Research Article Design and Microwave Assisted Synthesis ...downloads.hindawi.com/archive/2016/9890630.pdf · Research Article Design and Microwave Assisted Synthesis of Coumarin

Research ArticleDesign and Microwave Assisted Synthesis of CoumarinDerivatives as PDE Inhibitors

Mahadev N Kumbar1 Ravindra R Kamble1 Atulkumar A Kamble1

Sujith Raj Salian2 Sandhya Kumari2 Ramya Nair2 Guruprasad Kalthur2

Satish Kumar Adiga2 and D Jagadeesh Prasad3

1Department of Chemistry Karnatak University Pavate Nagar Dharwad 580003 India2Centre of Excellence in Clinical Embryology Level 2 Central Research Lab Kasturba Medical College Manipal UniversityManipal Karnataka 576104 India3Department of Studies in Chemistry Mangalore University Konaje Karnataka 574199 India

Correspondence should be addressed to Ravindra R Kamble kamchem9gmailcom

Received 30 October 2015 Revised 26 December 2015 Accepted 27 December 2015

Academic Editor Hussein El-Subbagh

Copyright copy 2016 Mahadev N Kumbar 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

Coumarins appended to benzimidazole through pyrazole are designed and synthesized using microwave irradiation Thesecompounds were analyzed for phosphodiesterase (PDE) inhibition indirectly by motility pattern in human spermatozoa Someof the synthesized compounds namely 5d 5e 5f 5g 5h and 5k have exhibited potent inhibitory activity on PDE

1 Introduction

The development of simple mild practicable cheap eco-benign method for the synthesis of heterocycles has grabbedthe attention of researchers In particular microwave assistedorganic synthesis has become a rapidly growing field inorganic chemistry as this technique makes reaction timeshorter and tolerates wide range reactions which are bestsuited to the increased demands of industry [1] and some ofthe synthesized compounds were screened by PDE

PDE inhibitors are therapeutic agents which target PDEisoenzymes and inhibit the catabolism of the secondary mes-sengers such as cyclic adenosine monophosphate (cAMP)and cyclic guanosine monophosphate (cGMP) thus pro-longing the biological effect determined by the type ofcell involved Cyclic nucleotide phosphodiesterases (PDEs)catalyze the hydrolysis of cAMP andor cGMPThey functionin conjunction with adenylyl and guanylyl cyclases to regulatethe amplitude and duration of cell signaling mechanismsmediated via cAMP and cGMP They therefore serve to reg-ulate a range of biological responses to first messengers suchas light vascular resistance cardiac output visceral motility

immune response [2] inflammation [3] neuroplasticityvision [4] and reproduction [5] Phosphodiesterases (PDEs)modulate the activity of cyclic nucleotides by regulating theirdegradation PDEs are critical determinants for modulationof cellular levels of cAMP andor cGMP by many stimuli[6] Thus the ubiquitously present PDEs play a pivotal rolein regulating cell signaling the breakdown of cAMP andcGMP

The fold selectivity for PDE5 over PDE11A4 for Sildenafil(1000-fold selectivity) and Vardenafil (9000-fold selectivity)reveals that these drugs are very unlikely to cross-react withPDE11A4 in patients treated with these medications On thecontrary it was suggested to use the newest PDE5 inhibitorTadalafil with caution In fact the 40-fold selectivity ratio ofTadalafil for PDE5 over PDE11A4 is significantly lower thanthose reported with the other two drugs and is nearly thesame as that reported for Sildenafil over PDE1 (41-fold) Inthis case it has been suggested that the 41-fold selectivity ofSildenafil for PDE5 over PDE1 may induce vasodilatationflushing and tachycardia Within human PDE11A familythe alternative splicing leads to generation of proteins whichdisplay unique properties [7 8]

Hindawi Publishing CorporationInternational Journal of Medicinal ChemistryVolume 2016 Article ID 9890630 16 pageshttpdxdoiorg10115520169890630

2 International Journal of Medicinal Chemistry

X

R

N

N

NN

N

O

R = 5-MeO 5-Me 4-MeO X = CH N

OO

N

N

NH

N NHN

F

S

O

O

R = methyl phenyl

V VI VII

NH

NNH

SO

N

HN

NH

OO

Ph

NH

N

NS

S

O

N

NH

I II III IV

OCH3OCH3O(CH2)3 3OCH

R998400

H3C

Figure 1 Some of the benzimidazole drugs and known PDE inhibitors

NO

NN

Ph NO N

N

Ph

RN

ON

O

Ph

VIII IX X

Figure 2 Representative drug molecules as PDE inhibitors VIIIndashX

Benzimidazole nucleus is the key building block fornumerous drugs that play beneficial roles in the functioningof biologically important molecules Specifically this nucleusis a constituent of Vit B

12and many currently existing

medications Almost all benzimidazoles with different het-erocyclic substituents led to essential modification in theirphysicochemical metabolic and pharmacokinetic properties[9] Benzimidazole is a core structural moiety found in someof the important drugs like albendazole (I)mebendazole (II)thiabendazole (III) rabeprazole (IV) and so forth Literaturesurvey revealed that coumarin (V) scaffolds were proved toincrease the cAMP levels through the specific inhibition ofPDE3 in accordance with their common structural features[10] and pyrazole (VI) derivatives have been explored for theidentification of phosphodiesterase (PDE4) inhibitors as isexemplified by the discovery and development of tofimilast[11] also most of the benzimidazole (VII) derivatives haveshown very prominent PDE (10A) activity [12] Coumarinpyrazole and benzimidazole core structuralmoiety are foundin some of the important PDE inhibition compounds by Yanget al [13] (Figure 1)

Also the scaffolds containing coumarin pyrazole andbenzimidazole are the key moieties in heterocyclic chemistryand are important structural units of various natural andsynthetic biologically active molecules They are known

to possess a wide range of pharmacological activities thatinclude antimicrobial and anti-inflammatory activitiesManycoumarin derivatives have shown anticancer anticoagulantanti-inflammatory antimicrobial antioxidant antiviral andcardiovascular activities [14ndash22]

During drug development of PDEs it was believed thatSAR of pyrazole and pyrazole replacements that remove thehydrogen bond donor were very promising The structuralanalogs viz compounds VIII and X contain benzoxazoleand benzimidazole attached to quinoline through oxygen aslinker groupThese have shown possess promising PDE inhi-bition as reported by Hamaguchi et al [23] Also substitutionof the pyrazole with simple alkyl groups retained potencywhile adding minimal molecular weight The methyl sub-stituted pyrazole IX (Figure 2) in an in vitro P-glycoprotein(PgP) overexpressing cell line had improved the efflux ratiosThese above drug development results and the structures ofvarious classes of clinically established PDEs conform to abroadly accepted pharmacophore (Figure 3) This suggeststhat three important structural requirements are to be presentto show PDE inhibition Those three important parametersare viz (i) fused heterocyclic ring for good oral bioavail-ability (ring A)and (ii) a five-membered heterocycle or alkylchain (B)which is connected to another fused five-memberedheterocycle (ring C) [24]

International Journal of Medicinal Chemistry 3

O O

NN

Ph

NH

N A B

C

Figure 3 Designed 3-(4-(1H-benzo[d]imidazol-2-yl)-1-phenyl-1H-pyrazol-3-yl)-2H-chromen-2-ones derivatives 5andashx

Reflux or MW

YX

1andashd 2andashd

3andashd

4andashf

5andashx

O O

NNPh

NH

N Y

O

O

O

R EtOHAcOH

RT stir

O

N

O

R

NH

Ph

O O

R

NN

CHO

Ph

R

X

DMFPOCl3

PhNHNH2

50ndash60∘C

4h

NH2

NH2

Scheme 1 Synthetic route for title compounds 5andashx where 5a R = -H X = -H Y = H 5b R = -H X = 6-Cl Y = H 5c R = -H X = 6-CH3

Y = H 5d R = -H X = 6-NO2 Y = H 5e R = -H X = 6-Br Y = N 5f R = -H X = 57-dimethyl Y = H 5g R = -6Cl X = -H Y = H 5h

R = -6Cl X = -4Cl Y = H 5i R = -6Cl X = -CH3 Y = H 5j R = -6Cl X = 6-NO

2 Y = H 5k R = -6Cl X = 6-Br Y = N 5l R = -6Cl X =

57-dimethyl Y = H 5m R = -6Br X = -H Y = H 5n R = -6Br X = -4Cl Y = H 5o R = -6Br X = -CH3 Y = H 5p R = -6Br X = 6-NO

2 Y =

H 5q R = -6Br X = 5-Br Y = N 5r R = -6Br X = 57-dimethyl Y = H 5s R = 8-OCH3 X = -H Y = H 5t R = 8-OCH

3 X = 4-Cl Y = H 5u

R = 8-OCH3 X = 6-CH

3 Y = H 5v R = 8-OCH

3 X = 6-NO

2 Y = H 5w R = 8-OCH

3 X = 5-Br Y = N 5x R = 8-OCH

3 X = 57-dimethyl

Y = H

In view of the above and in search of biologically potentnovel heterocyclic scaffolds herein we report facile and inex-pensive method for the synthesis of coumarin with pyrazolenucleus and functionalized benzimidazoles in a singlemoietywith an expectation to obtain potent PDE inhibitor

2 Results and Discussion

21 Chemistry The starting materials 3-acetyl-2H-chromen-2-one 1andashd and 3-(2-oxo-2H-chromen-3-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde 3andashdwere obtained using literaturemethods [25]The synthetic protocols for the title compounds3-(4-(1H-benzo[d]imidazol-2-yl)-1-phenyl-1H-pyrazol-3-yl)-2H-chromen-2-ones 5andashx are outlined in Scheme 1 Alsoan optimum condition was established under microwaveirradiation for the synthesis of the title compounds 5andashxby condensation of o-arylenediamines 4andashf and 3-(2-oxo-2H-chromen-3-yl)-1-phenyl-1H-pyrazole-4-carbaldehydes

3andashd in ethanol in 5ndash8min with excellent yields Comparedto conventional method (4ndash6 hrs) microwave irradiationgreatly reduced the reaction time from 3-4 h to 6ndash8min Theyield of the product was also increased up to 94 (Table 1)

Structures of all the synthesized compounds 5andashx wereconfirmed by various spectroscopic techniques viz IR 1H13CNMR MS and elemental analyses The compounds haveshown strong adsorption band for carbonyl of coumarin andN-H of benzimidazole ring at 1711ndash1737 and 3345ndash3368 cmminus1respectively In case of 1HNMR spectra all the compoundsexhibited a singlet in the range 1042ndash1336 ppm for benzim-idazole N-H ring and coumarin C

4H at 769ndash792 ppm The

aromatic protons of all pyrazole rings appeared as multipletsin the range 732ndash798 ppm In case of 13CNMR spectralstudy the numbers of signals are consistent with number ofmagnetically nonequivalent carbon atoms in the moleculeand in mass spectra all the synthesized title compounds haveshown the molecular ion peaks at their respectivemz values


Table1Com

paris

onof

conventio

naland

microwaves

ynthesisof

titlecompo

unds

5andashx

from

3andashd

and4andashf

inabsoluteethano

lund

erop

timized

cond

ition

s

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO 3a

4a

H2N

H2N

NN

Ph

N H

NO

O 5a

439

594

NN

Ph

CHO

OO

3a

Cl4b

H2N

H2N

NN

Ph

N H

NCl

OO

5b

435

590

NN

Ph

CHO

OO

3a4c

H2N

H2N

NN Ph

N H

NO

O 5c

438

588

NN

Ph

CHO

OO

3a4d

H2N

H2N

NO

2

NN

Ph

N H

N

OO

O 5d

N+ O

minus

432

586


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO 3a

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

OBr

5e

434

592

NN

Ph

CHO

OO 3a

4f

H2N

H2N

NN

Ph

N H

NO

O 5f

435

590

NN

Ph

CHO

OO

Cl3b

4a

H2N

H2N

NN

Ph

N H

NO

O

Cl

5g

540

694

NN

Ph

CHO

OO

Cl3b

Cl4b

H2N

H2N

NN

Ph

N H

NCl

OO

Cl

5h

532

685


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Cl3b

4c

H2N

H2N

NN

Ph

N H

NO

O

Cl

5i

530

687

NN

Ph

CHO

OO

Cl3b

4d

H2N

H2N

NO

2N

N

Ph

N H

N

OO

O

Cl

5j

N+ O

minus

535

684

NN

Ph

CHO

OO

Cl3b

N

Br

4e

H2N

H2N

NN

Ph

N N H

NO

O

Cl

Br

5k

534

686

NN

Ph

CHO

OO

Cl3b

4f

H2N

H2N

NN

Ph

N H

NO

O

Cl

5l

537

690


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Br3c

4a

H2N

H2N

NN

Ph

N H

NO

O

Br

5m

633

789

NN

Ph

CHO

OO

Br3c

Cl4b

H2N

H2N

NN

Ph

N H

NCl

OO

Br

5n

636

792

NN

Ph

CHO

OO

Br3c

4c

H2N

H2N

NN

Ph

N H

NO

O

Br

5o

639

794

NN

Ph

CHO

OO

Br3c

4d

H2N

H2N

NO

2

NN

Ph

N H

N

O

OO

Br

5p

N+

Ominus

636

784


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Br3c

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

O

Br

Br

5q

631

790

NN

Ph

CHO

OO

Br3c

4f

H2N

H2N

NN

Ph

N H

NO

O

Br

5r

634

792

NN

Ph

CHO

OO

O

3d4a

H2N

H2N

NN

Ph

N H

NO

O

O

5s

538

887

NN

Ph

CHO

OO

O

3d

Cl

4b

H2N

H2N

NN

Ph

N H

N

ClO

OO

5t

540

885


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

O

3d4c

H2N

H2N

NN

Ph

N H

NO

OO

5u

532

888

NN

Ph

CHO

OO

O

3d4d

H2N

H2N

NO

2

NN

Ph

N H

N

OO

OO

5v

N+

Ominus

536

886

NN

Ph

CHO

OO

O

3d

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

OO

Br

5w

538

880

NN

Ph

CHO

OO

O

3d4f

H2N

H2N

NN

Ph

N H

NO

OO

5x

534

882


3 PDE Inhibition Study

31 Effect on Motility of Frozen-Thawed Human SpermatozoaTo assess the effect of title compounds on themotility patternhuman spermatozoa subjected to freeze-thaw process wasused It is well documented that freeze-thaw process canhave detrimental effect on the motility and survival of thespermatozoa [26] Therefore they can be an excellent modelto study the effect of any test compounds on themotility [27]

In the present study we assessed the motility patternin spermatozoa processed with media containing variouscompounds manually at 1 4 and 24 h after incubationin vitro Three arbitrary doses were selected (05 10 and50 120583gmL) for each compound to assess their effect on spermmotility Pentoxifylline (PTF) which is known to enhancethe human sperm motility by elevating intracellular cyclicadenosine monophosphate (cAMP) level [27] was taken asa positive control Based on the previous report PTF at 1mMconcentration was used [28] Since the test compounds werenot soluble in water dimethyl sulfoxide (DMSO 005) wasused as vehicle control

The sperm motility enhancement property of the com-pounds was categorized as below

(a) Marginal which resulted in lt5 increase in themotility (b) Good which resulted in 5ndash10 increase inmotility (c) Excellent which resulted in gt10 increase inmotility (d) Poor where there was no enhancement inmotility

At 1 h after the in vitro incubation the majority of thecompounds had marginal effect on the sperm motility com-pared to control At this interval PTF had higher percentageof total and progressivelymotile spermatozoa compared to allthe test compounds A large number of studies have shownthat PTF can trigger the motility in fresh or frozen-thawedspermatozoa as early as 1 h [29] even though the majorityof the studies indicate that this effect is mainly due to theelevated cAMP level in the spermatozoa [30] it can also bemediated through tyrosine phosphorylation [31]

Compounds 5a 5b 5c 5d 5e 5g 5h and 5k inducedmarginal enhancement in total motility while compounds5a 5b 5c and 5j resulted in similar effect on progressivemotility (Tables 2(a) and 2(b)) A 5ndash10 increase in totalmotility was induced by compound 5j However with respectto progressive motility compounds 5d 5e 5f and 5k cameunder compounds with good effect on motility More than10 increase in progressive motility was observed only forcompound 5g (at 05 120583gmL concentration) and compound5h (at 5 120583gmL concentration)

A time-dependent decrease in total and progressivemotility was observed in all the groups However the declinewasmore evident at 24 h intervalThis phenomenon has beendocumented by earlier studies [28] These changes may berelated to the oxidative stress induced by in vitro cultureconditions Spermatozoa are highly susceptible to reactiveoxygen species (ROS) due to high polyunsaturated fatty acidcontent in their plasma membrane and negligible amount ofcytoplasmic antioxidants

At 4 h interval compounds 5e 5f and 5g enhancedthe progressive motility of spermatozoa by 5ndash10 while

compound 5h with two chloro substituents on coumarinand benzimidazole resulted in almost 15 increase in theprogressive motility However the effect was lower than thatof pentoxifylline The rest of the compounds (5a 5b 5c5f and 5j) induced a marginal increase in motility exceptin compound 5e in which the motility was lower than thecontrol group

At 24 h interval the majority of the compounds (5a5b 5d 5f 5h and 5j) had marginally higher percentageof motility or poor motility compounds (5c 5e and 5g)compared to control Interestingly compound 5k with chlorosubstituent on coumarin and bromo substitution on ben-zimidazole had higher percentage of motile spermatozoacompared to control (14 higher) and even PTF (9 higher)This indicates that compound5k canhelp in prolonging the invitro survival of spermatozoa which has significant beneficialrole in assisted reproductive technologies such as in vitrofertilization Previous studies have shown that even thoughPTF has triggering effect on themotility it induces prematureacrosome reaction and drastic decrease in motility at laterintervals In this context the compounds which increasethe motility and longevity of spermatozoa under in vitroconditions are of clinical relevance

Based on the manual motility assessment we observedthat compounds 5d 5f 5g 5h and 5k have considerablebeneficial role in spermmotilityTherefore these compoundswere further assessed for their effect on the kinematicsof spermatozoa at 1 h However there was no significantdifference in the kinematics of spermatozoa compared tocontrol and PTF (Table 3) In conclusion the newly synthe-sized coumarin derivatives have sperm motility enhancingproperty However in this preliminary screening we havetaken three arbitrary doses to assess their effect on motilityCompounds 5g 5h and 5k show considerable beneficialeffect which can be of clinical significance where spermmotility enhancement is achieved under in vitro condi-tions Compounds 5g and 5h triggered the motility at earlyintervals which was similar to the PTF while compound5k improved the longevity of the spermatozoa Since thecoumarin is known to have PDE inhibitory function themotility enhancement could be due to the elevated cAMPlevel in sperm However further detailed studies are essentialto understand the mechanism of action of these compoundsand their clinical utility

4 Experimental

All the chemicals and reagents were purchased from theMerck and Aldrich chemical suppliers Melting points (mp)were determined in open capillaries and are uncorrectedThe IR spectra were recorded on a Nicolet Impact 410 FTIR spectrometer using KBr pellets (range 4000ndash500 cmminus1)The 1HNMR spectra were recorded at 400MHz on BrukerAvance FT NMR spectrometer in DMSO-d

6solvent with

TMS as internal standard 13CNMR spectra were recordedat 100MHz on Bruker Avance FT NMR spectrometer inDMSO-d

6solvent with TMS as internal standard The mass

spectra were recorded on Shimadzu GC-MS operating at70 eV Thin-layer chromatography (TLC) was performed on


Table 2 Effect of supplementation of coumarin derivatives (5andashj) to sperm wash medium on the motility pattern in frozen-thawed humanspermatozoa at various time intervals

(a)

Compounds Time (h)Total motility (mean plusmn SE of percentage)

Concentrations in 120583gmL VC (005 DMSO) PTF (1mM)0 05 1 5

1 748 plusmn 70 763 plusmn 78 762 plusmn 86 747 plusmn 86 748 plusmn 70 825 plusmn 665a 4 774 plusmn 36 798 plusmn 28 798 plusmn 26 786 plusmn 46 782 plusmn 33 854 plusmn 38

24 283 plusmn 65 227 plusmn 56 252 plusmn 80 287 plusmn 71 280 plusmn 64 305 plusmn 661 813 plusmn 19 820 plusmn 30 855 plusmn 33 827 plusmn 29 813 plusmn 19 882 plusmn 20

5b 4 774 plusmn 36 818 plusmn 16 842 plusmn 35 804 plusmn 33 782 plusmn 33 854 plusmn 3824 285 plusmn 64 260 plusmn 51 242 plusmn 71 243 plusmn 82 282 plusmn 63 297 plusmn 711 813 plusmn 19 807 plusmn 15 817 plusmn 41 855 plusmn 31 813 plusmn 19 882 plusmn 20

5c 4 774 plusmn 36 806 plusmn 22 838 plusmn 09 854 plusmn 22 782 plusmn 33 854 plusmn 3824 283 plusmn 65 235 plusmn 67 250 plusmn 71 250 plusmn 74 280 plusmn 64 305 plusmn 661 813 plusmn 19 805 plusmn 20 865 plusmn 21 833 plusmn 18 813 plusmn 19 882 plusmn 20

5d 4 774 plusmn 36 870 plusmn 50 864 plusmn 26 786 plusmn 32 782 plusmn 33 854 plusmn 3824 285 plusmn 64 242 plusmn 67 255 plusmn 75 247 plusmn 92 282 plusmn 63 297 plusmn 711 743 plusmn 69 755 plusmn 47 757 plusmn 88 740 plusmn 92 745 plusmn 70 810 plusmn 62

5e 4 705 plusmn 75 767 plusmn 53 743 plusmn 65 745 plusmn 78 718 plusmn 75 787 plusmn 7424 283 plusmn 65 217 plusmn 65 267 plusmn 80 270 plusmn 76 280 plusmn 64 305 plusmn 661 762 plusmn 75 763 plusmn 70 758 plusmn 59 723 plusmn 67 708 plusmn 71 800 plusmn 59

5f 4 717 plusmn 75 778 plusmn 49 770 plusmn 73 753 plusmn 71 708 plusmn 78 772 plusmn 7324 268 plusmn 69 253 plusmn 73 200 plusmn 62 202 plusmn 65 188 plusmn 71 215 plusmn 721 803 plusmn 86 810 plusmn 78 820 plusmn 68 810 plusmn 60 800 plusmn 59 882 plusmn 33

5g 4 725 plusmn 70 767 plusmn 91 728 plusmn 65 720 plusmn 88 702 plusmn 95 803 plusmn 9124 288 plusmn 40 256 plusmn 69 258 plusmn 80 196 plusmn 67 336 plusmn 78 316 plusmn 851 710 plusmn 11 780 plusmn 64 740 plusmn 77 770 plusmn 71 794 plusmn 41 850 plusmn 31

5h 4 718 plusmn 95 754 plusmn 11 692 plusmn 10 760 plusmn 99 682 plusmn 126 774 plusmn 1124 508 plusmn 15 513 plusmn 19 498 plusmn 14 510 plusmn 17 370 plusmn 214 455 plusmn 211 743 plusmn 85 765 plusmn 61 777 plusmn 64 772 plusmn 63 740 plusmn 64 852 plusmn 32

5i 4 687 plusmn 76 690 plusmn 67 700 plusmn 83 705 plusmn 82 663 plusmn 102 747 plusmn 8424 294 plusmn 47 430 plusmn 12 280 plusmn 99 468 plusmn 12 204 plusmn 89 332 plusmn 131 753 plusmn 88 783 plusmn 48 795 plusmn 53 823 plusmn 23 783 plusmn 60 845 plusmn 31

5j 4 682 plusmn 75 665 plusmn 81 680 plusmn 83 698 plusmn 84 630 plusmn 93 715 plusmn 7324 152 plusmn 67 174 plusmn 62 204 plusmn 78 200 plusmn 59 152 plusmn 90 192 plusmn 92

(b)

Compounds Time (h)Progressive motility (mean plusmn SE of percentage)





5c 4 556 plusmn 41 608 plusmn 39 578 plusmn 28 590 plusmn 37 576 plusmn 40 692 plusmn 4224 158 plusmn 44 162 plusmn 46 157 plusmn 48 128 plusmn 46 152 plusmn 41 185 plusmn 47


(b) Continued



1 630 plusmn 34 643 plusmn 24 695 plusmn 27 652 plusmn 36 615 plusmn 29 737 plusmn 185d 4 556 plusmn 41 632 plusmn 46 634 plusmn 43 566 plusmn 78 576 plusmn 40 692 plusmn 42








020mm Aluchrosep silica gel 60 F254 plates (SD FineMumbai) Microwave irradiation experiments were carriedout using CEMDiscover SPMicrowave Synthesizer equippedwith IR sensor to monitor reaction temperatures

5 General Procedures for the Preparation ofTitle Compounds 5andashx

3-(2-Oxo-2H-chromen-3-yl)-1-phenyl-1H-pyrazole-4-car-baldehydes (3andashd 1 mmol) were prepared from 3-acetyl-coumarin (1andashd 1 mmol) phenylhydrazine (1mmol) andthe intermediate (Schiff base) (2andashd 1 mmol) followedby reaction with POCl

3in DMF by Vilsmeier Haack for-

mylation strategies [25] The target compounds 5andashxwere then achieved by stirring substituted carbaldehyde(3andashd 1 mmol) with different o-arylenediamine (4andashf1 mmol) under reflux for 4-5 hrs After completion (TLChexane ethylacetate 7 3) of the reaction the solid obtainedwas filtered washed with small quantity of ethanol anddried Further it was recrystallized in methanol to get thepure compound (5andashx)

51 Microwave Assisted Procedure for the Preparation of Com-pounds 5andashx A mixture of 3-(2-oxo-2H-chromen-3-yl)-1-phenyl-1H-pyrazole-4-carbaldehyde (3andashd 1 mmol) and o-phenylenediamine (4andashf 1 mmol) taken in ethanol (5mL)was introduced into a CEM microwave reaction vesselequipped with magnetic stirrer The reaction mixture was

prestirred for 1min at room temperature and irradiated at180W (150∘C) for about 6ndash8min (TLC using hexane ethylacetate (7 3 drops) as eluent) The reaction mixture wasthen quenched into crushed ice and the crude product wasfiltered washed and dried Recrystallization from methanolgave pure crystals of the compounds 5andashx

(Spectral as well as elemental analyses data are providedas electronic supplementary file in Supplementary Materialavailable online at httpdxdoiorg10115520169890630)

6 Assessment of Phosphodiesterase InhibitionUsing Human Spermatozoa as Model

Earlier studies have shown that PDE inhibitors can enhancethe spermmotility [32 33] Based on this in the present studywe have used an indirect approach to assess the inhibitoryeffect of the coumarin derivatives on PDE by assessing spermmotility pattern

61 Preparation of Test Solution Stock solution of the testcompounds (1mgmL) was prepared by dissolving them indimethyl sulfoxide (DMSO Sigma Cat number D5879)The stock solution was then diluted with Earlrsquos BalancedSalt Solution (EBSS) supplemented with 01 bovine serumalbumin (BSA) in a ratio of 1 200 1 1000 and 1 2000 to getworking solutions of 5 1 and 05 120583gmL concentrations Theworking solutions were preincubated at 37∘C and 5 CO

2

prior to use


Table 3 Effect of various coumarin derivatives on kinematics of frozen-thawed spermatozoa at one hour after incubation in vitro

Parameters Compounds Concentrations of compounds in 120583gmL VC PTFC 0 05 5 (005 DMSO) (1mM)

Velocity curvilinear(VCL)

5d 662 plusmn 66 640 plusmn 53 634 plusmn 63 710 plusmn 36 660 plusmn 66 824 plusmn 525f 795 plusmn 71 805 plusmn 74 838 plusmn 72 755 plusmn 82 770 plusmn 81 843 plusmn 755g 798 plusmn 115 753 plusmn 112 743 plusmn 63 710 plusmn 92 785 plusmn 106 855 plusmn 525h 885 plusmn 104 798 plusmn 90 910 plusmn 29 920 plusmn 61 853 plusmn 73 765 plusmn 1015k 718 plusmn 09 710 plusmn 47 733 plusmn 43 825 plusmn 119 700 plusmn 29 783 plusmn 53

Velocity straight line(VSL)


Velocity averagePath (VAP)


Amplitude of lateralhead displacement(ALH)


Linearity(LIN)


Straightness(STR)

5d 660 plusmn 12 690 plusmn 17 712 plusmn25 660 plusmn 12 690 plusmn 17 712 plusmn255f 613 plusmn 31 613 plusmn 46 618 plusmn 51 613 plusmn 31 613 plusmn 46 618 plusmn 515g 605 plusmn 38 628 plusmn 65 615 plusmn 51 605 plusmn 38 628 plusmn 65 615 plusmn 515h 688 plusmn 39 693 plusmn 58 650 plusmn 51 688 plusmn 39 693 plusmn 58 650 plusmn 515k 655 plusmn 79 638 plusmn 62 613 plusmn 75 655 plusmn 79 638 plusmn 62 613 plusmn 75

Wobble(WOB)


Beat cross frequency(BCF)


62 Study Subjects Infertile men who attended AndrologyLaboratory Kasturba Medical College Manipal UniversityManipal during the period of June-July 2015 for routinesemen evaluation were included in the study The subjects

with a sexual abstinence of 3ndash5 days were asked to providethe semen samples by masturbation in a sterile containerFollowing liquefaction the semen parameters were assessedas described by Kotdawala et al [34]The study was approved


by the Institutional Ethics Committee of Kasturba HospitalKasturba Medical College Manipal University (IEC number1552015)

63 Cryopreservation and Thawing The liquefied semensamples were cryopreserved by rapid freezing method asdescribed previously [34] with minor modifications Brieflythe semen samples were mixed with equal volume of freezingmedium (Sperm Freeze FertiPro Cat number 0344) in acryovial (Thermoscientific Nunc Cat number 138627) andkept at 4∘C for 10min in liquid nitrogen (LN2) vapor phasefor 5min and then finally plunged into liquid nitrogenThe samples were thawed after 1 week by rapid thawingmethod by placing themat 37∘C for 5minThe cryoprotectantmedium was completely removed by mixing the spermsuspension with EBSS medium and centrifuging at 1000 rpmfor 8min The resultant pellet was resuspended with freshEBSS medium and used for further analysis

64 Sample Preparation To screen the compounds withenhancing effect on themotility of spermatozoa under in vitroconditions the frozen-thawed semen samples were washedby mixing with equal volume of preincubated Earlrsquos BalancedSalt Solution (EBSS Sigma Cat number E2888) followed bycentrifugation at 1800 rpm for 8min The pellet was thengently mixed with 1mL of EBSS media containing 01bovine serum albumin (BSA Sigma Cat number A3311)and equally divided into control vehicle control and testgroups (with average sperm density of 5 times 104 spermatozoain each group) The motile sperm were extracted by swimup method as described earlier [35] The sperm suspensionwas centrifuged at 1200 rpm for 8min and the resultantpellet was overlaidwith EBSSmedium containing various testcompoundsThe sperm suspensions were incubated for 1 h at37∘Cand 5CO

2afterwhich themotile spermwere collected

from the supernatant

65 Motility Assessment Spermatozoa in the supernatantfraction were assessed for their motility patterns at 1 4 and24 h after incubation under light microscope as describedearlier [27] Sperm suspension was (10 120583L droplet) placed ona clean microscope slide and a coverslip was placed over itSpermatozoa with progressive motility and nonprogressivemotility and immotile spermatozoa were scored separatelyfrom a total of 200 spermatozoa in random fields at 400xmagnification

66 Sperm Kinematics Using Computer Assisted Semen Anal-ysis (CASA) The motion characteristics in the spermatozoawere assessed at 1 4 and 24 h after incubation using CASAsystem (ISAS Spain) Briefly 5 120583L of sperm suspension wasplaced on a clean microscope slide prewarmed at 37∘C Thesperm suspensionwas coveredwith prewarmed cover slip (22times 22mm) and observed under microscope (negative phasecontrast 10x objectives Proiser Spain) For each sample thekinematics was assessed randomly at ten different fields Theparameters such as curvilinear velocity (VCL) straight line

velocity (VSL) average path velocity (VAP) amplitude of lat-eral head displacement (ALH) linearity (LIN) straightness(STR) wobble (WOB) and beat cross frequency (BCF) wereanalyzed

7 Conclusions

In conclusion we have reported efficient and environmen-tally benignmethodologies for the synthesis of 3-[4-(1H-benzo[d]imidazol-2-yl)-1-phenyl-1H-pyrazol-3-yl]-2H-chromen-2-one derivatives 5andashx by using thermal and by microwaveirradiation under neat conditions in presence of ethanol Thereactions carried out under microwave irradiation affordedbenzimidazoles in short period of time with excellent yieldsHence this methodology would make an interesting strategyfor the synthesis of various substituted coumarin pyrazolebenzimidazoles Also compounds 5g 5h and 5k exhibitedimpressive sperm motility enhancing property whereas 5khas spermatozoa longevity property

Conflict of Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

The authors are grateful to University Scientific Instrumen-tation Centre (USIC) Karnatak University Dharwad forprovidingmass and IR spectral dataThe authors are thankfulto Indian Institute of Science (IISc) Bengaluru for carryingout NMR analyses and to UGC New Delhi for the financialassistance under UPE program vide no [F No 14-22012(NSPE) dated 22-01-2013] One of the authors (MNK)acknowledges University Grants Commission (UGC) NewDelhi for fellowship under UGC-UPE program

References

[1] P P Kattimani R R Kamble and G Y Meti ldquoExpedientsynthesis of benzimidazoles using amidesrdquo RSC Advances vol5 no 37 pp 29447ndash29455 2015

[2] L Li C Yee and J A Beavo ldquoCD3- and CD28-dependentinduction of PDE7 required for T cell activationrdquo Science vol283 no 5403 pp 848ndash849 1999

[3] T P Dousa ldquoCyclic-3101584051015840-nucleotide phosphodiesteraseisozymes in cell biology and pathophysiology of the kidneyrdquoKidney International vol 55 no 1 pp 29ndash62 1999

[4] C Pfister N Bennett F Bruckert et al ldquoInteractions of a G-protein with its effector transducin and cGMP phosphodi-esterase in retinal rodsrdquo Cell Signaling vol 5 no 3 pp 235ndash2411993

[5] S L C Jin F J Richard W-P Kuo A J DrsquoErcole andM Conti ldquoImpaired growth and fertility of cAMP-specificphosphodiesterase PDE4D-deficient micerdquo Proceedings of theNational Academy of Sciences of the United States of Americavol 96 no 21 pp 11998ndash12003 1999

[6] S H Francis I V Turko and J D Corbin ldquoCyclic nucleotidephosphodiesterases relating structure and functionrdquoProgress in


Nucleic Acid Research and Molecular Biology vol 65 pp 1ndash522000

[7] J M Hetman N Robas R Baxendale et al ldquoCloning and char-acterization of two splice variants of human phosphodiesterase11Ardquo Proceedings of the National Academy of Sciences of theUnited States of America vol 97 no 23 pp 12891ndash12895 2000

[8] K Yuasa T Ohgaru M Asahina and K Omori ldquoIdentificationof rat cyclic nucleotide phosphodiesterase 11A (PDE11A) com-parison of rat and human PDE11A splicing variantsrdquo EuropeanJournal of Biochemistry vol 268 no 16 pp 4440ndash4448 2001

[9] S K Sahu A Mishra and R K Behera ldquoSynthesis of thiazolebenzothiazole oxadiazole thiadiazole triazole and thiazolidi-none incorporated coumarinsrdquo Indian Journal of HeterocyclicChemistry vol 6 no 2 pp 91ndash94 1996

[10] G Roma M Di Braccio G Grossi et al ldquoSynthesis and in vitroantiplatelet activity of new 4-(1-piperazinyl) coumarin deriva-tives Human platelet phosphodiesterase 3 inhibitory propertiesof the two most effective compounds described and molecularmodeling study on their interactions with phosphodiesterase3A catalytic siterdquo Journal of Medicinal Chemistry vol 50 no 12pp 2886ndash2895 2007

[11] T Shyamsunder Reddy K Shiva Kumar C L T Medaet al ldquoConformationally restricted novel pyrazole deriva-tives synthesis of 18-disubstituted 55-dimethyl-45-dihydro-1H-benzo[g]indazoles as a new class of PDE4 inhibitorsrdquoBioorganic and Medicinal Chemistry Letters vol 22 no 9 pp3248ndash3255 2012

[12] A Chino N Masuda Y Amano et al ldquoNovel benzimidazolederivatives as phosphodiesterase 10A (PDE10A) inhibitors withimproved metabolic stabilityrdquo Bioorganic and Medicinal Chem-istry vol 22 no 13 pp 3515ndash3526 2014

[13] H Yang FNMurigi ZWang J Li H Jin andZ Tu ldquoSynthesisand in vitro characterization of cinnoline and benzimidazoleanalogues as phosphodiesterase 10A inhibitorsrdquo Bioorganic andMedicinal Chemistry Letters vol 25 pp 919ndash924 2015

[14] J Nawrot-Modranka E Nawrot and J Graczyk ldquoIn vivo antitu-mor in vitro antibacterial activity and alkylating properties ofphosphorohydrazine derivatives of coumarin and chromonerdquoEuropean Journal of Medicinal Chemistry vol 41 no 11 pp1301ndash1309 2006

[15] A A Bekhit and T Abdel-Aziem ldquoDesign synthesis andbiological evaluation of some pyrazole derivatives as anti-inflammatory-antimicrobial agentsrdquo Bioorganic and MedicinalChemistry vol 12 no 8 pp 1935ndash1945 2004

[16] T Devji C Reddy CWoo S Awale S Kadota and D Carrico-Moniz ldquoPancreatic anticancer activity of a novel geranylgerany-lated coumarin derivativerdquo Bioorganic andMedicinal ChemistryLetters vol 21 no 19 pp 5770ndash5773 2011

[17] I Kostova I Manolov I Nicolova S Konstantinov andM Karaivanova ldquoNew lanthanide complexes of 4-methyl-7-hydroxycoumarin and their pharmacological activityrdquo Euro-pean Journal of Medicinal Chemistry vol 36 no 4 pp 339ndash3472001

[18] M Ghate R A Kusanur and M V Kulkarni ldquoSynthesis andin vivo analgesic and anti-inflammatory activity of some bi-heterocyclic coumarin derivativesrdquo European Journal of Medic-inal Chemistry vol 40 no 9 pp 882ndash887 2005

[19] PM RonadMN Noolvi S Sapkal S Dharbhamulla andV SMaddi ldquoSynthesis and antimicrobial activity of 7-(2-substitutedphenylthiazolidinyl)-benzopyran-2-one derivativesrdquo EuropeanJournal of Medicinal Chemistry vol 45 no 1 pp 85ndash89 2010

[20] 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

[21] J C Trivedi J B Bariwal K D Upadhyay et al ldquoImprovedand rapid synthesis of new coumarinyl chalcone derivatives andtheir antiviral activityrdquo Tetrahedron Letters vol 48 no 48 pp8472ndash8474 2007

[22] S Vilar E Quezada L Santana et al ldquoDesign synthe-sis and vasorelaxant and platelet antiaggregatory activitiesof coumarinndashresveratrol hybridsrdquo Bioorganic and MedicinalChemistry Letters vol 16 no 2 pp 257ndash261 2006

[23] W Hamaguchi N Masuda M Isomura et al ldquoDesign and syn-thesis of novel benzimidazole derivatives as phosphodiesterase10A inhibitors with reduced CYP1A2 inhibitionrdquo Bioorganicand Medicinal Chemistry vol 21 no 24 pp 7612ndash7623 2013

[24] A Dore B Asproni A Scampuddu et al ldquoSynthesis and SARstudy of novel tricyclic pyrazoles as potent phosphodiesterase10A inhibitorsrdquo European Journal of Medicinal Chemistry vol84 pp 181ndash193 2014

[25] S V Laxmi B S Kuarm and B Rajitha ldquoSynthesis and anti-microbial activity of coumarin pyrazole pyrimidine 246(1H3H5H)triones and thioxopyrimidine46(1H5H)dionesrdquo Me-dicinal Chemistry Research vol 22 no 2 pp 768ndash774 2013

[26] G Kalthur S Raj AThiyagarajan S Kumar P Kumar and S KAdiga ldquoVitamin E supplementation in semen-freezingmediumimproves the motility and protects sperm from freeze-thaw-induced DNA damagerdquo Fertility and Sterility vol 95 no 3 pp1149ndash1151 2011

[27] J Tesarik C Mendoza and A Carreras ldquoEffects of phosphodi-esterase inhibitors caffeine and pentoxifylline on spontaneousand stimulus-induced acrosome reactions in human spermrdquoFertility and Sterility vol 58 no 6 pp 1185ndash1190 1992

[28] G Kalthur S R Salian F Keyvanifard et al ldquoSupplementationof biotin to sperm preparation medium increases the motilityand longevity in cryopreserved human spermatozoardquo Journalof Assisted Reproduction and Genetics vol 29 no 7 pp 631ndash6352012

[29] A E Calogero S Fishel J Hall et al ldquoCorrelation betweenintracellular cAMP content kinematic parameters and hyper-activation of human spermatozoa after incubation with pentox-ifyllinerdquo Human Reproduction vol 13 no 4 pp 911ndash915 1998

[30] R Ain K Uma Devi S Shivaji and P B Seshagiri ldquoPen-toxifylline-stimulated capacitation and acrosome reaction inhamster spermatozoa involvement of intracellular signallingmoleculesrdquo Molecular Human Reproduction vol 5 no 7 pp618ndash626 1999

[31] M Bajpai andG F Doncel ldquoInvolvement of tyrosine kinase andcAMP-dependent kinase cross-talk in the regulation of humanspermmotilityrdquo Reproduction vol 126 no 2 pp 183ndash195 2003

[32] R Yunes P Fernandez G F Doncel and A A Acosta ldquoCyclicnucleotide phosphodiesterase inhibition increases tyrosinephosphorylation and hypermotility in normal and pathologicalhuman spermatozoardquo Biocell vol 29 no 3 pp 287ndash293 2005

[33] F Dimitriadis D Giannakis N Pardalidis et al ldquoEffectsof phosphodiesterase 5 inhibitors on sperm parameters andfertilizing capacityrdquo Asian Journal of Andrology vol 10 no 1pp 115ndash133 2008

[34] A P Kotdawala S Kumar S R Salian et al ldquoAddition of zincto human ejaculate prior to cryopreservation prevents freeze-thaw-induced DNA damage and preserves sperm functionrdquo


Journal of Assisted Reproduction and Genetics vol 29 no 12 pp1447ndash1453 2012

[35] S Mutalik S R Salian K Avadhani et al ldquoLiposome encapsu-lated soy lecithin and cholesterol can efficiently replace chickenegg yolk in human semen cryopreservation mediumrdquo SystemsBiology in Reproductive Medicine vol 60 no 3 pp 183ndash1882014

Submit your manuscripts athttpwwwhindawicom

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Inorganic ChemistryInternational Journal of

Hindawi Publishing Corporation httpwwwhindawicom Volume 2014

International Journal ofPhotoenergy


Carbohydrate Chemistry

International Journal of


Journal of

Chemistry


Advances in

Physical Chemistry

Hindawi Publishing Corporationhttpwwwhindawicom

Analytical Methods in Chemistry

Journal of

Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Medicinal ChemistryInternational Journal of


Chromatography Research International


Applied ChemistryJournal of



Theoretical ChemistryJournal of


Journal of

Spectroscopy

Analytical ChemistryInternational Journal of


Journal of


Quantum Chemistry


Organic Chemistry International

ElectrochemistryInternational Journal of



CatalystsJournal of


X

R

N

N

NN

N

O

R = 5-MeO 5-Me 4-MeO X = CH N

OO

N

N

NH

N NHN

F

S

O

O

R = methyl phenyl

V VI VII

NH

NNH

SO

N

HN

NH

OO

Ph

NH

N

NS

S

O

N

NH

I II III IV

OCH3OCH3O(CH2)3 3OCH

R998400

H3C

Figure 1 Some of the benzimidazole drugs and known PDE inhibitors

NO

NN

Ph NO N

N

Ph

RN

ON

O

Ph

VIII IX X

Figure 2 Representative drug molecules as PDE inhibitors VIIIndashX

Benzimidazole nucleus is the key building block fornumerous drugs that play beneficial roles in the functioningof biologically important molecules Specifically this nucleusis a constituent of Vit B

12and many currently existing

medications Almost all benzimidazoles with different het-erocyclic substituents led to essential modification in theirphysicochemical metabolic and pharmacokinetic properties[9] Benzimidazole is a core structural moiety found in someof the important drugs like albendazole (I)mebendazole (II)thiabendazole (III) rabeprazole (IV) and so forth Literaturesurvey revealed that coumarin (V) scaffolds were proved toincrease the cAMP levels through the specific inhibition ofPDE3 in accordance with their common structural features[10] and pyrazole (VI) derivatives have been explored for theidentification of phosphodiesterase (PDE4) inhibitors as isexemplified by the discovery and development of tofimilast[11] also most of the benzimidazole (VII) derivatives haveshown very prominent PDE (10A) activity [12] Coumarinpyrazole and benzimidazole core structuralmoiety are foundin some of the important PDE inhibition compounds by Yanget al [13] (Figure 1)

Also the scaffolds containing coumarin pyrazole andbenzimidazole are the key moieties in heterocyclic chemistryand are important structural units of various natural andsynthetic biologically active molecules They are known

to possess a wide range of pharmacological activities thatinclude antimicrobial and anti-inflammatory activitiesManycoumarin derivatives have shown anticancer anticoagulantanti-inflammatory antimicrobial antioxidant antiviral andcardiovascular activities [14ndash22]

During drug development of PDEs it was believed thatSAR of pyrazole and pyrazole replacements that remove thehydrogen bond donor were very promising The structuralanalogs viz compounds VIII and X contain benzoxazoleand benzimidazole attached to quinoline through oxygen aslinker groupThese have shown possess promising PDE inhi-bition as reported by Hamaguchi et al [23] Also substitutionof the pyrazole with simple alkyl groups retained potencywhile adding minimal molecular weight The methyl sub-stituted pyrazole IX (Figure 2) in an in vitro P-glycoprotein(PgP) overexpressing cell line had improved the efflux ratiosThese above drug development results and the structures ofvarious classes of clinically established PDEs conform to abroadly accepted pharmacophore (Figure 3) This suggeststhat three important structural requirements are to be presentto show PDE inhibition Those three important parametersare viz (i) fused heterocyclic ring for good oral bioavail-ability (ring A)and (ii) a five-membered heterocycle or alkylchain (B)which is connected to another fused five-memberedheterocycle (ring C) [24]


O O

NN

Ph

NH

N A B

C


Reflux or MW

YX

1andashd 2andashd

3andashd

4andashf

5andashx

O O

NNPh

NH

N Y

O

O

O

R EtOHAcOH

RT stir

O

N

O

R

NH

Ph

O O

R

NN

CHO

Ph

R

X

DMFPOCl3

PhNHNH2

50ndash60∘C

4h

NH2

NH2






2 Y =


3 X = 4-Cl Y = H 5u

R = 8-OCH3 X = 6-CH

3 Y = H 5v R = 8-OCH

3 X = 6-NO

2 Y = H 5w R = 8-OCH

3 X = 5-Br Y = N 5x R = 8-OCH

3 X = 57-dimethyl

Y = H









Table1Com

paris

onof

conventio

naland

microwaves

ynthesisof

titlecompo

unds

5andashx

from

3andashd

and4andashf

inabsoluteethano

lund

erop

timized

cond

ition

s

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO 3a

4a

H2N

H2N

NN

Ph

N H

NO

O 5a

439

594

NN

Ph

CHO

OO

3a

Cl4b

H2N

H2N

NN

Ph

N H

NCl

OO

5b

435

590

NN

Ph

CHO

OO

3a4c

H2N

H2N

NN Ph

N H

NO

O 5c

438

588

NN

Ph

CHO

OO

3a4d

H2N

H2N

NO

2

NN

Ph

N H

N

OO

O 5d

N+ O

minus

432

586


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO 3a

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

OBr

5e

434

592

NN

Ph

CHO

OO 3a

4f

H2N

H2N

NN

Ph

N H

NO

O 5f

435

590

NN

Ph

CHO

OO

Cl3b

4a

H2N

H2N

NN

Ph

N H

NO

O

Cl

5g

540

694

NN

Ph

CHO

OO

Cl3b

Cl4b

H2N

H2N

NN

Ph

N H

NCl

OO

Cl

5h

532

685


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Cl3b

4c

H2N

H2N

NN

Ph

N H

NO

O

Cl

5i

530

687

NN

Ph

CHO

OO

Cl3b

4d

H2N

H2N

NO

2N

N

Ph

N H

N

OO

O

Cl

5j

N+ O

minus

535

684

NN

Ph

CHO

OO

Cl3b

N

Br

4e

H2N

H2N

NN

Ph

N N H

NO

O

Cl

Br

5k

534

686

NN

Ph

CHO

OO

Cl3b

4f

H2N

H2N

NN

Ph

N H

NO

O

Cl

5l

537

690


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Br3c

4a

H2N

H2N

NN

Ph

N H

NO

O

Br

5m

633

789

NN

Ph

CHO

OO

Br3c

Cl4b

H2N

H2N

NN

Ph

N H

NCl

OO

Br

5n

636

792

NN

Ph

CHO

OO

Br3c

4c

H2N

H2N

NN

Ph

N H

NO

O

Br

5o

639

794

NN

Ph

CHO

OO

Br3c

4d

H2N

H2N

NO

2

NN

Ph

N H

N

O

OO

Br

5p

N+

Ominus

636

784


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Br3c

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

O

Br

Br

5q

631

790

NN

Ph

CHO

OO

Br3c

4f

H2N

H2N

NN

Ph

N H

NO

O

Br

5r

634

792

NN

Ph

CHO

OO

O

3d4a

H2N

H2N

NN

Ph

N H

NO

O

O

5s

538

887

NN

Ph

CHO

OO

O

3d

Cl

4b

H2N

H2N

NN

Ph

N H

N

ClO

OO

5t

540

885


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

O

3d4c

H2N

H2N

NN

Ph

N H

NO

OO

5u

532

888

NN

Ph

CHO

OO

O

3d4d

H2N

H2N

NO

2

NN

Ph

N H

N

OO

OO

5v

N+

Ominus

536

886

NN

Ph

CHO

OO

O

3d

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

OO

Br

5w

538

880

NN

Ph

CHO

OO

O

3d4f

H2N

H2N

NN

Ph

N H

NO

OO

5x

534

882














4 Experimental


6solvent with






(a)














(b)








(b) Continued






















2

prior to use












Linearity(LIN)


Straightness(STR)


Wobble(WOB)















7 Conclusions




Acknowledgments


References

















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


O O

NN

Ph

NH

N A B

C


Reflux or MW

YX

1andashd 2andashd

3andashd

4andashf

5andashx

O O

NNPh

NH

N Y

O

O

O

R EtOHAcOH

RT stir

O

N

O

R

NH

Ph

O O

R

NN

CHO

Ph

R

X

DMFPOCl3

PhNHNH2

50ndash60∘C

4h

NH2

NH2






2 Y =


3 X = 4-Cl Y = H 5u

R = 8-OCH3 X = 6-CH

3 Y = H 5v R = 8-OCH

3 X = 6-NO

2 Y = H 5w R = 8-OCH

3 X = 5-Br Y = N 5x R = 8-OCH

3 X = 57-dimethyl

Y = H









Table1Com

paris

onof

conventio

naland

microwaves

ynthesisof

titlecompo

unds

5andashx

from

3andashd

and4andashf

inabsoluteethano

lund

erop

timized

cond

ition

s

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO 3a

4a

H2N

H2N

NN

Ph

N H

NO

O 5a

439

594

NN

Ph

CHO

OO

3a

Cl4b

H2N

H2N

NN

Ph

N H

NCl

OO

5b

435

590

NN

Ph

CHO

OO

3a4c

H2N

H2N

NN Ph

N H

NO

O 5c

438

588

NN

Ph

CHO

OO

3a4d

H2N

H2N

NO

2

NN

Ph

N H

N

OO

O 5d

N+ O

minus

432

586


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO 3a

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

OBr

5e

434

592

NN

Ph

CHO

OO 3a

4f

H2N

H2N

NN

Ph

N H

NO

O 5f

435

590

NN

Ph

CHO

OO

Cl3b

4a

H2N

H2N

NN

Ph

N H

NO

O

Cl

5g

540

694

NN

Ph

CHO

OO

Cl3b

Cl4b

H2N

H2N

NN

Ph

N H

NCl

OO

Cl

5h

532

685


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Cl3b

4c

H2N

H2N

NN

Ph

N H

NO

O

Cl

5i

530

687

NN

Ph

CHO

OO

Cl3b

4d

H2N

H2N

NO

2N

N

Ph

N H

N

OO

O

Cl

5j

N+ O

minus

535

684

NN

Ph

CHO

OO

Cl3b

N

Br

4e

H2N

H2N

NN

Ph

N N H

NO

O

Cl

Br

5k

534

686

NN

Ph

CHO

OO

Cl3b

4f

H2N

H2N

NN

Ph

N H

NO

O

Cl

5l

537

690


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Br3c

4a

H2N

H2N

NN

Ph

N H

NO

O

Br

5m

633

789

NN

Ph

CHO

OO

Br3c

Cl4b

H2N

H2N

NN

Ph

N H

NCl

OO

Br

5n

636

792

NN

Ph

CHO

OO

Br3c

4c

H2N

H2N

NN

Ph

N H

NO

O

Br

5o

639

794

NN

Ph

CHO

OO

Br3c

4d

H2N

H2N

NO

2

NN

Ph

N H

N

O

OO

Br

5p

N+

Ominus

636

784


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Br3c

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

O

Br

Br

5q

631

790

NN

Ph

CHO

OO

Br3c

4f

H2N

H2N

NN

Ph

N H

NO

O

Br

5r

634

792

NN

Ph

CHO

OO

O

3d4a

H2N

H2N

NN

Ph

N H

NO

O

O

5s

538

887

NN

Ph

CHO

OO

O

3d

Cl

4b

H2N

H2N

NN

Ph

N H

N

ClO

OO

5t

540

885


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

O

3d4c

H2N

H2N

NN

Ph

N H

NO

OO

5u

532

888

NN

Ph

CHO

OO

O

3d4d

H2N

H2N

NO

2

NN

Ph

N H

N

OO

OO

5v

N+

Ominus

536

886

NN

Ph

CHO

OO

O

3d

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

OO

Br

5w

538

880

NN

Ph

CHO

OO

O

3d4f

H2N

H2N

NN

Ph

N H

NO

OO

5x

534

882














4 Experimental


6solvent with






(a)














(b)








(b) Continued






















2

prior to use












Linearity(LIN)


Straightness(STR)


Wobble(WOB)















7 Conclusions




Acknowledgments


References

















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Table1Com

paris

onof

conventio

naland

microwaves

ynthesisof

titlecompo

unds

5andashx

from

3andashd

and4andashf

inabsoluteethano

lund

erop

timized

cond

ition

s

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO 3a

4a

H2N

H2N

NN

Ph

N H

NO

O 5a

439

594

NN

Ph

CHO

OO

3a

Cl4b

H2N

H2N

NN

Ph

N H

NCl

OO

5b

435

590

NN

Ph

CHO

OO

3a4c

H2N

H2N

NN Ph

N H

NO

O 5c

438

588

NN

Ph

CHO

OO

3a4d

H2N

H2N

NO

2

NN

Ph

N H

N

OO

O 5d

N+ O

minus

432

586


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO 3a

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

OBr

5e

434

592

NN

Ph

CHO

OO 3a

4f

H2N

H2N

NN

Ph

N H

NO

O 5f

435

590

NN

Ph

CHO

OO

Cl3b

4a

H2N

H2N

NN

Ph

N H

NO

O

Cl

5g

540

694

NN

Ph

CHO

OO

Cl3b

Cl4b

H2N

H2N

NN

Ph

N H

NCl

OO

Cl

5h

532

685


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Cl3b

4c

H2N

H2N

NN

Ph

N H

NO

O

Cl

5i

530

687

NN

Ph

CHO

OO

Cl3b

4d

H2N

H2N

NO

2N

N

Ph

N H

N

OO

O

Cl

5j

N+ O

minus

535

684

NN

Ph

CHO

OO

Cl3b

N

Br

4e

H2N

H2N

NN

Ph

N N H

NO

O

Cl

Br

5k

534

686

NN

Ph

CHO

OO

Cl3b

4f

H2N

H2N

NN

Ph

N H

NO

O

Cl

5l

537

690


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Br3c

4a

H2N

H2N

NN

Ph

N H

NO

O

Br

5m

633

789

NN

Ph

CHO

OO

Br3c

Cl4b

H2N

H2N

NN

Ph

N H

NCl

OO

Br

5n

636

792

NN

Ph

CHO

OO

Br3c

4c

H2N

H2N

NN

Ph

N H

NO

O

Br

5o

639

794

NN

Ph

CHO

OO

Br3c

4d

H2N

H2N

NO

2

NN

Ph

N H

N

O

OO

Br

5p

N+

Ominus

636

784


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Br3c

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

O

Br

Br

5q

631

790

NN

Ph

CHO

OO

Br3c

4f

H2N

H2N

NN

Ph

N H

NO

O

Br

5r

634

792

NN

Ph

CHO

OO

O

3d4a

H2N

H2N

NN

Ph

N H

NO

O

O

5s

538

887

NN

Ph

CHO

OO

O

3d

Cl

4b

H2N

H2N

NN

Ph

N H

N

ClO

OO

5t

540

885


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

O

3d4c

H2N

H2N

NN

Ph

N H

NO

OO

5u

532

888

NN

Ph

CHO

OO

O

3d4d

H2N

H2N

NO

2

NN

Ph

N H

N

OO

OO

5v

N+

Ominus

536

886

NN

Ph

CHO

OO

O

3d

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

OO

Br

5w

538

880

NN

Ph

CHO

OO

O

3d4f

H2N

H2N

NN

Ph

N H

NO

OO

5x

534

882














4 Experimental


6solvent with






(a)














(b)








(b) Continued






















2

prior to use












Linearity(LIN)


Straightness(STR)


Wobble(WOB)















7 Conclusions




Acknowledgments


References

















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO 3a

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

OBr

5e

434

592

NN

Ph

CHO

OO 3a

4f

H2N

H2N

NN

Ph

N H

NO

O 5f

435

590

NN

Ph

CHO

OO

Cl3b

4a

H2N

H2N

NN

Ph

N H

NO

O

Cl

5g

540

694

NN

Ph

CHO

OO

Cl3b

Cl4b

H2N

H2N

NN

Ph

N H

NCl

OO

Cl

5h

532

685


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Cl3b

4c

H2N

H2N

NN

Ph

N H

NO

O

Cl

5i

530

687

NN

Ph

CHO

OO

Cl3b

4d

H2N

H2N

NO

2N

N

Ph

N H

N

OO

O

Cl

5j

N+ O

minus

535

684

NN

Ph

CHO

OO

Cl3b

N

Br

4e

H2N

H2N

NN

Ph

N N H

NO

O

Cl

Br

5k

534

686

NN

Ph

CHO

OO

Cl3b

4f

H2N

H2N

NN

Ph

N H

NO

O

Cl

5l

537

690


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Br3c

4a

H2N

H2N

NN

Ph

N H

NO

O

Br

5m

633

789

NN

Ph

CHO

OO

Br3c

Cl4b

H2N

H2N

NN

Ph

N H

NCl

OO

Br

5n

636

792

NN

Ph

CHO

OO

Br3c

4c

H2N

H2N

NN

Ph

N H

NO

O

Br

5o

639

794

NN

Ph

CHO

OO

Br3c

4d

H2N

H2N

NO

2

NN

Ph

N H

N

O

OO

Br

5p

N+

Ominus

636

784


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Br3c

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

O

Br

Br

5q

631

790

NN

Ph

CHO

OO

Br3c

4f

H2N

H2N

NN

Ph

N H

NO

O

Br

5r

634

792

NN

Ph

CHO

OO

O

3d4a

H2N

H2N

NN

Ph

N H

NO

O

O

5s

538

887

NN

Ph

CHO

OO

O

3d

Cl

4b

H2N

H2N

NN

Ph

N H

N

ClO

OO

5t

540

885


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

O

3d4c

H2N

H2N

NN

Ph

N H

NO

OO

5u

532

888

NN

Ph

CHO

OO

O

3d4d

H2N

H2N

NO

2

NN

Ph

N H

N

OO

OO

5v

N+

Ominus

536

886

NN

Ph

CHO

OO

O

3d

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

OO

Br

5w

538

880

NN

Ph

CHO

OO

O

3d4f

H2N

H2N

NN

Ph

N H

NO

OO

5x

534

882














4 Experimental


6solvent with






(a)














(b)








(b) Continued






















2

prior to use












Linearity(LIN)


Straightness(STR)


Wobble(WOB)















7 Conclusions




Acknowledgments


References

















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Cl3b

4c

H2N

H2N

NN

Ph

N H

NO

O

Cl

5i

530

687

NN

Ph

CHO

OO

Cl3b

4d

H2N

H2N

NO

2N

N

Ph

N H

N

OO

O

Cl

5j

N+ O

minus

535

684

NN

Ph

CHO

OO

Cl3b

N

Br

4e

H2N

H2N

NN

Ph

N N H

NO

O

Cl

Br

5k

534

686

NN

Ph

CHO

OO

Cl3b

4f

H2N

H2N

NN

Ph

N H

NO

O

Cl

5l

537

690


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Br3c

4a

H2N

H2N

NN

Ph

N H

NO

O

Br

5m

633

789

NN

Ph

CHO

OO

Br3c

Cl4b

H2N

H2N

NN

Ph

N H

NCl

OO

Br

5n

636

792

NN

Ph

CHO

OO

Br3c

4c

H2N

H2N

NN

Ph

N H

NO

O

Br

5o

639

794

NN

Ph

CHO

OO

Br3c

4d

H2N

H2N

NO

2

NN

Ph

N H

N

O

OO

Br

5p

N+

Ominus

636

784


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Br3c

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

O

Br

Br

5q

631

790

NN

Ph

CHO

OO

Br3c

4f

H2N

H2N

NN

Ph

N H

NO

O

Br

5r

634

792

NN

Ph

CHO

OO

O

3d4a

H2N

H2N

NN

Ph

N H

NO

O

O

5s

538

887

NN

Ph

CHO

OO

O

3d

Cl

4b

H2N

H2N

NN

Ph

N H

N

ClO

OO

5t

540

885


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

O

3d4c

H2N

H2N

NN

Ph

N H

NO

OO

5u

532

888

NN

Ph

CHO

OO

O

3d4d

H2N

H2N

NO

2

NN

Ph

N H

N

OO

OO

5v

N+

Ominus

536

886

NN

Ph

CHO

OO

O

3d

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

OO

Br

5w

538

880

NN

Ph

CHO

OO

O

3d4f

H2N

H2N

NN

Ph

N H

NO

OO

5x

534

882














4 Experimental


6solvent with






(a)














(b)








(b) Continued






















2

prior to use












Linearity(LIN)


Straightness(STR)


Wobble(WOB)















7 Conclusions




Acknowledgments


References

















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Br3c

4a

H2N

H2N

NN

Ph

N H

NO

O

Br

5m

633

789

NN

Ph

CHO

OO

Br3c

Cl4b

H2N

H2N

NN

Ph

N H

NCl

OO

Br

5n

636

792

NN

Ph

CHO

OO

Br3c

4c

H2N

H2N

NN

Ph

N H

NO

O

Br

5o

639

794

NN

Ph

CHO

OO

Br3c

4d

H2N

H2N

NO

2

NN

Ph

N H

N

O

OO

Br

5p

N+

Ominus

636

784


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Br3c

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

O

Br

Br

5q

631

790

NN

Ph

CHO

OO

Br3c

4f

H2N

H2N

NN

Ph

N H

NO

O

Br

5r

634

792

NN

Ph

CHO

OO

O

3d4a

H2N

H2N

NN

Ph

N H

NO

O

O

5s

538

887

NN

Ph

CHO

OO

O

3d

Cl

4b

H2N

H2N

NN

Ph

N H

N

ClO

OO

5t

540

885


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

O

3d4c

H2N

H2N

NN

Ph

N H

NO

OO

5u

532

888

NN

Ph

CHO

OO

O

3d4d

H2N

H2N

NO

2

NN

Ph

N H

N

OO

OO

5v

N+

Ominus

536

886

NN

Ph

CHO

OO

O

3d

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

OO

Br

5w

538

880

NN

Ph

CHO

OO

O

3d4f

H2N

H2N

NN

Ph

N H

NO

OO

5x

534

882














4 Experimental


6solvent with






(a)














(b)








(b) Continued






















2

prior to use












Linearity(LIN)


Straightness(STR)


Wobble(WOB)















7 Conclusions




Acknowledgments


References

















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

Br3c

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

O

Br

Br

5q

631

790

NN

Ph

CHO

OO

Br3c

4f

H2N

H2N

NN

Ph

N H

NO

O

Br

5r

634

792

NN

Ph

CHO

OO

O

3d4a

H2N

H2N

NN

Ph

N H

NO

O

O

5s

538

887

NN

Ph

CHO

OO

O

3d

Cl

4b

H2N

H2N

NN

Ph

N H

N

ClO

OO

5t

540

885


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

O

3d4c

H2N

H2N

NN

Ph

N H

NO

OO

5u

532

888

NN

Ph

CHO

OO

O

3d4d

H2N

H2N

NO

2

NN

Ph

N H

N

OO

OO

5v

N+

Ominus

536

886

NN

Ph

CHO

OO

O

3d

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

OO

Br

5w

538

880

NN

Ph

CHO

OO

O

3d4f

H2N

H2N

NN

Ph

N H

NO

OO

5x

534

882














4 Experimental


6solvent with






(a)














(b)








(b) Continued






















2

prior to use












Linearity(LIN)


Straightness(STR)


Wobble(WOB)















7 Conclusions




Acknowledgments


References

















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


Table1Con

tinued

3andashd

4andashf

5andashx

Con

ventional

Microwave

Time(hr)

Yield(

)Time(min)

Yield

NN

Ph

CHO

OO

O

3d4c

H2N

H2N

NN

Ph

N H

NO

OO

5u

532

888

NN

Ph

CHO

OO

O

3d4d

H2N

H2N

NO

2

NN

Ph

N H

N

OO

OO

5v

N+

Ominus

536

886

NN

Ph

CHO

OO

O

3d

N

Br

4e

H2N

H2N

NN

Ph

N

N H

NO

OO

Br

5w

538

880

NN

Ph

CHO

OO

O

3d4f

H2N

H2N

NN

Ph

N H

NO

OO

5x

534

882














4 Experimental


6solvent with






(a)














(b)








(b) Continued






















2

prior to use












Linearity(LIN)


Straightness(STR)


Wobble(WOB)















7 Conclusions




Acknowledgments


References

















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of














4 Experimental


6solvent with






(a)














(b)








(b) Continued






















2

prior to use












Linearity(LIN)


Straightness(STR)


Wobble(WOB)















7 Conclusions




Acknowledgments


References

















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



(a)














(b)








(b) Continued






















2

prior to use












Linearity(LIN)


Straightness(STR)


Wobble(WOB)















7 Conclusions




Acknowledgments


References

















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


(b) Continued






















2

prior to use












Linearity(LIN)


Straightness(STR)


Wobble(WOB)















7 Conclusions




Acknowledgments


References

















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of












Linearity(LIN)


Straightness(STR)


Wobble(WOB)















7 Conclusions




Acknowledgments


References

















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of










7 Conclusions




Acknowledgments


References

















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of











































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of













Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of










Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of

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Research Article Design and Microwave Assisted Synthesis ...downloads.hindawi.com/archive/2016/9890630.pdf · Research Article Design and Microwave Assisted Synthesis of Coumarin