research article benign methodology and efficient catalysis for...

Research ArticleBenign Methodology and Efficient Catalysis for theOne-Pot Multicomponent Synthesis of Dihydropyrimidinonesand Thiones A New Key for Old Lock

Parvez Ali1 Naziyanaz Pathan2 and Taibi Ben Hadda3

1 Center for Health Studies Prince Sultan Military Medical City Riyadh 11159 Saudi Arabia2 Institute of Science Nagpur University Nagpur 440001 India3 Laboratoire de Chimie des Materiaux Universite Mohammed Premier 6000 Oujda Morocco

Correspondence should be addressed to Parvez Ali parvezali 81yahoocom

Received 29 October 2013 Accepted 13 March 2014 Published 9 April 2014

Academic Editor Guang-Fu Yang

Copyright copy 2014 Parvez Ali 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

In the present communication under the influence of microwaves cuprous chloride has been demonstrated to be safe mildefficient and inexpensive catalyst for the Biginelli discovered multicomponent reaction (MCR) between aromatic aldehydesureasubstituted urea and ethyl acetoacetate to produce structurally diverse dihydropyrimidin-2(1H)-ones (DHPMs) and thionesin an ecofriendly solvent-free protocol The practical and simple protocol led to excellent yields of the dihydropyrimidin-2(1H)-one derivatives under mild reaction conditions and within short span of reaction times with easy reaction workup by maintainingexcellent atom economy

1 Introduction

In multicomponent reactions (MCRs) three or more reac-tants come together in a single reaction vessel to form newproducts that contain portions of all the components [1ndash5]In this dynamic era of chemistry where a premium effort isput on speed diversity and efficiency in the drug discoveryprocess [6] MCR strategies offer significant advantages overconventional linear-type synthesis [1ndash5] One suchMCR thatbelongs to this category is the venerable Biginelli dihydropy-rimidinones synthesis In 1893 Italian chemist Pietro Biginellireported the acid catalyzed cyclocondensation reaction ofethyl acetoacetate (1) benzaldehyde (2) and urea (3) [7]The reaction was carried out by heating a mixture of thethree components by dissolving it in ethanol with a catalyticamount of HCl at reflux temperature The product of thisnovel one-pot three-component synthesis that precipitatedon cooling of the reaction mixture was identified correctlyby Biginelli as 34-dihydropyrimidin-2(1H)-one 4 (Scheme 1)[8 9]

Owing to their remarkable pharmacological propertiessuch as calcium channel blockers antitumor and anti-inflammatory activities dihydropyrimidinones and theirderivatives have increasingly attracted the attention of syn-thetic chemists [10ndash15] Moreover the dihydropyrimidine-5-carboxylate core has been found in several marine naturalproducts which are potent HIVgp-120-CD4 inhibitors [1617] However despite the potential utility of dihydropyrim-idinones as bioactive compounds their antifungal activitiesare also studied [18] Thus due to immense pharmacologicalprofile of this class of compounds research interest towardsthis area is growing day by day This in turn increases theattempts to develop various versatile safe and quick pro-cesses for their synthesisThe classical Biginelli condensationprotocol suffers from the drawbacks like harsh reactionconditions high reaction times and frequently low yieldsThis has led to multistep synthetic strategies that producesomewhat better yields but lack the simplicity of one-potsynthesis In recent years new methods for the synthesisof 34-dihydropyrimidin-2-(1H)-ones have been developed

Hindawi Publishing CorporationJournal of Applied ChemistryVolume 2014 Article ID 835758 6 pageshttpdxdoiorg1011552014835758

2 Journal of Applied Chemistry

R

R

H

O O O

O

OEt H2N NH2

HCl EtOHHeat 3hrs

EtO NHX

XNHH 3CC+ +

1 2 3 4Where X = O and S

Scheme 1 Traditional Biginelli reaction

R

R

H

O O OCuCl solvent-free

O

OEt H2N NH2

EtO NHX

XNHH 3CC+ +

1 2 3 4

60∘C MWI 240W

Where X = O and S

Scheme 2 CuCl catalysed Biginelli condensation

by different groups In order to improve the efficiency ofthe Biginelli reaction different Lewis catalysts such as ZrCl

4

[19] BiCl3[20] LiBr [21] Mn(OAc)

3sdot2H2O [22] InCl

3[23]

Cu(OTf)2[24] Zn(OTf)

2[25] FeCl

3sdotH2O [26] LiClO

4

[27] CuCl2[28] chloroacetic acid and LaCl

3as BF

3sdotOEt2

La(OTf)3 Yb(OTf)

3silica sulfuric acid H

3PW12O40 and

H3PMo12O40

[29] have been developed Some of them arereally fascinating from the synthetic chemistrsquos points ofview however some drawbacks still remain For examplesome catalysts are expensive complex or unavailable andorganic solvents are always used Furthermore many heavymetallic salts were used which resulted in the pollution ofthe environment to some extent Previous reported protocolsnormally required prolonged reaction times and high tem-perature withmoderate yields so there has been considerableinterest in exploring mild rapid and high yielding protocolat ambient temperature Recently there were some reportswhich utilized phenylboronic acid [30] triphenylphosphine[31] phosphate ester [32] calcium fluoride [33] and ammo-nium carbonate in water [34] But some of these protocolssuffered from longer reaction times and requirement ofsolvents Thus due to the immense biological importance ofdihydropyrimidinones it is essential to search for catalystswhich can provide excellent yield in a short reaction timeand can be used effectively for the preparation of a widevariety of functional dihydropyrimidinones under solvent-free conditions

In the recent years microwave heating has emerged outas a powerful technique to promote a variety of chemi-cal reactions [35] Microwave reactions under solvent-freeconditions andor in the presence of a solid support suchas clays alumina silica and graphite resulting in shorterreaction times and higher product yields than those obtainedby using conventional heating offer low cost together withsimplicity in processing and handling [36] Keeping in mindall these parameters and in continuation of our interest in het-erocyclic compounds [37 38] microwave-assisted [39 40]and solvent-free synthesis [41] we wish to report the CuCl

catalyzed synthesis of dihydropyrimidinones and thionesunder microwave conditions (Scheme 2)

2 Materials and Methods

21 General The solvents and reagents used in the syntheticwork were of analytical grade obtained from QualigensIndia and were purified by distillation or crystallizationwhere necessary and their boiling or melting points werecompared with the available literature values Melting pointswere determined in open capillaries and are uncorrected 1H-NMR spectra were recorded on a Perkin Elmer FT-NMRCryomagnet Spectrometer 400MHz (Bruker) instrumentusing tetramethylsilane (TMS) as an internal standard andDMSO-119889

6as a solvent Chemical shifts are given in parts per

million (ppm) Infrared spectra were recorded on Shimadzu-IRPrestige 21Mass spectrawere recorded on aWatersMicro-mass Q-T of Microspectrometer The microwave-assistedreactions were carried out in a ldquoCEM DISCOVERrdquo man-ufactured by CEM Technologies Corporation In this unitmicrowaves are generated by magnetron at a frequency of2450MHz having an output energy range of 100 to 500WThe reactions were monitored and the purity of productswas checked out on precoated TLC plates (Silica gel 60F254Merck) visualizing the spots under ultraviolet light andiodine chamber

22 General Procedure for the Synthesis of Dihydropyrim-idinones and Thiones In a typical solventless prepara-tion mixture of aldehyde (25mmol) ethyl acetoacetate(275mmol) urea or thiourea (375mmol) and cuprous chlo-ride (125mmol 5mol) in a reaction flask was stirred wellkept in the microwave generator and allowed to irradiatewith microwaves at MW 60∘C 240W for the required timeas mentioned in Table 1 based on reaction monitoring byTLC After completion of the reaction it was allowed to cooland the reaction was quenched with 5 NH

4OH solution

Journal of Applied Chemistry 3

R R

R

O

O

ORO

O

O

H+

H

H2

H2N

H2N

N N

HN

NH

NH

2

X

C

X

X

NH

X

C

1 2

CuCl

Cu Cu

Cu

CuOEt

EtOEtO

H3CH3C

3

56

4

Where X = O and S

H2Ominus

H2Ominus

Scheme 3 Plausible reaction mechanism

Table 1 Comparison of catalyst loading with percent yield for themodel reaction (Scheme 2)

Catalyst loading (mol) yield20 9615 9510 955 94

and stirred for 15min The solid was filtered under suctionwashed with ice cold water twice and then recrystallizedfrom ethanol to afford pure products 4 (andashm)

23 Spectral Data

231 4d Mp 200ndash202∘C (Lit Mp 198ndash200∘C) [29] IR (KBr)] = 3520 3230 3150 1705 1690 cmminus1 1H NMR (DMSO-119889

6)

118 (t 119869 = 75Hz 3H CH3) 228 (s 3H CH

3) 40 (q 119869 =

75Hz 2H ndashOCH2) 518 (s 1H) 67 (d 119869 = 89Hz 2H Ar)

709 (d 119869 = 89Hz 2H Ar) 725 (s 1H) 895 and 90 (2s 2Hbrs NH) MS 119898119911() = 276 (15) (M+) 248 (100) 231 (28)204 (80) 168 (87) 136 (48) Anal calcd for C

14H16N2O4 C

6086 H 584 N 1014 O 2316 Found C 6089 H 586 N1019 O 2319

232 4j Mp 201ndash203∘C (Lit Mp 202ndash204∘C) [29] IR (KBr)] = 3260 3198 3100 1720 1690 cmminus1 1H NMR (DMSO-119889

6) 120 (t 119869 = 73Hz 3H CH

3) 229 (s 3H CH

3) 410

(q 119869 = 73Hz 2H ndashOCH2) 522 (s 1H CH) 725 (m 5H

Ar) 925 and 99 (2s 2H 2brs NH) MS119898119911() = 276 (65)(M+) 237 (45) 204 (100) 172 (35) 142 (20) Anal calcd forC14H16N2O2S C 6085 H 584 N 1014 S 1160 Found C

6088 H 586 N 1016 S 1165

3 Result and Discussion

Copper is one of the oldest transition metals used inorganic synthesis and copper salts are still broadly employednowadays [42 43] Among these copper salts CuCl is aspecial choice of chemists due to its inexpensiveness lack oftoxicity and easy handling It is a well-known soft Lewis acidcatalyst which has been used for several important organictransformations It is a weak Lewis acid capable of catalyzingthe reaction under mild conditions as compared to otheracids Carrying out reactions under solvent-free conditionscoupled with microwaves is an important strategy in organicsynthesis which significantly reduces the production of wasteand precludes postsynthesis steps such as product isolationsolvent recycling and reaction timeThis employed system ofcatalysis under microwaves is extremely new for the Biginellitype of condensation

To establish the reaction conditions for the CuCl cat-alyzed Biginelli condensation undermicrowaves the reactionof benzaldehydewith ethyl acetoacetate and ureawas taken asmodel reaction as shown in Scheme 2

We have tried to optimize the reaction conditions bytaking various amounts of CuCl in the range of 5ndash20molat room temperature It was observed that the condensationreaction can be efficiently carried out by taking 5mol ofthe catalyst at 240W in a short time span of just 20 to 35minutes which is much lesser as compared to other catalystsusingmore than 5 to 20mol Further increase in the catalystamount does not show any marked increase in the productyield (Table 1)

To ascertain the generality of the protocol a series ofaromatic aldehydes carrying both electron-donating or -withdrawing substituent and heterocyclic aldehydes weresubjected to reaction with 120573-ketoesters urea and thioureaunder the optimized reaction conditions Thiourea has beenused with similar success to provide the correspondingdihydropyrimidin-2(1H)-thiones which are also of much


Table 2 CuCl catalysed solvent-free synthesis of dihydropyrimidin-2(1H)-ones and thiones under microwaves (Scheme 2)

Compound R X Time (min) isolated yield () MP (∘C)Found Reported

4a C6H5 O 25 94 197ndash199 200ndash202 [29]4b 2-Cl C6H5 O 20 98 215ndash217 216ndash218 [44]4c 4-Cl C6H5 O 24 97 210ndash212 211ndash213 [44]4d 4-HOC6H5 O 25 96 200ndash202 198ndash200 [29]4e 2-NO2 C6H5 O 25 90 207ndash209 206ndash208 [44]4f 3-NO2 C6H5 O 20 89 226ndash228 229-230 [44]4g 4-OMe O 25 96 203-204 201-202 [29]4h CH3CH2CH2 O 25 70 178ndash180 180ndash182 [44]4i (CH3)2CH O 25 88 195ndash197 196-197 [44]4j C6H5 S 30 89 201ndash203 202ndash204 [29]4k 3-NO2 C6H5 S 35 85 203ndash205 206-207 [29]4l 4-Cl C6H5 S 30 92 181ndash183 184-185 [29]4m 4-HOC6H5 S 35 88 192ndash194 193-194 [29]

interest with regard to biological activity It is pleasing toobserve the remarkable stability of a variety of functionalgroups under the established reaction conditions

The authors investigated the mechanism of the Biginellireaction in the literature and proposed anN-acyliminium ionformed in situ by reaction of the aldehydewith urea as the keyintermediate followed by metal ligation to generate the targetthings That is this reaction may proceed via generationof acyl imine intermediate formed by the reaction of thealdehyde and urea which was stabilized by CuCl Subsequentaddition of 120573-ketoester enolate to the acylimine followedby cyclization and dehydration afforded the correspondingdihydropyrimidinones (Scheme 3)

Table 2 shows the generality of the present protocolwhich is equally effective for urea or thiourea and also foraromatic and aliphatic aldehydes Under these conditionsthe yields were significantly better in comparison with theclassical Biginelli procedure Several aromatic aldehydescarrying either electron-releasing or electron-withdrawingsubstituents in the ortho meta and para positions affordedhigh yields of the products

An important feature of this procedure is the survival ofa variety of functional groups such as ethers nitro groupshydroxy groups and halides under these reaction conditionsAnother advantage of thismethod is its efficiency for the highyield synthesis of DHPMs from aliphatic aldehydes

4 Conclusion

In conclusion the present protocol provides a benign highyielding efficient and improved route for the synthesis ofBiginelli discovered dihydropyrimidinones and thionesMildreaction conditions solvent-free protocol ease of workuphigh yields stability cost reduction and quick reactionexecution are the features of this new protocolMoreover thismethod has an ability to tolerate a wide variety of substituentin all three components

Conflict of Interests

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

Acknowledgment

The authors are grateful to SAIF Punjab University Chandi-garh for the help in undertakingNMRMass and IR spectra

References

[1] I Ugi A Domling andW Horl ldquoMulticomponent reactions inorganic chemistryrdquo Endeavour vol 18 no 3 pp 115ndash122 1994

[2] R W Armstrong A P Combs P A Tempest S D Brown andT A Keating ldquoMultiple-component condensation strategies forcombinatorial library synthesisrdquoAccounts of Chemical Researchvol 29 no 3 pp 123ndash131 1996

[3] L F Tietze andM Lieb ldquoDomino reactions for library synthesisof small molecules in combinatorial chemistryrdquo Current Opin-ion in Chemical Biology vol 2 no 3 pp 363ndash371 1998

[4] S L Dax J J McNally and M A Youngman ldquoMulti-component methodologies in solid-phase organic synthesisrdquoCurrent Medicinal Chemistry vol 6 no 3 pp 255ndash270 1999

[5] A Domling ldquoIsocyanide based multi component reactionsin combinatorial chemistryrdquo Combinatorial Chemistry amp HighThroughput Screening vol 1 pp 1ndash22 1998

[6] M J Plunkett and J A Ellman ldquoCombinatorial chemistry andnew drugsrdquo Scientific American vol 276 no 4 pp 68ndash73 1997

[7] P Biginelli ldquoAldehyde-urea derivatives of aceto-and oxaloaceticacidsrdquo Gazzetta Chimica Italiana vol 23 pp 360ndash413 1893

[8] K Folkers and T B Johnson ldquoResearches on pyrimidines CVUracil-glycolrdquo Journal of the American Chemical Society vol 55no 9 pp 3781ndash3783 1933

[9] C O Kappe ldquo100 years of the Biginelli dihydropyrimidinesynthesisrdquo Tetrahedron vol 49 no 32 pp 6937ndash6963 1993

[10] K S Atwal B N Swanson S E Unger et al ldquoDihydropy-rimidinecalcium channel blockers 3 3-carbamoyl-4-aryl-1234-tetrahydro-6-methyl-5-pyrimidinecarboxylic acid esters


as orally effective antihypertensive agentsrdquo Journal of MedicinalChemistry vol 34 no 2 pp 806ndash811 1991

[11] G C Rovnyak S D Kimball B Beyer et al ldquoCalcium entryblockers and activators conformational and structural deter-minants of dihydropyrimidine calcium channel modulatorsrdquoJournal of Medicinal Chemistry vol 38 no 1 pp 119ndash129 1995

[12] C O Kappe ldquoBiologically active dihydropyrimidones of theBiginelli-typemdasha literature surveyrdquo European Journal of Medic-inal Chemistry vol 35 no 12 pp 1043ndash1052 2000

[13] C O Kappe ldquoThe generation of dihydropyrimidine librariesutilizing Biginelli multicomponent chemistryrdquoQSAR and Com-binatorial Science vol 22 no 6 pp 630ndash645 2003

[14] Y S Sadanandam M M Shetty and P V DiwanldquoSynthesis and biological evaluation of new 34-dihydro-6-methyl-5-N-methyl-carbamoyl-4-(substituted phenyl)-2(1H)pyrimidinones and pyrimidinethionesrdquo European Journalof Medicinal Chemistry vol 27 no 1 pp 87ndash92 1992

[15] D A Horton G T Bourne and M L Smythe ldquoThe combi-natorial synthesis of bicyclic privileged structures or privilegedsubstructuresrdquo Chemical Reviews vol 103 no 3 pp 893ndash9302003

[16] L Heys C G Moore and P Murphy ldquoThe guanidine metabo-lites of Ptilocaulisspiculifer and related compounds isolationand synthesisrdquo Chemical Society Reviews vol 29 no 1 pp 57ndash67 2000

[17] Z D Aron and L E Overman ldquoThe tethered Biginelli conden-sation in natural product synthesisrdquoChemical Communicationsno 3 pp 253ndash265 2004

[18] A K Chhillar P Arya C Mukherjee et al ldquoMicrowave-assisted synthesis of antimicrobial dihydropyridines andtetrahydropyrimidin-2-ones novel compounds againstaspergillosisrdquo Bioorganic and Medicinal Chemistry vol 14 no4 pp 973ndash981 2006

[19] B B Snider J Chen A D Patil and A J Freyer ldquoSynthesis ofthe tricyclic portions of batzelladinesA B andDRevision of thestereochemistry of batzelladines A and Drdquo Tetrahedron Lettersvol 37 no 39 pp 6977ndash6980 1996

[20] J Barluenga M Tomas A Ballesteros and L A Lopez ldquo14-cycloaddition of 13-diazabutadienes with enamines an efficientroute to the pyrimidine ringrdquo Tetrahedron Letters vol 30 no34 pp 4573ndash4576 1989

[21] B C OrsquoReilly and K S Atwal ldquoSynthesis of substituted1234-tetrahydro-6-methyl-2-oxo-5-pyrimidinecarboxylicacid esters the Biginelli condensation revisitedrdquo Heterocyclesvol 26 no 5 pp 1185ndash1188 1987

[22] J Lu and H Ma ldquoIron(III)-catalyzed synthesis of dihydropy-rimidinones Improved conditions for the Biginelli reactionrdquoSynlett no 1 pp 63ndash64 2000

[23] E H Hu D R Sidler and U-H Dolling ldquoUnprece-dented catalytic three component one-pot condensation reac-tion an efficient synthesis of 5-alkoxycarbonyl-4-aryl-34-dihydropyrimidin- 2(1H)-onesrdquo Journal of Organic Chemistryvol 63 no 10 pp 3454ndash3457 1998

[24] K Ramalinga P Vijayalakshmi and T N B KaimalldquoBismuth(III)-catalyzed synthesis of dihydropyrimidinonesimproved protocol conditions for the Biginelli reactionrdquoSynlett no 6 pp 863ndash865 2001

[25] X Hui and W Yan-Guang ldquoA rapid and efficient Biginellireaction catalyzed by zinc triflaterdquoChinese Journal of Chemistryvol 21 no 3 pp 327ndash331 2003

[26] A S Paraskar G K Dewkar and A Sudalai ldquoCu(OTf)2

a reusable catalyst for high-yield synthesis of 34-dihydropyrimidin-2(1H)-onesrdquo Tetrahedron Letters vol44 no 16 pp 3305ndash3308 2003

[27] L Wang C Qian H Tian and Y Ma ldquoLanthanide triflatecatalyzed one-pot synthesis of dihydropyrimidin-2(1H)-thionesby a three-component of 13-dicarbonyl compounds aldehydesand thiourea using a solvent-free Biginelli condensationrdquo Syn-thetic Communications vol 33 no 9 pp 1459ndash1468 2003

[28] Q Sun Y-Q Wang Z-M Ge T-M Cheng and R-T Li ldquoAhighly efficient solvent-free synthesis of dihydropyrimidinonescatalyzed by zinc chloriderdquo Synthesis no 7 pp 1047ndash1051 2004

[29] Y Yu D Liu C Liu and G Luo ldquoOne-pot synthesis of34-dihydropyrimidin-2(1H)-ones using chloroacetic acid ascatalystrdquo Bioorganic amp Medicinal Chemistry Letters vol 17 no12 pp 3508ndash3510 2007

[30] A Debache B Boumoud M Amimour A Belfaitah SRhouati and B Carboni ldquoPhenylboronic acid as a mild andefficient catalyst for Biginelli reactionrdquo Tetrahedron Letters vol47 no 32 pp 5697ndash5699 2006

[31] A Debache M Amimour A Belfaitah S Rhouati and B Car-boni ldquoA one-pot Biginelli synthesis of 34-dihydropyrimidin-2-(1H)-onesthiones catalyzed by triphenylphosphine as Lewisbaserdquo Tetrahedron Letters vol 49 no 42 pp 6119ndash6121 2008

[32] R J Schmidt L J Lombardo S C Traeger and D KWilliamsldquoOne-pot two step synthesis of 5-cyano-dihydropyrimidinonesusing polyphosphate esterrdquo Tetrahedron Letters vol 49 no 18pp 3009ndash3010 2008

[33] S Chitra and K Pandiarajan ldquoCalcium fluoride an efficientand reusable catalyst for the synthesis of 34-dihydropyrimidin-2(1H)-ones and their corresponding 2(1H)thione an improvedhigh yielding protocol for the Biginelli reactionrdquo TetrahedronLetters vol 50 no 19 pp 2222ndash2224 2009

[34] F Tamaddon Z Razmi and A A Jafari ldquoSynthesis of 34-dihydropyrimidin-2(1H)-ones and 14-dihydropyridines usingammonium carbonate in waterrdquo Tetrahedron Letters vol 51 no8 pp 1187ndash1189 2010

[35] A R Katritzky and S K Singh ldquoMicrowave-assisted hetero-cyclic synthesisrdquo Arkivoc vol 2003 no 13 pp 68ndash86 2003

[36] K Tanaka and F Toda ldquoSolvent-free organic synthesisrdquo Chem-ical Reviews vol 100 no 3 pp 1025ndash1074 2000

[37] A Parvez J Meshram M H Youssoufi and T B HaddaldquoTheoretical calculations and experimental verification of theantibacterial potential of some monocyclic 120573-lactams contain-ing two synergetic buried antibacterial pharmacophore sitesrdquoPhosphorus Sulfur and Silicon and the Related Elements vol 185no 7 pp 1500ndash1510 2010

[38] JMeshram A Parvez andV Tiwari ldquoToward a novel approachto bis-120573-lactam synthesis using Vilsmeier reagent as an efficiententity via Staudinger cycloaddition reactionrdquo Journal of Hetero-cyclic Chemistry vol 47 no 6 pp 1454ndash1458 2010

[39] R Pagadala A Parvez and J Meshram ldquoMicrowaveassisted synthesis and characterization of NN1015840-bis(salicylaldehydo)ethylenediimine complexes of Mn(II)Co(II) Ni(II) and Zn(II)rdquo Journal of Coordination Chemistryvol 62 no 24 pp 4009ndash4017 2009

[40] A Parvez R Pagadala and J Meshram ldquoExploring microwavesynthesis for co-ordination synthesis spectral characterizationand comparative study of transition metal complexes withbinuclear core derived from 4-amino-23-dimethyl-1-phenyl-3-pyrazolin-5-onerdquo Journal of CoordinationChemistry vol 63 no2 pp 323ndash329 2010


[41] J Meshram A Parvez and V Tiwari ldquoZeolite as an efficientand recyclable activation surface for the synthesis of bis-thiazolidinones theoretical screening owing to experimentalbiologyrdquo Green Chemistry Letters and Reviews vol 3 no 3 pp195ndash200 2010

[42] N Krause Modern Organocopper Chemistry Wiley-VCHWeinheim Germany 2002

[43] J Hassan M Sevignon C Gozzi et al ldquoAryl-aryl bond forma-tion one century after the discovery of the ullmann reactionrdquoChemical Reviews vol 102 no 5 pp 1359ndash1470 2002

[44] H Khabazzadeh K Saidi and H Sheibani ldquoMicrowave-assisted synthesis of dihydropyrimidin-2(1H)-ones usinggraphite supported lanthanum chloride as a mild and efficientcatalystrdquo Bioorganic and Medicinal Chemistry Letters vol 18no 1 pp 278ndash280 2008

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


R

R

H

O O O

O

OEt H2N NH2

HCl EtOHHeat 3hrs

EtO NHX

XNHH 3CC+ +

1 2 3 4Where X = O and S

Scheme 1 Traditional Biginelli reaction

R

R

H

O O OCuCl solvent-free

O

OEt H2N NH2

EtO NHX

XNHH 3CC+ +

1 2 3 4

60∘C MWI 240W

Where X = O and S

Scheme 2 CuCl catalysed Biginelli condensation

by different groups In order to improve the efficiency ofthe Biginelli reaction different Lewis catalysts such as ZrCl

4

[19] BiCl3[20] LiBr [21] Mn(OAc)

3sdot2H2O [22] InCl

3[23]

Cu(OTf)2[24] Zn(OTf)

2[25] FeCl

3sdotH2O [26] LiClO

4

[27] CuCl2[28] chloroacetic acid and LaCl

3as BF

3sdotOEt2

La(OTf)3 Yb(OTf)

3silica sulfuric acid H

3PW12O40 and

H3PMo12O40

[29] have been developed Some of them arereally fascinating from the synthetic chemistrsquos points ofview however some drawbacks still remain For examplesome catalysts are expensive complex or unavailable andorganic solvents are always used Furthermore many heavymetallic salts were used which resulted in the pollution ofthe environment to some extent Previous reported protocolsnormally required prolonged reaction times and high tem-perature withmoderate yields so there has been considerableinterest in exploring mild rapid and high yielding protocolat ambient temperature Recently there were some reportswhich utilized phenylboronic acid [30] triphenylphosphine[31] phosphate ester [32] calcium fluoride [33] and ammo-nium carbonate in water [34] But some of these protocolssuffered from longer reaction times and requirement ofsolvents Thus due to the immense biological importance ofdihydropyrimidinones it is essential to search for catalystswhich can provide excellent yield in a short reaction timeand can be used effectively for the preparation of a widevariety of functional dihydropyrimidinones under solvent-free conditions

In the recent years microwave heating has emerged outas a powerful technique to promote a variety of chemi-cal reactions [35] Microwave reactions under solvent-freeconditions andor in the presence of a solid support suchas clays alumina silica and graphite resulting in shorterreaction times and higher product yields than those obtainedby using conventional heating offer low cost together withsimplicity in processing and handling [36] Keeping in mindall these parameters and in continuation of our interest in het-erocyclic compounds [37 38] microwave-assisted [39 40]and solvent-free synthesis [41] we wish to report the CuCl

catalyzed synthesis of dihydropyrimidinones and thionesunder microwave conditions (Scheme 2)

2 Materials and Methods

21 General The solvents and reagents used in the syntheticwork were of analytical grade obtained from QualigensIndia and were purified by distillation or crystallizationwhere necessary and their boiling or melting points werecompared with the available literature values Melting pointswere determined in open capillaries and are uncorrected 1H-NMR spectra were recorded on a Perkin Elmer FT-NMRCryomagnet Spectrometer 400MHz (Bruker) instrumentusing tetramethylsilane (TMS) as an internal standard andDMSO-119889

6as a solvent Chemical shifts are given in parts per

million (ppm) Infrared spectra were recorded on Shimadzu-IRPrestige 21Mass spectrawere recorded on aWatersMicro-mass Q-T of Microspectrometer The microwave-assistedreactions were carried out in a ldquoCEM DISCOVERrdquo man-ufactured by CEM Technologies Corporation In this unitmicrowaves are generated by magnetron at a frequency of2450MHz having an output energy range of 100 to 500WThe reactions were monitored and the purity of productswas checked out on precoated TLC plates (Silica gel 60F254Merck) visualizing the spots under ultraviolet light andiodine chamber

22 General Procedure for the Synthesis of Dihydropyrim-idinones and Thiones In a typical solventless prepara-tion mixture of aldehyde (25mmol) ethyl acetoacetate(275mmol) urea or thiourea (375mmol) and cuprous chlo-ride (125mmol 5mol) in a reaction flask was stirred wellkept in the microwave generator and allowed to irradiatewith microwaves at MW 60∘C 240W for the required timeas mentioned in Table 1 based on reaction monitoring byTLC After completion of the reaction it was allowed to cooland the reaction was quenched with 5 NH

4OH solution


R R

R

O

O

ORO

O

O

H+

H

H2

H2N

H2N

N N

HN

NH

NH

2

X

C

X

X

NH

X

C

1 2

CuCl

Cu Cu

Cu

CuOEt

EtOEtO

H3CH3C

3

56

4

Where X = O and S

H2Ominus

H2Ominus





23 Spectral Data


6)

118 (t 119869 = 75Hz 3H CH3) 228 (s 3H CH

3) 40 (q 119869 =



14H16N2O4 C

6086 H 584 N 1014 O 2316 Found C 6089 H 586 N1019 O 2319


6) 120 (t 119869 = 73Hz 3H CH

3) 229 (s 3H CH

3) 410



6088 H 586 N 1016 S 1165














4 Conclusion




Acknowledgment


References


























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


R R

R

O

O

ORO

O

O

H+

H

H2

H2N

H2N

N N

HN

NH

NH

2

X

C

X

X

NH

X

C

1 2

CuCl

Cu Cu

Cu

CuOEt

EtOEtO

H3CH3C

3

56

4

Where X = O and S

H2Ominus

H2Ominus





23 Spectral Data


6)

118 (t 119869 = 75Hz 3H CH3) 228 (s 3H CH

3) 40 (q 119869 =



14H16N2O4 C

6086 H 584 N 1014 O 2316 Found C 6089 H 586 N1019 O 2319


6) 120 (t 119869 = 73Hz 3H CH

3) 229 (s 3H CH

3) 410



6088 H 586 N 1016 S 1165














4 Conclusion




Acknowledgment


References


























































Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of









4 Conclusion




Acknowledgment


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 benign methodology and efficient catalysis for...

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