research article green chemical synthesis and analgesic activity of fluorinated ... · 2019. 7....

Hindawi Publishing CorporationOrganic Chemistry InternationalVolume 2013 Article ID 976032 8 pageshttpdxdoiorg1011552013976032

Research ArticleGreen Chemical Synthesis and Analgesic Activity of FluorinatedThiazolidinone Pyrazolidinone and Dioxanedione Derivatives

Harshita Sachdeva1 Diksha Dwivedi1 and Pradeep Goyal2

1 Department of Chemistry Faculty of Engineering and Technology Mody Institute of Technology and ScienceLakshmangarh Sikar Rajasthan 332311 India

2 Goenka College of Pharmacy Goenka Institute of Education and Research (GIER) Lakshmangarh Sikar Rajasthan 332311 India

Correspondence should be addressed to Harshita Sachdeva drhmsachdevastergmailcom

Received 7 April 2013 Revised 28 June 2013 Accepted 28 June 2013

Academic Editor William Setzer

Copyright copy 2013 Harshita Sachdeva 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

Facile lemon juice catalyzed green and efficient synthesis of a series of new classes of 5-(fluorinatedbenzylidene)-2-thi-oxo-13-thiazolidin-4-ones (3andashe) 5-methyl-4-(fluorinatedbenzylidene)-2-phenylpyrazolidin-3-ones (5andashe) and 22-dimethyl-5-(fluorinatedbenzylidene)-13-dioxane-46-diones (7andashe) by the reaction of fluorinated aromatic aldehydes with active methylenecompounds is reported Lemon juice is natural acid catalyst which is readily available cheap nontoxic and ecofriendlyThismethodis experimentally simple clean high yielding green and with reduced reaction times The product is purified by simple filtrationfollowed by washing with water and drying process Some of the synthesized compounds have been evaluated ldquoin vivordquo for theiranalgesic activity and all the synthesized compounds are characterized by IR 1H NMR 13C NMR 19F NMR and mass spectralstudies

1 Introduction

The steady growth of interest in the synthesis of heterocycliccompounds is connected with their raised biological activityand also with the fact that these compounds make possiblethe development of novel materials of unique propertiesPyrazolone is a biologically important scaffold associatedwith multiple pharmacological activities such as antimicro-bial [1] anti-inflammatory [2] analgesic [3] antidepressant[4] anticonvulsant [5] antidiabetic [6] antihyperlipidemic[7] antiviral [8] antitubercular [9] antioxidant [10] and anti-cancer activites [11 12] The synthesis of pyrazolone and itsderivatives has engrossed substantial attention from organicand medicinal chemists for many years as they belong to aclass of compounds with proven utility in medicinal chem-istry

One very interesting and promising class of heterocyclesis the 4-thiazolidinone ring system It represents a class ofchemical products with interesting pharmacological and bio-logical activities [13ndash18] including antidiabetic antitubercu-lar anti-HIV antiparasitic hypnotic and anathematic agents

Furthermore the reactivity of the Meldrumrsquos acid (22-dim-ethyl-13-dioxan-46-dione) as a methylene active compoundwas explored about 40 years after its preparation when thestructure was correctly attributed by Davidson and Bernhard[19] assigning the acidic proton to the central carbon and itshigh acidity is still object of study [20] It is known that theMeldrumrsquos acid undergoes standard Knoevenagel condensa-tion with aromatic and heteroaromatic aldehydes furnishingthe corresponding arylidene derivatives which are versatilesubstrates for different kinds of reactions [21 22] They areuseful intermediates for cycloaddition reaction and for thesynthesis of heterocyclic compounds with potential pharma-cological activity [23]

Several methods have been developed for the preparationof thiazolidinone pyrazolone and dioxanedione derivativesThe most common is Knoevenagel condensation betweenaromatic aldehydes and various activemethylene compoundscarried out in glacial acetic acid containing anhydroussodium acetate [24] Instead of sodium acetate acetic anhy-dride [25] ethanolamine [26] and ammonium chloride inammonia [27ndash29] have also been used as catalysts Other

2 Organic Chemistry International

F3COO N

O

N

F3CO SNH2

NO

ClO

Cl

N

F3CO

Celikalim Roflumilast Riluzole

H

Figure 1 Fluorine containing drugs

derivatives were also prepared using glycine and sodium car-bonate as catalysts ionic liquid and acidic alumina as solidsupport borate zirconia [30ndash34]

More recent methods for the preparation of 5-ben-zylidene-2-thioxothiazolidin-4-ones 4-arylidene-3-methyl-1-phenyl-5-pyrazolone derivatives and 5-benzylidene-22-dimethyl-13-dioxane-46-dione have been reported whichinvolve Knoevenagel condensation of aromatic aldehydeswith 2-thioxothiazolidin-4-one3-methyl-1-phenyl-1H-pyra-zol-5(4H)-oneMeldrum acid catalyzed by a basic function-alized ionic liquid [35] nanoparticles [36 37] triphenylphos-phine [38] and 1-butyl-3-methylimidazolium hydroxide([bmim][OH]) [39 40] Knoevenagel condensation is alsoreported under microwave irradiation for the synthesis of 5-arylidene-4-thiazolidinones [41] These derivatives are alsosynthesized using tetrabutylammoniumbromide (TBAB) as aphase transfer catalyst in water under microwave irradiation[42] However in spite of their utility some methods sufferfrom disadvantages like long reaction times low yieldschemical hazards and environmental pollution

In recent years organic research is mainly focused on thedevelopment of green methods to synthesize various organiccompounds through the use of alternative green catalystto replace hazardous strong acidic or basic catalyst com-monly used in organic synthesis Nowadays many organictransformations have been carried out using biocatalysts orintact plant systems Recently use of lemon juice as naturalcatalyst is reported [43] in few chemical reactions because itis inexpensive most abundant in nature nonhazardous andecofriendly It exhibits unique reactivity and selectivity Aslemon juice is acidic in nature (pH asymp 2-3) and percentage ofcitric acid (5ndash7) is more than other acids it works as acidcatalyst

In addition incorporation of fluorine further enhancesthe biological activity by increasing solubility in lipoid mate-rial and fat deposits in the body Compounds of medicinalinterest containing trifluoromethyl substituents includinganaesthetics antipsychotics antibiotics and a few antimalar-ials were reviewed in 1958 [44] Antibiotic multi drug resis-tance is a major and continuing public health concern andsome clinicians are switching to replacements such as thefluoroquinolones [45] A recent review [46] has highlightedpesticides containing the CF

3O group and its authors have

argued that a CF3O substituent can advantageously replace a

fluorine atom inmost molecules with the benefit of increasedlipid solubility Many drugs with enhanced effectiveness andselectivity contain the CF

3Omoiety (eg celikalim roflumi-

last and riluzole) (Figure 1)

CHO

R

SNH

O

O

S

NN

H

Ph

H3C

O

O

S

NH

S

N

Ph

H3C

O

R

R

O

OO

O O

OO R

Lemon juice rt

Lemon juice rt

Lemon juice rt

HN

R = 3-F 4-OCF3 4-CF3 2-NO2 4-CF3 2-F 5-NO2

(1)

(2)

(4)

(3andashe)

(5andashe)

(7andashe)

(6)

Scheme 1

In Scheme 1 we have synthesized for the first time aseries of new class of fluorine containing olefinic compoundsfrom Knoevenagel condensation of fluoro-substituted aro-matic aldehydes (1) with active methylene compounds 2-thioxo-4-thiazolidinone (2)3-methyl-1-phenyl-2-pyrazolin-5-one (4)Meldrumrsquos acid (6) in the presence of lemon juiceas natural acid catalyst at room temperatureThe compoundssynthesized by various methods have been characterizedby their melting points elemental analyses IR 1HNMR13CNMR 19FNMR and mass spectral studies

2 Results and Discussion

In continuation to our interest on environmentally benignsynthesis of heterocyclic compounds [47ndash50] we now reportthe green synthesis of fluorinated thiazolidinone (3andashe)pyrazolidinone (5andashe) and dioxanedione derivatives (7andashe)via Knoevenagel condensation at room temperature in thepresence of catalytic amount of lemon juice as natural acidcatalyst (Scheme 1) We have extensively studied the titlereaction taking two parameters namely type of catalysts andtype of solvent In order to optimize the reaction conditions

Organic Chemistry International 3

Table 1 Synthesis of 5-benzylidene-2-thioxo-13-thiazolidin-4-one3a under different catalysts

Entry Catalyst Solventtemperature(∘C)

Time(hrs)

Yield()

1 Boric acid H2O80 5 672 Oxalic acid H2O80 5 723 Alum H2O80 3 824 Lemon juice H2O80 3 84

the synthesis of compound 3a was used as a model reactionand a mixture of 3-fluoro benzaldehyde and 2-thioxo-4-thiazolidinone was magnetically stirred in presence of vari-ous catalysts as shown in Table 1 When reaction was carriedout in aqueous medium in the presence of oxalic acid boricacid alum and lemon juice (Table 1 entry 1ndash4) lemon juiceprovided the best yield as compared to other catalysts

Furthermore we studied the role of solvent on the syn-thesis of title compounds and found that the solvent playeda crucial role in this reaction (Table 2 entry 1 2 3) Ethanolmethanol dichloromethane were all able to facilitate but ittook longer time (4-5 hrs) to complete the reaction with lowyield (66ndash75) of the product We extended our studies andcarried out the reaction in the absence of any solvent andpresence of lemon juice at room temperature 92 yield ofthe product was obtained in 15 hrs (Table 2 entry 4) Withthese optimal conditions in hand we examined the scope ofthis Knoevenagel condensation reaction Results indicate thatlemon juice is the best catalyst at room temperature for thesynthesis of olefinic compounds (Table 3) As lemon juice isacidic in nature (pH asymp 2-3) and percentage of citric acid (5ndash7) is more than other acids it works as acid catalyst forthe synthesis of fluorinated thiazolidinone (3andashe) pyrazolidi-none (5andashe) and dioxanedione derivatives (7andashe) Using thismethodology these reactionswere completed in shorter reac-tion times (1-2 hrs) at room temperature (25∘C) with yieldsof the product ranging from 90 to 95 For the Knoeve-nagel condensation reaction we have used extract of Citruslimonum species of lemon as natural catalyst for synthesis ofarylidenes To our satisfaction we found that the use of 2mLof lemon juice resulted in quantitative yield (90ndash95) ofthe corresponding olefinic compounds within 1 to 2 hrs Thepurity of the compoundswas checked by TLCusing silica gel-G as adsorbent We have also carried out this reaction usingcitric acid separately reaction took place successfully asobserved on TLC

The product is isolated in pure form and does not requirefurther purification and crystallization Hence other com-pounds were also synthesized at room temperature follow-ing the similar procedureThe chemical structures all the syn-thesized compounds have been confirmed by IR 1HNMR19FNMR 13CNMR and mass spectral studies

The IR spectra of 3andashe showed absorption bands at3320ndash3350 cmminus1 due to NH stretching of amide 1680ndash1692 cmminus1 due to C=O 1578ndash1596 cmminus1 due to C=C and 1131ndash1211 cmminus1 due to C=S Stretching which confirms with theformation of compounds 3andashe The 1HNMR spectrum of 3b

Table 2 Synthesis of 5-benzylidene-2-thioxo-13-thiazolidin-4-one(3a) under different solvents


Time(hrs)

Yield()

1 Lemon juice EtOH78 4 752 Lemon juice CH3OH65 4 723 Lemon juice CH2Cl240 5 664 Lemon juice Room temperature 15 92

showed peaks at 120575 865 (s 1H NH) 802 (s 1H CH) and679ndash798 (m 4H Ar-H) ppm Formation of compound 3bwas further confirmed on the basis of 13CNMR spectrum Inthe 13CNMR spectrum sharp signals were observed at 120575 200(C=S) 16837 (C=O) 16123 (C-O) 143 (CH) 12048 (C=Caliphatic carbon) 122 (OCF

3) and 13825ndash11936 (aromatic

carbons) ppm Mass spectrum of compound 3b showedmolecular ion peak [M+ + 1] at 306mz (54) correspondingto its molecular weight along with base peak observed at mz122 (100) and other relevant peaks were observed atmz 246(39) 236 (84) 220 (70) 95 (15) and 79 (58)

The IR spectra of 5andashe showed absorption bands at 2915ndash3129 cmminus1 due to CH str of methine 1670ndash1688 cmminus1 due toC=O str and 1586ndash1591 cmminus1 due to C=C which confirmswith the formation of compounds 5andashe The 1HNMR spec-trum of 5d showed peaks at 120575 773 (s 1H CH) 719ndash771(comp 8H Ar-H) 351 (s 1H CH) 252 (s 1H NH) and 124(s 3H CH

3) ppm Formation of compound 5d was further

confirmed on the basis of 13CNMRspectrum In the 13CNMRspectrum sharp signals were observed at 120575 16250 (C=O)13482 (CH) 13082 (C=C aliphatic carbon) 12313 (CF

3)

13982ndash11212 (aromatic carbons) and 2173 (CH3) ppm

The IR spectra of 7andashe showed absorption bands at 2915ndash3083 cmminus1 due to CH str of methine 1630ndash1685 cmminus1 due toC=O str 1554ndash1590 cmminus1 due toC=C and 1055ndash1145 cmminus1 (C-O) which confirms with the formation of compounds The1HNMR spectrum of 7a showed peaks at 120575 897 (s 1H CH)770ndash784 (m 4H Ar-H) and 212 (s 6H CH

3) ppm Forma-

tion of compound 7a was further confirmed on the basisof 13CNMR spectrum In the 13CNMR spectrum sharp sig-nals were observed at 120575 16491 (C=O) 16042 (C-F) 15408(CH) 12374 (C=C aliphatic carbon) 13402ndash11812 (aromaticcarbons) 10518 (O-C-O) and 2616 (CH

3) ppm The mass

spectrum of compound 7a showed molecular ion peak [M+]at 250mz (30) corresponding to itsmolecular weight alongwith base peak observed at mz 176 (100) and other relevantpeakswere observed atmz 123 (13) 100 (34) and 63 (9)Spectral analyses of all the synthesized compounds are givenin Tables 4 5 and 6

3 Experimental

General Reagents and solvents were obtained from commer-cial sources and used without further purification Meltingpoints were determined on a Toshniwal apparatus The 1HNMR and 13C NMR of synthesized compounds have beencarried out at SAIF Punjab University Chandigarh India


Table 3 Experimental and analytical data of 5-(fluorinatedbenzylidene)-2-thioxo-13-thiazolidin-4-ones (3andashe) 5-methyl-4-(fluorinated-benzylidene)-2-phenylpyrazolidin-3-ones (5andashe) and 22-dimethyl-5-(fluorinatedbenzylidene)-13-dioxane-46-diones (7andashe)

Entry R Time (hrsmin) Yield () MP (∘C) Analysis calcd (found) ()C H N

3a 3-F 15 hrs 95 132 5019 (5004) 253 (250) 585 (588)3b 4-OCF3 1 hrs 90 115 4328 (4308) 198 (195) 459 (461)3c 4-CF3 70min 92 172 4567 (4535) 209 (207) 484 (482)3d 2-NO2 4-CF3 100min 91 110 3952 (3975) 151 (153) 838 (835)3e 2-F 5-NO2 2 hrs 94 89 4225 (4205) 177 (175) 985 (981)5a 3-F 40min 90 102 7232 (7215) 536 (533) 992 (995)5b 4-OCF3 50min 93 85 6207 (6225) 434 (436) 804 (800)5c 4-CF3 1 hrs 94 105 6506 (6525) 455 (452) 843 (840)5d 2-NO2 4-CF3 60min 90 162 5730 (5708) 374 (372) 1114 (1111)5e 2-F 5-NO2 70min 93 180 6238 (6220) 431 (434) 1284 (1282)7a 3-F 15 hrs 91 104 6240 (6256) 443 (445) mdash7b 4-OCF3 2 hrs 90 143 5317 (5334) 351 (349) mdash7c 4-CF3 2 hrs 95 164 5601 (5622) 369 (367) mdash7d 2-NO2 4-CF3 2 hrs 92 110 4871 (4851) 292 (294) 406 (403)7e 2-F 5-NO2 160min 94 115 5289 (5269) 341 (339) 474 (471)

Table 4 Spectral data of 5-(fluorinatedbenzylidene)-2-thioxo-13-thiazolidin-4-ones (3andashe)

Entry IR (cmminus1) 1H NMR (120575 ppm) 13C NMR (120575 ppm)

3a 3350 (NH str of amide) 1590(C=C) 1131 (C=S str) 1680 (C=O)

801 (s 1H NH) 742 (s 1H CH)714 (d 2H Ar-H 119869 = 82Hz) 730

(d 2H Ar-H 119869 = 82Hz)

200 (C=S) 16831 (C=O) 14233 (CH) 12048 (C=Caliphatic carbon) 13825ndash11936 (aromatic carbons)

3b 3357 (NH str of amide) 1596 (C=C)1211 (C=S str) 1682 (C=O)


(d 2H Ar-H 119869 = 80Hz)

200 (C=S) 16837 (C=O) 16123 (CndashO) 143 (CH)12048 (C=C aliphatic carbon) 122 (CF3) 13825ndash11936

(aromatic carbons)

3c 3348 (NH str of amide) 1578(C=C) 1168 (C=S str) 1686 (C=O)


(d 2H Ar-H 119869 = 85Hz)

19855 (C=S) 16930 (C=O) 143 (CH) 12048 (C=Caliphatic carbon) 12206 (CF3) 13825ndash11992 (aromatic

carbons)

3d 3320 (NH str of amide) 1590(C=C) 1136 (C=S str) 1688 (C=O)

862 (s 1H NH) 750 (s 1H CH)743 (s 1H Ar-H) 726 (d 2H Ar-H

119869 = 82Hz)


carbons)

3e 3342 (NH str of amide) 1584(C=C) 1161 (C=S str) 1692 (C=O)

851 (s 1H NH) 744 (s 1H Ar-H)728 (d 2H Ar-H 119869 = 80Hz)

200 (C=S) 16837 (C=O) 16103 (CndashF) 143 (CH)12048 (C=C aliphatic carbon) 13825ndash11936 (aromatic

carbons)

Table 5 Spectral data of 5-methyl-4-(fluorinatedbenzylidene)-2-phenylpyrazolidin-3-ones (5andashe)

Entry IR (cmminus1) 1H NMR (120575) 13C NMR (120575)

5a 3129 (CH) 1670(C=O) 1586 (C=C)

742 (s 1H CH) 714ndash730 (comp 9H Ar-H)348 (s 1H CH) 201 (s 1H NH) 120 (s

3H CH3)

16317 (CndashF) 16131 (C=O) 13533 (CH) 13048 (C=Caliphatic carbon) 14205ndash11516 (aromatic carbons)

2413 (CH3)

5b 3073 (CH) 1677(C=O) 1586 (C=C)

767 (s 1H CH) 738ndash720 (comp 9HAr-H) 346 (s 1H CH) 211 (s 1H NH)

123 (s 3H CH3)

16217 (CndashO) 16140 (C=O) 13368 (CH) 13083 (C=Caliphatic carbon) 122 (CF3) 14185ndash11432 (aromatic

carbons) 2393 (CH3)

5c 2915 (CH) 1675(C=O) 1589 (C=C)


3H CH3)

16178 (C=O) 13521 (CH) 13083 (C=C aliphaticcarbon) 12254 (CF3) 14108ndash11536 (aromatic carbons)

2340 (CH3)

5d 3060 (CH) 1688(C=O) 1591 (C=C)

773 (s 1H CH) 719ndash771 (comp 8H Ar-H)351 (s 1H CH) 252 (s 1H NH) 124 (s 3H

CH3)


2173 (CH3)

5e 3069 (CH) 1678(C=O) 1590 (C=C)


3H CH3)


2310 (CH3)


Table 6 Spectral data of 22-dimethyl-5-(fluorinatedbenzylidene)-13-dioxane-46-diones (7andashe)


7a 3083 (CH) 1630 (C=O)1554 (C=C str) 1055 (CndashO)

897 (s 1H CH) 770 (d 2H Ar-H119869 = 81Hz) 764 (d 2H Ar-H 119869 = 81Hz)

212 (s 6H CH3)

16491 (C=O) 16042 (CndashF) 15408 (CH) 12374 (C=Caliphatic carbon) 13402ndash11812 (aromatic carbons)

10518 (OndashCndashO) 2616 (CH3)

7b 2915 (CH) 1682 (C=O)1577 (C=C str) 1130 (CndashO)


183 (s 6H CH3)

16427 (CndashO) 16546ndash16530 (C=O) 15003 (CH) 12418(C=C aliphatic carbon) 12242 (CF3) 13485ndash12006

(aromatic carbons) 10792 (OndashCndashO) 2712ndash2697 (CH3)

7c 3072 (CH) 1680 (C=O)1583 (C=C str) 1145 (CndashO)


185 (s 6H CH3)

16740ndash16730 (C=O) 14926 (CH) 12615 (C=Caliphatic carbon) 12242 (CF3) 13505ndash12193 (aromatic

carbons) 10694 (OndashCndashO) 2772ndash2764 (CH3)

7d 3060 (CH) 1685 (C=O)1584 (C=C str) 1095 (CndashO)

881 (s 1H CH) 780 (s 1H Ar-H) 743 (d2H Ar-H 119869 = 65Hz) 175 (s 6H CH3)



7e 2979 (CH) 1680 (C=O)1590 (C=C str) 1130 (CndashO)


16540ndash16530 (C=O) 16322 (CndashF) 14691 (CH) 12705(C=C aliphatic carbon) 13435ndash12063 (aromaticcarbons) 10697 (OndashCndashO) 2650ndash2642 (CH3)

IR spectra of compounds have been carried out at FETMITS Laxmangarh Sikar Rajasthan India The purity ofcompounds was checked on thin layers of silica gel invarious nonaqueous solvent systems for example ethylacetate n-hexane (1 9) IR spectra were recorded in KBr ona PerkinElmer Infrared L1600300 Spectrum Two Li Ta spec-trophotometer and 1H NMR spectra were recorded onBruker Avance II 400 NMR spectrometer using DMSO-d

6

andCDCl3as solvent and tetramethylsilane (TMS) as internal

reference standard The analgesic activity of synthesizedcompounds was carried out in Goenka College of Phar-macy Department of Pharmacology Lakshmangarh SikarRajasthan India

General Procedure for Extraction of Lemon Juice Fresh lemonwas cut by using knife and then pieces were pressedmanuallyusing domestic presser to extract juice Then juice was thenfiltered through cottonmuslin cloth and then through filterpaper to remove solid material and to get clear juice whichwas used as a catalyst

General Procedure for the Preparation of 3andashe 5andashe and7andashe A mixture of fluorinated aromatic aldehyde (1mmol)and 2-thioxo-4-thiazolidinone3-methyl-1-phenyl-2-pyra-zolin-5-oneMeldrumrsquos acid (1mmol) was taken in singleneck round bottom flask and to this lemon juice (2mL)was added as catalyst The reaction mixture was stirred atroom temperature for the appropriate time required forthe completion of reaction given in Table 2 The progress ofreactionwasmonitored by TLCusing ethyl acetate n-hexane(1 9) as eluent After the completion of the reaction mixturewas poured onto crushed ice and the solid product obtainedwas filtered and isolated in pure form with no need of furtherpurification For comparative studies 3a was synthesizedusing various solvents and catalysts Results of synthesis of 3aunder different reaction conditions are given in Tables 1 and2 The structures of the newly synthesized compounds aredetermined on the basis of their FTIR 1H NMR 19F NMR13C NMR and mass spectral data

4 Analgesic Activity

Few compounds have been screened for analgesic activityThe analgesic properties of the target compounds were testedusing a model of central analgesia where the painful stimulusis represented by a hot plate heated to 56∘C Seven groups of6 mice each having an average weight of 25ndash35 g were takenfor studyThe animals were kept for a week before the experi-ment under standard laboratory environment with access towater ad libitum The experiment consisted in measuring thereaction to pain as the time (in seconds) between themomentwhen the animal was placed on the plate and the momentwhen it begins to lick its back paws in response to painfulstimulus

The animals were treated as follows

Group 1 control group received 05 sodium CMC(1mgkg) IPGroup 2 nimesulide 5mgkg was administered IPGroup 3 the 3a in dose level of 50mgkg was admin-istered IPGroup 4 the 3b in dose level of 50mgkg was admin-istered IPGroup 5 the 3d in dose level of 50mgkg was admin-istered IPGroup 6 the 5b in dose level of 50mgkg was admin-istered IPGroup 7 the 5d in dose level of 50mgkg was admin-istered IP

The time response of the animal to painful stimulus wasevaluated at 0 30 60 and 90 minutes interval after theadministration of the tested substances The recorded resultswere used to calculate for each group of animals the averageresponse time to painful stimulus and the standard errorStatistical analysis (ANOVA followed by usingDunnettrsquos test)was performed for analgesic activity to ascertain the signifi-cance of the exhibited activity Compounds 3b 5d and 5d


Table 7 Analgesic activity of the fluorinated 5-Substitutedbenzylidene derivatives

0min 30min 60min 90minControl 133 plusmn 0210 166 plusmn 0210 150 plusmn 0223 183 plusmn 0307

Standard Drug 15 plusmn 0223

35 plusmn 0428

lowastlowast

53783 plusmn 0477

lowastlowast

811316plusmn0166

lowastlowast

86

3a 116 plusmn 0166

2 plusmn 0258

ns

172 plusmn 0258

ns

25256 plusmn 0210

ns

27

3b 166 plusmn 0210

316 plusmn 0307

lowastlowast

48483 plusmn 0307

lowastlowast

69966 plusmn 0557

lowastlowast

81

3d 166 plusmn 0166

183 plusmn 0307

ns

92 plusmn 0258

ns

25256 plusmn 0210

ns

27

5b 15 plusmn 0223

316 plusmn 0307

lowastlowast

4855 plusmn 0223

lowastlowast

731083plusmn0600

lowastlowast

83

5d 166 plusmn 0210

30 plusmn 00258

lowastlowast

4545 plusmn 0428

lowastlowast

67852 plusmn 0670

lowastlowast

78All values mean plusmn SEM values using 6 animals in each groupSignificant differences with respect to control group were evaluated by ANOVA Dunnettrsquos testlowast119875 lt 005 lowastlowast119875 lt 001 lowastlowastlowast119875 lt 0001 ns nonsignificant

0

20

40

60

80

100

Drug 3a 3b 3d 5b 5d

30min60min90min

Ana

lges

ia (

)

Figure 2 Comparison of the analgesic activity exhibited () by thetest and standard compounds at time interval of 30min 60min and90min

have shown excellent analgesic activity as compared to othercompounds which indicate that OCF

3group is more potent

than CF3and NO

2groups (Table 7 Figure 2)

5 Conclusion

The use lemon juice as green catalyst offers a convenientnontoxic inexpensive reaction medium for the synthesis ofolefinic compounds This procedure is simpler economicalmilder and faster including cleaner reactions high yields ofproducts and a simple experimental and work-up procedurewhichmakes it a useful and attractive process and is also con-sistent with the green chemistry theme which affords excel-lent yields Compounds bearing OCF

3group possess excel-

lent analgesic activity With further molecular modificationandmanipulation of these compounds several other promis-ing bioactive molecules can be developed in future

Acknowledgments

The authors are thankful to the Dean and HOD (Science andHumanities) FET MITS for providing necessary researchfacilities in the department Financial assistance from FETMITS is gratefully acknowledged They are also thankful toSAIF Punjab University Chandigarh India for the spectralanalyses and Goenka College of Pharmacy Department ofPharmacology Lakshmangarh Rajasthan India for helpingin performing analgesic activity

References

[1] S G Kucukguzel S Rollas H Erdeniz M Kiraz A CevdetEkinci and A Vidin ldquoSynthesis characterization and pharma-cological properties of some 4-arylhydrazono-2-pyrazoline-5-one derivatives obtained from heterocyclic aminesrdquo EuropeanJournal of Medicinal Chemistry vol 35 no 7-8 pp 761ndash7712000

[2] S A F Rostom I M El-Ashmawy H A Abd El Razik M HBadr and HM A Ashour ldquoDesign and synthesis of some thia-zolyl and thiadiazolyl derivatives of antipyrine as potential non-acidic anti-inflammatory analgesic and antimicrobial agentsrdquoBioorganic and Medicinal Chemistry vol 17 no 2 pp 882ndash8952009

[3] S Khode V Maddi P Aragade et al ldquoSynthesis and pharmac-ological evaluation of a novel series of 5-(substituted)aryl-3-(3-coumarinyl)-1-phenyl-2-pyrazolines as novel anti-inflam-matory and analgesic agentsrdquo European Journal of MedicinalChemistry vol 44 no 4 pp 1682ndash1688 2009

[4] M Abdel-Aziz G E A Abuo-Rahma and A A HassanldquoSynthesis of novel pyrazole derivatives and evaluation of theirantidepressant and anticonvulsant activitiesrdquo European Journalof Medicinal Chemistry vol 44 no 9 pp 3480ndash3487 2009

[5] Z S Quan R L Li and Y Z Ling ldquoStudy of the rela-tionship between structure and anticonvulsant activities of5-substituted-1-butry-3-pyrazolidinones and their synthesisrdquoActa Pharmaceutica Sinica vol 27 no 9 pp 711ndash716 1992


[6] N Das A Verma P K Shrivastava and S K ShrivastavaldquoSynthesis and biological evaluation of some new aryl pyrazol-3-one derivatives as potential hypoglycemic agentsrdquo IndianJournal of Chemistry B vol 47 no 10 pp 1555ndash1558 2008

[7] G A Idrees O M Aly G E A A Abuo-Rahma and M FRadwan ldquoDesign synthesis and hypolipidemic activity of novel2-(naphthalen-2-yloxy)propionic acid derivatives as desmethylfibrate analogsrdquo European Journal of Medicinal Chemistry vol44 no 10 pp 3973ndash3980 2009

[8] G Ouyang Z Chen X Cai et al ldquoSynthesis and antiviralactivity of novel pyrazole derivatives containing oxime estersgrouprdquo Bioorganic and Medicinal Chemistry vol 16 no 22 pp9699ndash9707 2008

[9] D Castagnolo F Manetti M Radi et al ldquoSynthesis biologicalevaluation and SAR study of novel pyrazole analogues asinhibitors of Mycobacterium tuberculosis part 2 Synthesis ofrigid pyrazolonesrdquo Bioorganic and Medicinal Chemistry vol 17no 15 pp 5716ndash5721 2009

[10] K B Umesha K M L Rai and M A Harish Nayaka ldquoAnti-oxidant and antimicrobial activity of 5-methyl-2-(5-methyl-13-diphenyl-1H-pyrazole-4-carbonyl)-24-dihydro-pyrazol-3-onerdquo International Journal of Biomedical Science vol 5 no 4pp 359ndash368 2009

[11] R Tripathy A Ghose J Singh et al ldquo123-Thiadiazole substi-tuted pyrazolones as potent KDRVEGFR-2 kinase inhibitorsrdquoBioorganic and Medicinal Chemistry Letters vol 17 no 6 pp1793ndash1798 2007

[12] H Park K Lee S Park et al ldquoIdentification of antitumoractivity of pyrazole oxime ethersrdquo Bioorganic and MedicinalChemistry Letters vol 15 no 13 pp 3307ndash3312 2005

[13] R Murugan S Anbazhagan and S S Narayanan ldquoSynthesisand in vivo antidiabetic activity of novel dispiropyrrolidinesthrough [3 + 2] cycloaddition reactions with thiazolidinedioneand rhodanine derivativesrdquo European Journal of MedicinalChemistry vol 44 no 8 pp 3272ndash3279 2009

[14] S Chandrappa C V KavithaM S Shahabuddin et al ldquoSynthe-sis of 2-(5-((5-(4-chlorophenyl)furan-2-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid derivatives and evaluationof their cytotoxicity and induction of apoptosis in human leuke-mia cellsrdquo Bioorganic andMedicinal Chemistry vol 17 no 6 pp2576ndash2584 2009

[15] EW Brooke S G Davies AWMulvaney et al ldquoSynthesis andin vitro evaluation of novel small molecule inhibitors of bac-terial arylamine N-acetyltransferases (NATs)rdquo Bioorganic andMedicinal Chemistry Letters vol 13 no 15 pp 2527ndash2530 2003

[16] S Ozkirimli F Kazan and Y Tunali ldquoSynthesis antibacterialand antifungal activities of 3-(124-triazol-3-yl)-4-thiazolid-inonesrdquo Journal of Enzyme Inhibition and Medicinal Chemistryvol 24 no 2 pp 447ndash452 2009

[17] S Chandrappa S B Benaka Prasad K Vinaya C S AnandaKumar N R Thimmegowda and K S Rangappa ldquoSynthesisand in vitro antiproliferative activity against human cancercell lines of novel 5-(4-methyl-benzylidene)-thiazolidine-24-dionesrdquo Investigational New Drugs vol 26 no 5 pp 437ndash4442008

[18] A Verma and S K Saraf ldquo4-Thiazolidinonemdasha biologicallyactive scaffoldrdquo European Journal of Medicinal Chemistry vol43 no 5 pp 897ndash905 2008

[19] D Davidson and S A Bernhard ldquoThe structure of Meldrumrsquossupposed 120573-lactonic acidrdquo Journal of the American ChemicalSociety vol 70 no 10 pp 3426ndash3428 1948

[20] K Byun Y Mo and J Gao ldquoNew insight on the origin of theunusual acidity ofMeldrumrsquos acid from120572120573-initio and combinedQMMM simulation studyrdquo Journal of the American ChemicalSociety vol 123 no 17 pp 3974ndash3979 2001

[21] B Chen ldquoMeldrumrsquos acid in organic synthesisrdquo Heterocyclesvol 32 no 3 pp 529ndash597 1991

[22] L F Tietze and U Beifuss ldquoThe knoevenagel reactionrdquo in Com-prehensive Organic Synthesis vol 2 pp 341ndash394 1991

[23] B Pita E Sotelo M Suarez et al ldquoPyridazine derivatives Part21 synthesis and structural study of novel 4-aryl-25-dioxo-8-phenylpyrido[23-d]pyridazinesrdquo Tetrahedron vol 56 no 16pp 2473ndash2479 2000

[24] F C Brown C K Bradsher and S M Bond ldquoSome 5-substi-tuted rhodaninesrdquo Industrial amp Engineering Chemistry vol 45pp 1030ndash1032 1953

[25] K Ramkumar V N Yarovenko A S Nikitina et al ldquoDesignsynthesis and structure-activity studies of rhodanine derivativesasHIV-1 integrase inhibitorsrdquoMolecules vol 15 no 6 pp 3958ndash3992 2010

[26] J Iwao andK J Tomino ldquoSynthesis of pyrazolo [3 4-b] pyridineby knovengel condensationrdquo Pharmaceutical Society of Japanvol 76 pp 748ndash755 1956

[27] B A Alekseenko T E Gorizdra and S N Baranov ldquoSynthesisand structure of noncondensed bicyclic thiazolidino-4-onederivativesrdquo Khimiya Geterotsiklicheskikh Soedinenii vol 5 pp230ndash231 1969

[28] G G Allan D Maclean and G T Newbold ldquoCondensationproducts of rhodanine and keto-acidsrdquo Journal of the ChemicalSociety pp 5132ndash5153 1952

[29] F C Brown C K Bradsher S G McCallum and M PotterldquoRhodanine derivatives of ketonesrdquo Journal of Organic Chem-istry vol 15 no 1 pp 174ndash176 1950

[30] M M Chowdhry D M P Mingos A J P White and D JWilliams ldquoSyntheses and characterization of 5-substitutedhydantoins and thiazolines - Implications for crystal engineer-ing of hydrogen bonded assemblies Crystal structures t of 5-(2-pyridylmethylene)-hydantoin 5-(2-pyridylmethylene)-2-thio-hydantoin5-(2-pyridylmethylene)thiazolidine-24-dione 5-(2-pyridylmethylene)rhodanine and 5-(2-pyridylmethylene)pseu-dothiohydantoinrdquo Journal of the Chemical Society Perkin Trans-actions 1 vol 1 no 20 pp 3495ndash3504 2000

[31] R VHangarge D V Jarikote andM S Shingare ldquoKnoevenagelcondensation reactions in an ionic liquidrdquoGreenChemistry vol4 no 3 pp 266ndash268 2002

[32] S S Shindalkar B R Madje and M S Shingare ldquoMicrowaveinduced solvent-free Knoevenagel condensation of 4-oxo-(4H)-1-benzopyran-3-carbaldehyde with Meldrumrsquos acid usingalumina supportrdquo Indian Journal of Chemistry B vol 45 no 11pp 2571ndash2573 2006

[33] S Santosh B R Shindalkar R V Madje P T Hangarge M KD Patil and M S Shingare ldquoBorate zirconia mediated Kno-evenagel condensation reaction in waterrdquo Journal of the KoreanChemical Society vol 49 pp 377ndash380 2005

[34] S S Shindalkar B RMadje andM S Shingare ldquoUltrasonicallyaccelerated Knoevenagel condensation reaction at room tem-perature in distilled waterrdquo Indian Journal of Chemistry B vol44 no 7 pp 1519ndash1521 2005

[35] N B Darvatkar A R Deorukhkar S V Bhilare and M MSalunkhe ldquoIonic liquid-mediated knoevenagel condensation ofMeldrumrsquos acid and aldehydesrdquo Synthetic Communications vol36 no 20 pp 3043ndash3051 2006


[36] J M Khurana and K Vij ldquoNickel nanoparticles catalyzed che-moselective Knoevenagel condensation of Meldrumrsquos acid andtandem enol lactonizations via cascade cyclization sequencerdquoTetrahedron Letters vol 52 no 28 pp 3666ndash3669 2011

[37] S Ghosh J Das and S Chattopadhyay ldquoA novel light inducedKnoevenagel condensation of Meldrumrsquos acid with aromaticaldehydes in aqueous ethanolrdquo Tetrahedron Letters vol 52 no22 pp 2869ndash2872 2011

[38] A M Dumas A Seed A K Zorzitto and E Fillion ldquoTriph-enylphosphine mediated Knoevenagel condensation of Mel-drumrsquos acid with aromatic aldehydesrdquo Tetrahedron Letters vol48 pp 7072ndash7276 2007

[39] K Gong Z He Y Xu D Fang and Z Liu ldquoGreen synthesisof 5-benzylidene rhodanine derivatives catalyzed by 1-butyl-3-methyl imidazolium hydroxide in waterrdquo Monatshefte furChemie vol 139 no 8 pp 913ndash915 2008

[40] K F Shelke S B Sapkal B R Madja B B Shingate and M SShingare ldquoIonic liquid promoted an efficient synthesis of 5-arylidene-2 4-thiazolidinedionerdquo Bulletin of the Catalysis Soci-ety of India vol 8 pp 30ndash34 2009

[41] J Zhou Y Song F Zhu and Y Zhu ldquoFacile synthesis of 5-benzylidene rhodamine derivatives under microwave irradia-tionrdquo Synthetic Communications vol 36 no 22 pp 3297ndash33032006

[42] K Bourahla A Derdour M Rahmouni F Carreaux and JP Bazureau ldquoA practical access to novel 2-amino-5-arylidene-13-thiazol-4(5H)-ones via sulfurnitrogen displacement undersolvent-free microwave irradiationrdquo Tetrahedron Letters vol48 no 33 pp 5785ndash5789 2007

[43] S Patil S D Jadhav and U P Patil ldquoNatural acid catalyzedsynthesis of schiff base under solvent-free condition as a greenapproachrdquo Journal of Applied Sciences Research vol 4 no 2 pp1074ndash1078 2012

[44] H L Yale ldquoThe trifluoromethyl group in medicinal chemistryrdquoJournal of Medicinal and Pharmaceutical Chemistry vol 1 no2 pp 121ndash133 1959

[45] P C Appelbaum and P A Hunter ldquoThe fluoroquinolone anti-bacterials past present and future perspectivesrdquo InternationalJournal of Antimicrobial Agents vol 16 no 1 pp 5ndash15 2000

[46] F M D Ismail G B D Michael and J Michael ldquoModulationof drug pharmacokinetics and pharmacodynamics by fluorinesubstitutionrdquo Chemistry today vol 27 no 3 pp 18ndash21 2009

[47] H Sachdeva D Dwivedi K Arya S Khaturia and R SarojldquoAnti-inflammatory activity and QSAR study of some Schiffbases derived from5-mercapto-3-(41015840-pyridyl)-4H-124-triazol-4-yl-thiosemicarbaziderdquoMedicinal Chemistry Research 2013

[48] A Dandia H Sachdeva and R Singh ldquoImproved synthesis of3-spiro indolines in dry media under microwave irradiationrdquoSynthetic Communications vol 31 no 12 pp 1879ndash1892 2001

[49] H Sachdeva D Dwivedi and S Khaturia ldquoAqua mediatedfacile synthesis of 2-(57-fluorinated-2-oxoindolin-3-ylidene)-N- (4-substituted phenyl) hydrazine carbothioamidesrdquo Re-search Journal of Pharmaceutical Biological and Chemical Sci-ences vol 2 no 2 pp 213ndash219 2011

[50] H Sachdeva and D Dwivedi ldquoLithium-acetate-mediated big-inelli one-pot multicomponent synthesis under solvent-freeconditions and cytotoxic activity against the human lung Can-cer Cell line A549 and Breast Cancer cell line MCF7rdquo The Sci-entificWorld Journal vol 2012 Article ID 109432 9 pages 2012

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


F3COO N

O

N

F3CO SNH2

NO

ClO

Cl

N

F3CO

Celikalim Roflumilast Riluzole

H

Figure 1 Fluorine containing drugs

derivatives were also prepared using glycine and sodium car-bonate as catalysts ionic liquid and acidic alumina as solidsupport borate zirconia [30ndash34]

More recent methods for the preparation of 5-ben-zylidene-2-thioxothiazolidin-4-ones 4-arylidene-3-methyl-1-phenyl-5-pyrazolone derivatives and 5-benzylidene-22-dimethyl-13-dioxane-46-dione have been reported whichinvolve Knoevenagel condensation of aromatic aldehydeswith 2-thioxothiazolidin-4-one3-methyl-1-phenyl-1H-pyra-zol-5(4H)-oneMeldrum acid catalyzed by a basic function-alized ionic liquid [35] nanoparticles [36 37] triphenylphos-phine [38] and 1-butyl-3-methylimidazolium hydroxide([bmim][OH]) [39 40] Knoevenagel condensation is alsoreported under microwave irradiation for the synthesis of 5-arylidene-4-thiazolidinones [41] These derivatives are alsosynthesized using tetrabutylammoniumbromide (TBAB) as aphase transfer catalyst in water under microwave irradiation[42] However in spite of their utility some methods sufferfrom disadvantages like long reaction times low yieldschemical hazards and environmental pollution

In recent years organic research is mainly focused on thedevelopment of green methods to synthesize various organiccompounds through the use of alternative green catalystto replace hazardous strong acidic or basic catalyst com-monly used in organic synthesis Nowadays many organictransformations have been carried out using biocatalysts orintact plant systems Recently use of lemon juice as naturalcatalyst is reported [43] in few chemical reactions because itis inexpensive most abundant in nature nonhazardous andecofriendly It exhibits unique reactivity and selectivity Aslemon juice is acidic in nature (pH asymp 2-3) and percentage ofcitric acid (5ndash7) is more than other acids it works as acidcatalyst

In addition incorporation of fluorine further enhancesthe biological activity by increasing solubility in lipoid mate-rial and fat deposits in the body Compounds of medicinalinterest containing trifluoromethyl substituents includinganaesthetics antipsychotics antibiotics and a few antimalar-ials were reviewed in 1958 [44] Antibiotic multi drug resis-tance is a major and continuing public health concern andsome clinicians are switching to replacements such as thefluoroquinolones [45] A recent review [46] has highlightedpesticides containing the CF

3O group and its authors have

argued that a CF3O substituent can advantageously replace a

fluorine atom inmost molecules with the benefit of increasedlipid solubility Many drugs with enhanced effectiveness andselectivity contain the CF

3Omoiety (eg celikalim roflumi-

last and riluzole) (Figure 1)

CHO

R

SNH

O

O

S

NN

H

Ph

H3C

O

O

S

NH

S

N

Ph

H3C

O

R

R

O

OO

O O

OO R

Lemon juice rt

Lemon juice rt

Lemon juice rt

HN

R = 3-F 4-OCF3 4-CF3 2-NO2 4-CF3 2-F 5-NO2

(1)

(2)

(4)

(3andashe)

(5andashe)

(7andashe)

(6)

Scheme 1

In Scheme 1 we have synthesized for the first time aseries of new class of fluorine containing olefinic compoundsfrom Knoevenagel condensation of fluoro-substituted aro-matic aldehydes (1) with active methylene compounds 2-thioxo-4-thiazolidinone (2)3-methyl-1-phenyl-2-pyrazolin-5-one (4)Meldrumrsquos acid (6) in the presence of lemon juiceas natural acid catalyst at room temperatureThe compoundssynthesized by various methods have been characterizedby their melting points elemental analyses IR 1HNMR13CNMR 19FNMR and mass spectral studies

2 Results and Discussion

In continuation to our interest on environmentally benignsynthesis of heterocyclic compounds [47ndash50] we now reportthe green synthesis of fluorinated thiazolidinone (3andashe)pyrazolidinone (5andashe) and dioxanedione derivatives (7andashe)via Knoevenagel condensation at room temperature in thepresence of catalytic amount of lemon juice as natural acidcatalyst (Scheme 1) We have extensively studied the titlereaction taking two parameters namely type of catalysts andtype of solvent In order to optimize the reaction conditions




Time(hrs)

Yield()








Time(hrs)

Yield()








3)



3) ppm Forma-


3) ppm The mass


3 Experimental










(d 2H Ar-H 119869 = 82Hz)




(d 2H Ar-H 119869 = 80Hz)


(aromatic carbons)



(d 2H Ar-H 119869 = 85Hz)


carbons)



119869 = 82Hz)


carbons)




carbons)



5a 3129 (CH) 1670(C=O) 1586 (C=C)


3H CH3)


2413 (CH3)

5b 3073 (CH) 1677(C=O) 1586 (C=C)


123 (s 3H CH3)


carbons) 2393 (CH3)

5c 2915 (CH) 1675(C=O) 1589 (C=C)


3H CH3)


2340 (CH3)

5d 3060 (CH) 1688(C=O) 1591 (C=C)


CH3)


2173 (CH3)

5e 3069 (CH) 1678(C=O) 1590 (C=C)


3H CH3)


2310 (CH3)






212 (s 6H CH3)





183 (s 6H CH3)





185 (s 6H CH3)











6














35 plusmn 0428

lowastlowast

53783 plusmn 0477

lowastlowast

811316plusmn0166

lowastlowast

86

3a 116 plusmn 0166

2 plusmn 0258

ns

172 plusmn 0258

ns

25256 plusmn 0210

ns

27

3b 166 plusmn 0210

316 plusmn 0307

lowastlowast

48483 plusmn 0307

lowastlowast

69966 plusmn 0557

lowastlowast

81

3d 166 plusmn 0166

183 plusmn 0307

ns

92 plusmn 0258

ns

25256 plusmn 0210

ns

27

5b 15 plusmn 0223

316 plusmn 0307

lowastlowast

4855 plusmn 0223

lowastlowast

731083plusmn0600

lowastlowast

83

5d 166 plusmn 0210

30 plusmn 00258

lowastlowast

4545 plusmn 0428

lowastlowast

67852 plusmn 0670

lowastlowast


0

20

40

60

80

100

Drug 3a 3b 3d 5b 5d

30min60min90min

Ana

lges

ia (

)




than CF3and NO


5 Conclusion




Acknowledgments


References






























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of




Time(hrs)

Yield()








Time(hrs)

Yield()








3)



3) ppm Forma-


3) ppm The mass


3 Experimental










(d 2H Ar-H 119869 = 82Hz)




(d 2H Ar-H 119869 = 80Hz)


(aromatic carbons)



(d 2H Ar-H 119869 = 85Hz)


carbons)



119869 = 82Hz)


carbons)




carbons)



5a 3129 (CH) 1670(C=O) 1586 (C=C)


3H CH3)


2413 (CH3)

5b 3073 (CH) 1677(C=O) 1586 (C=C)


123 (s 3H CH3)


carbons) 2393 (CH3)

5c 2915 (CH) 1675(C=O) 1589 (C=C)


3H CH3)


2340 (CH3)

5d 3060 (CH) 1688(C=O) 1591 (C=C)


CH3)


2173 (CH3)

5e 3069 (CH) 1678(C=O) 1590 (C=C)


3H CH3)


2310 (CH3)






212 (s 6H CH3)





183 (s 6H CH3)





185 (s 6H CH3)











6














35 plusmn 0428

lowastlowast

53783 plusmn 0477

lowastlowast

811316plusmn0166

lowastlowast

86

3a 116 plusmn 0166

2 plusmn 0258

ns

172 plusmn 0258

ns

25256 plusmn 0210

ns

27

3b 166 plusmn 0210

316 plusmn 0307

lowastlowast

48483 plusmn 0307

lowastlowast

69966 plusmn 0557

lowastlowast

81

3d 166 plusmn 0166

183 plusmn 0307

ns

92 plusmn 0258

ns

25256 plusmn 0210

ns

27

5b 15 plusmn 0223

316 plusmn 0307

lowastlowast

4855 plusmn 0223

lowastlowast

731083plusmn0600

lowastlowast

83

5d 166 plusmn 0210

30 plusmn 00258

lowastlowast

4545 plusmn 0428

lowastlowast

67852 plusmn 0670

lowastlowast


0

20

40

60

80

100

Drug 3a 3b 3d 5b 5d

30min60min90min

Ana

lges

ia (

)




than CF3and NO


5 Conclusion




Acknowledgments


References






























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of









(d 2H Ar-H 119869 = 82Hz)




(d 2H Ar-H 119869 = 80Hz)


(aromatic carbons)



(d 2H Ar-H 119869 = 85Hz)


carbons)



119869 = 82Hz)


carbons)




carbons)



5a 3129 (CH) 1670(C=O) 1586 (C=C)


3H CH3)


2413 (CH3)

5b 3073 (CH) 1677(C=O) 1586 (C=C)


123 (s 3H CH3)


carbons) 2393 (CH3)

5c 2915 (CH) 1675(C=O) 1589 (C=C)


3H CH3)


2340 (CH3)

5d 3060 (CH) 1688(C=O) 1591 (C=C)


CH3)


2173 (CH3)

5e 3069 (CH) 1678(C=O) 1590 (C=C)


3H CH3)


2310 (CH3)






212 (s 6H CH3)





183 (s 6H CH3)





185 (s 6H CH3)











6














35 plusmn 0428

lowastlowast

53783 plusmn 0477

lowastlowast

811316plusmn0166

lowastlowast

86

3a 116 plusmn 0166

2 plusmn 0258

ns

172 plusmn 0258

ns

25256 plusmn 0210

ns

27

3b 166 plusmn 0210

316 plusmn 0307

lowastlowast

48483 plusmn 0307

lowastlowast

69966 plusmn 0557

lowastlowast

81

3d 166 plusmn 0166

183 plusmn 0307

ns

92 plusmn 0258

ns

25256 plusmn 0210

ns

27

5b 15 plusmn 0223

316 plusmn 0307

lowastlowast

4855 plusmn 0223

lowastlowast

731083plusmn0600

lowastlowast

83

5d 166 plusmn 0210

30 plusmn 00258

lowastlowast

4545 plusmn 0428

lowastlowast

67852 plusmn 0670

lowastlowast


0

20

40

60

80

100

Drug 3a 3b 3d 5b 5d

30min60min90min

Ana

lges

ia (

)




than CF3and NO


5 Conclusion




Acknowledgments


References






























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of






212 (s 6H CH3)





183 (s 6H CH3)





185 (s 6H CH3)











6














35 plusmn 0428

lowastlowast

53783 plusmn 0477

lowastlowast

811316plusmn0166

lowastlowast

86

3a 116 plusmn 0166

2 plusmn 0258

ns

172 plusmn 0258

ns

25256 plusmn 0210

ns

27

3b 166 plusmn 0210

316 plusmn 0307

lowastlowast

48483 plusmn 0307

lowastlowast

69966 plusmn 0557

lowastlowast

81

3d 166 plusmn 0166

183 plusmn 0307

ns

92 plusmn 0258

ns

25256 plusmn 0210

ns

27

5b 15 plusmn 0223

316 plusmn 0307

lowastlowast

4855 plusmn 0223

lowastlowast

731083plusmn0600

lowastlowast

83

5d 166 plusmn 0210

30 plusmn 00258

lowastlowast

4545 plusmn 0428

lowastlowast

67852 plusmn 0670

lowastlowast


0

20

40

60

80

100

Drug 3a 3b 3d 5b 5d

30min60min90min

Ana

lges

ia (

)




than CF3and NO


5 Conclusion




Acknowledgments


References






























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of





35 plusmn 0428

lowastlowast

53783 plusmn 0477

lowastlowast

811316plusmn0166

lowastlowast

86

3a 116 plusmn 0166

2 plusmn 0258

ns

172 plusmn 0258

ns

25256 plusmn 0210

ns

27

3b 166 plusmn 0210

316 plusmn 0307

lowastlowast

48483 plusmn 0307

lowastlowast

69966 plusmn 0557

lowastlowast

81

3d 166 plusmn 0166

183 plusmn 0307

ns

92 plusmn 0258

ns

25256 plusmn 0210

ns

27

5b 15 plusmn 0223

316 plusmn 0307

lowastlowast

4855 plusmn 0223

lowastlowast

731083plusmn0600

lowastlowast

83

5d 166 plusmn 0210

30 plusmn 00258

lowastlowast

4545 plusmn 0428

lowastlowast

67852 plusmn 0670

lowastlowast


0

20

40

60

80

100

Drug 3a 3b 3d 5b 5d

30min60min90min

Ana

lges

ia (

)




than CF3and NO


5 Conclusion




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

research article green chemical synthesis and analgesic activity of fluorinated ... · 2019. 7....

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