baseused therefore to find out the appropriate base we examinedK2CO3and triethylamine in the intermolecular cyclization
Advances in Pharmacological Sciences 5
Prob= 50
Temp = 293
Z 154 ambl-s4 Pbca R = 009 Res = 0
PLAT
ON
-Mar
2807
25
252011
- (160211
)
C23O3
C19 C20C21
C17C18
C22
C5
C9C4
C3
C2
No move forced
C1
C8
C16 C6
C10
C15C14
C11
C12
C13
C7
O1
O2
(a) (b)
Figure 3 (a) ORTEPPLATON structure of (vi-e) (b) Packing structure of (vi-e) showing Z-like packing
Table 2 Derivatives of 4-aryl-3-phenyl-coumarin-2-one and theiryield () for Scheme 2
S number Compound R R2
Time (h) Yielda ()1 (vi-a) -OH H 7 742 (vi-b) -OH -CH
37 77
3 (vi-c) -OH -OCH3
6 804 (vi-d) -OH -C
2H5
8 705 (vi-e) -OCH
3H 7 75
6 (vi-f) -OCH3
-CH3
8 797 (vi-g) -OCH
3-OCH
37 82
8 (vi-h) -OCH3
-C2H5
7 809 (vi-i) -OAc H 6 90aThe reaction yield refers to product isolated through column chromatogra-phy
reaction of (ix-a) with (v) and found that the reaction in thepresence of K
2CO3afforded the cyclized product (vi-a) in
74yield after 7 h whereas triethylamine gave this product in57 yield We believe that potassium carbonate may be moredissociated in aprotic polar solvents and consequently provedto be more reactive
3 Conclusion
In conclusion a simple efficient and novel method hasbeen developed for an easy access to synthesis of the 4-(4-hydroxy-benzyl)-3-phenyl-chromen-2-one via Scheme 2and this has been supported by 1H NMR FTIR 13C NMRmass spectroscopy and single crystal X-ray data analysisSynthetic pathway with just 2 steps proved to be the bestwith less side reactions and greater yield Thus the numberof steps has been decreased and the yield was increasedHerein we reported some precursors of coumarin basedSERMs which could be useful in designing new SERMs Thepure products were obtained by column chromatography
This methodology presents several advantages including (a)mild reaction conditions (b) simple workup procedure (c)moderately high yields of the desired products (d) theselectivity of the product and finally (e) economic availabilityof the reagents making the whole process simple and feasibleEfforts to extend the span of the procedure on SERMs areunder progress in our laboratory
4 Experimental Section
41 General Methods All the required chemicals are pur-chased since they are commercially available and used asreceived without further purification Commercially avail-able acetone and benzene were further purified and driedfollowing the known procedure Thin-layer chromatography(TLC) was performed using silica gel 60 F254 precoatedplates Column chromatography was carried out on silica gel60 (100ndash200mesh) Infrared (FTIR) spectra were recordedin KBr and wavelengths (]) have been reported in cmminus1 1Hand 13C NMR spectra were recorded on NMR spectrometersoperating at 300 and 755MHz respectively Chemical shifts(120575) were given in parts per million (ppm) using the residuesolvent peaks as reference relative to TMS 119869 values have beengiven in Hz Mass spectra were recorded using electrosprayionization (ESI) mass spectrometer The melting points weretaken in open capillary and uncorrected
411 Procedure for Scheme 1
Compound (ii) To a solution of 4-methoxy phenyl acetic acid(425 g 025mol) in dry benzene (50mL) was added thionylchloride (30mL 025mol) dropwise with syringe After thereaction was complete the reaction mixture was distilledto remove excess thionyl chloride and the solvent benzeneBrown colored liquid was obtained Yield- 50 1H NMR-(300MHz CDCl
Compound (iii) A solution of p-methoxy phenyl acetylchloride (24 g 013mol) and phenol (122mL 013mol) in drybenzene (63mL) was refluxed for 21 h till the reaction wascomplete as monitored by TLC Then the reaction mixturewas washed with 5 aqueous NaOH to remove excessunreacted phenol and then washed with water three timesand dried over anhydrous Na
Compounds (vi (a-h)) To a solution of ortho substituted phe-nol (236mg 1mmol) and K
2CO3(690mg 5mmol) in dry
acetone (25mL) was added phenyl acetyl chloride (308mg2mmol) dropwise The reaction mixture was refluxed at100∘C for 7 h After the reaction was completed (asmonitoredby TLC) the reaction mixture was cooled filtered and con-centrated The residue was chromatographed to obtain thepure compound with 20 ethyl acetate-hexane Yield- 70
412 Procedure for Scheme 2
Compound (ix-e) To a solution of 4-methoxy phenyl aceticacid (166mg 1mmol) in dry acetone (10mL) was addedBF3sdotEt2O (04mL 3mmol) at 0∘C After 30 minutes we
added phenol (01mL 1mmol) and refluxed it till the reactionwas completed as monitored by TLC Then we filtered thereaction mixture and evaporated the solvent in vacuum
White solid was obtained recrystallized from ethanol Yield-80 mp 65∘C 1H NMR- (300MHz CDCl
Compound (vi-e) Phenyl acetyl chloride (013mL 1mmol)was added to a solution of (ix-e) (242mg 1mmol) in dryacetone and K
2CO3(552mg 4mmol) and refluxed for 6 h
Then the reaction mixture was filtered and concentrated invacuumThe obtained crude was recrystallized from ethanolto obtain the pure product Yield- 75
Procedure for Compound (vi-i) Acetic anhydride (920mg1mL) was added to a solution of (vi-a) (328mg 1mmol)and pyridine (025mL 9mmol) and refluxed under nitrogenatmosphere for 6 h at 90∘C After the reaction was completed(as monitored by TLC) solvent was removed under vacuumThe residuewaswashedwith saturatedNa
2HCO3until excess
pyridine was removed and then it was washed with aqueousHCl and finally with saturated brine solution and dried andchromatographed with 20 ethyl acetate-hexane Yield 90mp 160∘C
Analytical Data for Compounds (vi (andashi))
(vi-a) 1H NMR- (300MHz CDCl3) 120575 403 (s 2H -CH
864Hz 2H Ar-H) 720 (t 119869 = 144Hz 1H Ar-H) 730 (m2H Ar-H) 743 (m 4H Ar-H) 753 (m 2H Ar-H) (FigureS7)119898119911 37012 Elemental Analysis C 7782 H 490 O 1728119898119911 370 C 8106 H 599 O 1296
Note Crystallographic information is given in the supportingfile with details of refinement and other structural parame-ters
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The authors are thankful to the Department of ChemistryBHU for proving NMR FTIR and single crystal X-ray dataFinancial assistance from CSIR (Grant no 01(2362)10EMR-II) New Delhi in the form of a project and fellowships toAmbika Srivastava and Pooja Singh andCSIR andUGCNewDelhi in the form of SRF and UGC Fellowship respectivelyis gratefully acknowledged
References
[1] L J Black C D Jones and J F Falcone ldquoAntagonism of estro-gen action with a new benzothiophene derived antiestrogenrdquoLife Sciences vol 32 no 9 pp 1031ndash1036 1983
[2] A U Buzdar CMarcus F Holmes V Hug and G HortobagyildquoPhase II evaluation of LY156758 in metastatic breast cancerrdquoOncology vol 45 no 5 pp 344ndash345 1988
[3] K R Snyder N Sparano and J M Malinowski ldquoRaloxifenehydrochloriderdquo American Journal of Health-System Pharmacyvol 57 no 18 pp 1669ndash1678 2000
[4] V C Jordan E Phelps and J U Lindgren ldquoEffects of anti-estrogens on bone in castrated and intact female ratsrdquo BreastCancer Research and Treatment vol 10 no 1 pp 31ndash35 1987
[5] L J Black M Sato E R Rowley et al ldquoRaloxifene (LY139481HCI) prevents bone loss and reduces serum cholesterol withoutcausing uterine hypertrophy in ovariectomized ratsrdquo The Jour-nal of Clinical Investigation vol 93 no 1 pp 63ndash69 1994
[6] M M Gottardis and V C Jordan ldquoAntitumor actions ofkeoxifene and tamoxifen in the N-nitrosomethylurea-inducedrat mammary carcinoma modelrdquo Cancer Research vol 47 no15 pp 4020ndash4024 1987
[7] M A Anzano C W Peer J M Smith et al ldquoChemopreventionof mammary carcinogenesis in the rat combined use of ralox-ifene and 9-cis-retinoic acidrdquo Journal of the National CancerInstitute vol 88 no 2 pp 123ndash125 1996
[8] B Ettinger D M Black B H Mitlak et al ldquoReduction of verte-bral fracture risk in postmenopausal women with osteoporosistreated with raloxifene results from a 3-year randomizedclinical trialrdquo The Journal of the American Medical Associationvol 282 no 7 pp 637ndash645 1999
[9] S R Cummings S Eckert K A Krueger et al ldquoThe effect ofraloxifene on risk of breast cancer in postmenopausal womenresults from the MORE randomized trialrdquo The Journal of theAmerican Medical Association vol 281 no 23 pp 2189ndash21971999
[10] MClarke R Collins CDavies J Godwin R Gray andR PetoldquoThe EBCTCG secretariat clinical trial service unit radcliffeinfirmary Oxford OX2 6HE UKrdquoThe Lancet vol 351 pp 1451ndash1467 1998
[11] B Fisher J P Costantino D L Wickerham et al ldquoTamoxifenfor prevention of breast cancer report of the National SurgicalAdjuvant Breast and Bowel Project P-1 Studyrdquo Journal of theNational Cancer Institute vol 90 no 18 pp 1371ndash1388 1998
[12] R R Love R BMazessH S Barden et al ldquoEffects of tamoxifenon bonemineral density in postmenopausal women with breastcancerrdquo The New England Journal of Medicine vol 326 no 13pp 852ndash856 1992
[13] V J Assikis P Neven V C Jordan and I Vergote ldquoA realisticclinical perspective of tamoxifen and endometrial carcinogene-sisrdquo European Journal of Cancer A vol 32 no 9 pp 1464ndash14761996
[14] E J Lederer ldquoChemistry and biochemistry of somemammaliansecretions and excretionsrdquo Journal of the Chemical Society pp2115ndash2125 1949
[15] G G Freeman ldquoIsolation of alternariol and alternariol mono-methyl ether from Alternaria dauci (kuhn) groves and skolkordquoPhytochemistry vol 5 no 4 pp 719ndash725 1966
[16] W T L Sidwell H Fritz and C Tamm ldquoAutumnariol undAutumnariniol zwei neue Dibenzo-120572-pyrone aus Eucomisautumnalis Graeb Nachweis einer Fernkopplung uber sechsBindungen in den magnetischen ProtonenresonanzmdashSpek-trenrdquo Helvetica Chimica Acta vol 54 no 1 pp 207ndash215 1971
[17] L Farkas F Soti M Incze and M Nogradi ldquoSynthesenaturlicher Dibenzo-120572-pyrone I Synthese des Autumnariniolsund des Autumnariniolsrdquo Chemische Berichte vol 107 no 12pp 3874ndash3877 1974
[18] S Ghosal J P Reddy and V K Lal ldquoShilajit I chemicalconstituentsrdquo Journal of Pharmaceutical Sciences vol 65 no 5pp 772ndash773 1976
8 Advances in Pharmacological Sciences
[19] B Naser-Hijazi B Stolze and K S Zanker Second Proceed-ings of the International Society of the Coumarin InvestigatorsSpringer Berlin Germany 1994
[20] R D H Murray J Mendez and S A Brown The Natu-ral Coumarin Occurrence Chemistry and Biochemistry JohnWiley Chichester UK 1982
[21] J D Hepworth C D Gabbutt and B N Heron ComprehensiveHeterocyclic Chemistry II vol 5 Pergamon Press Oxford UK1996
[22] F M Deans Naturally Occurring Oxygen Ring CompoundsButterworths London UK 1963
[23] J A Joule and K Mills Eds Heterocyclic Chemistry BlackwellScience Oxford UK 4th edition 2006
[24] R D H Murray ldquoNaturally occurring plant coumarinsrdquo Fort-schritte der Chemie Organischer Naturstoffe vol 35 pp 199ndash2491978
[25] G R Geen J M Evans and A K Vong in ComprehensiveHeterocyclic Chemistry II A R Katritzky C W Rees and EF V Scriven Eds vol 5 p 469 Pergamon Press Oxford UK1984
[26] H-X Xu and S F Lee ldquoActivity of plant flavonoids againstantibiotic-resistant bacteriardquo Phytotherapy Research vol 15 no1 pp 39ndash43 2001
[27] J M Hamilton-Miller ldquoAntimicrobial properties of tea (Camel-lia sinensis L)rdquoAntimicrobial Agents and Chemotherapy vol 39no 11 pp 2375ndash2377 1995
[28] K C Fylaktakidou D J Hadjipavlou-Litina K E Litinas andD N Nicolaides ldquoNatural and synthetic coumarin derivativeswith anti-inflammatoryantioxidant activitiesrdquo Current Phar-maceutical Design vol 10 no 30 pp 3813ndash3833 2004
[29] J R Hwu R Singha S C Hong et al ldquoSynthesis of newbenzimidazole-coumarin conjugates as anti-hepatitis C virusagentsrdquo Antiviral Research vol 77 no 2 pp 157ndash162 2008
[30] S Sardari Y Mori K Horita R G Micetich S Nishibe andMDaneshtalab ldquoSynthesis and antifungal activity of coumarinsand angular furanocoumarinsrdquo Bioorganic amp Medicinal Chem-istry vol 7 no 9 pp 1933ndash1940 1999
[31] D Egan P James D Cooke and R OrsquoKennedy ldquoStudies on thecytostatic and cytotoxic effects and mode of action of 8-nitro-7-hydroxycoumarinrdquo Cancer Letters vol 118 no 2 pp 201ndash2111997
[32] P Valenti A Rampa M Recanatini et al ldquoSynthesis cytotoxic-ity and SAR of simple geiparvarin analoguesrdquoAnti-Cancer DrugDesign vol 12 no 6 pp 443ndash451 1997
[33] C Spino M Dodier and S Sotheeswaran ldquoAnti-HIV coum-arins from calophyllum seed oilrdquo Bioorganic and MedicinalChemistry Letters vol 8 no 24 pp 3475ndash3478 1998
[34] L M Bedoya M Beltran R Sancho et al ldquo4-Phenylcoumarinsas HIV transcription inhibitorsrdquo Bioorganic ampMedicinal Chem-istry Letters vol 15 no 20 pp 4447ndash4450 2005
[35] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[36] D Yu M Suzuki L Xie S L Morris-Natschke and K-H LeeldquoRecent progress in the development of coumarin derivativesas potent anti-HIV agentsrdquoMedicinal Research Reviews vol 23no 3 pp 322ndash345 2003
[37] S Kirkiacharian D T Thuy S Sicsic R Bakhchinian RKurkjian and T Tonnaire ldquoStructurendashactivity relationshipsof some 3-substituted-4-hydroxycoumarins as HIV-1 proteaseinhibitorsrdquo Farmaco vol 57 no 9 pp 703ndash708 2002
[38] A G Kidane H Salacinski A Tiwari K R Bruckdorfer andA M Seifalian ldquoAnticoagulant and antiplatelet agents theirclinical and device application(s) together with usages to engi-neer surfacesrdquo Biomacromolecules vol 5 no 3 pp 798ndash8132004
[39] KMKhan Z S SaifyM Z Khan et al ldquoSynthesis of coumarinderivatives with cytotoxic antibacterial and antifungal activityrdquoJournal of Enzyme Inhibition and Medicinal Chemistry vol 19no 4 pp 373ndash379 2004
[40] G Appendino E Mercalli N Fuzzati et al ldquoAntimycobacterialcoumarins from the Sardinian giant fennel (Ferula communis)rdquoJournal of Natural Products vol 67 no 12 pp 2108ndash2110 2004
[41] NHamdiM Saoud andARomerosa ldquo4-Hydroxy coumarinea versatile reagent for the synthesis of heterocyclic and vanillinether coumarins with biological activitiesrdquo in Bioactive Hetero-cycles V vol 11 of Topics in Heterocyclic Chemistry pp 283ndash301Springer Berlin Germany 2007
[42] F Chimenti B Bizzarri A Bolasco et al ldquoSynthesis and in vitroselective anti-Helicobacter pylori activity of N-substituted-2-oxo-2H-1-benzopyran-3-carboxamidesrdquo European Journal ofMedicinal Chemistry vol 41 no 2 pp 208ndash212 2006
[43] C Ito M Itoigawa Y Mishina et al ldquoChemical con-stituents of Calophyllum brasiliense 2 Structure of three newcoumarins and cancer chemopreventive activity of 4-substi-tuted coumarinsrdquo Journal of Natural Products vol 66 no 3 pp368ndash371 2003
[44] I Kostova ldquoSynthetic and natural coumarins as cytotoxicagentsrdquo Current Medicinal ChemistrymdashAnti-Cancer Agents vol5 no 1 pp 29ndash46 2005
[45] GMelagraki A Afantitis O Igglessi-Markopoulou et al ldquoSyn-thesis and evaluation of the antioxidant and anti-inflammatoryactivity of novel coumarin-3-aminoamides and their alpha-lipoic acid adductsrdquo European Journal of Medicinal Chemistryvol 44 no 7 pp 3020ndash3026 2009
[46] C A Kontogiorgis and D J Hadjipavlou-Litina ldquoSynthesis andantiinflammatory activity of coumarin derivativesrdquo Journal ofMedicinal Chemistry vol 48 no 20 pp 6400ndash6408 2005
[47] S Stanchev V Hadjimitova T Traykov T Boyanov and IManolov ldquoInvestigation of the antioxidant properties of somenew 4-hydroxycoumarin derivativesrdquo European Journal ofMed-icinal Chemistry vol 44 no 7 pp 3077ndash3082 2009
[48] C A Kontogiorgis and D J Hadjipavlou-Litina ldquoSynthesis andbiological evaluation of novel coumarin derivatives with a 7-azomethine linkagerdquo Bioorganic and Medicinal Chemistry Let-ters vol 14 no 3 pp 611ndash614 2004
[49] C Xiao Z-G Song and Z-Q Liu ldquoSynthesis of methyl-substi-tuted xanthotoxol to clarify prooxidant effect of methyl onradical-induced oxidation of DNArdquo European Journal of Medic-inal Chemistry vol 45 no 6 pp 2559ndash2566 2010
[50] O M Abdel Hafez K M Amin N A Abdel-Latif T KMohamed E Y Ahmed and T Maher ldquoSynthesis and antitu-mor activity of some new xanthotoxin derivativesrdquo EuropeanJournal of Medicinal Chemistry vol 44 no 7 pp 2967ndash29742009
[51] V Reutrakul P Leewanich P Tuchinda et al ldquoCytotoxic coum-arins fromMammea harmandiirdquo Planta Medica vol 69 no 11pp 1048ndash1051 2003
[52] I Kempen D Papapostolou N Thierry et al ldquo3-Bromophenyl6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylateinhibits cancer cell invasion in vitro and tumour growth invivordquo British Journal of Cancer vol 88 no 7 pp 1111ndash1118 2003
Advances in Pharmacological Sciences 9
[53] P OrsquoKennedy and R D Thornes Eds Coumarins BiologyApplications andMode ofAction JohnWileyampSons ChichesterUK 1997
[54] L Zhi C M Tegley E A Kallel et al ldquo5-Aryl-12-dihydrochro-meno[34-f]quinolines a novel class of nonsteroidal humanprogesterone receptor agonistsrdquo Journal ofMedicinal Chemistryvol 41 no 3 pp 291ndash302 1998
[55] J M Schmidt G B Tremblay M Page et al ldquoSynthesisand evaluation of a novel nonsteroidal-specific endothelial cellproliferation inhibitorrdquo Journal of Medicinal Chemistry vol 46no 8 pp 1289ndash1292 2003
[56] K Hajela K Kapoor and R Kapil ldquoSynthesis and post-coitalcontraceptive activity of ether and ester analogues of 23-diaryl-2H-1-benzopyransrdquo Bioorganic amp Medicinal Chemistry vol 3pp 1417ndash1420 1995
[57] K Hajela and R S Kapil ldquoSynthesis and post-coital contra-ceptive activity of a new series of substituted 23-diaryl-2H-1-benzopyransrdquo European Journal of Medicinal Chemistry vol 32no 2 pp 135ndash139 1997
[58] K Hajela J Pandey A Dwivedy et al ldquoResolution molecularstructure and biological activities of the D- and L-enan-tiomers of potent anti-implantation agent DL-2-[4-(2-piperi-dinoethoxy)phenyl]-3-phenyl-2H-1-benzopyranrdquo Bioorganic ampMedicinal Chemistry vol 7 no 9 pp 2083ndash2090 1999
[59] H Pechmann and C Duisberg ldquoNeue Bildungsweise derCumarine Synthese desDaphnetins IrdquoChemische Berichte vol17 no 1 pp 929ndash936 1884
[60] J Johnson ldquoThe Perkin reaction and related reactionsrdquoOrganicReactions vol 1 pp 210ndash265 1942
[61] G Jones ldquoThe Knoevenagel condensationrdquo Organic Reactionsvol 15 pp 204ndash599 1967
[62] G Brufola F Fringuelli O Piermatti and F Pizzo ldquoSimpleand efficient one-pot preparation of 3-substituted coumarins inwaterrdquo Heterocycles vol 43 no 6 pp 1257ndash1266 1996
[63] R L Shriner ldquoThe reformatsky reactionrdquo in Organic Reactionsvol 1 pp 1ndash58 John Wiley amp Sons 1942
[64] I Yavari RHekmat-Shoar andA Zonouzi ldquoAnewand efficientroute to 4-carboxymethylcoumarins mediated by vinyltriph-enylphosphonium saltrdquo Tetrahedron Letters vol 39 no 16 pp2391ndash2392 1998
[65] J R Johnson ldquoPerkin reaction and related reactionsrdquo OrganicReactions vol 1 p 210 1942
[66] M H Elnagdi S O Abdallah K M Ghoneim E M Ebiedand K N Kassab ldquoSynthesis of some Coumarin derivatives aspotential LaserDyesrdquo Journal of Chemical Research Synopsesno 2 pp 44ndash45 1997
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
structure reflects that the coumarin ring is planar phenylring which is attached at position 3 is slightly out of planeand substituted benzylic group is perpendicular to the ringcoumarin (Figure 3(a)) Compound (vi-e) exhibited ldquoZ-rdquo likepacking diagram (Figure 3(b))
This new procedure allows facile introduction of sub-stituents at position 4 of the 4-(4-substituted-benzyl)-3-phenyl-chromen-2-one skeleton and gives the flexibility forthe construction of novel precursors
Various derivatives have been prepared with para sub-stituted benzyl chloride with hydroxyl methoxy acetoxymethyl and ethyl groups as shown in Table 2 All thederivatives have been prepared smoothly under the samereaction conditions The reactions are simple easy to handleand feasible and have simple workup procedures
After the establishment of the protocol for the syn-thesis of substituted SERMs precursors (4-benzyl-3-phenylcoumarins) we shifted our focus towards the role of solventslike CH
2Cl2 CHCl
3 acetone and toluene upon yield and
the reaction time The results illustrated that the reactionin toluene did not give the desired precursors whereas the
Table 1 Bond lengths and bond angles of (vi-e) have beendemonstrated
S number Atoms Bond lengths Atoms Bond angles1 O3-C20 13772(1) C20-O3-C23 117762 O3-C23 13963(1) C8-O1-C7 121713 O1-C8 13848(1) O3-C20-C21 115934 O1-C7 13722(1) O1-C8-C1 115405 C5-C6 13610(1) O3-C20-C19 124736 C6-C7 14647(1) O1-C7-C6 117787 O2-C7 12114(1) C6-C7-O2 12571
reaction in CHCl3was slow and the yield was low However
for this cyclization CH2Cl2was found to be good in terms
of yield and handling but took a slightly longer time toafford the products Eventually acetone appeared as a solventof choice for intermolecular cyclization in very good yieldIntermolecular cyclization was greatly influenced by the baseused therefore to find out the appropriate base we examinedK2CO3and triethylamine in the intermolecular cyclization
Advances in Pharmacological Sciences 5
Prob= 50
Temp = 293
Z 154 ambl-s4 Pbca R = 009 Res = 0
PLAT
ON
-Mar
2807
25
252011
- (160211
)
C23O3
C19 C20C21
C17C18
C22
C5
C9C4
C3
C2
No move forced
C1
C8
C16 C6
C10
C15C14
C11
C12
C13
C7
O1
O2
(a) (b)
Figure 3 (a) ORTEPPLATON structure of (vi-e) (b) Packing structure of (vi-e) showing Z-like packing
Table 2 Derivatives of 4-aryl-3-phenyl-coumarin-2-one and theiryield () for Scheme 2
S number Compound R R2
Time (h) Yielda ()1 (vi-a) -OH H 7 742 (vi-b) -OH -CH
37 77
3 (vi-c) -OH -OCH3
6 804 (vi-d) -OH -C
2H5
8 705 (vi-e) -OCH
3H 7 75
6 (vi-f) -OCH3
-CH3
8 797 (vi-g) -OCH
3-OCH
37 82
8 (vi-h) -OCH3
-C2H5
7 809 (vi-i) -OAc H 6 90aThe reaction yield refers to product isolated through column chromatogra-phy
reaction of (ix-a) with (v) and found that the reaction in thepresence of K
2CO3afforded the cyclized product (vi-a) in
74yield after 7 h whereas triethylamine gave this product in57 yield We believe that potassium carbonate may be moredissociated in aprotic polar solvents and consequently provedto be more reactive
3 Conclusion
In conclusion a simple efficient and novel method hasbeen developed for an easy access to synthesis of the 4-(4-hydroxy-benzyl)-3-phenyl-chromen-2-one via Scheme 2and this has been supported by 1H NMR FTIR 13C NMRmass spectroscopy and single crystal X-ray data analysisSynthetic pathway with just 2 steps proved to be the bestwith less side reactions and greater yield Thus the numberof steps has been decreased and the yield was increasedHerein we reported some precursors of coumarin basedSERMs which could be useful in designing new SERMs Thepure products were obtained by column chromatography
This methodology presents several advantages including (a)mild reaction conditions (b) simple workup procedure (c)moderately high yields of the desired products (d) theselectivity of the product and finally (e) economic availabilityof the reagents making the whole process simple and feasibleEfforts to extend the span of the procedure on SERMs areunder progress in our laboratory
4 Experimental Section
41 General Methods All the required chemicals are pur-chased since they are commercially available and used asreceived without further purification Commercially avail-able acetone and benzene were further purified and driedfollowing the known procedure Thin-layer chromatography(TLC) was performed using silica gel 60 F254 precoatedplates Column chromatography was carried out on silica gel60 (100ndash200mesh) Infrared (FTIR) spectra were recordedin KBr and wavelengths (]) have been reported in cmminus1 1Hand 13C NMR spectra were recorded on NMR spectrometersoperating at 300 and 755MHz respectively Chemical shifts(120575) were given in parts per million (ppm) using the residuesolvent peaks as reference relative to TMS 119869 values have beengiven in Hz Mass spectra were recorded using electrosprayionization (ESI) mass spectrometer The melting points weretaken in open capillary and uncorrected
411 Procedure for Scheme 1
Compound (ii) To a solution of 4-methoxy phenyl acetic acid(425 g 025mol) in dry benzene (50mL) was added thionylchloride (30mL 025mol) dropwise with syringe After thereaction was complete the reaction mixture was distilledto remove excess thionyl chloride and the solvent benzeneBrown colored liquid was obtained Yield- 50 1H NMR-(300MHz CDCl
Compound (iii) A solution of p-methoxy phenyl acetylchloride (24 g 013mol) and phenol (122mL 013mol) in drybenzene (63mL) was refluxed for 21 h till the reaction wascomplete as monitored by TLC Then the reaction mixturewas washed with 5 aqueous NaOH to remove excessunreacted phenol and then washed with water three timesand dried over anhydrous Na
Compounds (vi (a-h)) To a solution of ortho substituted phe-nol (236mg 1mmol) and K
2CO3(690mg 5mmol) in dry
acetone (25mL) was added phenyl acetyl chloride (308mg2mmol) dropwise The reaction mixture was refluxed at100∘C for 7 h After the reaction was completed (asmonitoredby TLC) the reaction mixture was cooled filtered and con-centrated The residue was chromatographed to obtain thepure compound with 20 ethyl acetate-hexane Yield- 70
412 Procedure for Scheme 2
Compound (ix-e) To a solution of 4-methoxy phenyl aceticacid (166mg 1mmol) in dry acetone (10mL) was addedBF3sdotEt2O (04mL 3mmol) at 0∘C After 30 minutes we
added phenol (01mL 1mmol) and refluxed it till the reactionwas completed as monitored by TLC Then we filtered thereaction mixture and evaporated the solvent in vacuum
White solid was obtained recrystallized from ethanol Yield-80 mp 65∘C 1H NMR- (300MHz CDCl
Compound (vi-e) Phenyl acetyl chloride (013mL 1mmol)was added to a solution of (ix-e) (242mg 1mmol) in dryacetone and K
2CO3(552mg 4mmol) and refluxed for 6 h
Then the reaction mixture was filtered and concentrated invacuumThe obtained crude was recrystallized from ethanolto obtain the pure product Yield- 75
Procedure for Compound (vi-i) Acetic anhydride (920mg1mL) was added to a solution of (vi-a) (328mg 1mmol)and pyridine (025mL 9mmol) and refluxed under nitrogenatmosphere for 6 h at 90∘C After the reaction was completed(as monitored by TLC) solvent was removed under vacuumThe residuewaswashedwith saturatedNa
2HCO3until excess
pyridine was removed and then it was washed with aqueousHCl and finally with saturated brine solution and dried andchromatographed with 20 ethyl acetate-hexane Yield 90mp 160∘C
Analytical Data for Compounds (vi (andashi))
(vi-a) 1H NMR- (300MHz CDCl3) 120575 403 (s 2H -CH
864Hz 2H Ar-H) 720 (t 119869 = 144Hz 1H Ar-H) 730 (m2H Ar-H) 743 (m 4H Ar-H) 753 (m 2H Ar-H) (FigureS7)119898119911 37012 Elemental Analysis C 7782 H 490 O 1728119898119911 370 C 8106 H 599 O 1296
Note Crystallographic information is given in the supportingfile with details of refinement and other structural parame-ters
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The authors are thankful to the Department of ChemistryBHU for proving NMR FTIR and single crystal X-ray dataFinancial assistance from CSIR (Grant no 01(2362)10EMR-II) New Delhi in the form of a project and fellowships toAmbika Srivastava and Pooja Singh andCSIR andUGCNewDelhi in the form of SRF and UGC Fellowship respectivelyis gratefully acknowledged
References
[1] L J Black C D Jones and J F Falcone ldquoAntagonism of estro-gen action with a new benzothiophene derived antiestrogenrdquoLife Sciences vol 32 no 9 pp 1031ndash1036 1983
[2] A U Buzdar CMarcus F Holmes V Hug and G HortobagyildquoPhase II evaluation of LY156758 in metastatic breast cancerrdquoOncology vol 45 no 5 pp 344ndash345 1988
[3] K R Snyder N Sparano and J M Malinowski ldquoRaloxifenehydrochloriderdquo American Journal of Health-System Pharmacyvol 57 no 18 pp 1669ndash1678 2000
[4] V C Jordan E Phelps and J U Lindgren ldquoEffects of anti-estrogens on bone in castrated and intact female ratsrdquo BreastCancer Research and Treatment vol 10 no 1 pp 31ndash35 1987
[5] L J Black M Sato E R Rowley et al ldquoRaloxifene (LY139481HCI) prevents bone loss and reduces serum cholesterol withoutcausing uterine hypertrophy in ovariectomized ratsrdquo The Jour-nal of Clinical Investigation vol 93 no 1 pp 63ndash69 1994
[6] M M Gottardis and V C Jordan ldquoAntitumor actions ofkeoxifene and tamoxifen in the N-nitrosomethylurea-inducedrat mammary carcinoma modelrdquo Cancer Research vol 47 no15 pp 4020ndash4024 1987
[7] M A Anzano C W Peer J M Smith et al ldquoChemopreventionof mammary carcinogenesis in the rat combined use of ralox-ifene and 9-cis-retinoic acidrdquo Journal of the National CancerInstitute vol 88 no 2 pp 123ndash125 1996
[8] B Ettinger D M Black B H Mitlak et al ldquoReduction of verte-bral fracture risk in postmenopausal women with osteoporosistreated with raloxifene results from a 3-year randomizedclinical trialrdquo The Journal of the American Medical Associationvol 282 no 7 pp 637ndash645 1999
[9] S R Cummings S Eckert K A Krueger et al ldquoThe effect ofraloxifene on risk of breast cancer in postmenopausal womenresults from the MORE randomized trialrdquo The Journal of theAmerican Medical Association vol 281 no 23 pp 2189ndash21971999
[10] MClarke R Collins CDavies J Godwin R Gray andR PetoldquoThe EBCTCG secretariat clinical trial service unit radcliffeinfirmary Oxford OX2 6HE UKrdquoThe Lancet vol 351 pp 1451ndash1467 1998
[11] B Fisher J P Costantino D L Wickerham et al ldquoTamoxifenfor prevention of breast cancer report of the National SurgicalAdjuvant Breast and Bowel Project P-1 Studyrdquo Journal of theNational Cancer Institute vol 90 no 18 pp 1371ndash1388 1998
[12] R R Love R BMazessH S Barden et al ldquoEffects of tamoxifenon bonemineral density in postmenopausal women with breastcancerrdquo The New England Journal of Medicine vol 326 no 13pp 852ndash856 1992
[13] V J Assikis P Neven V C Jordan and I Vergote ldquoA realisticclinical perspective of tamoxifen and endometrial carcinogene-sisrdquo European Journal of Cancer A vol 32 no 9 pp 1464ndash14761996
[14] E J Lederer ldquoChemistry and biochemistry of somemammaliansecretions and excretionsrdquo Journal of the Chemical Society pp2115ndash2125 1949
[15] G G Freeman ldquoIsolation of alternariol and alternariol mono-methyl ether from Alternaria dauci (kuhn) groves and skolkordquoPhytochemistry vol 5 no 4 pp 719ndash725 1966
[16] W T L Sidwell H Fritz and C Tamm ldquoAutumnariol undAutumnariniol zwei neue Dibenzo-120572-pyrone aus Eucomisautumnalis Graeb Nachweis einer Fernkopplung uber sechsBindungen in den magnetischen ProtonenresonanzmdashSpek-trenrdquo Helvetica Chimica Acta vol 54 no 1 pp 207ndash215 1971
[17] L Farkas F Soti M Incze and M Nogradi ldquoSynthesenaturlicher Dibenzo-120572-pyrone I Synthese des Autumnariniolsund des Autumnariniolsrdquo Chemische Berichte vol 107 no 12pp 3874ndash3877 1974
[18] S Ghosal J P Reddy and V K Lal ldquoShilajit I chemicalconstituentsrdquo Journal of Pharmaceutical Sciences vol 65 no 5pp 772ndash773 1976
8 Advances in Pharmacological Sciences
[19] B Naser-Hijazi B Stolze and K S Zanker Second Proceed-ings of the International Society of the Coumarin InvestigatorsSpringer Berlin Germany 1994
[20] R D H Murray J Mendez and S A Brown The Natu-ral Coumarin Occurrence Chemistry and Biochemistry JohnWiley Chichester UK 1982
[21] J D Hepworth C D Gabbutt and B N Heron ComprehensiveHeterocyclic Chemistry II vol 5 Pergamon Press Oxford UK1996
[22] F M Deans Naturally Occurring Oxygen Ring CompoundsButterworths London UK 1963
[23] J A Joule and K Mills Eds Heterocyclic Chemistry BlackwellScience Oxford UK 4th edition 2006
[24] R D H Murray ldquoNaturally occurring plant coumarinsrdquo Fort-schritte der Chemie Organischer Naturstoffe vol 35 pp 199ndash2491978
[25] G R Geen J M Evans and A K Vong in ComprehensiveHeterocyclic Chemistry II A R Katritzky C W Rees and EF V Scriven Eds vol 5 p 469 Pergamon Press Oxford UK1984
[26] H-X Xu and S F Lee ldquoActivity of plant flavonoids againstantibiotic-resistant bacteriardquo Phytotherapy Research vol 15 no1 pp 39ndash43 2001
[27] J M Hamilton-Miller ldquoAntimicrobial properties of tea (Camel-lia sinensis L)rdquoAntimicrobial Agents and Chemotherapy vol 39no 11 pp 2375ndash2377 1995
[28] K C Fylaktakidou D J Hadjipavlou-Litina K E Litinas andD N Nicolaides ldquoNatural and synthetic coumarin derivativeswith anti-inflammatoryantioxidant activitiesrdquo Current Phar-maceutical Design vol 10 no 30 pp 3813ndash3833 2004
[29] J R Hwu R Singha S C Hong et al ldquoSynthesis of newbenzimidazole-coumarin conjugates as anti-hepatitis C virusagentsrdquo Antiviral Research vol 77 no 2 pp 157ndash162 2008
[30] S Sardari Y Mori K Horita R G Micetich S Nishibe andMDaneshtalab ldquoSynthesis and antifungal activity of coumarinsand angular furanocoumarinsrdquo Bioorganic amp Medicinal Chem-istry vol 7 no 9 pp 1933ndash1940 1999
[31] D Egan P James D Cooke and R OrsquoKennedy ldquoStudies on thecytostatic and cytotoxic effects and mode of action of 8-nitro-7-hydroxycoumarinrdquo Cancer Letters vol 118 no 2 pp 201ndash2111997
[32] P Valenti A Rampa M Recanatini et al ldquoSynthesis cytotoxic-ity and SAR of simple geiparvarin analoguesrdquoAnti-Cancer DrugDesign vol 12 no 6 pp 443ndash451 1997
[33] C Spino M Dodier and S Sotheeswaran ldquoAnti-HIV coum-arins from calophyllum seed oilrdquo Bioorganic and MedicinalChemistry Letters vol 8 no 24 pp 3475ndash3478 1998
[34] L M Bedoya M Beltran R Sancho et al ldquo4-Phenylcoumarinsas HIV transcription inhibitorsrdquo Bioorganic ampMedicinal Chem-istry Letters vol 15 no 20 pp 4447ndash4450 2005
[35] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[36] D Yu M Suzuki L Xie S L Morris-Natschke and K-H LeeldquoRecent progress in the development of coumarin derivativesas potent anti-HIV agentsrdquoMedicinal Research Reviews vol 23no 3 pp 322ndash345 2003
[37] S Kirkiacharian D T Thuy S Sicsic R Bakhchinian RKurkjian and T Tonnaire ldquoStructurendashactivity relationshipsof some 3-substituted-4-hydroxycoumarins as HIV-1 proteaseinhibitorsrdquo Farmaco vol 57 no 9 pp 703ndash708 2002
[38] A G Kidane H Salacinski A Tiwari K R Bruckdorfer andA M Seifalian ldquoAnticoagulant and antiplatelet agents theirclinical and device application(s) together with usages to engi-neer surfacesrdquo Biomacromolecules vol 5 no 3 pp 798ndash8132004
[39] KMKhan Z S SaifyM Z Khan et al ldquoSynthesis of coumarinderivatives with cytotoxic antibacterial and antifungal activityrdquoJournal of Enzyme Inhibition and Medicinal Chemistry vol 19no 4 pp 373ndash379 2004
[40] G Appendino E Mercalli N Fuzzati et al ldquoAntimycobacterialcoumarins from the Sardinian giant fennel (Ferula communis)rdquoJournal of Natural Products vol 67 no 12 pp 2108ndash2110 2004
[41] NHamdiM Saoud andARomerosa ldquo4-Hydroxy coumarinea versatile reagent for the synthesis of heterocyclic and vanillinether coumarins with biological activitiesrdquo in Bioactive Hetero-cycles V vol 11 of Topics in Heterocyclic Chemistry pp 283ndash301Springer Berlin Germany 2007
[42] F Chimenti B Bizzarri A Bolasco et al ldquoSynthesis and in vitroselective anti-Helicobacter pylori activity of N-substituted-2-oxo-2H-1-benzopyran-3-carboxamidesrdquo European Journal ofMedicinal Chemistry vol 41 no 2 pp 208ndash212 2006
[43] C Ito M Itoigawa Y Mishina et al ldquoChemical con-stituents of Calophyllum brasiliense 2 Structure of three newcoumarins and cancer chemopreventive activity of 4-substi-tuted coumarinsrdquo Journal of Natural Products vol 66 no 3 pp368ndash371 2003
[44] I Kostova ldquoSynthetic and natural coumarins as cytotoxicagentsrdquo Current Medicinal ChemistrymdashAnti-Cancer Agents vol5 no 1 pp 29ndash46 2005
[45] GMelagraki A Afantitis O Igglessi-Markopoulou et al ldquoSyn-thesis and evaluation of the antioxidant and anti-inflammatoryactivity of novel coumarin-3-aminoamides and their alpha-lipoic acid adductsrdquo European Journal of Medicinal Chemistryvol 44 no 7 pp 3020ndash3026 2009
[46] C A Kontogiorgis and D J Hadjipavlou-Litina ldquoSynthesis andantiinflammatory activity of coumarin derivativesrdquo Journal ofMedicinal Chemistry vol 48 no 20 pp 6400ndash6408 2005
[47] S Stanchev V Hadjimitova T Traykov T Boyanov and IManolov ldquoInvestigation of the antioxidant properties of somenew 4-hydroxycoumarin derivativesrdquo European Journal ofMed-icinal Chemistry vol 44 no 7 pp 3077ndash3082 2009
[48] C A Kontogiorgis and D J Hadjipavlou-Litina ldquoSynthesis andbiological evaluation of novel coumarin derivatives with a 7-azomethine linkagerdquo Bioorganic and Medicinal Chemistry Let-ters vol 14 no 3 pp 611ndash614 2004
[49] C Xiao Z-G Song and Z-Q Liu ldquoSynthesis of methyl-substi-tuted xanthotoxol to clarify prooxidant effect of methyl onradical-induced oxidation of DNArdquo European Journal of Medic-inal Chemistry vol 45 no 6 pp 2559ndash2566 2010
[50] O M Abdel Hafez K M Amin N A Abdel-Latif T KMohamed E Y Ahmed and T Maher ldquoSynthesis and antitu-mor activity of some new xanthotoxin derivativesrdquo EuropeanJournal of Medicinal Chemistry vol 44 no 7 pp 2967ndash29742009
[51] V Reutrakul P Leewanich P Tuchinda et al ldquoCytotoxic coum-arins fromMammea harmandiirdquo Planta Medica vol 69 no 11pp 1048ndash1051 2003
[52] I Kempen D Papapostolou N Thierry et al ldquo3-Bromophenyl6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylateinhibits cancer cell invasion in vitro and tumour growth invivordquo British Journal of Cancer vol 88 no 7 pp 1111ndash1118 2003
Advances in Pharmacological Sciences 9
[53] P OrsquoKennedy and R D Thornes Eds Coumarins BiologyApplications andMode ofAction JohnWileyampSons ChichesterUK 1997
[54] L Zhi C M Tegley E A Kallel et al ldquo5-Aryl-12-dihydrochro-meno[34-f]quinolines a novel class of nonsteroidal humanprogesterone receptor agonistsrdquo Journal ofMedicinal Chemistryvol 41 no 3 pp 291ndash302 1998
[55] J M Schmidt G B Tremblay M Page et al ldquoSynthesisand evaluation of a novel nonsteroidal-specific endothelial cellproliferation inhibitorrdquo Journal of Medicinal Chemistry vol 46no 8 pp 1289ndash1292 2003
[56] K Hajela K Kapoor and R Kapil ldquoSynthesis and post-coitalcontraceptive activity of ether and ester analogues of 23-diaryl-2H-1-benzopyransrdquo Bioorganic amp Medicinal Chemistry vol 3pp 1417ndash1420 1995
[57] K Hajela and R S Kapil ldquoSynthesis and post-coital contra-ceptive activity of a new series of substituted 23-diaryl-2H-1-benzopyransrdquo European Journal of Medicinal Chemistry vol 32no 2 pp 135ndash139 1997
[58] K Hajela J Pandey A Dwivedy et al ldquoResolution molecularstructure and biological activities of the D- and L-enan-tiomers of potent anti-implantation agent DL-2-[4-(2-piperi-dinoethoxy)phenyl]-3-phenyl-2H-1-benzopyranrdquo Bioorganic ampMedicinal Chemistry vol 7 no 9 pp 2083ndash2090 1999
[59] H Pechmann and C Duisberg ldquoNeue Bildungsweise derCumarine Synthese desDaphnetins IrdquoChemische Berichte vol17 no 1 pp 929ndash936 1884
[60] J Johnson ldquoThe Perkin reaction and related reactionsrdquoOrganicReactions vol 1 pp 210ndash265 1942
[61] G Jones ldquoThe Knoevenagel condensationrdquo Organic Reactionsvol 15 pp 204ndash599 1967
[62] G Brufola F Fringuelli O Piermatti and F Pizzo ldquoSimpleand efficient one-pot preparation of 3-substituted coumarins inwaterrdquo Heterocycles vol 43 no 6 pp 1257ndash1266 1996
[63] R L Shriner ldquoThe reformatsky reactionrdquo in Organic Reactionsvol 1 pp 1ndash58 John Wiley amp Sons 1942
[64] I Yavari RHekmat-Shoar andA Zonouzi ldquoAnewand efficientroute to 4-carboxymethylcoumarins mediated by vinyltriph-enylphosphonium saltrdquo Tetrahedron Letters vol 39 no 16 pp2391ndash2392 1998
[65] J R Johnson ldquoPerkin reaction and related reactionsrdquo OrganicReactions vol 1 p 210 1942
[66] M H Elnagdi S O Abdallah K M Ghoneim E M Ebiedand K N Kassab ldquoSynthesis of some Coumarin derivatives aspotential LaserDyesrdquo Journal of Chemical Research Synopsesno 2 pp 44ndash45 1997
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Figure 3 (a) ORTEPPLATON structure of (vi-e) (b) Packing structure of (vi-e) showing Z-like packing
Table 2 Derivatives of 4-aryl-3-phenyl-coumarin-2-one and theiryield () for Scheme 2
S number Compound R R2
Time (h) Yielda ()1 (vi-a) -OH H 7 742 (vi-b) -OH -CH
37 77
3 (vi-c) -OH -OCH3
6 804 (vi-d) -OH -C
2H5
8 705 (vi-e) -OCH
3H 7 75
6 (vi-f) -OCH3
-CH3
8 797 (vi-g) -OCH
3-OCH
37 82
8 (vi-h) -OCH3
-C2H5
7 809 (vi-i) -OAc H 6 90aThe reaction yield refers to product isolated through column chromatogra-phy
reaction of (ix-a) with (v) and found that the reaction in thepresence of K
2CO3afforded the cyclized product (vi-a) in
74yield after 7 h whereas triethylamine gave this product in57 yield We believe that potassium carbonate may be moredissociated in aprotic polar solvents and consequently provedto be more reactive
3 Conclusion
In conclusion a simple efficient and novel method hasbeen developed for an easy access to synthesis of the 4-(4-hydroxy-benzyl)-3-phenyl-chromen-2-one via Scheme 2and this has been supported by 1H NMR FTIR 13C NMRmass spectroscopy and single crystal X-ray data analysisSynthetic pathway with just 2 steps proved to be the bestwith less side reactions and greater yield Thus the numberof steps has been decreased and the yield was increasedHerein we reported some precursors of coumarin basedSERMs which could be useful in designing new SERMs Thepure products were obtained by column chromatography
This methodology presents several advantages including (a)mild reaction conditions (b) simple workup procedure (c)moderately high yields of the desired products (d) theselectivity of the product and finally (e) economic availabilityof the reagents making the whole process simple and feasibleEfforts to extend the span of the procedure on SERMs areunder progress in our laboratory
4 Experimental Section
41 General Methods All the required chemicals are pur-chased since they are commercially available and used asreceived without further purification Commercially avail-able acetone and benzene were further purified and driedfollowing the known procedure Thin-layer chromatography(TLC) was performed using silica gel 60 F254 precoatedplates Column chromatography was carried out on silica gel60 (100ndash200mesh) Infrared (FTIR) spectra were recordedin KBr and wavelengths (]) have been reported in cmminus1 1Hand 13C NMR spectra were recorded on NMR spectrometersoperating at 300 and 755MHz respectively Chemical shifts(120575) were given in parts per million (ppm) using the residuesolvent peaks as reference relative to TMS 119869 values have beengiven in Hz Mass spectra were recorded using electrosprayionization (ESI) mass spectrometer The melting points weretaken in open capillary and uncorrected
411 Procedure for Scheme 1
Compound (ii) To a solution of 4-methoxy phenyl acetic acid(425 g 025mol) in dry benzene (50mL) was added thionylchloride (30mL 025mol) dropwise with syringe After thereaction was complete the reaction mixture was distilledto remove excess thionyl chloride and the solvent benzeneBrown colored liquid was obtained Yield- 50 1H NMR-(300MHz CDCl
Compound (iii) A solution of p-methoxy phenyl acetylchloride (24 g 013mol) and phenol (122mL 013mol) in drybenzene (63mL) was refluxed for 21 h till the reaction wascomplete as monitored by TLC Then the reaction mixturewas washed with 5 aqueous NaOH to remove excessunreacted phenol and then washed with water three timesand dried over anhydrous Na
Compounds (vi (a-h)) To a solution of ortho substituted phe-nol (236mg 1mmol) and K
2CO3(690mg 5mmol) in dry
acetone (25mL) was added phenyl acetyl chloride (308mg2mmol) dropwise The reaction mixture was refluxed at100∘C for 7 h After the reaction was completed (asmonitoredby TLC) the reaction mixture was cooled filtered and con-centrated The residue was chromatographed to obtain thepure compound with 20 ethyl acetate-hexane Yield- 70
412 Procedure for Scheme 2
Compound (ix-e) To a solution of 4-methoxy phenyl aceticacid (166mg 1mmol) in dry acetone (10mL) was addedBF3sdotEt2O (04mL 3mmol) at 0∘C After 30 minutes we
added phenol (01mL 1mmol) and refluxed it till the reactionwas completed as monitored by TLC Then we filtered thereaction mixture and evaporated the solvent in vacuum
White solid was obtained recrystallized from ethanol Yield-80 mp 65∘C 1H NMR- (300MHz CDCl
Compound (vi-e) Phenyl acetyl chloride (013mL 1mmol)was added to a solution of (ix-e) (242mg 1mmol) in dryacetone and K
2CO3(552mg 4mmol) and refluxed for 6 h
Then the reaction mixture was filtered and concentrated invacuumThe obtained crude was recrystallized from ethanolto obtain the pure product Yield- 75
Procedure for Compound (vi-i) Acetic anhydride (920mg1mL) was added to a solution of (vi-a) (328mg 1mmol)and pyridine (025mL 9mmol) and refluxed under nitrogenatmosphere for 6 h at 90∘C After the reaction was completed(as monitored by TLC) solvent was removed under vacuumThe residuewaswashedwith saturatedNa
2HCO3until excess
pyridine was removed and then it was washed with aqueousHCl and finally with saturated brine solution and dried andchromatographed with 20 ethyl acetate-hexane Yield 90mp 160∘C
Analytical Data for Compounds (vi (andashi))
(vi-a) 1H NMR- (300MHz CDCl3) 120575 403 (s 2H -CH
864Hz 2H Ar-H) 720 (t 119869 = 144Hz 1H Ar-H) 730 (m2H Ar-H) 743 (m 4H Ar-H) 753 (m 2H Ar-H) (FigureS7)119898119911 37012 Elemental Analysis C 7782 H 490 O 1728119898119911 370 C 8106 H 599 O 1296
Note Crystallographic information is given in the supportingfile with details of refinement and other structural parame-ters
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The authors are thankful to the Department of ChemistryBHU for proving NMR FTIR and single crystal X-ray dataFinancial assistance from CSIR (Grant no 01(2362)10EMR-II) New Delhi in the form of a project and fellowships toAmbika Srivastava and Pooja Singh andCSIR andUGCNewDelhi in the form of SRF and UGC Fellowship respectivelyis gratefully acknowledged
References
[1] L J Black C D Jones and J F Falcone ldquoAntagonism of estro-gen action with a new benzothiophene derived antiestrogenrdquoLife Sciences vol 32 no 9 pp 1031ndash1036 1983
[2] A U Buzdar CMarcus F Holmes V Hug and G HortobagyildquoPhase II evaluation of LY156758 in metastatic breast cancerrdquoOncology vol 45 no 5 pp 344ndash345 1988
[3] K R Snyder N Sparano and J M Malinowski ldquoRaloxifenehydrochloriderdquo American Journal of Health-System Pharmacyvol 57 no 18 pp 1669ndash1678 2000
[4] V C Jordan E Phelps and J U Lindgren ldquoEffects of anti-estrogens on bone in castrated and intact female ratsrdquo BreastCancer Research and Treatment vol 10 no 1 pp 31ndash35 1987
[5] L J Black M Sato E R Rowley et al ldquoRaloxifene (LY139481HCI) prevents bone loss and reduces serum cholesterol withoutcausing uterine hypertrophy in ovariectomized ratsrdquo The Jour-nal of Clinical Investigation vol 93 no 1 pp 63ndash69 1994
[6] M M Gottardis and V C Jordan ldquoAntitumor actions ofkeoxifene and tamoxifen in the N-nitrosomethylurea-inducedrat mammary carcinoma modelrdquo Cancer Research vol 47 no15 pp 4020ndash4024 1987
[7] M A Anzano C W Peer J M Smith et al ldquoChemopreventionof mammary carcinogenesis in the rat combined use of ralox-ifene and 9-cis-retinoic acidrdquo Journal of the National CancerInstitute vol 88 no 2 pp 123ndash125 1996
[8] B Ettinger D M Black B H Mitlak et al ldquoReduction of verte-bral fracture risk in postmenopausal women with osteoporosistreated with raloxifene results from a 3-year randomizedclinical trialrdquo The Journal of the American Medical Associationvol 282 no 7 pp 637ndash645 1999
[9] S R Cummings S Eckert K A Krueger et al ldquoThe effect ofraloxifene on risk of breast cancer in postmenopausal womenresults from the MORE randomized trialrdquo The Journal of theAmerican Medical Association vol 281 no 23 pp 2189ndash21971999
[10] MClarke R Collins CDavies J Godwin R Gray andR PetoldquoThe EBCTCG secretariat clinical trial service unit radcliffeinfirmary Oxford OX2 6HE UKrdquoThe Lancet vol 351 pp 1451ndash1467 1998
[11] B Fisher J P Costantino D L Wickerham et al ldquoTamoxifenfor prevention of breast cancer report of the National SurgicalAdjuvant Breast and Bowel Project P-1 Studyrdquo Journal of theNational Cancer Institute vol 90 no 18 pp 1371ndash1388 1998
[12] R R Love R BMazessH S Barden et al ldquoEffects of tamoxifenon bonemineral density in postmenopausal women with breastcancerrdquo The New England Journal of Medicine vol 326 no 13pp 852ndash856 1992
[13] V J Assikis P Neven V C Jordan and I Vergote ldquoA realisticclinical perspective of tamoxifen and endometrial carcinogene-sisrdquo European Journal of Cancer A vol 32 no 9 pp 1464ndash14761996
[14] E J Lederer ldquoChemistry and biochemistry of somemammaliansecretions and excretionsrdquo Journal of the Chemical Society pp2115ndash2125 1949
[15] G G Freeman ldquoIsolation of alternariol and alternariol mono-methyl ether from Alternaria dauci (kuhn) groves and skolkordquoPhytochemistry vol 5 no 4 pp 719ndash725 1966
[16] W T L Sidwell H Fritz and C Tamm ldquoAutumnariol undAutumnariniol zwei neue Dibenzo-120572-pyrone aus Eucomisautumnalis Graeb Nachweis einer Fernkopplung uber sechsBindungen in den magnetischen ProtonenresonanzmdashSpek-trenrdquo Helvetica Chimica Acta vol 54 no 1 pp 207ndash215 1971
[17] L Farkas F Soti M Incze and M Nogradi ldquoSynthesenaturlicher Dibenzo-120572-pyrone I Synthese des Autumnariniolsund des Autumnariniolsrdquo Chemische Berichte vol 107 no 12pp 3874ndash3877 1974
[18] S Ghosal J P Reddy and V K Lal ldquoShilajit I chemicalconstituentsrdquo Journal of Pharmaceutical Sciences vol 65 no 5pp 772ndash773 1976
8 Advances in Pharmacological Sciences
[19] B Naser-Hijazi B Stolze and K S Zanker Second Proceed-ings of the International Society of the Coumarin InvestigatorsSpringer Berlin Germany 1994
[20] R D H Murray J Mendez and S A Brown The Natu-ral Coumarin Occurrence Chemistry and Biochemistry JohnWiley Chichester UK 1982
[21] J D Hepworth C D Gabbutt and B N Heron ComprehensiveHeterocyclic Chemistry II vol 5 Pergamon Press Oxford UK1996
[22] F M Deans Naturally Occurring Oxygen Ring CompoundsButterworths London UK 1963
[23] J A Joule and K Mills Eds Heterocyclic Chemistry BlackwellScience Oxford UK 4th edition 2006
[24] R D H Murray ldquoNaturally occurring plant coumarinsrdquo Fort-schritte der Chemie Organischer Naturstoffe vol 35 pp 199ndash2491978
[25] G R Geen J M Evans and A K Vong in ComprehensiveHeterocyclic Chemistry II A R Katritzky C W Rees and EF V Scriven Eds vol 5 p 469 Pergamon Press Oxford UK1984
[26] H-X Xu and S F Lee ldquoActivity of plant flavonoids againstantibiotic-resistant bacteriardquo Phytotherapy Research vol 15 no1 pp 39ndash43 2001
[27] J M Hamilton-Miller ldquoAntimicrobial properties of tea (Camel-lia sinensis L)rdquoAntimicrobial Agents and Chemotherapy vol 39no 11 pp 2375ndash2377 1995
[28] K C Fylaktakidou D J Hadjipavlou-Litina K E Litinas andD N Nicolaides ldquoNatural and synthetic coumarin derivativeswith anti-inflammatoryantioxidant activitiesrdquo Current Phar-maceutical Design vol 10 no 30 pp 3813ndash3833 2004
[29] J R Hwu R Singha S C Hong et al ldquoSynthesis of newbenzimidazole-coumarin conjugates as anti-hepatitis C virusagentsrdquo Antiviral Research vol 77 no 2 pp 157ndash162 2008
[30] S Sardari Y Mori K Horita R G Micetich S Nishibe andMDaneshtalab ldquoSynthesis and antifungal activity of coumarinsand angular furanocoumarinsrdquo Bioorganic amp Medicinal Chem-istry vol 7 no 9 pp 1933ndash1940 1999
[31] D Egan P James D Cooke and R OrsquoKennedy ldquoStudies on thecytostatic and cytotoxic effects and mode of action of 8-nitro-7-hydroxycoumarinrdquo Cancer Letters vol 118 no 2 pp 201ndash2111997
[32] P Valenti A Rampa M Recanatini et al ldquoSynthesis cytotoxic-ity and SAR of simple geiparvarin analoguesrdquoAnti-Cancer DrugDesign vol 12 no 6 pp 443ndash451 1997
[33] C Spino M Dodier and S Sotheeswaran ldquoAnti-HIV coum-arins from calophyllum seed oilrdquo Bioorganic and MedicinalChemistry Letters vol 8 no 24 pp 3475ndash3478 1998
[34] L M Bedoya M Beltran R Sancho et al ldquo4-Phenylcoumarinsas HIV transcription inhibitorsrdquo Bioorganic ampMedicinal Chem-istry Letters vol 15 no 20 pp 4447ndash4450 2005
[35] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[36] D Yu M Suzuki L Xie S L Morris-Natschke and K-H LeeldquoRecent progress in the development of coumarin derivativesas potent anti-HIV agentsrdquoMedicinal Research Reviews vol 23no 3 pp 322ndash345 2003
[37] S Kirkiacharian D T Thuy S Sicsic R Bakhchinian RKurkjian and T Tonnaire ldquoStructurendashactivity relationshipsof some 3-substituted-4-hydroxycoumarins as HIV-1 proteaseinhibitorsrdquo Farmaco vol 57 no 9 pp 703ndash708 2002
[38] A G Kidane H Salacinski A Tiwari K R Bruckdorfer andA M Seifalian ldquoAnticoagulant and antiplatelet agents theirclinical and device application(s) together with usages to engi-neer surfacesrdquo Biomacromolecules vol 5 no 3 pp 798ndash8132004
[39] KMKhan Z S SaifyM Z Khan et al ldquoSynthesis of coumarinderivatives with cytotoxic antibacterial and antifungal activityrdquoJournal of Enzyme Inhibition and Medicinal Chemistry vol 19no 4 pp 373ndash379 2004
[40] G Appendino E Mercalli N Fuzzati et al ldquoAntimycobacterialcoumarins from the Sardinian giant fennel (Ferula communis)rdquoJournal of Natural Products vol 67 no 12 pp 2108ndash2110 2004
[41] NHamdiM Saoud andARomerosa ldquo4-Hydroxy coumarinea versatile reagent for the synthesis of heterocyclic and vanillinether coumarins with biological activitiesrdquo in Bioactive Hetero-cycles V vol 11 of Topics in Heterocyclic Chemistry pp 283ndash301Springer Berlin Germany 2007
[42] F Chimenti B Bizzarri A Bolasco et al ldquoSynthesis and in vitroselective anti-Helicobacter pylori activity of N-substituted-2-oxo-2H-1-benzopyran-3-carboxamidesrdquo European Journal ofMedicinal Chemistry vol 41 no 2 pp 208ndash212 2006
[43] C Ito M Itoigawa Y Mishina et al ldquoChemical con-stituents of Calophyllum brasiliense 2 Structure of three newcoumarins and cancer chemopreventive activity of 4-substi-tuted coumarinsrdquo Journal of Natural Products vol 66 no 3 pp368ndash371 2003
[44] I Kostova ldquoSynthetic and natural coumarins as cytotoxicagentsrdquo Current Medicinal ChemistrymdashAnti-Cancer Agents vol5 no 1 pp 29ndash46 2005
[45] GMelagraki A Afantitis O Igglessi-Markopoulou et al ldquoSyn-thesis and evaluation of the antioxidant and anti-inflammatoryactivity of novel coumarin-3-aminoamides and their alpha-lipoic acid adductsrdquo European Journal of Medicinal Chemistryvol 44 no 7 pp 3020ndash3026 2009
[46] C A Kontogiorgis and D J Hadjipavlou-Litina ldquoSynthesis andantiinflammatory activity of coumarin derivativesrdquo Journal ofMedicinal Chemistry vol 48 no 20 pp 6400ndash6408 2005
[47] S Stanchev V Hadjimitova T Traykov T Boyanov and IManolov ldquoInvestigation of the antioxidant properties of somenew 4-hydroxycoumarin derivativesrdquo European Journal ofMed-icinal Chemistry vol 44 no 7 pp 3077ndash3082 2009
[48] C A Kontogiorgis and D J Hadjipavlou-Litina ldquoSynthesis andbiological evaluation of novel coumarin derivatives with a 7-azomethine linkagerdquo Bioorganic and Medicinal Chemistry Let-ters vol 14 no 3 pp 611ndash614 2004
[49] C Xiao Z-G Song and Z-Q Liu ldquoSynthesis of methyl-substi-tuted xanthotoxol to clarify prooxidant effect of methyl onradical-induced oxidation of DNArdquo European Journal of Medic-inal Chemistry vol 45 no 6 pp 2559ndash2566 2010
[50] O M Abdel Hafez K M Amin N A Abdel-Latif T KMohamed E Y Ahmed and T Maher ldquoSynthesis and antitu-mor activity of some new xanthotoxin derivativesrdquo EuropeanJournal of Medicinal Chemistry vol 44 no 7 pp 2967ndash29742009
[51] V Reutrakul P Leewanich P Tuchinda et al ldquoCytotoxic coum-arins fromMammea harmandiirdquo Planta Medica vol 69 no 11pp 1048ndash1051 2003
[52] I Kempen D Papapostolou N Thierry et al ldquo3-Bromophenyl6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylateinhibits cancer cell invasion in vitro and tumour growth invivordquo British Journal of Cancer vol 88 no 7 pp 1111ndash1118 2003
Advances in Pharmacological Sciences 9
[53] P OrsquoKennedy and R D Thornes Eds Coumarins BiologyApplications andMode ofAction JohnWileyampSons ChichesterUK 1997
[54] L Zhi C M Tegley E A Kallel et al ldquo5-Aryl-12-dihydrochro-meno[34-f]quinolines a novel class of nonsteroidal humanprogesterone receptor agonistsrdquo Journal ofMedicinal Chemistryvol 41 no 3 pp 291ndash302 1998
[55] J M Schmidt G B Tremblay M Page et al ldquoSynthesisand evaluation of a novel nonsteroidal-specific endothelial cellproliferation inhibitorrdquo Journal of Medicinal Chemistry vol 46no 8 pp 1289ndash1292 2003
[56] K Hajela K Kapoor and R Kapil ldquoSynthesis and post-coitalcontraceptive activity of ether and ester analogues of 23-diaryl-2H-1-benzopyransrdquo Bioorganic amp Medicinal Chemistry vol 3pp 1417ndash1420 1995
[57] K Hajela and R S Kapil ldquoSynthesis and post-coital contra-ceptive activity of a new series of substituted 23-diaryl-2H-1-benzopyransrdquo European Journal of Medicinal Chemistry vol 32no 2 pp 135ndash139 1997
[58] K Hajela J Pandey A Dwivedy et al ldquoResolution molecularstructure and biological activities of the D- and L-enan-tiomers of potent anti-implantation agent DL-2-[4-(2-piperi-dinoethoxy)phenyl]-3-phenyl-2H-1-benzopyranrdquo Bioorganic ampMedicinal Chemistry vol 7 no 9 pp 2083ndash2090 1999
[59] H Pechmann and C Duisberg ldquoNeue Bildungsweise derCumarine Synthese desDaphnetins IrdquoChemische Berichte vol17 no 1 pp 929ndash936 1884
[60] J Johnson ldquoThe Perkin reaction and related reactionsrdquoOrganicReactions vol 1 pp 210ndash265 1942
[61] G Jones ldquoThe Knoevenagel condensationrdquo Organic Reactionsvol 15 pp 204ndash599 1967
[62] G Brufola F Fringuelli O Piermatti and F Pizzo ldquoSimpleand efficient one-pot preparation of 3-substituted coumarins inwaterrdquo Heterocycles vol 43 no 6 pp 1257ndash1266 1996
[63] R L Shriner ldquoThe reformatsky reactionrdquo in Organic Reactionsvol 1 pp 1ndash58 John Wiley amp Sons 1942
[64] I Yavari RHekmat-Shoar andA Zonouzi ldquoAnewand efficientroute to 4-carboxymethylcoumarins mediated by vinyltriph-enylphosphonium saltrdquo Tetrahedron Letters vol 39 no 16 pp2391ndash2392 1998
[65] J R Johnson ldquoPerkin reaction and related reactionsrdquo OrganicReactions vol 1 p 210 1942
[66] M H Elnagdi S O Abdallah K M Ghoneim E M Ebiedand K N Kassab ldquoSynthesis of some Coumarin derivatives aspotential LaserDyesrdquo Journal of Chemical Research Synopsesno 2 pp 44ndash45 1997
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
Compound (iii) A solution of p-methoxy phenyl acetylchloride (24 g 013mol) and phenol (122mL 013mol) in drybenzene (63mL) was refluxed for 21 h till the reaction wascomplete as monitored by TLC Then the reaction mixturewas washed with 5 aqueous NaOH to remove excessunreacted phenol and then washed with water three timesand dried over anhydrous Na
Compounds (vi (a-h)) To a solution of ortho substituted phe-nol (236mg 1mmol) and K
2CO3(690mg 5mmol) in dry
acetone (25mL) was added phenyl acetyl chloride (308mg2mmol) dropwise The reaction mixture was refluxed at100∘C for 7 h After the reaction was completed (asmonitoredby TLC) the reaction mixture was cooled filtered and con-centrated The residue was chromatographed to obtain thepure compound with 20 ethyl acetate-hexane Yield- 70
412 Procedure for Scheme 2
Compound (ix-e) To a solution of 4-methoxy phenyl aceticacid (166mg 1mmol) in dry acetone (10mL) was addedBF3sdotEt2O (04mL 3mmol) at 0∘C After 30 minutes we
added phenol (01mL 1mmol) and refluxed it till the reactionwas completed as monitored by TLC Then we filtered thereaction mixture and evaporated the solvent in vacuum
White solid was obtained recrystallized from ethanol Yield-80 mp 65∘C 1H NMR- (300MHz CDCl
Compound (vi-e) Phenyl acetyl chloride (013mL 1mmol)was added to a solution of (ix-e) (242mg 1mmol) in dryacetone and K
2CO3(552mg 4mmol) and refluxed for 6 h
Then the reaction mixture was filtered and concentrated invacuumThe obtained crude was recrystallized from ethanolto obtain the pure product Yield- 75
Procedure for Compound (vi-i) Acetic anhydride (920mg1mL) was added to a solution of (vi-a) (328mg 1mmol)and pyridine (025mL 9mmol) and refluxed under nitrogenatmosphere for 6 h at 90∘C After the reaction was completed(as monitored by TLC) solvent was removed under vacuumThe residuewaswashedwith saturatedNa
2HCO3until excess
pyridine was removed and then it was washed with aqueousHCl and finally with saturated brine solution and dried andchromatographed with 20 ethyl acetate-hexane Yield 90mp 160∘C
Analytical Data for Compounds (vi (andashi))
(vi-a) 1H NMR- (300MHz CDCl3) 120575 403 (s 2H -CH
864Hz 2H Ar-H) 720 (t 119869 = 144Hz 1H Ar-H) 730 (m2H Ar-H) 743 (m 4H Ar-H) 753 (m 2H Ar-H) (FigureS7)119898119911 37012 Elemental Analysis C 7782 H 490 O 1728119898119911 370 C 8106 H 599 O 1296
Note Crystallographic information is given in the supportingfile with details of refinement and other structural parame-ters
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The authors are thankful to the Department of ChemistryBHU for proving NMR FTIR and single crystal X-ray dataFinancial assistance from CSIR (Grant no 01(2362)10EMR-II) New Delhi in the form of a project and fellowships toAmbika Srivastava and Pooja Singh andCSIR andUGCNewDelhi in the form of SRF and UGC Fellowship respectivelyis gratefully acknowledged
References
[1] L J Black C D Jones and J F Falcone ldquoAntagonism of estro-gen action with a new benzothiophene derived antiestrogenrdquoLife Sciences vol 32 no 9 pp 1031ndash1036 1983
[2] A U Buzdar CMarcus F Holmes V Hug and G HortobagyildquoPhase II evaluation of LY156758 in metastatic breast cancerrdquoOncology vol 45 no 5 pp 344ndash345 1988
[3] K R Snyder N Sparano and J M Malinowski ldquoRaloxifenehydrochloriderdquo American Journal of Health-System Pharmacyvol 57 no 18 pp 1669ndash1678 2000
[4] V C Jordan E Phelps and J U Lindgren ldquoEffects of anti-estrogens on bone in castrated and intact female ratsrdquo BreastCancer Research and Treatment vol 10 no 1 pp 31ndash35 1987
[5] L J Black M Sato E R Rowley et al ldquoRaloxifene (LY139481HCI) prevents bone loss and reduces serum cholesterol withoutcausing uterine hypertrophy in ovariectomized ratsrdquo The Jour-nal of Clinical Investigation vol 93 no 1 pp 63ndash69 1994
[6] M M Gottardis and V C Jordan ldquoAntitumor actions ofkeoxifene and tamoxifen in the N-nitrosomethylurea-inducedrat mammary carcinoma modelrdquo Cancer Research vol 47 no15 pp 4020ndash4024 1987
[7] M A Anzano C W Peer J M Smith et al ldquoChemopreventionof mammary carcinogenesis in the rat combined use of ralox-ifene and 9-cis-retinoic acidrdquo Journal of the National CancerInstitute vol 88 no 2 pp 123ndash125 1996
[8] B Ettinger D M Black B H Mitlak et al ldquoReduction of verte-bral fracture risk in postmenopausal women with osteoporosistreated with raloxifene results from a 3-year randomizedclinical trialrdquo The Journal of the American Medical Associationvol 282 no 7 pp 637ndash645 1999
[9] S R Cummings S Eckert K A Krueger et al ldquoThe effect ofraloxifene on risk of breast cancer in postmenopausal womenresults from the MORE randomized trialrdquo The Journal of theAmerican Medical Association vol 281 no 23 pp 2189ndash21971999
[10] MClarke R Collins CDavies J Godwin R Gray andR PetoldquoThe EBCTCG secretariat clinical trial service unit radcliffeinfirmary Oxford OX2 6HE UKrdquoThe Lancet vol 351 pp 1451ndash1467 1998
[11] B Fisher J P Costantino D L Wickerham et al ldquoTamoxifenfor prevention of breast cancer report of the National SurgicalAdjuvant Breast and Bowel Project P-1 Studyrdquo Journal of theNational Cancer Institute vol 90 no 18 pp 1371ndash1388 1998
[12] R R Love R BMazessH S Barden et al ldquoEffects of tamoxifenon bonemineral density in postmenopausal women with breastcancerrdquo The New England Journal of Medicine vol 326 no 13pp 852ndash856 1992
[13] V J Assikis P Neven V C Jordan and I Vergote ldquoA realisticclinical perspective of tamoxifen and endometrial carcinogene-sisrdquo European Journal of Cancer A vol 32 no 9 pp 1464ndash14761996
[14] E J Lederer ldquoChemistry and biochemistry of somemammaliansecretions and excretionsrdquo Journal of the Chemical Society pp2115ndash2125 1949
[15] G G Freeman ldquoIsolation of alternariol and alternariol mono-methyl ether from Alternaria dauci (kuhn) groves and skolkordquoPhytochemistry vol 5 no 4 pp 719ndash725 1966
[16] W T L Sidwell H Fritz and C Tamm ldquoAutumnariol undAutumnariniol zwei neue Dibenzo-120572-pyrone aus Eucomisautumnalis Graeb Nachweis einer Fernkopplung uber sechsBindungen in den magnetischen ProtonenresonanzmdashSpek-trenrdquo Helvetica Chimica Acta vol 54 no 1 pp 207ndash215 1971
[17] L Farkas F Soti M Incze and M Nogradi ldquoSynthesenaturlicher Dibenzo-120572-pyrone I Synthese des Autumnariniolsund des Autumnariniolsrdquo Chemische Berichte vol 107 no 12pp 3874ndash3877 1974
[18] S Ghosal J P Reddy and V K Lal ldquoShilajit I chemicalconstituentsrdquo Journal of Pharmaceutical Sciences vol 65 no 5pp 772ndash773 1976
8 Advances in Pharmacological Sciences
[19] B Naser-Hijazi B Stolze and K S Zanker Second Proceed-ings of the International Society of the Coumarin InvestigatorsSpringer Berlin Germany 1994
[20] R D H Murray J Mendez and S A Brown The Natu-ral Coumarin Occurrence Chemistry and Biochemistry JohnWiley Chichester UK 1982
[21] J D Hepworth C D Gabbutt and B N Heron ComprehensiveHeterocyclic Chemistry II vol 5 Pergamon Press Oxford UK1996
[22] F M Deans Naturally Occurring Oxygen Ring CompoundsButterworths London UK 1963
[23] J A Joule and K Mills Eds Heterocyclic Chemistry BlackwellScience Oxford UK 4th edition 2006
[24] R D H Murray ldquoNaturally occurring plant coumarinsrdquo Fort-schritte der Chemie Organischer Naturstoffe vol 35 pp 199ndash2491978
[25] G R Geen J M Evans and A K Vong in ComprehensiveHeterocyclic Chemistry II A R Katritzky C W Rees and EF V Scriven Eds vol 5 p 469 Pergamon Press Oxford UK1984
[26] H-X Xu and S F Lee ldquoActivity of plant flavonoids againstantibiotic-resistant bacteriardquo Phytotherapy Research vol 15 no1 pp 39ndash43 2001
[27] J M Hamilton-Miller ldquoAntimicrobial properties of tea (Camel-lia sinensis L)rdquoAntimicrobial Agents and Chemotherapy vol 39no 11 pp 2375ndash2377 1995
[28] K C Fylaktakidou D J Hadjipavlou-Litina K E Litinas andD N Nicolaides ldquoNatural and synthetic coumarin derivativeswith anti-inflammatoryantioxidant activitiesrdquo Current Phar-maceutical Design vol 10 no 30 pp 3813ndash3833 2004
[29] J R Hwu R Singha S C Hong et al ldquoSynthesis of newbenzimidazole-coumarin conjugates as anti-hepatitis C virusagentsrdquo Antiviral Research vol 77 no 2 pp 157ndash162 2008
[30] S Sardari Y Mori K Horita R G Micetich S Nishibe andMDaneshtalab ldquoSynthesis and antifungal activity of coumarinsand angular furanocoumarinsrdquo Bioorganic amp Medicinal Chem-istry vol 7 no 9 pp 1933ndash1940 1999
[31] D Egan P James D Cooke and R OrsquoKennedy ldquoStudies on thecytostatic and cytotoxic effects and mode of action of 8-nitro-7-hydroxycoumarinrdquo Cancer Letters vol 118 no 2 pp 201ndash2111997
[32] P Valenti A Rampa M Recanatini et al ldquoSynthesis cytotoxic-ity and SAR of simple geiparvarin analoguesrdquoAnti-Cancer DrugDesign vol 12 no 6 pp 443ndash451 1997
[33] C Spino M Dodier and S Sotheeswaran ldquoAnti-HIV coum-arins from calophyllum seed oilrdquo Bioorganic and MedicinalChemistry Letters vol 8 no 24 pp 3475ndash3478 1998
[34] L M Bedoya M Beltran R Sancho et al ldquo4-Phenylcoumarinsas HIV transcription inhibitorsrdquo Bioorganic ampMedicinal Chem-istry Letters vol 15 no 20 pp 4447ndash4450 2005
[35] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[36] D Yu M Suzuki L Xie S L Morris-Natschke and K-H LeeldquoRecent progress in the development of coumarin derivativesas potent anti-HIV agentsrdquoMedicinal Research Reviews vol 23no 3 pp 322ndash345 2003
[37] S Kirkiacharian D T Thuy S Sicsic R Bakhchinian RKurkjian and T Tonnaire ldquoStructurendashactivity relationshipsof some 3-substituted-4-hydroxycoumarins as HIV-1 proteaseinhibitorsrdquo Farmaco vol 57 no 9 pp 703ndash708 2002
[38] A G Kidane H Salacinski A Tiwari K R Bruckdorfer andA M Seifalian ldquoAnticoagulant and antiplatelet agents theirclinical and device application(s) together with usages to engi-neer surfacesrdquo Biomacromolecules vol 5 no 3 pp 798ndash8132004
[39] KMKhan Z S SaifyM Z Khan et al ldquoSynthesis of coumarinderivatives with cytotoxic antibacterial and antifungal activityrdquoJournal of Enzyme Inhibition and Medicinal Chemistry vol 19no 4 pp 373ndash379 2004
[40] G Appendino E Mercalli N Fuzzati et al ldquoAntimycobacterialcoumarins from the Sardinian giant fennel (Ferula communis)rdquoJournal of Natural Products vol 67 no 12 pp 2108ndash2110 2004
[41] NHamdiM Saoud andARomerosa ldquo4-Hydroxy coumarinea versatile reagent for the synthesis of heterocyclic and vanillinether coumarins with biological activitiesrdquo in Bioactive Hetero-cycles V vol 11 of Topics in Heterocyclic Chemistry pp 283ndash301Springer Berlin Germany 2007
[42] F Chimenti B Bizzarri A Bolasco et al ldquoSynthesis and in vitroselective anti-Helicobacter pylori activity of N-substituted-2-oxo-2H-1-benzopyran-3-carboxamidesrdquo European Journal ofMedicinal Chemistry vol 41 no 2 pp 208ndash212 2006
[43] C Ito M Itoigawa Y Mishina et al ldquoChemical con-stituents of Calophyllum brasiliense 2 Structure of three newcoumarins and cancer chemopreventive activity of 4-substi-tuted coumarinsrdquo Journal of Natural Products vol 66 no 3 pp368ndash371 2003
[44] I Kostova ldquoSynthetic and natural coumarins as cytotoxicagentsrdquo Current Medicinal ChemistrymdashAnti-Cancer Agents vol5 no 1 pp 29ndash46 2005
[45] GMelagraki A Afantitis O Igglessi-Markopoulou et al ldquoSyn-thesis and evaluation of the antioxidant and anti-inflammatoryactivity of novel coumarin-3-aminoamides and their alpha-lipoic acid adductsrdquo European Journal of Medicinal Chemistryvol 44 no 7 pp 3020ndash3026 2009
[46] C A Kontogiorgis and D J Hadjipavlou-Litina ldquoSynthesis andantiinflammatory activity of coumarin derivativesrdquo Journal ofMedicinal Chemistry vol 48 no 20 pp 6400ndash6408 2005
[47] S Stanchev V Hadjimitova T Traykov T Boyanov and IManolov ldquoInvestigation of the antioxidant properties of somenew 4-hydroxycoumarin derivativesrdquo European Journal ofMed-icinal Chemistry vol 44 no 7 pp 3077ndash3082 2009
[48] C A Kontogiorgis and D J Hadjipavlou-Litina ldquoSynthesis andbiological evaluation of novel coumarin derivatives with a 7-azomethine linkagerdquo Bioorganic and Medicinal Chemistry Let-ters vol 14 no 3 pp 611ndash614 2004
[49] C Xiao Z-G Song and Z-Q Liu ldquoSynthesis of methyl-substi-tuted xanthotoxol to clarify prooxidant effect of methyl onradical-induced oxidation of DNArdquo European Journal of Medic-inal Chemistry vol 45 no 6 pp 2559ndash2566 2010
[50] O M Abdel Hafez K M Amin N A Abdel-Latif T KMohamed E Y Ahmed and T Maher ldquoSynthesis and antitu-mor activity of some new xanthotoxin derivativesrdquo EuropeanJournal of Medicinal Chemistry vol 44 no 7 pp 2967ndash29742009
[51] V Reutrakul P Leewanich P Tuchinda et al ldquoCytotoxic coum-arins fromMammea harmandiirdquo Planta Medica vol 69 no 11pp 1048ndash1051 2003
[52] I Kempen D Papapostolou N Thierry et al ldquo3-Bromophenyl6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylateinhibits cancer cell invasion in vitro and tumour growth invivordquo British Journal of Cancer vol 88 no 7 pp 1111ndash1118 2003
Advances in Pharmacological Sciences 9
[53] P OrsquoKennedy and R D Thornes Eds Coumarins BiologyApplications andMode ofAction JohnWileyampSons ChichesterUK 1997
[54] L Zhi C M Tegley E A Kallel et al ldquo5-Aryl-12-dihydrochro-meno[34-f]quinolines a novel class of nonsteroidal humanprogesterone receptor agonistsrdquo Journal ofMedicinal Chemistryvol 41 no 3 pp 291ndash302 1998
[55] J M Schmidt G B Tremblay M Page et al ldquoSynthesisand evaluation of a novel nonsteroidal-specific endothelial cellproliferation inhibitorrdquo Journal of Medicinal Chemistry vol 46no 8 pp 1289ndash1292 2003
[56] K Hajela K Kapoor and R Kapil ldquoSynthesis and post-coitalcontraceptive activity of ether and ester analogues of 23-diaryl-2H-1-benzopyransrdquo Bioorganic amp Medicinal Chemistry vol 3pp 1417ndash1420 1995
[57] K Hajela and R S Kapil ldquoSynthesis and post-coital contra-ceptive activity of a new series of substituted 23-diaryl-2H-1-benzopyransrdquo European Journal of Medicinal Chemistry vol 32no 2 pp 135ndash139 1997
[58] K Hajela J Pandey A Dwivedy et al ldquoResolution molecularstructure and biological activities of the D- and L-enan-tiomers of potent anti-implantation agent DL-2-[4-(2-piperi-dinoethoxy)phenyl]-3-phenyl-2H-1-benzopyranrdquo Bioorganic ampMedicinal Chemistry vol 7 no 9 pp 2083ndash2090 1999
[59] H Pechmann and C Duisberg ldquoNeue Bildungsweise derCumarine Synthese desDaphnetins IrdquoChemische Berichte vol17 no 1 pp 929ndash936 1884
[60] J Johnson ldquoThe Perkin reaction and related reactionsrdquoOrganicReactions vol 1 pp 210ndash265 1942
[61] G Jones ldquoThe Knoevenagel condensationrdquo Organic Reactionsvol 15 pp 204ndash599 1967
[62] G Brufola F Fringuelli O Piermatti and F Pizzo ldquoSimpleand efficient one-pot preparation of 3-substituted coumarins inwaterrdquo Heterocycles vol 43 no 6 pp 1257ndash1266 1996
[63] R L Shriner ldquoThe reformatsky reactionrdquo in Organic Reactionsvol 1 pp 1ndash58 John Wiley amp Sons 1942
[64] I Yavari RHekmat-Shoar andA Zonouzi ldquoAnewand efficientroute to 4-carboxymethylcoumarins mediated by vinyltriph-enylphosphonium saltrdquo Tetrahedron Letters vol 39 no 16 pp2391ndash2392 1998
[65] J R Johnson ldquoPerkin reaction and related reactionsrdquo OrganicReactions vol 1 p 210 1942
[66] M H Elnagdi S O Abdallah K M Ghoneim E M Ebiedand K N Kassab ldquoSynthesis of some Coumarin derivatives aspotential LaserDyesrdquo Journal of Chemical Research Synopsesno 2 pp 44ndash45 1997
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
864Hz 2H Ar-H) 720 (t 119869 = 144Hz 1H Ar-H) 730 (m2H Ar-H) 743 (m 4H Ar-H) 753 (m 2H Ar-H) (FigureS7)119898119911 37012 Elemental Analysis C 7782 H 490 O 1728119898119911 370 C 8106 H 599 O 1296
Note Crystallographic information is given in the supportingfile with details of refinement and other structural parame-ters
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Acknowledgments
The authors are thankful to the Department of ChemistryBHU for proving NMR FTIR and single crystal X-ray dataFinancial assistance from CSIR (Grant no 01(2362)10EMR-II) New Delhi in the form of a project and fellowships toAmbika Srivastava and Pooja Singh andCSIR andUGCNewDelhi in the form of SRF and UGC Fellowship respectivelyis gratefully acknowledged
References
[1] L J Black C D Jones and J F Falcone ldquoAntagonism of estro-gen action with a new benzothiophene derived antiestrogenrdquoLife Sciences vol 32 no 9 pp 1031ndash1036 1983
[2] A U Buzdar CMarcus F Holmes V Hug and G HortobagyildquoPhase II evaluation of LY156758 in metastatic breast cancerrdquoOncology vol 45 no 5 pp 344ndash345 1988
[3] K R Snyder N Sparano and J M Malinowski ldquoRaloxifenehydrochloriderdquo American Journal of Health-System Pharmacyvol 57 no 18 pp 1669ndash1678 2000
[4] V C Jordan E Phelps and J U Lindgren ldquoEffects of anti-estrogens on bone in castrated and intact female ratsrdquo BreastCancer Research and Treatment vol 10 no 1 pp 31ndash35 1987
[5] L J Black M Sato E R Rowley et al ldquoRaloxifene (LY139481HCI) prevents bone loss and reduces serum cholesterol withoutcausing uterine hypertrophy in ovariectomized ratsrdquo The Jour-nal of Clinical Investigation vol 93 no 1 pp 63ndash69 1994
[6] M M Gottardis and V C Jordan ldquoAntitumor actions ofkeoxifene and tamoxifen in the N-nitrosomethylurea-inducedrat mammary carcinoma modelrdquo Cancer Research vol 47 no15 pp 4020ndash4024 1987
[7] M A Anzano C W Peer J M Smith et al ldquoChemopreventionof mammary carcinogenesis in the rat combined use of ralox-ifene and 9-cis-retinoic acidrdquo Journal of the National CancerInstitute vol 88 no 2 pp 123ndash125 1996
[8] B Ettinger D M Black B H Mitlak et al ldquoReduction of verte-bral fracture risk in postmenopausal women with osteoporosistreated with raloxifene results from a 3-year randomizedclinical trialrdquo The Journal of the American Medical Associationvol 282 no 7 pp 637ndash645 1999
[9] S R Cummings S Eckert K A Krueger et al ldquoThe effect ofraloxifene on risk of breast cancer in postmenopausal womenresults from the MORE randomized trialrdquo The Journal of theAmerican Medical Association vol 281 no 23 pp 2189ndash21971999
[10] MClarke R Collins CDavies J Godwin R Gray andR PetoldquoThe EBCTCG secretariat clinical trial service unit radcliffeinfirmary Oxford OX2 6HE UKrdquoThe Lancet vol 351 pp 1451ndash1467 1998
[11] B Fisher J P Costantino D L Wickerham et al ldquoTamoxifenfor prevention of breast cancer report of the National SurgicalAdjuvant Breast and Bowel Project P-1 Studyrdquo Journal of theNational Cancer Institute vol 90 no 18 pp 1371ndash1388 1998
[12] R R Love R BMazessH S Barden et al ldquoEffects of tamoxifenon bonemineral density in postmenopausal women with breastcancerrdquo The New England Journal of Medicine vol 326 no 13pp 852ndash856 1992
[13] V J Assikis P Neven V C Jordan and I Vergote ldquoA realisticclinical perspective of tamoxifen and endometrial carcinogene-sisrdquo European Journal of Cancer A vol 32 no 9 pp 1464ndash14761996
[14] E J Lederer ldquoChemistry and biochemistry of somemammaliansecretions and excretionsrdquo Journal of the Chemical Society pp2115ndash2125 1949
[15] G G Freeman ldquoIsolation of alternariol and alternariol mono-methyl ether from Alternaria dauci (kuhn) groves and skolkordquoPhytochemistry vol 5 no 4 pp 719ndash725 1966
[16] W T L Sidwell H Fritz and C Tamm ldquoAutumnariol undAutumnariniol zwei neue Dibenzo-120572-pyrone aus Eucomisautumnalis Graeb Nachweis einer Fernkopplung uber sechsBindungen in den magnetischen ProtonenresonanzmdashSpek-trenrdquo Helvetica Chimica Acta vol 54 no 1 pp 207ndash215 1971
[17] L Farkas F Soti M Incze and M Nogradi ldquoSynthesenaturlicher Dibenzo-120572-pyrone I Synthese des Autumnariniolsund des Autumnariniolsrdquo Chemische Berichte vol 107 no 12pp 3874ndash3877 1974
[18] S Ghosal J P Reddy and V K Lal ldquoShilajit I chemicalconstituentsrdquo Journal of Pharmaceutical Sciences vol 65 no 5pp 772ndash773 1976
8 Advances in Pharmacological Sciences
[19] B Naser-Hijazi B Stolze and K S Zanker Second Proceed-ings of the International Society of the Coumarin InvestigatorsSpringer Berlin Germany 1994
[20] R D H Murray J Mendez and S A Brown The Natu-ral Coumarin Occurrence Chemistry and Biochemistry JohnWiley Chichester UK 1982
[21] J D Hepworth C D Gabbutt and B N Heron ComprehensiveHeterocyclic Chemistry II vol 5 Pergamon Press Oxford UK1996
[22] F M Deans Naturally Occurring Oxygen Ring CompoundsButterworths London UK 1963
[23] J A Joule and K Mills Eds Heterocyclic Chemistry BlackwellScience Oxford UK 4th edition 2006
[24] R D H Murray ldquoNaturally occurring plant coumarinsrdquo Fort-schritte der Chemie Organischer Naturstoffe vol 35 pp 199ndash2491978
[25] G R Geen J M Evans and A K Vong in ComprehensiveHeterocyclic Chemistry II A R Katritzky C W Rees and EF V Scriven Eds vol 5 p 469 Pergamon Press Oxford UK1984
[26] H-X Xu and S F Lee ldquoActivity of plant flavonoids againstantibiotic-resistant bacteriardquo Phytotherapy Research vol 15 no1 pp 39ndash43 2001
[27] J M Hamilton-Miller ldquoAntimicrobial properties of tea (Camel-lia sinensis L)rdquoAntimicrobial Agents and Chemotherapy vol 39no 11 pp 2375ndash2377 1995
[28] K C Fylaktakidou D J Hadjipavlou-Litina K E Litinas andD N Nicolaides ldquoNatural and synthetic coumarin derivativeswith anti-inflammatoryantioxidant activitiesrdquo Current Phar-maceutical Design vol 10 no 30 pp 3813ndash3833 2004
[29] J R Hwu R Singha S C Hong et al ldquoSynthesis of newbenzimidazole-coumarin conjugates as anti-hepatitis C virusagentsrdquo Antiviral Research vol 77 no 2 pp 157ndash162 2008
[30] S Sardari Y Mori K Horita R G Micetich S Nishibe andMDaneshtalab ldquoSynthesis and antifungal activity of coumarinsand angular furanocoumarinsrdquo Bioorganic amp Medicinal Chem-istry vol 7 no 9 pp 1933ndash1940 1999
[31] D Egan P James D Cooke and R OrsquoKennedy ldquoStudies on thecytostatic and cytotoxic effects and mode of action of 8-nitro-7-hydroxycoumarinrdquo Cancer Letters vol 118 no 2 pp 201ndash2111997
[32] P Valenti A Rampa M Recanatini et al ldquoSynthesis cytotoxic-ity and SAR of simple geiparvarin analoguesrdquoAnti-Cancer DrugDesign vol 12 no 6 pp 443ndash451 1997
[33] C Spino M Dodier and S Sotheeswaran ldquoAnti-HIV coum-arins from calophyllum seed oilrdquo Bioorganic and MedicinalChemistry Letters vol 8 no 24 pp 3475ndash3478 1998
[34] L M Bedoya M Beltran R Sancho et al ldquo4-Phenylcoumarinsas HIV transcription inhibitorsrdquo Bioorganic ampMedicinal Chem-istry Letters vol 15 no 20 pp 4447ndash4450 2005
[35] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[36] D Yu M Suzuki L Xie S L Morris-Natschke and K-H LeeldquoRecent progress in the development of coumarin derivativesas potent anti-HIV agentsrdquoMedicinal Research Reviews vol 23no 3 pp 322ndash345 2003
[37] S Kirkiacharian D T Thuy S Sicsic R Bakhchinian RKurkjian and T Tonnaire ldquoStructurendashactivity relationshipsof some 3-substituted-4-hydroxycoumarins as HIV-1 proteaseinhibitorsrdquo Farmaco vol 57 no 9 pp 703ndash708 2002
[38] A G Kidane H Salacinski A Tiwari K R Bruckdorfer andA M Seifalian ldquoAnticoagulant and antiplatelet agents theirclinical and device application(s) together with usages to engi-neer surfacesrdquo Biomacromolecules vol 5 no 3 pp 798ndash8132004
[39] KMKhan Z S SaifyM Z Khan et al ldquoSynthesis of coumarinderivatives with cytotoxic antibacterial and antifungal activityrdquoJournal of Enzyme Inhibition and Medicinal Chemistry vol 19no 4 pp 373ndash379 2004
[40] G Appendino E Mercalli N Fuzzati et al ldquoAntimycobacterialcoumarins from the Sardinian giant fennel (Ferula communis)rdquoJournal of Natural Products vol 67 no 12 pp 2108ndash2110 2004
[41] NHamdiM Saoud andARomerosa ldquo4-Hydroxy coumarinea versatile reagent for the synthesis of heterocyclic and vanillinether coumarins with biological activitiesrdquo in Bioactive Hetero-cycles V vol 11 of Topics in Heterocyclic Chemistry pp 283ndash301Springer Berlin Germany 2007
[42] F Chimenti B Bizzarri A Bolasco et al ldquoSynthesis and in vitroselective anti-Helicobacter pylori activity of N-substituted-2-oxo-2H-1-benzopyran-3-carboxamidesrdquo European Journal ofMedicinal Chemistry vol 41 no 2 pp 208ndash212 2006
[43] C Ito M Itoigawa Y Mishina et al ldquoChemical con-stituents of Calophyllum brasiliense 2 Structure of three newcoumarins and cancer chemopreventive activity of 4-substi-tuted coumarinsrdquo Journal of Natural Products vol 66 no 3 pp368ndash371 2003
[44] I Kostova ldquoSynthetic and natural coumarins as cytotoxicagentsrdquo Current Medicinal ChemistrymdashAnti-Cancer Agents vol5 no 1 pp 29ndash46 2005
[45] GMelagraki A Afantitis O Igglessi-Markopoulou et al ldquoSyn-thesis and evaluation of the antioxidant and anti-inflammatoryactivity of novel coumarin-3-aminoamides and their alpha-lipoic acid adductsrdquo European Journal of Medicinal Chemistryvol 44 no 7 pp 3020ndash3026 2009
[46] C A Kontogiorgis and D J Hadjipavlou-Litina ldquoSynthesis andantiinflammatory activity of coumarin derivativesrdquo Journal ofMedicinal Chemistry vol 48 no 20 pp 6400ndash6408 2005
[47] S Stanchev V Hadjimitova T Traykov T Boyanov and IManolov ldquoInvestigation of the antioxidant properties of somenew 4-hydroxycoumarin derivativesrdquo European Journal ofMed-icinal Chemistry vol 44 no 7 pp 3077ndash3082 2009
[48] C A Kontogiorgis and D J Hadjipavlou-Litina ldquoSynthesis andbiological evaluation of novel coumarin derivatives with a 7-azomethine linkagerdquo Bioorganic and Medicinal Chemistry Let-ters vol 14 no 3 pp 611ndash614 2004
[49] C Xiao Z-G Song and Z-Q Liu ldquoSynthesis of methyl-substi-tuted xanthotoxol to clarify prooxidant effect of methyl onradical-induced oxidation of DNArdquo European Journal of Medic-inal Chemistry vol 45 no 6 pp 2559ndash2566 2010
[50] O M Abdel Hafez K M Amin N A Abdel-Latif T KMohamed E Y Ahmed and T Maher ldquoSynthesis and antitu-mor activity of some new xanthotoxin derivativesrdquo EuropeanJournal of Medicinal Chemistry vol 44 no 7 pp 2967ndash29742009
[51] V Reutrakul P Leewanich P Tuchinda et al ldquoCytotoxic coum-arins fromMammea harmandiirdquo Planta Medica vol 69 no 11pp 1048ndash1051 2003
[52] I Kempen D Papapostolou N Thierry et al ldquo3-Bromophenyl6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylateinhibits cancer cell invasion in vitro and tumour growth invivordquo British Journal of Cancer vol 88 no 7 pp 1111ndash1118 2003
Advances in Pharmacological Sciences 9
[53] P OrsquoKennedy and R D Thornes Eds Coumarins BiologyApplications andMode ofAction JohnWileyampSons ChichesterUK 1997
[54] L Zhi C M Tegley E A Kallel et al ldquo5-Aryl-12-dihydrochro-meno[34-f]quinolines a novel class of nonsteroidal humanprogesterone receptor agonistsrdquo Journal ofMedicinal Chemistryvol 41 no 3 pp 291ndash302 1998
[55] J M Schmidt G B Tremblay M Page et al ldquoSynthesisand evaluation of a novel nonsteroidal-specific endothelial cellproliferation inhibitorrdquo Journal of Medicinal Chemistry vol 46no 8 pp 1289ndash1292 2003
[56] K Hajela K Kapoor and R Kapil ldquoSynthesis and post-coitalcontraceptive activity of ether and ester analogues of 23-diaryl-2H-1-benzopyransrdquo Bioorganic amp Medicinal Chemistry vol 3pp 1417ndash1420 1995
[57] K Hajela and R S Kapil ldquoSynthesis and post-coital contra-ceptive activity of a new series of substituted 23-diaryl-2H-1-benzopyransrdquo European Journal of Medicinal Chemistry vol 32no 2 pp 135ndash139 1997
[58] K Hajela J Pandey A Dwivedy et al ldquoResolution molecularstructure and biological activities of the D- and L-enan-tiomers of potent anti-implantation agent DL-2-[4-(2-piperi-dinoethoxy)phenyl]-3-phenyl-2H-1-benzopyranrdquo Bioorganic ampMedicinal Chemistry vol 7 no 9 pp 2083ndash2090 1999
[59] H Pechmann and C Duisberg ldquoNeue Bildungsweise derCumarine Synthese desDaphnetins IrdquoChemische Berichte vol17 no 1 pp 929ndash936 1884
[60] J Johnson ldquoThe Perkin reaction and related reactionsrdquoOrganicReactions vol 1 pp 210ndash265 1942
[61] G Jones ldquoThe Knoevenagel condensationrdquo Organic Reactionsvol 15 pp 204ndash599 1967
[62] G Brufola F Fringuelli O Piermatti and F Pizzo ldquoSimpleand efficient one-pot preparation of 3-substituted coumarins inwaterrdquo Heterocycles vol 43 no 6 pp 1257ndash1266 1996
[63] R L Shriner ldquoThe reformatsky reactionrdquo in Organic Reactionsvol 1 pp 1ndash58 John Wiley amp Sons 1942
[64] I Yavari RHekmat-Shoar andA Zonouzi ldquoAnewand efficientroute to 4-carboxymethylcoumarins mediated by vinyltriph-enylphosphonium saltrdquo Tetrahedron Letters vol 39 no 16 pp2391ndash2392 1998
[65] J R Johnson ldquoPerkin reaction and related reactionsrdquo OrganicReactions vol 1 p 210 1942
[66] M H Elnagdi S O Abdallah K M Ghoneim E M Ebiedand K N Kassab ldquoSynthesis of some Coumarin derivatives aspotential LaserDyesrdquo Journal of Chemical Research Synopsesno 2 pp 44ndash45 1997
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
[19] B Naser-Hijazi B Stolze and K S Zanker Second Proceed-ings of the International Society of the Coumarin InvestigatorsSpringer Berlin Germany 1994
[20] R D H Murray J Mendez and S A Brown The Natu-ral Coumarin Occurrence Chemistry and Biochemistry JohnWiley Chichester UK 1982
[21] J D Hepworth C D Gabbutt and B N Heron ComprehensiveHeterocyclic Chemistry II vol 5 Pergamon Press Oxford UK1996
[22] F M Deans Naturally Occurring Oxygen Ring CompoundsButterworths London UK 1963
[23] J A Joule and K Mills Eds Heterocyclic Chemistry BlackwellScience Oxford UK 4th edition 2006
[24] R D H Murray ldquoNaturally occurring plant coumarinsrdquo Fort-schritte der Chemie Organischer Naturstoffe vol 35 pp 199ndash2491978
[25] G R Geen J M Evans and A K Vong in ComprehensiveHeterocyclic Chemistry II A R Katritzky C W Rees and EF V Scriven Eds vol 5 p 469 Pergamon Press Oxford UK1984
[26] H-X Xu and S F Lee ldquoActivity of plant flavonoids againstantibiotic-resistant bacteriardquo Phytotherapy Research vol 15 no1 pp 39ndash43 2001
[27] J M Hamilton-Miller ldquoAntimicrobial properties of tea (Camel-lia sinensis L)rdquoAntimicrobial Agents and Chemotherapy vol 39no 11 pp 2375ndash2377 1995
[28] K C Fylaktakidou D J Hadjipavlou-Litina K E Litinas andD N Nicolaides ldquoNatural and synthetic coumarin derivativeswith anti-inflammatoryantioxidant activitiesrdquo Current Phar-maceutical Design vol 10 no 30 pp 3813ndash3833 2004
[29] J R Hwu R Singha S C Hong et al ldquoSynthesis of newbenzimidazole-coumarin conjugates as anti-hepatitis C virusagentsrdquo Antiviral Research vol 77 no 2 pp 157ndash162 2008
[30] S Sardari Y Mori K Horita R G Micetich S Nishibe andMDaneshtalab ldquoSynthesis and antifungal activity of coumarinsand angular furanocoumarinsrdquo Bioorganic amp Medicinal Chem-istry vol 7 no 9 pp 1933ndash1940 1999
[31] D Egan P James D Cooke and R OrsquoKennedy ldquoStudies on thecytostatic and cytotoxic effects and mode of action of 8-nitro-7-hydroxycoumarinrdquo Cancer Letters vol 118 no 2 pp 201ndash2111997
[32] P Valenti A Rampa M Recanatini et al ldquoSynthesis cytotoxic-ity and SAR of simple geiparvarin analoguesrdquoAnti-Cancer DrugDesign vol 12 no 6 pp 443ndash451 1997
[33] C Spino M Dodier and S Sotheeswaran ldquoAnti-HIV coum-arins from calophyllum seed oilrdquo Bioorganic and MedicinalChemistry Letters vol 8 no 24 pp 3475ndash3478 1998
[34] L M Bedoya M Beltran R Sancho et al ldquo4-Phenylcoumarinsas HIV transcription inhibitorsrdquo Bioorganic ampMedicinal Chem-istry Letters vol 15 no 20 pp 4447ndash4450 2005
[35] K-H Lee ldquoCurrent developments in the discovery and designof new drug candidates from plant natural product leadsrdquoJournal of Natural Products vol 67 no 2 pp 273ndash283 2004
[36] D Yu M Suzuki L Xie S L Morris-Natschke and K-H LeeldquoRecent progress in the development of coumarin derivativesas potent anti-HIV agentsrdquoMedicinal Research Reviews vol 23no 3 pp 322ndash345 2003
[37] S Kirkiacharian D T Thuy S Sicsic R Bakhchinian RKurkjian and T Tonnaire ldquoStructurendashactivity relationshipsof some 3-substituted-4-hydroxycoumarins as HIV-1 proteaseinhibitorsrdquo Farmaco vol 57 no 9 pp 703ndash708 2002
[38] A G Kidane H Salacinski A Tiwari K R Bruckdorfer andA M Seifalian ldquoAnticoagulant and antiplatelet agents theirclinical and device application(s) together with usages to engi-neer surfacesrdquo Biomacromolecules vol 5 no 3 pp 798ndash8132004
[39] KMKhan Z S SaifyM Z Khan et al ldquoSynthesis of coumarinderivatives with cytotoxic antibacterial and antifungal activityrdquoJournal of Enzyme Inhibition and Medicinal Chemistry vol 19no 4 pp 373ndash379 2004
[40] G Appendino E Mercalli N Fuzzati et al ldquoAntimycobacterialcoumarins from the Sardinian giant fennel (Ferula communis)rdquoJournal of Natural Products vol 67 no 12 pp 2108ndash2110 2004
[41] NHamdiM Saoud andARomerosa ldquo4-Hydroxy coumarinea versatile reagent for the synthesis of heterocyclic and vanillinether coumarins with biological activitiesrdquo in Bioactive Hetero-cycles V vol 11 of Topics in Heterocyclic Chemistry pp 283ndash301Springer Berlin Germany 2007
[42] F Chimenti B Bizzarri A Bolasco et al ldquoSynthesis and in vitroselective anti-Helicobacter pylori activity of N-substituted-2-oxo-2H-1-benzopyran-3-carboxamidesrdquo European Journal ofMedicinal Chemistry vol 41 no 2 pp 208ndash212 2006
[43] C Ito M Itoigawa Y Mishina et al ldquoChemical con-stituents of Calophyllum brasiliense 2 Structure of three newcoumarins and cancer chemopreventive activity of 4-substi-tuted coumarinsrdquo Journal of Natural Products vol 66 no 3 pp368ndash371 2003
[44] I Kostova ldquoSynthetic and natural coumarins as cytotoxicagentsrdquo Current Medicinal ChemistrymdashAnti-Cancer Agents vol5 no 1 pp 29ndash46 2005
[45] GMelagraki A Afantitis O Igglessi-Markopoulou et al ldquoSyn-thesis and evaluation of the antioxidant and anti-inflammatoryactivity of novel coumarin-3-aminoamides and their alpha-lipoic acid adductsrdquo European Journal of Medicinal Chemistryvol 44 no 7 pp 3020ndash3026 2009
[46] C A Kontogiorgis and D J Hadjipavlou-Litina ldquoSynthesis andantiinflammatory activity of coumarin derivativesrdquo Journal ofMedicinal Chemistry vol 48 no 20 pp 6400ndash6408 2005
[47] S Stanchev V Hadjimitova T Traykov T Boyanov and IManolov ldquoInvestigation of the antioxidant properties of somenew 4-hydroxycoumarin derivativesrdquo European Journal ofMed-icinal Chemistry vol 44 no 7 pp 3077ndash3082 2009
[48] C A Kontogiorgis and D J Hadjipavlou-Litina ldquoSynthesis andbiological evaluation of novel coumarin derivatives with a 7-azomethine linkagerdquo Bioorganic and Medicinal Chemistry Let-ters vol 14 no 3 pp 611ndash614 2004
[49] C Xiao Z-G Song and Z-Q Liu ldquoSynthesis of methyl-substi-tuted xanthotoxol to clarify prooxidant effect of methyl onradical-induced oxidation of DNArdquo European Journal of Medic-inal Chemistry vol 45 no 6 pp 2559ndash2566 2010
[50] O M Abdel Hafez K M Amin N A Abdel-Latif T KMohamed E Y Ahmed and T Maher ldquoSynthesis and antitu-mor activity of some new xanthotoxin derivativesrdquo EuropeanJournal of Medicinal Chemistry vol 44 no 7 pp 2967ndash29742009
[51] V Reutrakul P Leewanich P Tuchinda et al ldquoCytotoxic coum-arins fromMammea harmandiirdquo Planta Medica vol 69 no 11pp 1048ndash1051 2003
[52] I Kempen D Papapostolou N Thierry et al ldquo3-Bromophenyl6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylateinhibits cancer cell invasion in vitro and tumour growth invivordquo British Journal of Cancer vol 88 no 7 pp 1111ndash1118 2003
Advances in Pharmacological Sciences 9
[53] P OrsquoKennedy and R D Thornes Eds Coumarins BiologyApplications andMode ofAction JohnWileyampSons ChichesterUK 1997
[54] L Zhi C M Tegley E A Kallel et al ldquo5-Aryl-12-dihydrochro-meno[34-f]quinolines a novel class of nonsteroidal humanprogesterone receptor agonistsrdquo Journal ofMedicinal Chemistryvol 41 no 3 pp 291ndash302 1998
[55] J M Schmidt G B Tremblay M Page et al ldquoSynthesisand evaluation of a novel nonsteroidal-specific endothelial cellproliferation inhibitorrdquo Journal of Medicinal Chemistry vol 46no 8 pp 1289ndash1292 2003
[56] K Hajela K Kapoor and R Kapil ldquoSynthesis and post-coitalcontraceptive activity of ether and ester analogues of 23-diaryl-2H-1-benzopyransrdquo Bioorganic amp Medicinal Chemistry vol 3pp 1417ndash1420 1995
[57] K Hajela and R S Kapil ldquoSynthesis and post-coital contra-ceptive activity of a new series of substituted 23-diaryl-2H-1-benzopyransrdquo European Journal of Medicinal Chemistry vol 32no 2 pp 135ndash139 1997
[58] K Hajela J Pandey A Dwivedy et al ldquoResolution molecularstructure and biological activities of the D- and L-enan-tiomers of potent anti-implantation agent DL-2-[4-(2-piperi-dinoethoxy)phenyl]-3-phenyl-2H-1-benzopyranrdquo Bioorganic ampMedicinal Chemistry vol 7 no 9 pp 2083ndash2090 1999
[59] H Pechmann and C Duisberg ldquoNeue Bildungsweise derCumarine Synthese desDaphnetins IrdquoChemische Berichte vol17 no 1 pp 929ndash936 1884
[60] J Johnson ldquoThe Perkin reaction and related reactionsrdquoOrganicReactions vol 1 pp 210ndash265 1942
[61] G Jones ldquoThe Knoevenagel condensationrdquo Organic Reactionsvol 15 pp 204ndash599 1967
[62] G Brufola F Fringuelli O Piermatti and F Pizzo ldquoSimpleand efficient one-pot preparation of 3-substituted coumarins inwaterrdquo Heterocycles vol 43 no 6 pp 1257ndash1266 1996
[63] R L Shriner ldquoThe reformatsky reactionrdquo in Organic Reactionsvol 1 pp 1ndash58 John Wiley amp Sons 1942
[64] I Yavari RHekmat-Shoar andA Zonouzi ldquoAnewand efficientroute to 4-carboxymethylcoumarins mediated by vinyltriph-enylphosphonium saltrdquo Tetrahedron Letters vol 39 no 16 pp2391ndash2392 1998
[65] J R Johnson ldquoPerkin reaction and related reactionsrdquo OrganicReactions vol 1 p 210 1942
[66] M H Elnagdi S O Abdallah K M Ghoneim E M Ebiedand K N Kassab ldquoSynthesis of some Coumarin derivatives aspotential LaserDyesrdquo Journal of Chemical Research Synopsesno 2 pp 44ndash45 1997
Submit your manuscripts athttpwwwhindawicom
PainResearch and TreatmentHindawi Publishing Corporationhttpwwwhindawicom Volume 2014
The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
[53] P OrsquoKennedy and R D Thornes Eds Coumarins BiologyApplications andMode ofAction JohnWileyampSons ChichesterUK 1997
[54] L Zhi C M Tegley E A Kallel et al ldquo5-Aryl-12-dihydrochro-meno[34-f]quinolines a novel class of nonsteroidal humanprogesterone receptor agonistsrdquo Journal ofMedicinal Chemistryvol 41 no 3 pp 291ndash302 1998
[55] J M Schmidt G B Tremblay M Page et al ldquoSynthesisand evaluation of a novel nonsteroidal-specific endothelial cellproliferation inhibitorrdquo Journal of Medicinal Chemistry vol 46no 8 pp 1289ndash1292 2003
[56] K Hajela K Kapoor and R Kapil ldquoSynthesis and post-coitalcontraceptive activity of ether and ester analogues of 23-diaryl-2H-1-benzopyransrdquo Bioorganic amp Medicinal Chemistry vol 3pp 1417ndash1420 1995
[57] K Hajela and R S Kapil ldquoSynthesis and post-coital contra-ceptive activity of a new series of substituted 23-diaryl-2H-1-benzopyransrdquo European Journal of Medicinal Chemistry vol 32no 2 pp 135ndash139 1997
[58] K Hajela J Pandey A Dwivedy et al ldquoResolution molecularstructure and biological activities of the D- and L-enan-tiomers of potent anti-implantation agent DL-2-[4-(2-piperi-dinoethoxy)phenyl]-3-phenyl-2H-1-benzopyranrdquo Bioorganic ampMedicinal Chemistry vol 7 no 9 pp 2083ndash2090 1999
[59] H Pechmann and C Duisberg ldquoNeue Bildungsweise derCumarine Synthese desDaphnetins IrdquoChemische Berichte vol17 no 1 pp 929ndash936 1884
[60] J Johnson ldquoThe Perkin reaction and related reactionsrdquoOrganicReactions vol 1 pp 210ndash265 1942
[61] G Jones ldquoThe Knoevenagel condensationrdquo Organic Reactionsvol 15 pp 204ndash599 1967
[62] G Brufola F Fringuelli O Piermatti and F Pizzo ldquoSimpleand efficient one-pot preparation of 3-substituted coumarins inwaterrdquo Heterocycles vol 43 no 6 pp 1257ndash1266 1996
[63] R L Shriner ldquoThe reformatsky reactionrdquo in Organic Reactionsvol 1 pp 1ndash58 John Wiley amp Sons 1942
[64] I Yavari RHekmat-Shoar andA Zonouzi ldquoAnewand efficientroute to 4-carboxymethylcoumarins mediated by vinyltriph-enylphosphonium saltrdquo Tetrahedron Letters vol 39 no 16 pp2391ndash2392 1998
[65] J R Johnson ldquoPerkin reaction and related reactionsrdquo OrganicReactions vol 1 p 210 1942
[66] M H Elnagdi S O Abdallah K M Ghoneim E M Ebiedand K N Kassab ldquoSynthesis of some Coumarin derivatives aspotential LaserDyesrdquo Journal of Chemical Research Synopsesno 2 pp 44ndash45 1997
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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014
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