research article uncatalysed production of coumarin-3...

Research ArticleUncatalysed Production of Coumarin-3-carboxylic AcidsA Green Approach

Joel Martiacutenez12 Lilibeth Saacutenchez1 F Javier Peacuterez3 Vladimir Carranza4

Francisco Delgado5 Leonor Reyes5 and Reneacute Miranda1

1Departamento de Ciencias Quımicas Facultad de Estudios Superiores Cuautitlan Universidad Nacional Autonoma de Mexico54740 Cuautitlan Izcalli MEX Mexico2Facultad de Ciencias Quımicas Posgrado en Ciencias en Ingenierıa Quımica Universidad Autonoma de San Luis Potosı78210 San Luis Potosı SLP Mexico3Instituto de Quımica Universidad Nacional Autonoma de Mexico Ciudad Universitaria 04510 Ciudad de Mexico Mexico4Laboratorio de Espectrometrıa de Masas Centro de Quımica ICUAP Benemerita Universidad Autonoma de Puebla72570 Puebla PUE Mexico5Escuela Nacional de Ciencias Biologicas Instituto Politecnico Nacional Casco de Santo Tomas 11340 Ciudad de Mexico Mexico

Correspondence should be addressed to Joel Martınez atlanta126gmailcom

Received 10 June 2016 Accepted 1 August 2016

Academic Editor Artur M S Silva

Copyright copy 2016 Joel Martınez et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

A green contribution in short reaction times with moderate yields to produce coumarin-3-carboxylic acids is offered Five differentmodes to activate the reactions (microwave near-infraredmechanicalmilling and ultrasound)were comparedwithmantle heatingin the presence or absence of ethanol a green solvent Near-infrared and microwave irradiations deliver the best yields in contrastto ultrasound and mechanical milling moreover these four processes offered shorter reaction times in comparison with theconventional mantle heating method It is also important to highlight that the obtained molecules were produced without therequirement of a catalyst and two nonconventional energies forms are presented as new processes

1 Introduction

Coumarins benzo-2-pyrone derivatives are an importantclass of compounds in the field of natural products becausethey display a broad array of biological activities [1] inparticular as antioxidants [2] anti-HIV agents [3] anticanceragents [4] and vasorelaxants [5 6] They have also been usedin the pharmaceutical perfumery and agrochemical indus-tries as startingmaterials or intermediates Consequently thisclass of molecules has been incorporated in the preparationof numerous organic compounds [7] Various protocols havebeen used for their synthesis including the Pechmann [8]Perkin [9] Knoevenagel [10] Reformatsky [11] Wittig [12]and Claisen reactions [13]

On the other hand 22-dimethyl-13-dioxane-46-dione(Meldrumrsquos acid) has attracted considerable attention due toits high acidity and rigid cyclic structure [14] This versatile

molecule is an important substrate for many interestingorganic transformations such as the preparation of pyridones[15] pyrimidines and azoloazines in tandem reactions [16]and the synthesis of natural products [17] and of particularinterest for this work as a condensation partner to generatecoumarins [18ndash21]

Owing to the value of these molecules a search for newand more convenient methods of preparation is desirablemainly if the novel offered procedure diminished pollutionin other words with proper green approach the adoption ofnovel cleaner methods must be an urgent priority Someeffortswithoccurrence in theGreenChemistryProtocolhavebeen explored to prepare coumarins derivatives many ofthem using green approaches for example zeolites [23] clays[22] cation exchange resins [24] solventless [25] and solid-phase [26] conditions reflux inwater [18]microwave irradia-tion [19] oxidative cyclocarbonylation [27] usingmixtures of

Hindawi Publishing CorporationJournal of ChemistryVolume 2016 Article ID 4678107 6 pageshttpdxdoiorg10115520164678107

2 Journal of Chemistry

PEG400H2O or PEG400EtOH as solvents [28] ultrasound[29] and room temperature [30] However many of theseprocedures involve long time reactions and the presence ofa solvent or catalyst or both

As a part of our ongoing research program we arevery interested in the development of green proceduresfor the production of different heterocycles with interestingpharmacological properties Consequently the goal of thepresent work was to create a green approach [31] for theproduction of several coumarins using Meldrumrsquos acid as areagent offering an insightful study by comparison of fivedifferent modes to activate the reaction microwave (MW)and near-infrared (NIR) irradiations ultrasound (US) andmechanical milling (MM) versus the typical mantle heating(MH) Some of experiments were carried out in ethanol agreen solvent according to the TRI-EPA [32] It is also worthnoting that a careful search of the literature revealed thatthis is the first report wherein near-infrared irradiation [33]and mechanical milling or tribochemistry [34] have beenemployed to carry out reaction successfully In general in thiswork an acute procedure for the green synthesis of variouscoumarin-3-carboxylic acids in moderate yields and in shortreaction times is provided

2 Materials and Methods

General Startingmaterials salicylaldehyde (1a) 2-hydroxy-5-methylbenzaldehyde (1b) 2-hydroxy-3-methylbenzaldehyde(1c) 2-hydroxy-4-methoxybenzaldehyde (1d) 2-hydroxy-1-naphthaldehyde (1e) and solvents were purchased fromSigma Aldrich Chemical and used without further purifi-cation Meldrumrsquos acid was prepared according to a litera-ture procedure [35] 1H and 13C NMR (DMSO-1198896) spectrawere recorded using a Varian Mercury-300 spectrometer at300MHz and 75MHz for hydrogen and carbon respectivelyThe multiplicities are reported as singlet (s) doublet (d)triplet (t) doublet of doublet (dd) and triplet doublet (td)The EIMS (70 eV) were determined using a JEOL JMS-700 MStation mass spectrometer The HRMS-DART+ datawere obtained using a JEOL AccuTOF (Direct Analysisin Real Time) mass spectrometer The measurements wereperformed using a DART experiment with PEG (polyethy-lene glycol) 400 as internal reference at 6000 resolutionsand triplet helium as carrier gas at 350∘C In the firstorifice the temperature and voltage were 120∘C and 15Vrespectively and the voltage in the second orifice was5V Elemental composition was calculated within a massrange of plusmn10 ppm from the measured mass Melting pointswere determined using a Fisher-Johns apparatus and areuncorrected Microwave-assisted synthesis of the target com-pounds was performed using a CEM Focused MicrowaveSynthesis System Near-infrared irradiation was generatedusing a commercial ldquoFlavor-Waverdquo (1300W110V120V-60Hz|220V240V-60Hz) device [33] Ultrasound-assistedsynthesis was performed using a Transonic 460H Elmaultrasound bath (35 kHz) Mechanical milling was conductedusing a Ball Mill PM 100 Retch using25 carbon steel balls

(weight 11050mg 31610158401015840 diameter) It was not possible todetermine temperature andpressure in this device In theNIRand ultrasound experiments the temperature was measuredusing an infrared thermometer (Infrared + Type K Ther-mometer Extech Instruments Sigma Aldrich 2509388-1 EA)with the laser pointer directed to the center of reaction Theprogress of the reactions was monitored by TLC using silicagel 60-F254 coated aluminum sheets (n-hexane-ethyl acetate6 4) visualized using a UV light at 254 nm

21 Method A (with Solvent) A mixture of aldehyde 1a(120mg 09833mmol) 1b (140mg 10290mmol) 1c (140mg10290mmol) 1d (140mg 09865mmol) or 1e (140mg09881mmol) Meldrumrsquos acid 2 (150mg 10408mmol) andEtOH (5mL for US and NIR 2mL for MW and 05mLfor MM) was placed in an appropriate Erlenmeyer flaskbottom flask or steel container The mixtures were treatedusing different activationmodes near-infrared irradiation for20min at 70∘C with vigorous magnetic stirring placing themagnetic agitator under Flavor-Wave microwave irradiationfor 1min at 70∘C (run time) and then 5min at 70∘C (holdtime) with medium level stirring and 100 W power ultra-sound bath for 30min at 70∘C mechanical milling for 25minwith 400 rpm and 27 power All reactions were conductedin open vessels and monitored by TLC (silica gel n-hexane-ethyl acetate 6 4) After cooling ice-water was added to theflask to precipitate the product and the solid collected to givethe corresponding pure coumarin-3-carboxylic acid

22 Method B (Solventless) A mixture of aldehyde 1a(120mg 09833mmol) 1b (140mg 10290mmol) 1c (140mg10290mmol) 1d (140mg 09865mmol) or 1e (140mg09881mmol) and Meldrumrsquos acid 2 (150mg 10408mmol)was placed in an appropriate Erlenmeyer flask bottom flaskor steel container The mixtures were treated using differentactivation modes near-infrared irradiation for 25min at80∘C microwave irradiation for 1min at 80∘C (run time)and then 10min at 80∘C (hold time) ultrasound bath for60min at 65∘C mechanical milling for 40min with 400 rpmand 27 power mantle heating for 90min at 90∘C Allreactions were conducted in open vessels and monitored byTLC (silica gel n-hexane-ethyl acetate 6 4) After coolingice-water was added to the flask to extract the product andthe solid collected to give the corresponding pure coumarin-3-carboxylic acid

2-Oxo-2H-chromene-3-carboxylic Acid (3a) White powdermp 190-191∘C 1HNMR (300MHz DMSO-1198896) (120575ppm) 871(s 1H H4) 787 (dd J = 765Hz 1H H5) 769 (td J = 787Hz1H H7) 740 (t J = 63Hz 1H H6) 735 (d J = 765Hz1H H8) the proton of COH2 was not observable probablybecause the concentration of nuclei which produce the signalwas poor or because of fast dissociation [36] in addition theexchange with the deuterated solvent or water from solventitself can occur 13C NMR (75MHz DMSO-1198896) (120575ppm)1640 (CO2H) 1567 (C2) 1545 (C8a) 1484 (C4) 1343 (C7)1302 (C5) 1248 (C8) 1184 (C3) 1180 (C6) 1162 (C4a)

Journal of Chemistry 3

2 EtOH or solventlessR

OH

CHO

O O

O O

O

R

O

+

R1

R2

R3

R1

R2

R3

CO2H

(e) MH 350min 78∘C

(c) US 30min 70∘C(b) NIR 20min 70∘C(a) MW 5min 70∘C

(d) MM 25 min

3andashe1andashe

Scheme 1 Production of coumarins Reagent or Product a R = R1 = R2 = R3 = H b R = R1 = H R2 = Me R3 = H c R = Me R1 = R2 = R3 =H d R = H R1 = OMe R2 = R3 = H e R = R1 = H R2-R3 = CHCH=CHCH

EIMS (70 eV) mz () 190 (47) M+∙ 173 (13) [M minus 17]+ 146(100) [M minus 44]+∙ 118 (61) [M minus 72]+∙

6-Methyl-2-oxo-2H-chromene-3-carboxylic Acid (3b) Whitepowder mp 158-159∘C 1H NMR (300MHz DMSO-1198896)(120575ppm) 862 (s 1H H4) 764 (s 1H H5) 752 (d J = 84Hz1H H8) 731 (dd J = 84Hz 1H H7) 235 (s 3H H9)the proton of COH2 was not observable probably becausethe concentration of nuclei which produce the signal waspoor or because of fast dissociation [36] in addition theexchange with the deuterated solvent or water from solventitself can occur 13C NMR (75MHz DMSO-1198896) (120575ppm)1641 (CO2H) 1570 (C2) 1526 (C8a) 1481 (C4) 1352 (C7)1342 (C6) 1296 (C5) 1184 (C3) 1177 (C4a) 1159 (C8) 202(C9) EIMS (70 eV) mz () 204 (12) M+∙ 205 (100) [M +H]+ 187 (85) [Mminus 17]+ 160 (9) [Mminus 44]+∙ 103 (5) [Mminus 101]+

8-Methyl-2-oxo-2H-chromene-3-carboxylic Acid (3c) Whiteneedless mp 155-156∘C 1H NMR (300MHz DMSO-1198896)(120575ppm) 868 (s 1H H4) 769 (d J = 795Hz 1H H5) 756(d J = 705Hz 1H H7) 726 (t J = 765Hz 1H H6) 234 (s3H H9) the proton of COH2 was not observable probablybecause the concentration of nuclei which produce the signalwas poor or because of fast dissociation [36] in addition theexchange with the deuterated solvent or water from solventitself can occur 13C NMR (75MHz DMSO-1198896) (120575ppm)1641 (CO2H) 1568 (C2) 1528 (C8a) 1487 (C4) 1353 (C7)1279 (C5) 1251 (C8) 1244 (C6) 1179 (C3) 1177 (C4a) 149(C9) EIMS (70 eV) mz () 204 (18) M+∙ 187 (2) [M minus17]+ 160 (100) [M minus 44]+∙ 132 (78) [M minus 72]+∙ 103 (29) [Mminus 101]+ HRMS-DART+ for C11H9O4 [M + H]+ calculated2050501Da experimental 2050509Da

7-Methoxy-2-oxo-2H-chromene-3-carboxylicAcid (3d)Whitepowder mp 187-188∘C 1H NMR (300MHz DMSO-1198896)(120575ppm) 871 (s 1H H4) 782 (d J = 90Hz 1H H5) 702(d J = 81Hz 1H H6) 698 (s 1H H8) 386 (s 3H H9) theproton of COH2 was not observable probably because theconcentration of nuclei which produce the signal was pooror because of fast dissociation [36] in addition the exchangewith the deuterated solvent or water from solvent itself canoccur 13C NMR (75MHz DMSO-1198896) (120575ppm) 1647 (C7)1642 (CO2H) 1572 (C2) 1569 (C8a) 1491 (C4) 1316 (C5)1139 (C3) 1133 (C6) 1116 (C4a) 1003 (C8) 563 (C9) EIMS(70 eV) mz () 220 (100) M+∙ 203 (16) [M minus 17]+ 192 (14)[M minus 28]+∙ 176 (77) [M minus 44]+∙ 148 (43) [M minus 72]+∙ 133 (50)[M minus 87]+

3-Oxo-3H-benzo[f]chromene-2-carboxylic Acid (3e) Yellowpowder mp 239ndash241∘C 1H NMR (300MHz DMSO-1198896)(120575ppm) 926 (s 1H H1) 887 (d J = 87Hz 1H H10) 807(d J = 90Hz 1H H6) 784 (d J = 78Hz 1H H5) 758 (tJ = 765Hz 1H H9) 739 (t J = 78Hz 1H H8) 720 (d J= 93Hz 1H H7) the proton of COH2 was not observableprobably because the concentration of nuclei which producethe signal was poor or because of fast dissociation [36] inaddition the exchange with the deuterated solvent or waterfrom solvent itself can occur 13CNMR (75MHz DMSO-1198896)(120575ppm) 1644 (CO2H) 1640 (C3) 1569 (C4a) 1550 (C1)1358 (C6) 1317 (C10a) 1293 (C6a) 1276 (C10) 1264 (C9)1222 (C7) 1221 (C8) 1172 (C2) 1124 (C5) 1121 (C1a) EIMS(70 eV)mz () 240 (10)M+∙ 223 (2) [M minus 17]+ 194 (100) [Mminus 46]+∙ 168 (11) [M minus 72]+∙

3 Results and Discussion

31 Synthesis In order to minimize the energy requirementsof a given process various attempts were made to make theenergy input as efficient as possible for the production ofthe 3-carboxycoumarins (3andashe) Five salicylaldehydes (1andashe)were treated with Meldrumrsquos acid (2) under four noncon-ventional activating methods (MW NIR US and MM) andwith mantle heating (MH) under solventless conditions or inethanol without a catalyst (Scheme 1) In general these one-pot processes occur via a typical Knoevenagel condensationaccording to the literature [17]The results are summarized inTable 1

The performance of US-assistance may be due to ultra-sonic acceleration effects on the liquid system explained bycavitation-collapse promoting low-energy chemical reactions[29] With regard to the low yields for MM it is known thatvarious tribophysical phenomena exist [37] it is possible thatthe formation of electrons and positive ions to produce therequired plasmawas not generated in an appropriate quantityreducing the production of triboplasma leading to poorlubrication of the tribosystem and consequently affording lowyields The yields obtained with NIR and MW were similardue to the fact that both must be directly absorbed by thesolvent and the reagents resulting in a rapid temperature risein the system and consequently increasing reactivity [38]

All of these methods fit appropriately with the sixthprinciple of the Green Chemistry Protocol that is decreasingenergy consumption The solvent ethanol has a high tan 120575


Table 1 Formation of coumarins using five activating modes

Product Yield ()reaction time (min) mp (∘C)MW IR US MM MH Explit

3a1

2

34567

8

4a

O O8a

CO2H735a2110b

6220a2125b

7330a560b

3225a1140b

89350ac1190b 190-191191-192c

3b1 28 8a

34567

4a9

O

CO2H

O525a910b

3820a925b

4830a960b

2825a940b

911440ad990b 158-159166-167d

3c1

2

34567

8

4a

9O O8a

CO2H385a910b

4820a925b

4830a960b

1925a940b

mdash990b 155-156mdash

3d1

2

34567

8

4a

9O O8aMeO

CO2H565a1710b

6220a825b

4530a760b

1725a840b

88350ac890b 187-188192ndash194c

3e

1 23

456

78

1a4a

9

O O

10a10

6aCO2H 915a

1610b9120a825b

3530a860b

1625a840b

77350ac890b 239ndash241236-237c

MW microwave irradiation NIR near-infrared irradiation US ultrasound MM mechanical milling MH mantle heating Exp experimental Lit literatureain EtOH bsolventless csee [21] dsee [22]

value (0941) a measure of its ability to convert electromag-netic energy into heat [39] also favoring efficient energyabsorption It is also important to take into account thatit is a green solvent because of its low toxicity and gooddegradability [31 32 40] in accordancewith the fifth principleof the green protocol moreover the use of ethanol insteadof pyridine or piperidine as solvent supports the third andtwelfth green chemistry principles The use of sodium azidelithium bromide ammonium acetate potassium carbonatepalladium and other catalyst several of which consideredas toxic by TRI-EPA was avoided in agreement with thethird and twelfth green chemistry principlesThe byproductsgenerated are water green molecule and ketone all classifiedas nontoxic (TRI-EPA) favoring the first and third principlesIn addition the atom economy is in the order of 7143 avalue considered as a good approach to the second principle

Consequently the best processes were developed employ-ing EtOH as solvent offering higher yields in comparisonwith solventless conditions From these strategies the MWand NIR irradiations are the best alternatives because theyoffer in general the same yields but the microwavesrsquo usein obtaining the title molecules is well known howeverNIR irradiation is offered as clean energy source to activatereactions being easily controllable and with the quality of afast responding heat source [33]

The structural identification of products 3andashe was madeon the basis of their corresponding spectral data The com-pounds 3a 3b 3d and 3ewere consistent with authentic onesin literature [21 22] Since compound 3c is a novel moleculethe corresponding spectroscopic data is discussed

32 Spectroscopic Attribution The 1H NMR exhibited theexpected singlet for the allylic proton (H4) at 120575 868 also twodouble signals were assigned at 120575 769 (J = 795Hz) and at756 (J = 705Hz) to H5 and H7 respectively a triplet at 120575726 (J = 765Hz) was assigned to H6 finally the hydrogensof the methyl group (H9) were unequivocally assigned to asinglet at 120575 234 the proton of CO2H was not observableprobably because the concentration of nuclei which producethe signal was poor or because of fast dissociation [36]in addition the exchange with the deuterated solvent orwater from solvent itself can occur The 13C NMR spectrumcontained four signals at 120575 1641 1568 1487 and 1251 whichwere appropriately assigned to CO2H C2 (C=O) C4 and C8respectively the patterns for aryl and methyl groups werealso observed in the experimental data and these signalswere corroborated by a HMBC experiment (three bondsdistance) H4 correlated with C8a at 120575 1528 with C5 at 1205751279 with C2 (C=O) at 120575 1568 and with CO2H at 120575 1641


The hydrogen of the methyl group correlated with C7 at 1205751353 and H5 correlated with C8a at 120575 1528 and C7 at 1205751353 In EIMS spectrum the molecular ion at mz 204 wasobserved in addition to the base peak at mz 160 assignedto ion-fragment [M minus 44]+∙ some other worthy of notefragments aremz 187 [M minus 17]+mz 132 [M minus 72]+∙ andmz103 [M minus 101]+ Finally the respective HRMS-DART+ resultswere in agreement with the expected elemental compositionC11H9O4 calculated mz 2050501 and experimental mz2050509 (380 ppm error) [M + H]+

4 Conclusions

In conclusion coumarin-3-carboxylic acids 3andashe have beenprepared using a one-pot procedure where the best syn-thetic strategy was obtained in solution conditions Differentactivating energy sources were employed providing severalenvironmental benefits less energy consumption productisolation by simple filtration and use of ethanol as a greensolvent without catalyst and very good atom economy Inother words the overall process occurs with a good incidencein the Green Chemistry Protocol (the twelve principles) TheNIR irradiation is proposed as a new alternative and as a cleanenergy to produce this kind of molecules

Competing Interests

The authors declare no potential conflict of interests

Acknowledgments

The authors appreciate the financial support to theCatedra Quımica Verde-PIAPIC13 FESC-UNAM andalso CONACyT-Mexico 205289 for the postdoctoralscholarship to Joel Martınez

References

[1] M J Matos L Santana E Uriarte O A Abreu E Molina andE G Yordi ldquoCoumarinsmdashan important class of phytochemi-calsrdquo in PhytochemicalsmdashIsolation Characterization and Rolein Human Health A V Rao and L G Rao Eds pp 113ndash140InTech 2015

[2] C Kontogiorgis and D Hadjipavlou-Litina ldquoBiological evalua-tion of several coumarin derivatives designed as possible anti-inflammatoryantioxidant agentsrdquo Journal of Enzyme Inhibitionand Medicinal Chemistry vol 18 no 1 pp 63ndash69 2003

[3] C Spino M Dodier and S Sotheeswaran ldquoAnti-HIVcoumarins from calophyllum seed oilrdquo Bioorganic andMedicinal Chemistry Letters vol 8 no 24 pp 3475ndash3478 1998

[4] I Kempen D Papapostolou N Thierry et al ldquo3-Bromophenyl6-acetoxymethyl-2-oxo-2H-1-benzopyran-3-carboxylateinhibits cancer cell invasion in vitro and tumour growth invivordquo British Journal of Cancer vol 88 no 7 pp 1111ndash1118 2003

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

[6] E Quezada G Delogu C Picciau et al ldquoSynthesis andvasorelaxant and platelet antiaggregatory activities of a newseries of 6-Halo-3-phenylcoumarinsrdquo Molecules vol 15 no 1pp 270ndash279 2010

[7] R O Kennedy and R DThornes Coumarins Biology Applica-tions and Mode of Action John Wiley amp Sons New York NYUSA 1997

[8] H von Pechmann ldquoNeue bildungsweise der cumarine Syn-these des daphnetins Irdquo Berichte der Deutschen ChemischenGesellschaft vol 17 no 1 pp 929ndash936 1884

[9] J R Johnson ldquoThe Perkin and related reactionsrdquo OrganicReactions vol 1 pp 210ndash265 1942

[10] G Brufola F Fringuelli O Piermatti and F Pizzo ldquoSimpleand efficient one-pot preparation of 3-substituted coumarins inwaterrdquo Heterocycles vol 43 no 6 pp 1257ndash1266 1996

[11] R L Shriner ldquoThe Reformatsky reactionrdquo Organic Reactionsvol 1 pp 1ndash37 1942

[12] I Yavari RHekmat-Shoar andA Zonouzi ldquoAnew and efficientroute to 4-carboxymethylcoumarins mediated by vinyltriph-enylphosphonium saltrdquo Tetrahedron Letters vol 39 no 16 pp2391ndash2392 1998

[13] N Cairns L M Harwood and D P Astles ldquoTandem thermalClaisen-cope rearrangements of coumarate derivatives Totalsyntheses of the naturally occurring coumarins suberosindemethylsuberosin ostruthin balsamiferone and gravellifer-onerdquo Journal of the Chemical Society Perkin Transactions 1 no21 pp 3101ndash3107 1994

[14] K Pihlaja M Seilo U Svanholm A M Duffield A TBalaban and J CCraig ldquoThe acidity and general base-catalyzedhydrolysis of Meldrumrsquos acid and its methyl derivativesrdquo ActaChemica Scandinavica vol 23 pp 3003ndash3010 1969

[15] M O Noguez V Marcelino H Rodrıguez et al ldquoInfraredassisted production of 34-dihydro-2(1H)-pyridones in solvent-free conditionsrdquo International Journal ofMolecular Sciences vol12 no 4 pp 2641ndash2649 2011

[16] V V Lipson and N Y Gorobets ldquoOne hundred years ofMeldrumrsquos acid advances in the synthesis of pyridine andpyrimidine derivativesrdquo Molecular Diversity vol 13 no 4 pp399ndash419 2009

[17] A S Ivanov ldquoMeldrumrsquos acid and related compounds in thesynthesis of natural products and analogsrdquo Chemical SocietyReviews vol 37 no 4 pp 789ndash811 2008

[18] R Maggi F Bigi S Carloni A Mazzacani and G SartorildquoUncatalysed reactions in watermdashpart 2 Preparation of 3-carboxycoumarinsrdquo Green Chemistry vol 3 no 4 pp 173ndash1742001

[19] B P Bandgar L S Uppalla and D S Kurule ldquoSolvent-freeone-pot rapid synthesis of 3-carboxycoumarins using focusedmicrowavesrdquo Green Chemistry vol 1 no 5 pp 243ndash245 1999

[20] B Bandgar L Uppalla and V Sadavarte ldquoLithium perchlorateand lithium bromide catalysed solvent free one pot rapidsynthesis of 3-carboxycoumarins undermicrowave irradiationrdquoJournal of Chemical Research vol 2002 no 1 pp 40ndash41 2002

[21] A Song X Wang and K S Lam ldquoA convenient synthesis ofcoumarin-3-carboxylic acids via Knoevenagel condensation ofMeldrumrsquos acid with ortho-hydroxyaryl aldehydes or ketonesrdquoTetrahedron Letters vol 44 no 9 pp 1755ndash1758 2003

[22] F Bigi L Chesini R Maggi and G Sartori ldquoMontmorilloniteKSF as an inorganic water stable and reusable catalyst forthe Knoevenagel synthesis of coumarin-3-carboxylic acidsrdquoTheJournal of Organic Chemistry vol 64 no 3 pp 1033ndash1035 1999


[23] E A Gunnewegh A J Hoefnagel R S Downing and Hvan Bekkum ldquoEnvironmentally friendly synthesis of coumarinderivatives employing heterogeneous catalysisrdquo Recueil desTravaux Chimiques des Pays-Bas vol 115 no 4 pp 226ndash2301996

[24] A de la Hoz A Moreno and E Vazquez ldquoUse of microwaveirradiation and solid acid catalysts in an enhanced and environ-mentally friendly synthesis of coumarin derivativesrdquo Synlett no5 pp 608ndash610 1999

[25] J L Scott and C L Raston ldquoSolvent-free synthesis of 3-carboxycoumarinsrdquo Green Chemistry vol 2 no 5 pp 245ndash2472000

[26] B T Watson and G E Christiansen ldquoSolid phase synthesis ofsubstituted coumarin-3-carboxylic acids via the Knoevenagelcondensationrdquo Tetrahedron Letters vol 39 no 33 pp 6087ndash6090 1998

[27] J Ferguson F Zeng and H Alper ldquoSynthesis of coumarins viaPd-catalyzed oxidative cyclocarbonylation of 2-vinylphenolsrdquoOrganic Letters vol 14 no 21 pp 5602ndash5605 2012

[28] L C CVieiraMW Paixao andAG Correa ldquoGreen synthesisof novel chalcone and coumarin derivatives via Suzuki couplingreactionrdquo Tetrahedron Letters vol 53 no 22 pp 2715ndash27182012

[29] N G Khaligh ldquoUltrasound-assisted one-pot synthesis ofsubstituted coumarins catalyzed by poly(4-vinylpyridinium)hydrogen sulfate as an efficient and reusable solid acid catalystrdquoUltrasonics Sonochemistry vol 20 no 4 pp 1062ndash1068 2013

[30] G Brahmachari ldquoRoom temperature one-pot green synthesisof coumarin-3-carboxylic acids in water a practical methodfor the large-scale synthesisrdquo ACS Sustainable Chemistry andEngineering vol 3 no 9 pp 2350ndash2358 2015

[31] MMorales J Martınez L Reyes-Sanchez et al ldquoHow green anexperiment isrdquo Educacion Quimica vol 22 no 3 pp 240ndash2482011

[32] Toxics Release Inventory (TRI) Program httpswwwepagovtoxics-release-inventory-tri-programtri-listed-chemicals

[33] R Escobedo RMiranda and JMartınez ldquoInfrared irradiationtoward green chemistry a reviewrdquo International Journal ofMolecular Sciences vol 17 no 4 p 453 2016

[34] G-W Wang ldquoMechanochemical organic synthesisrdquo ChemicalSociety Reviews vol 42 no 18 pp 7668ndash7700 2013

[35] A N Meldrum ldquoLIVmdasha 120573-lactonic acid from acetone andmalonic acidrdquo Journal of the Chemical Society Transactions vol93 pp 598ndash601 1908

[36] L M Jackman and S Sternell Applications of Nuclear Mag-netic Resonance Spectroscopy in Organic Chemistry PergamonOxford UK 2nd edition 1972

[37] KNakayama and J-MMartin ldquoTribochemical reactions at andin the vicinity of a sliding contactrdquo Wear vol 261 no 3-4 pp235ndash240 2006

[38] CO Kappe ldquoControlledmicrowave heating inmodern organicsynthesisrdquo Angewandte ChemiemdashInternational Edition vol 43no 46 pp 6250ndash6284 2004

[39] B Hayes Microwave Synthesis Chemistry at the Speed of LightCEM Publishing Matthews NC USA 2002

[40] M Doxsee and E Hutchison Green Organic Chemistry Strate-gies Tools and Laboratory ExperimentsThomson BrooksColeMinister Ohio USA 1st edition 2004

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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


PEG400H2O or PEG400EtOH as solvents [28] ultrasound[29] and room temperature [30] However many of theseprocedures involve long time reactions and the presence ofa solvent or catalyst or both

As a part of our ongoing research program we arevery interested in the development of green proceduresfor the production of different heterocycles with interestingpharmacological properties Consequently the goal of thepresent work was to create a green approach [31] for theproduction of several coumarins using Meldrumrsquos acid as areagent offering an insightful study by comparison of fivedifferent modes to activate the reaction microwave (MW)and near-infrared (NIR) irradiations ultrasound (US) andmechanical milling (MM) versus the typical mantle heating(MH) Some of experiments were carried out in ethanol agreen solvent according to the TRI-EPA [32] It is also worthnoting that a careful search of the literature revealed thatthis is the first report wherein near-infrared irradiation [33]and mechanical milling or tribochemistry [34] have beenemployed to carry out reaction successfully In general in thiswork an acute procedure for the green synthesis of variouscoumarin-3-carboxylic acids in moderate yields and in shortreaction times is provided

2 Materials and Methods

General Startingmaterials salicylaldehyde (1a) 2-hydroxy-5-methylbenzaldehyde (1b) 2-hydroxy-3-methylbenzaldehyde(1c) 2-hydroxy-4-methoxybenzaldehyde (1d) 2-hydroxy-1-naphthaldehyde (1e) and solvents were purchased fromSigma Aldrich Chemical and used without further purifi-cation Meldrumrsquos acid was prepared according to a litera-ture procedure [35] 1H and 13C NMR (DMSO-1198896) spectrawere recorded using a Varian Mercury-300 spectrometer at300MHz and 75MHz for hydrogen and carbon respectivelyThe multiplicities are reported as singlet (s) doublet (d)triplet (t) doublet of doublet (dd) and triplet doublet (td)The EIMS (70 eV) were determined using a JEOL JMS-700 MStation mass spectrometer The HRMS-DART+ datawere obtained using a JEOL AccuTOF (Direct Analysisin Real Time) mass spectrometer The measurements wereperformed using a DART experiment with PEG (polyethy-lene glycol) 400 as internal reference at 6000 resolutionsand triplet helium as carrier gas at 350∘C In the firstorifice the temperature and voltage were 120∘C and 15Vrespectively and the voltage in the second orifice was5V Elemental composition was calculated within a massrange of plusmn10 ppm from the measured mass Melting pointswere determined using a Fisher-Johns apparatus and areuncorrected Microwave-assisted synthesis of the target com-pounds was performed using a CEM Focused MicrowaveSynthesis System Near-infrared irradiation was generatedusing a commercial ldquoFlavor-Waverdquo (1300W110V120V-60Hz|220V240V-60Hz) device [33] Ultrasound-assistedsynthesis was performed using a Transonic 460H Elmaultrasound bath (35 kHz) Mechanical milling was conductedusing a Ball Mill PM 100 Retch using25 carbon steel balls

(weight 11050mg 31610158401015840 diameter) It was not possible todetermine temperature andpressure in this device In theNIRand ultrasound experiments the temperature was measuredusing an infrared thermometer (Infrared + Type K Ther-mometer Extech Instruments Sigma Aldrich 2509388-1 EA)with the laser pointer directed to the center of reaction Theprogress of the reactions was monitored by TLC using silicagel 60-F254 coated aluminum sheets (n-hexane-ethyl acetate6 4) visualized using a UV light at 254 nm

21 Method A (with Solvent) A mixture of aldehyde 1a(120mg 09833mmol) 1b (140mg 10290mmol) 1c (140mg10290mmol) 1d (140mg 09865mmol) or 1e (140mg09881mmol) Meldrumrsquos acid 2 (150mg 10408mmol) andEtOH (5mL for US and NIR 2mL for MW and 05mLfor MM) was placed in an appropriate Erlenmeyer flaskbottom flask or steel container The mixtures were treatedusing different activationmodes near-infrared irradiation for20min at 70∘C with vigorous magnetic stirring placing themagnetic agitator under Flavor-Wave microwave irradiationfor 1min at 70∘C (run time) and then 5min at 70∘C (holdtime) with medium level stirring and 100 W power ultra-sound bath for 30min at 70∘C mechanical milling for 25minwith 400 rpm and 27 power All reactions were conductedin open vessels and monitored by TLC (silica gel n-hexane-ethyl acetate 6 4) After cooling ice-water was added to theflask to precipitate the product and the solid collected to givethe corresponding pure coumarin-3-carboxylic acid

22 Method B (Solventless) A mixture of aldehyde 1a(120mg 09833mmol) 1b (140mg 10290mmol) 1c (140mg10290mmol) 1d (140mg 09865mmol) or 1e (140mg09881mmol) and Meldrumrsquos acid 2 (150mg 10408mmol)was placed in an appropriate Erlenmeyer flask bottom flaskor steel container The mixtures were treated using differentactivation modes near-infrared irradiation for 25min at80∘C microwave irradiation for 1min at 80∘C (run time)and then 10min at 80∘C (hold time) ultrasound bath for60min at 65∘C mechanical milling for 40min with 400 rpmand 27 power mantle heating for 90min at 90∘C Allreactions were conducted in open vessels and monitored byTLC (silica gel n-hexane-ethyl acetate 6 4) After coolingice-water was added to the flask to extract the product andthe solid collected to give the corresponding pure coumarin-3-carboxylic acid

2-Oxo-2H-chromene-3-carboxylic Acid (3a) White powdermp 190-191∘C 1HNMR (300MHz DMSO-1198896) (120575ppm) 871(s 1H H4) 787 (dd J = 765Hz 1H H5) 769 (td J = 787Hz1H H7) 740 (t J = 63Hz 1H H6) 735 (d J = 765Hz1H H8) the proton of COH2 was not observable probablybecause the concentration of nuclei which produce the signalwas poor or because of fast dissociation [36] in addition theexchange with the deuterated solvent or water from solventitself can occur 13C NMR (75MHz DMSO-1198896) (120575ppm)1640 (CO2H) 1567 (C2) 1545 (C8a) 1484 (C4) 1343 (C7)1302 (C5) 1248 (C8) 1184 (C3) 1180 (C6) 1162 (C4a)



OH

CHO

O O

O O

O

R

O

+

R1

R2

R3

R1

R2

R3

CO2H

(e) MH 350min 78∘C


(d) MM 25 min

3andashe1andashe














3a1

2

34567

8

4a

O O8a

CO2H735a2110b

6220a2125b

7330a560b

3225a1140b

89350ac1190b 190-191191-192c

3b1 28 8a

34567

4a9

O

CO2H

O525a910b

3820a925b

4830a960b

2825a940b

911440ad990b 158-159166-167d

3c1

2

34567

8

4a

9O O8a

CO2H385a910b

4820a925b

4830a960b

1925a940b


3d1

2

34567

8

4a

9O O8aMeO

CO2H565a1710b

6220a825b

4530a760b

1725a840b

88350ac890b 187-188192ndash194c

3e

1 23

456

78

1a4a

9

O O

10a10

6aCO2H 915a

1610b9120a825b

3530a860b

1625a840b

77350ac890b 239ndash241236-237c








4 Conclusions


Competing Interests


Acknowledgments


References



















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



OH

CHO

O O

O O

O

R

O

+

R1

R2

R3

R1

R2

R3

CO2H

(e) MH 350min 78∘C


(d) MM 25 min

3andashe1andashe














3a1

2

34567

8

4a

O O8a

CO2H735a2110b

6220a2125b

7330a560b

3225a1140b

89350ac1190b 190-191191-192c

3b1 28 8a

34567

4a9

O

CO2H

O525a910b

3820a925b

4830a960b

2825a940b

911440ad990b 158-159166-167d

3c1

2

34567

8

4a

9O O8a

CO2H385a910b

4820a925b

4830a960b

1925a940b


3d1

2

34567

8

4a

9O O8aMeO

CO2H565a1710b

6220a825b

4530a760b

1725a840b

88350ac890b 187-188192ndash194c

3e

1 23

456

78

1a4a

9

O O

10a10

6aCO2H 915a

1610b9120a825b

3530a860b

1625a840b

77350ac890b 239ndash241236-237c








4 Conclusions


Competing Interests


Acknowledgments


References



















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of




3a1

2

34567

8

4a

O O8a

CO2H735a2110b

6220a2125b

7330a560b

3225a1140b

89350ac1190b 190-191191-192c

3b1 28 8a

34567

4a9

O

CO2H

O525a910b

3820a925b

4830a960b

2825a940b

911440ad990b 158-159166-167d

3c1

2

34567

8

4a

9O O8a

CO2H385a910b

4820a925b

4830a960b

1925a940b


3d1

2

34567

8

4a

9O O8aMeO

CO2H565a1710b

6220a825b

4530a760b

1725a840b

88350ac890b 187-188192ndash194c

3e

1 23

456

78

1a4a

9

O O

10a10

6aCO2H 915a

1610b9120a825b

3530a860b

1625a840b

77350ac890b 239ndash241236-237c








4 Conclusions


Competing Interests


Acknowledgments


References



















































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of



4 Conclusions


Competing Interests


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 uncatalysed production of coumarin-3...

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