Research Article Three Component Reaction: An Efficient...

Hindawi Publishing CorporationISRN Organic ChemistryVolume 2013 Article ID 706437 13 pageshttpdxdoiorg1011552013706437

Research ArticleThree Component Reaction An Efficient Synthesis andReactions of 34-Dihydropyrimidin-2(1H)-Ones and ThionesUsing New Natural Catalyst

A M Elmaghraby I A Mousa A A Harb and M Y Mahgoub

Department of Chemistry Faculty of Science South Valley University Qena 83523 Egypt

Correspondence should be addressed to A M Elmaghraby awatef elmaghrabyyahoocom

Received 28 May 2013 Accepted 1 July 2013

Academic Editors S Bellemin-Laponnaz D K Chand T C Dinadayalane and J Wu

Copyright copy 2013 A M Elmaghraby 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

Synthesis of 34-dihydropyrimidin-2(1H)-one and 34-dihydropyrimidin-2(1H)-thione derivatives from aldehydes 13-dicarbonylderivatives and urea or thiourea using granite and quartz as new natural and reusable catalysts Some of the 34-dihydropyrimidin-2(1H)-thione derivatives were used to prepare new heterocyclic compounds The antimicrobial activity of selected examples of thesynthesized compounds was tested and showed moderate activity

1 Introduction

Aryl-34-dihydropyrimidines derivatives have recently re-ceived great attention because of their wide range of ther-apeutic and pharmacological properties such as antiviral[1] antitumor antibacterial and antifungal [2] anti-inflam-matory [3] antihypertensive agents and neuropeptide Y(NPY) antagonists [4] Furthermore these compounds haveemerged as the integral backbones of several calcium-channelblockers [5] Also several alkaloids containing the dihydro-pyrimidine were isolated from marine sources for exampleof these are the batzelladine alkaloids which are found to bepotent HIVgp-120-CD4 inhibitors [6 7]

In general the classic Biginelli approach to 34-dihy-dropyrimidinones is based on the condensation of ethylacetoacetate aromatic aldehyde and urea under strongacidic conditions this suffers however from low yields ofproducts particularly in case of substituted aromatic andaliphatic aldehydes [8 9] This problem has led to thedevelopment of multistep synthetic strategies that producerelatively higher yields but lack the simplicity of the orig-inal one-pot-Biginelli protocol Thus the Biginelli reactionhas received renewed interest from researchers interestedin discovering milder and more efficient procedures thatare applicable to a wide range of substituents in all three

components and proceed in better yields So the one-pot-Biginelli protocol for 34-dihydropyrimidines synthesis wasexplored by varying all components and catalysts [10ndash18]in protic aprotic solvents and solvent free conditions [19]using either classical heating microwave [20 21] ultrasound[22 23] and visible light (100W Lamp THF) irradiations[24] Also several improved procedures have been reportedrecently using not only acidic media such as Lewis acidsprotic acids and ionic liquids as promoters [25 26] butalso nonacidic substances such as bakerrsquos yeast [27] graphite[28] and iodine [29 30] Heterogeneous solid acids areused also however these are advantageous over conventionalhomogeneous acid catalysts as they can be easily recoveredfrom the reaction mixture by simple filtration and canbe reused after activation or without activation therebymaking the process economically viable [31] Bakibaev andFilimonov [32] reported that piperidine as a base catalystcan promote the Biginelli protocol also to afford the corre-sponding 34-dihydropyrimidines along with Hantzsch 14-dihydropyridines which may form in spite of urea decompo-sition in the reaction media releasing ammonia We wouldlike to propose a new naturally and very cheap catalysts gran-ite and quartz for the synthesis of 34-dihydropyrimidinonesand 34-dihydropyrimidenthiones using one-pot-Biginelliprotocol in refluxing ethanol

2 ISRN Organic Chemistry

Table 1 34-Dihydropyrimidin-2(1H)ones (I)

Entry R1 R2Time (h) MP [Reference] Yielda

Quartz Granite Found Reported Quartz GraniteIa C6H5 OEt 3 35 201-202 200ndash202 [33] 68 64Ib 2-(OH)-C6H4 OEt 35 5 202ndash204 200ndash202 [34] 62 60Ic 4-(OCH3)-C6H4 OEt 3 3 199-200 201-202 [35] 64 60Id Ph-CH=CH OEt 3 4 232ndash234 232ndash235 [36] 58 55Ie 25-(OCH3)-C6H3 OEt 4 5 210ndash212 212ndash214 [37] 61 58If 345-(OCH3)-C6H2 OEt 3 45 180-181 180ndash182 [25] 60 56Ig 2-furyl OEt 3 4 205-206 203ndash205 [38] 66 61Ih 2-(Cl)-C6H4 OEt 3 4 214-215 215-216 [39] 65 62Ii 4-(OCH3)-C6H4 CH3 3 4 165ndash167 166ndash168 [40] 69 65Ij 4-N(CH3)2-C6H4 OEt 3 4 233ndash235 230ndash232 [25] 62 58Ik 4-(CH3)-C6H4 OEt 2 3 210ndash212 214-215 [35] 65 62Il 26-(Cl)-C6H3 OEt 4 45 302-303 305 [41] 57 61Im 2-thienyl OEt 2 3 214ndash216 215ndash217 [42] 66 63In 4-(F)-C6H4 OEt 2 3 175ndash177 175ndash177 [43] 71 68Io 3-(OCH2Ph)-C6H4 OEt 3 35 178ndash180 New 65 62Ip 3-(OCH2Ph)-C6H4 CH3 35 4 192ndash194 New 40 63Iq 23-(OCH3)-C6H3 OEt 3 4 178ndash180 New 63 60aIsolated yield

H3CH3C

R2

O O++ H2N NH2

O

EtOH reflux

NH

NH

R1O

O

R2Granite or quartzR1minusCHO

Iandashq

Scheme 1

2 Result and Discussion

It is interesting to report that the one pot reaction of amixtureof benzaldehyde ethyl acetoacetate and urea in the presenceof granite or quartz as a catalyst in refluxing ethanol resultedin the formation of 4-phenyl-34-dihydropyrimidinone IaTable 1 in 64 or 68 yield according to the catalyst(Scheme 1) In a similar way urea was condensed smoothlywith variety of aromatic or heterocyclic aldehydes and varietyof 13-dicarbonyl compounds in the presence of granite orquartz in refluxing ethanol as one pot reaction to afford thecorresponding 34-dihydropyrimidines Ibndashq (Table 1) whosecomposition and structures were confirmed by elementalanalysis Mass IR and 1H NMR spectra of the isolatedproducts (cf experimental section)

On the other hand carrying out of the above reac-tion using of 3-benzyloxybenzaldehyde acetyl acetone andurea in refluxing ethanol using granite as catalyst the cor-responding 5-acetyl-4-(3-(benzyloxy)phenyl)-6-methyl-34-dihydropyrimidin-2(1H)-one Io was isolated However oncarrying the above reaction using quartz as a catalyst besidethe proposed 34-dihydropyrimidinone Io another productwith molecular formula (C

16H16N4O2) 119898119911 = 296 was

isolated from the reaction media in 25 yield This product

can be identified as 4-amino-6-(3-(benzyloxy)phenyl)-56-dihydro-135-triazin-2(1H)-one III based on the analyticaland the spectral data of the isolated product which revealedthe presence of characteristic stretching vibrations due toNH NH

2 and amidic CO at ] = 3450 3300 and 1640 cmminus1

regions respectively in the IR spectrum Also the 1H-NMRspectrum of the isolated product shows signals at 120575 = 507(s 2H ndashCH

2ndash) 543 (s 1H ndashCHndash) 568 (s 2H ndashNH

2)

670ndash746 (m 9H Ar) and 100 (s 1H NH) ppm The 13C-NMR spectrum of the isolated product shows signals at120575 = 512 (CH aliphatic) 6232 (CH

2aliphatic) 1653 (C

triazine ring) 1904 (C=O amidic) and 111ndash160 (Benzenerings) This expectation is based on the observation that the3-benzyloxybenzaldehyde condensed with two moles of ureato give the corresponding bis-ureide II as key intermediatewhich cyclized via elimination of H

2O to give the extremely

low yield triazine derivative III [44] (Scheme 2)In generality of this process various 13-diketones and

aldehydes were reacted with thiourea in refluxing ethanolusing granite or quartz as the reaction catalyst to give the cor-responding 34-dihydropyrimidin-2(1H)-thione derivativesIV (Table 2) which their structures were confirmed on thebases of the analytical and spectral data of the isolatedproducts (cf experimental section) (Scheme 3)

ISRN Organic Chemistry 3

CHO

O Ph

H2N NH2

O

QuartizEtOHReflux

Me

O O

Me

+

NH

NHMe

O O

Me

O

Ph

H2N

NH

NH

O

O

PhH2N

O

Me

O

OMe NH

HNO

NH

Me

Me

O

O

Ph O

H2NH2N

NH

NH

O

OPh

H2N

O

HN NH

NH

HO

O Ph

HN

N

NH

O

O

Ph

H2N

minusH2O

minusNH2CONH2

II

IIIH2

N

O

Io

Scheme 2

+ R2 R3

O O+ H2N NH2

S

EtOH refluxNH

NH

R1

R2 S

O

R3Granite or quartz

IVandashh

R1minusCHO

Scheme 3

On reading of the experimental results we noted thataromatic aldehydes carrying either electron-donating orelectron-withdrawing substituents reacted well under thereaction conditions to give the corresponding products inmoderate to good yields high purity in case of granite orquartz However the obtained yields on using quartz arehigher than granite either in case of urea or thiourea Thismay be due to the high percentage of SiO

2in quartz This

procedure not only preserves the simplicity of the Biginellireaction but also produces good yields of the productswith high purity Also the catalyst was recovered by simplefiltration and reused in subsequent reactions with consistentactivity

We can use the prepared 34-dihydropyrimidenthionesIVandashc to synthesize newly derivativesThus heating of IVandashcwith methyl iodide in dry acetone in the presence of anhy-drous potassium carbonate afforded the SndashCH

3derivatives

Vandashc which was confirmed by using elemental analysis andspectral data The 1HNMR illustrated the presence of singletSndashCH

3protons

On the other hand heating of IVandashc in acetic anhydrideafforded the corresponding 3-N-acetyl derivatives VIandashcStructureVIcwas deduced from elemental and spectral dataThe mass spectrum showed the molecular ion peak at 119898119911() = 378 (M+ 4803) for molecular formula C

18H22N2O5S

The 1H NMR illustrated the presence singlet NndashCOCH3

protons at 120575 = 260 ppm in addition to other singlet peaksat 120575 = 227 367 and 377 ppm for methyl and two methoxygroups respectively and the absence of the NH proton at120575 = 727

In the same time we can use the same conditions toprepare VIab which was elucidated by correct elementalanalysis and spectral data (cf experimental data) AlsoVIandashcwas synthesized by the reaction of IVandashcwith acetyl chloridein DMF (melting and mixed melting point) (Scheme 4)

In the same time the pyrimidine derivatives VIIabcan be synthesized via acetylation of the corresponding SndashCH3derivatives Vab using acetic anhydride Also it can be

prepared via methylation of the N-acetyl derivatives VIabStructures VIIab were elucidated by elemental analysis and


NH

NH

R

R1OC

S N

N

N

N

HNR

R1OC

S N

N

NH

RR

R

R1OC R1OC

R1OC

SCH3SCH3

SCH3

CH3

CH3

CH3

OO

CH3I dry acetone CH3I dry acetone

CH3I dry acetone

K2CO3 anhydrousK2CO3 anhydrous

K2CO3 anhydrousCH3COCl

AC2OReflux

AC2OReflux

DMF

R2 R2

R2

R2R2

IV R(a) = Ph R1 = OEt R2 = H

(b) R = R1 = CH3 R2 = 4-OCH3

(c) R = CH3 R1 = OEt R2 =

Vandashc

VIandashc

VIIIa

23-OCH3

VIIab

Scheme 4

Table 2 34-Dihydropyrimidin-2(1H)-thiones (IV)

Entry R1 R2 R3Time (h) MP [Reference] Yielda

Quartz Granite Found Reported Quartz GraniteIVa C6H5 OEt Ph 3 3 183-184 183ndash185 [45] 63 60IVb 4-(OCH3)-C6H4 CH3 CH3 35 4 181-182 183-184 [46] 67 65IVc 23-(OCH3)-C6H3 OEt CH3 35 4 181ndash183 New 64 63IVd 4-(OCH3)-C6H4 OEt CH3 3 4 152-153 150ndash152 [43] 59 56IVe 2-(OH)-C6H4 OEt CH3 3 4 210-211 206ndash208 [47] 63 59IVf 26-(Cl)-C6H3 OEt CH3 4 5 222ndash224 New 55 60IVg 3-(OCH2Ph)-C6H4 OEt CH3 3 4 180ndash182 New 66 60IVh 25-(OCH3)-C6H3 OEt CH3 45 5 188ndash190 New 64 60aIsolated yield

spectral data The mass spectrum for VIIa showed themolecular ion peak atmz () = 394 (M+ 1251) while VIIbillustrated the molecular ion peak at 119898119911 () = 332 (M+4322) The 1H NMR revealed the presence of singlet peakat 120575 = 250 ppm for COCH

3protons and the absence of

the singlet peak at 120575 = 727 ppm for NH proton Also IRspectrum showed the absence of NH peak (Scheme 4)

Methylation of Va was carried out in methyl iodide inDMF in the presence of K

2CO3anhydrous that yieldedVIIIa

which was confirmed by correct elemental analysis as wellas spectral data The 1H NMR showed the absence of singletpeak at 120575 = 727 ppm for NH proton and the appearance of asinglet peak at 120575 = 333 ppm for NndashCH

3protons (Scheme 4)

Heating of IVa with ethylchloroacetate in ethanol andsodium acetate afforded ethyl 3-oxo-57-diphenyl-3588a-tetrahydro-2H-thiazolo[32-a]pyrimidine-6-carboxylate Xaover the unisolated intermediate ethyl 2-(2-ethoxy-2-ox-oethylthio)-46-diphenyl-16 dihydropyrimidine-5-carboxy-late IXa as shown in elemental analysis as well as spec-tral data The mass spectrum showed the molecular ionpeak at mz () = 378 (M+ 6003) for molecular formulaC21H18N2O3S The 1H NMR revealed also the presence of

one only ethyl ester group at 120575 = 085 for CH3protons (t)

and 385 for CH2(q) and also the absence of NH proton at

120575 = 727 ppm The IR spectrum showed absorption bands at1752 1675 and 1589 cmminus1 for carbonyl ester amidic carbonyl


HN

N N

N

N

NR

R R

R

R

R1OCR1OC R1OC

SS S

S

NHNH

R2

R2 R2

XO

O

O

OH X = Cl or Br

ACONa anhy

ClCH2COOEtEtOHACONa3H2O

BenzeneTEAOX

YX = Y = Cl or Br

IV R(a) = Ph R1 = OEt R2 = H(b) R = R1 = CH3 R2 = 4-OCH3

CO2Et

XI R(a) = 4-Cl

(b) R =

(c) R = 4-NO2

CHO

EtO2C

IXabXab

23-(OCH3)

Scheme 5

groups and C=N respectively Also the isolated productXa was obtained via the reaction of IVa with chloroacetylchloride or bromoacetyl bromide in benzene and dropsof triethylamine as catalyst In the same time compoundXa can be isolated from the reaction of IVa with chloro-or bromoacetic acid in acetic acid and acetic anhydridemixture in presence of anhydrous sodium acetate Similarlycompound Xb was prepared from the reaction of IVbwith ethylchloroacetate chloroacetic acid or chloroacetyl-chloride as shown in previous conditions (Scheme 5)

Compound Xa was condensed with different aromaticaldehydes in refluxing ethanolic pipredine solution to give thecorresponding arylidene derivativesXIandashc StructuresXIandashcwere deduced from its elemental analysis and spectral dataThe 1H NMR showed the absence of singlet peak for CH

2

protons at 120575 = 388 ppm and the appearance of singlet peakfor =CH proton at 120575 = 774 ppm (Scheme 5)

Aiming to the synthesizing of thiazolopyrimidine XIIwe refluxed IVb with chloroacetone in ethanolic piperidinesolution However the corresponding 1-(5-acetyl-6-(4-me-thoxyphenyl)-4-methyl-16-dihydropyrimidin-2-ylthio)pro-pan-2-one XIII was formed which was identified byelemental analysis as well as spectral data The massspectrum showed the molecular ion peak at 119898119911 () = 332(M+ 530) for molecular formula C

17H20N2O3S The 1H

NMR confirmed the presence of only one NH proton at120575 = 711 ppm and singlet peak at 120575 = 246 ppm due to CH

2

protons (Scheme 6)On the other hand compound Vab was reacted with

thiosemicarbazide in refluxing ethanol to give the corre-sponding carbazide XIVab instead of the corresponding

fused pyrimidinotriazoles XV and XVI Structures XIVabwere established by elemental analysis and spectral datawhere the mass spectrum showed the molecular ion peak at119898119911 () = 395 (M+ 2413) forXIVa and atmz () = 333 (M+1218) for XIVb (Scheme 7)

On the other hand refluxing of IVab in methyl alcoholin the presence of acetic acid and water (4 1 1) afforded34-dihydropyrimidinone derivatives XVIIab CompoundXVIIa was confirmed by compare mp (Found) = 160∘Cmp (Reported) = 158∘C [48] Also compound XVIIb wasestablished by compare mp (Found) = 164ndash166∘C mp(Reported) = 166-167∘C [48] (Scheme 8)

3 Antimicrobial Activity

There are 5 compounds (III IVg IVf IVh and IVc) that weretested and showed promising positive antibacterial activity

All the compounds showed activity against bacteria suchas Staphylococcus aureus and Escherichia coliThe IVh amp IVccompounds showed positive antibacterial against S aureuswhich are 145mm and 14mm respectively which are 025and 075mm less than the zone around Streptomphenicoldisc This may be due the presence of sulfur atomandpyrimidine ring

The other three most active compounds tested are com-pounds IVg IVf and III The activity of these compoundsagainst Staphylococcus aureus showed positive reactions1275 125 and 12mm of inhibition zones respectively com-pared to the inhibition zone of antibiotic used as indicated in


ClCH2COCH3

EtOHPip

SCH2COCH3

IV (b) R = R1 = CH3 R2 = 4-OCH3

HN

N

N

N

R

R

R

R1OC

R1OC

R1OC

S

S

NH

NH

R2

R2

R2 XII

XIII

CH3

Scheme 6

N

NN

NN

N N

N

N

R

RR

R

R1OC

R1OCR1OC

R1OC

NH

NH

NH

R2

R2

R2

R2

V R(a) = Ph R1 = OEt R2 = H(b) R = R1 = CH3 R2 = 4-OCH3

SCH3

NH2NHCSNH2

EtOH reflux

XV XVI

Or

XIVabNHNHCSNH2

HH

2N

N2H

Scheme 7

NH

NH

R S NH

NH

R O

MeOHACOHH2O reflux

XVIIab

R1OCR1OC

R2R2


Scheme 8


Table 3 Inhibition zone resulted from the effect of the antibiotic (Streptophenicol) and tested compounds on Escherichia coli andStaphylococcus aureus

Compounds no(1 times 10minus2)

Escherichia coli Staphylococcus aureusZone of inhibition

Antibiotic (Streptophenicol) 25 1475

HN

N

NH

O

O Ph

III

H2N

12 12

NH

NHEtO2C

H3C S

O Ph

IVg 11 1275

NH

NHEtO2C

H3C S

ClCl

IVf 11 125

NH

NHEtO2C

H3C S

OCH3

H3CO

IVh 12 145

NH

NHEtO2C

H3C S

OCH3

OCH3

IVc 105 14

(Table 3) this may be due to sulfur atom two chlorine atomsand triazine ring respectively

All the compounds have approximately the same effectagainst Escherichia coli bacteria as indicated by the zone ofinhibition (Table 3) In case of using these compounds asantimicrobial cytotoxicity effect of these compoundsmust beexamined

4 Conclusion

In summary we have found that quartz and granite areextremely useful and highly efficient new natural solids forthe synthesis of biologically potent aryl 34-dihydropyrim-idines by means of three-component condensations of an

aldehyde 13-dicarbonyl compound and urea or thioureain a one-pot operation This method is applicable to awide range of substrates including aromatic and heterocyclicaldehydes and provides a variety of biologically relevant 34-dihydropyrimidinones and 34-dihydropyrimidinthiones inhigh yields after short reaction times

5 Experimental Section

51 General All melting points were measured with a Gal-lenkamp apparatus The IR spectra of samples were recordedin KBr via a Shimadzu FT-IR 8101 PC infrared spectropho-tometer 1HNMR spectra were run at 300MHz and recordedin CDCl

3[D6] DMSO using TMS as the internal standard


Chemical shifts were related to that of the solvent Massspectra weremeasured on a GCMS-QP1000 EX spectrometerat 70 eV TLC was conducted on 025mm precoated silica gelplates (60F-254) Elemental analyses were carried out at theMicroanalytical Center of Cairo University Giza Egypt Thecatalyst is ground until it became fine powder

511 General Procedure for the Synthesis of the Newly 34-Dihydropyrimidinones (Iopq) and 34-Dihydropyrimidin-thiones (IVchgf) A mixture of aldehyde (1mmol) 13-dicarbonyl compounds (1mmol) urea or thiourea (1mmol)and granite or quartz (05 g) in ethanol (15mL) was heatedunder reflux for the required time After completion of thereaction as monitored by TLC the reaction mixture wasfiltered to separate the catalyst Keep the reaction mixtureovernight The solid product was filtered under suction thenrecrystallized from ethanol to afford pure product

Ethyl-4-(3-(benzyloxy)phenyl)-6-methyl-2-oxo-1234-tetra-hydropyrimidine-5-carboxylate (Io) mp = 178ndash180∘C IR(KBr) ] = 3300 3100 2950 1700 1630 cmminus1 1H NMR(300MHz CDCl

3) 120575 = 116 (t 119869 = 72Hz 3H ndashOndashCH

2ndash

CH3) 233 (s 3H CH

3) 408 (q 2H ndashOndashCH

2ndashCH3) 503

(s 2H ndashOndashCH2ndashPh) 537 (s 1H ndashCHndash) 592 (s 1H ndashNH)

685ndash694 (m 4H Ar) 719ndash739 (m 5H Ar) 831 (s 1HndashNH) ppm Mass mz () 366 (M+ 631) 275 (2272)183 (2494) 91 (1000) C

21H22N2O4(366) calculated C

6884 H 605 N 765 O 1747 found C 6882 H 610 N755 O 1746 Yield quartz (65) granite (62)

5-Acetyl-4-(3-(benzyloxy)phenyl)-6-methyl-34-dihydropy-rimidin-2(1H)-one (Ip) mp= 192ndash194∘C IR (KBr) ] = 34503200 2950 1640 1590 cmminus1 1H NMR (300MHz DMSO)120575 = 208 (s 3H CH

3) 227 (s 3H ndashCOCH

3) 505 (s 2H

ndashOndashCH2ndashPh) 520 (s 1H ndashCHndash) 681ndash692 (m 4H Ar)

721ndash745 (m 5H Ar) 781 (s 1H ndashNH) 917 (s 1H ndashNH)ppm Mass 119898119911 () 336 (M+ 16) 293 (19) 245 (33) 153(146) 91 (1000) C

20H20N2O3(336) calculated C 7141

H 599 N 833 O 1427 found C 7140 H 60 N 830 O1421 Yield quartz (40) granite (63)

Ethyl-4-(23-dimethoxyphenyl)-6-methyl-2-oxo-1234-tetra-hydropyrimidine-5-carboxylate (Iq) mp = 178ndash180∘C IR(KBr) ] = 3250 3100 2950 1700 1640 cmminus1 1H NMR(300MHz CDCl


2ndash

CH3) 240 (s 3H CH

3) 387 (s 3H ndashOCH

3) 392 (s 3H

ndashOCH3) 406 (q 2H ndashOndashCH

2ndashCH3) 571 (s 1H ndashCHndash)

572 (s 1H ndashNH) 673 (d 1H Ar) 687 (d 1H Ar) 698 (t1H Ar) 727 (s 1H ndashNH) ppm Mass mz () 320 (M+137) 288 (1000) 243 (552) 183 (949) 155 (689) 137 (601)77 (473) C

16H20N2O5(320) calculated C 5999 H 629

N 874 O 2497 found C 5995 H 622 N 870 O 2499Yield quartz (63) granite (60)

Ethyl-4-(3-(benzyloxy)phenyl)-6-methyl-2-thioxo-1234-tet-rahydropyrimidine-5-carboxylate (IVg) mp = 180ndash182∘C IR(KBr) ] = 3400 3150 2950 1650 cmminus1 1H NMR (300MHzDMSO) 120575 = 110 (t 119869 = 72Hz 3H ndashOndashCH

2ndashCH3)

227 (s 3H CH3) 401 (q 2H ndashOndashCH

2ndashCH3) 505 (s

2H ndashOndashCH2ndashPh) 515 (s 1H ndashCHndash) 680 (m 4H Ar)

723ndash742 (m 5H Ar) 960 (s 1H ndashNH) 1030 (s 1H ndashNH)ppm Mass mz () 382 (M+ 176) 199 (122) 91 (1000)C21H22N2O3S (382) calculated C 6595 H 580 N 732

O 1255 S 838 found C 6589 H 560 N 735 O 1746 S836 Yield quartz (66) granite (60)

Ethyl-4-(23-dimethoxyphenyl)-6-methyl-2-thioxo-1234-tet-rahydropyrimidine-5-carboxylate (IVc) mp = 181ndash183∘C IR(KBr) ] = 3200 3100 2950 1705 cmminus1 1H NMR (300MHzCDCl


2ndashCH3) 242 (s

3H CH3) 386 (s 3H ndashOCH


3) 405

(q 2H ndashOndashCH2ndashCH3) 571 (s 1H ndashCHndash) 668 (d 1H Ar)

688 (d 1H Ar) 699 (t 1H Ar) 726 (s 1H ndashNH) 810 (s1H ndashNH) ppm Mass 119898119911 () 336 (M+ 764) 305 (861)289 (815) 263 (1000) 199 (877) 171 (633) 153 (315) 77(446) C

16H20N2O4S (336) calculated C 5712 H 599

N 833 O 1902 S 953 found C 5713 H 596 N 835 O1906 S 951 Yield quartz (64) granite (63)

Ethyl-4-(25-dimethoxyphenyl)-6-methyl-2-thioxo-1234-tet-rahydropyrimidine-5-carboxylate (IVh) mp = 188ndash190∘C IR(KBr) ] = 3200 3100 2940 1700 cmminus1 1H NMR (300MHzDMSO) 120575 = 105 (t 119869 = 82Hz 3H ndashOndashCH

2ndashCH3) 227 (s



3) 396

(q 2H ndashOndashCH2ndashCH3) 544 (s 1H ndashCHndash) 657 (s 1H Ar)

683 (d 1H Ar) 694 (d 1H Ar) 924 (s 1H ndashNH) 1024 (s1H ndashNH) ppm Mass mz () 338 (M+ 1097) 279 (1049)256 (1923) 166 (4538) 149 (1000) 105 (2813) 69 (9057)C16H20N2O4S (336) calculated C 5712 H 599 N 833


Ethyl-4-(26-dichlorophenyl)-6-methyl-2-thioxo-1234-tetra-hydropyrimidine-5-carboxylate (IVf) mp = 222ndash224∘C IR(KBr) ] = 3150 3000 2900 1750 1640 cmminus1 1H NMR(300MHz CDCl


2ndash

CH3) 223 (s 3H CH


2ndashCH3) 628

(s 1H ndashCHndash) 705ndash723 (m 3H Ar) 794 (s 1H ndashNH)832 (s 1H ndashNH) ppm Mass mz () 344 (M+ 239)348 (M+4 76) 315 (345) 199 (1000) 171 (364) 153 (162)C14H14Cl2N2O2S (344) calculated C 4870 H 409 Cl

2054 N 811 O 927 S 929 found C 4872 H 404 Cl2050 N 813 O 929 S 930 Yield quartz (55) granite(60)

4-Amino-6-(3-(benzyloxy)phenyl)-56-dihydro-135-triazin-2(1H)-one (III) mp = 172ndash174∘C IR (KBr) ] = 3450 33001640 cmminus1 1H NMR (300MHz DMSO) 120575 = 507 (s 2HndashCH2ndash) 543 (s 1H ndashCHndash) 568 (s 2H ndashNH

2) 670ndash692

(m 4H Ar) 698 (s 1H NH) 723ndash746 (m 5H Ar) 100 (s1H NH) ppm The 13C-NMR (300MHz DMSO) 120575 = 512(CH aliphatic) 6232 (CH

2aliphatic) 1653 (C triazine ring)

1904 (C=O amidic) 111ndash160 (benzene rings) Mass mz() 296 (M+ 5458) 294 (8276) 253 (5720) 227 (6330)203 (1000) 182 (3101) 171 (5577) 131 (9909) 104 (2973)C16H16N4O2(296) calculated C 6485 H 544 N 1891

O 1080 found C 6482 H 540 N 1893 O 1082 Yieldquartz (25)


512 General Procedure of Methylation of Compounds IVandashc A mixture of IVandashc (0005mol) and methyl iodide(0005mol) was dissolved in dry acetone in the presence ofpot Carbonate anhydrous was refluxed in water bath for 5hours The reaction mixture was filtered on hot then kept forovernight The formed solid was filtered off and crystallizedfrom an appropriate solvent to give Vabc

Ethyl-2-(methylthio)-46-diphenyl-16-dihydropyrimidine-5-carboxylate (Va) The formed solid was crystallized frompetroleum etherbenzene 2 1 mp = 158ndash160∘C IR (KBr)] = 3280 2982 2807 1676 1614 1493 cmminus1 1H NMR(300MHz CDCl


2ndash

CH3) 249 (s 3H ndashSCH


2ndashCH3) 574

(s 1H ndashCHndash) 727 (s 1H NH) 728ndash748 (m 10H Ar) ppmmass 119898119911 () 352 (M+ 2335) 337 (3358) 323 (6832)275 (1000) 77 (2552) C

20H20N2O2S (352) calculated

C 6816 H 572 N 795 O 908 S 910 Found C 6813 H575 N 797 O 910 S 912 yield (77)

1-(6-(4-Methoxyphenyl)-4-methyl-2-(methylthio)-16-dihy-dropyrimidin-5-yl)ethanone (Vb) The formed solid wascrystallized from petroleum etherethanol 1 1 mp = 126ndash128∘C IR (KBr) ] = 3285 2950 2928 1639 1594 cmminus1 1HNMR (300MHz DMSO) 120575 = 209 (s 3H ndashCH

3) 223 (s

3H ndashSCH3) 228 (s 3H ndashCOCH


3)

554 (s 1H ndashCHndash) 682ndash715 (d d 4H Ar) 957 (s 1H ndashNH)ppm mass119898119911 () 288 (M+ 2940) 250 (2210) 183 (1910)73 (6760) 57 (1000) C

15H18N2O2S (290) calculated C

6204 H 625 N 965 O 1102 S 1104 found C 6203 H626 N 965 O 1104 S 1103 yield (86)

Ethyl-6-(23-dimethoxyphenyl)-4-methyl-2-(methylthio)-16-dihydropyrimidine-5-carboxylate (Vc) The solid product wascrystallized from petroleum ether (60ndash80) mp = 140∘CIR (KBr) ] = 3321 2935 2832 1706 1669 1594 cmminus1 1HNMR (300MHz DMSO) 120575 = 113 (t 119869 = 75Hz 3HCH3CH2Ondash) 239 (s 3H ndashCH

3) 245 (s 3H ndashSCH

3)

387 (s 3H ndashOCH3) 393 (s 3H ndashOCH

3) 406 (q 2H

CH3CH2Ondash) 585 (s 1H ndashCH) 677ndash702 (m 3H Ar)

727 (s 1H ndashNH) ppm mass mz () 350 (M+ 2056)335 (3697) 321 (6429) 303 (4044) 213 (1000) 77 (2314)C17H22N2O4S (350) calculated C 5827 H 633 N 799 O

1826 S 915 found C 5826 H 633 N 797 O 1827 S 916yield (74)

513 Acylation of Compounds IVandashc

Method (A) A mixture of IVandashc (0005mol) and acetylchloride (001mol) was refluxed in DMF (15mL) as a solventcontaining (5 drops) of triethylamine (TEA) for 1 hour andthen stirred at room temperature for overnight and thenthe solution was poured into ice with vigorous stirring andthen the solid product was filtered off and recrystallized fromsuitable solvent to afford compounds VIabc

Method (B) A solution of IVandashc (001mol) in 15mL ofacetic anhydride was heated under reflux for 130 hour The

solution was then poured into 150mL of ice-water and stirredfor several hours until crystallization was complete Theprecipitate was filtered and crystallized from suitable solventto afford compounds VIabc

Ethyl 3-acetyl-4-(23-dimethoxyphenyl)-6-methyl-2-thioxo-1234-tetrahydropyrimidine-5-carboxylate (VIc) The solidproduct was recrystallized from ethanol method (A) yield(81) method (B) yield (78) mp = 186∘C IR (KBr)] = 3237 2996 2944 2837 1702 1671 cmminus1 1H NMR(300MHz DMSO) 120575 = 117 (t 119869 = 66Hz 3H CH

3CH2Ondash

) 227 (s 3H ndashCH3) 260 (s 3H ndashCOCH

3) 367 (s 3H

ndashOCH3) 377 (s 3H ndashOCH

3) 408 (q 2H CH

3CH2Ondash)

550 (s 1H ndashCH) 668ndash70 (m 3H Ar) 116 (s 1H ndashNH)ppm mass 119898119911 () 378 (M+ 4803) 335 (9681) 289(1000) 263 (4557) 199 (3362) 77 (2244) C

18H22N2O5S

(378) calculated C 5713 H 586 N 740 O 2114 S 847found C 5714 H 585 N 741 O 2113 S 845

Ethyl 3-acetyl-46-diphenyl-2-thioxo-1234-tetrahydropyrim-idine-5-carboxylate (VIa) The solid product was recrystal-lized from benzene method (A) yield (80) method (B)yield (85) mp = 136∘C IR (KBr) ] = 3215 2986 16421599 1494 cmminus1 mass119898119911 () 380 (M+ 3739) 337 (1000)307 (257) 265 (5772) 104 (6503) C

21H20N2O3S (380)

calculated C 6629 H 530 N 736 O 1262 S 843 found C 6628 H 531 N 735 O 1263 S 842

111015840 -(6-(4-Methoxyphenyl)-4-methyl-2-thioxo-23-dihydropy-rimidine-15(6H)-diyl)diethanone (VIb) The solid productwas recrystallized from ethanol method (A) yield (65)method (B) yield (70) mp = 130∘C IR (KBr) ] = 32432962 1698 1609 1509 cmminus1

514 Synthesis of Compounds (VIIab) A solution of Vab(001mol) in 15mL of acetic anhydride was heated underreflux for one hourThe solutionwas then poured into 150mLof ice-water and stirred for several hours until crystallizationwas completeTheprecipitatewas filtered off andwashedwithwater then crystallized from an appropriate solvent to affordVIIab

Ethyl 1-acetyl-2-(methylthio)-46-diphenyl-16-dihydropyrim-idine-5-carboxylate (VIIa) The solid product crystallizedfrom petroleum ether (60ndash80) yield (90) mp = 102∘C IR(KBr) ] = 2978 1697 1601 1533 cmminus1 1H NMR (300MHzCDCl

3) 097 (t 119869 = 66Hz 3H CH

3CH2Ondash) 250 (s 3H

ndashSCH3) 250 (s 3H ndashCOCH

3) 402 (q 2H CH

3CH2Ondash)

666 (s 1H ndashCH) 727ndash760 (m 10H Ar) ppm mass 119898119911() 394 (M+ 1251) 351 (1000) 337 (1086) 323 (2806)275 (8424) 129 (1840) 77 (2931) C

22H22N2O3S (394)


111015840 -(6-(4-Methoxyphenyl)-4-methyl-2-(methylthio)pyrimi-dine-15(6H)-diyl)diethanone (VIIb) The precipitated prod-uct was crystallized from benzene yield (86) mp =180∘C IR (KBr) ] = 2990 1675 1568 cmminus1 mass 119898119911


() 332 (M+ 4322) 312 (3956) 278 (5128) 100 (1000) 67(5055) C


N 843 O 1444 S 965 found C 6143 H 604 N 846 O1445 S 966

Synthesis of Ethyl 1-Methyl-2-(methylthio)-46-diphenyl-16-dihydro-pyrimidine-5-carboxylate (VIIIa) A mixture of Va(0005mol) and methyl iodide (0005mol) was dissolvedin DMF in the presence of pot Carbonate anhydrous wasrefluxed in water bath for 4 hours The reaction mixture wasfiltered on hot then the filtrate was cooled and poured ontocold water with stirring the formed solid was filtered offand crystallized from ethanol benzene (3 1) mp = 92∘CIR (KBr) ] = 3058 2977 2932 1717 1580 cmminus1 1H NMR(300MHz CDCl


2ndash


3) 333 (s 3H ndashNCH

3) 401 (q 2H

ndashOndashCH2ndashCH3) 574 (s 1H ndashCHndash) 749ndash764 (m 10H Ar)

ppm mass119898119911 () 366 (M+ 521) 350 (1000) 321 (2848)129 (3096) 77 (1587) C


6882 H 605 N 764 O 873 S 875 found C 6881 H 604N 765 O 873 S 875 yield (25)

515 General Procedure for the Preparationof Compounds (Xab)

Method (A) A mixture of IVab (1mmol) and chloroaceticacid (1mmol) was dissolved in 40mL of a mixture of(AC)2OACOH (1 3) in the presence of 3 gm anhydrous

sodium acetate that was refluxed for 4 hours The reactionmixture was cold and poured onto cold water with stirringthe solid formation was filtered off and crystallized frombenzeneethanol (3 1) to give Xab

Method (B) A mixture of IVab (0005mol) and chloroacetylchloride with 2 drops of TEA was refluxed in benzene for3 hours Then the reaction mixture was filtered off throughheating then dried and crystallized from benzeneethanol(3 1) to give Xab

Method (C) A mixture of IVab (0005mol) ethylchloroacetate (0005mol) and sodium acetate trihydrate (1 gm)was refluxed in ethanol for 5 hours The reaction mixturewas filtered and kept for overnight The solid formation wasfiltered off then dried and crystallized from benzeneethanol31 to afforded Xab

Ethyl 3-oxo-57-diphenyl-3588a-tetrahydro-2H-thiazolo[32-a]pyrimidine-6-carboxylate (Xa) The formed solid wascrystallized from benzeneethanol (3 1) method (A) yield(72) method (B) yield (75) method (C) yield (84)mp = 136ndash8∘C IR (KBr) ] = 2976 2931 2900 1752 16751589 cmminus1 1H NMR (300MHz CDCl

3) 120575 = 085 (t 119869 =

69Hz 3H ndashOndashCH2ndashCH3) 385 (q 2H ndashOndashCH

2ndashCH3) 388

(s 2H ndashCH2COndash) 619 (s 1H ndashCHndash) 727ndash751 (m 10H

Ar) ppm mass 119898119911 () 378 (M+ 6003) 350 (1630) 301(1000) 273 (3562) 129 (2511) 77 (3557) C

21H18N2O3S


6-Acetyl-5-(4-methoxyphenyl)-7-methyl-88a-dihydro-2H-thiazolo[32-a]pyrimidin-3(5H)-one (Xb) The formed solidwas crystallized from benzene and drops of ethanol method(A) yield (42) method (B) yield (34) method (C) yield(40) mp = 160ndash162∘C IR (KBr) ] = 2983 2936 28761756 1655 1612 cmminus1 1H NMR (300MHz DMSO) 120575 = 216(s 3H CH


3) 370 (s 3H OCH

3)

415 (s 2H ndashCH2COndash) 598 (s 1H ndashCHndash) 686ndash721 (d d

4H Ar) ppm mass 119898119911 () 316 (M+ 3508) 301 (532)273 (1000) 245 (2808) 230 (472) 181 (1936) 115 (2514) 77(260) C

16H18N2O3S (316) calculated C 6036 H 570 N

880 O 1508 S 1007 found C 6035 H 570 N 881 O1506 S 1008

516 Synthesis of Compounds (XIabc) A mixture of com-poundXa (1mmol) aromatic aldehyde (1mmol) and 2 dropsof piperidine was refluxed in ethanol for 2 hoursThe reactionmixture kept overnight then the solid product was filtered offand crystallized from EtOH to afford compound XI

(E)-Ethyl 2-(4-chlorobenzylidene)-3-oxo-57-diphenyl-35-di-hydro-2H-thiazolo[32-a]pyrimidine-6-carboxylate (XIa)mp = 164ndash6∘C IR (KBr) ] = 3446 1721 1620 1559 cmminus11H NMR (300MHz CDCl

3) 120575 = 087 (t 119869 = 69Hz 3H

ndashOndashCH2ndashCH3) 389 (q 2H ndashOndashCH

2ndashCH3) 634 (s 1H

ndashCHndash) 727ndash754 (m 14H Ar) 774 (s 1H =CHndash) ppmmass119898119911 () 500 (M+2 4580) 503 (M+4 982) 423 (6799) 168(1000) 77 (7769) C

28H21ClN2O3S (500) calculated C

6713 H 422 Cl 708 N 559 O 958 S 640 found C 6714H 424 Cl 707 N 560 O 959 S 642 yield (88)

(E)-Ethyl 2-(23-dimethoxybenzylidene)-3-oxo-57-diphenyl-35-dihydro-2H-thiazolo[32-a]pyrimidine-6-carboxylate(XIb) mp = 148∘C IR (KBr) ] = 34454 1712 16301581 cmminus1 1H NMR (300MHz CDCl

3) 120575 = 087 (t

119869 = 66Hz 3H ndashOndashCH2ndashCH3) 377 (s 3H ndashOCH

3) 385

(s 3H ndashOCH3) 634 (s 1H ndashCHndash) 684 (d 1H Ar) 696 (s

1H Ar) 698 (d 1H Ar) 735ndash755 (m 10H Ar) 809 (s 1H=CHndash) ppm mass 119898119911 () 526 (M+1 4298) 449 (1000)363 (270) 77 (537) C


6842 H 498 N 532 O 1519 S 609 found C 6843 H499 N 533 O 1520 S 610 Yield (85)

(E)-Ethyl2-(3-nitrobenzylidene)-3-oxo-57-diphenyl-35-dihy-dro-2H-thiazolo[32-a]pyrimidine-6-carboxylate (XIc) mp= 158ndash160∘C IR (KBr) ] = 3100 2998 1716 1617 15571563 1530 cmminus1 1H NMR (300MHz CDCl

3) 120575 = 084 (t

119869 = 69Hz 3H ndashOndashCH2ndashCH3) 386 (q 2H ndashOndashCH

2ndashCH3)

631 (s 1H ndashCHndash) 720ndash775 (m 14H Ar) 831 (s 1H =CHndash)ppm C


821 O 1564 S 627 found C 6575 H 413 N 822 O1563 S 628 yield (92)

Synthesis of 1-[5-Acetyl-6-(4-methoxy-phenyl)-4-methyl-16-dihydro-pyrimidin-2-ylsulfanyl]-propan-2-one (XIII) A mix-ture of IVb (0005mol) chloroacetone (0005mol) and2 drops of piperidine was refluxed in ethanol for 6 hoursThe reaction mixture was kept for overnight The solidformation was filtered off then dried and crystallized from


benzeneethanol (1 1) mp = 215∘C IR (KBr) ] = 31123004 1644 1608 1524 cmminus1 1H NMR (300MHz DMSO)120575 = 225 (s 3H ndashCH


3) 230 (s 3H

ndashCOCH3) 246 (s 2H CH


3) 644 (s

1H ndashCH) 690ndash728 (d d 4H Ar) 711 (s 1H ndashNH) mass119898119911 () 332 (M+ 530) 298 (530) 270 (3360) 245 (257)91 (1000) C


N 843 O 1444 S 965 found C 6143 H 605 N 843 O1442 S 966 yield (48)

517 Reaction of Compounds Vab with ThiosemicarbazideA mixture of Vab (0005mol) and thiosemicarbazide(007mol) was refluxed in ethanol (20mL) for 7 hours in awater bath then the reaction mixture was allowed to standfor several hours at room temperature then the solid productwas filtered off and recrystallized from ethanol to formedcompounds XIVab

Ethyl 2-(2-carbamothioylhydrazinyl)-46-diphenyl-16-dihy-dro-pyrimidine-5-carboxylate (XIVa) Method (A) yield(51) method (B) yield (46) mp = 170ndash172∘C IR (KBr)] = 3370 3262 3175 1644 1620 cmminus1 1H NMR (300MHzDMSO) 120575 = 071 (t 119869 = 75Hz 3H OCH

2CH3) 374

(q 2H OCH2CH3) 450 (s 2H ndashNH

2) 526 (s ndashCH)

719ndash758 (m 10H Ar) 865 (s 1H ndashNH) 978 (s 1H ndashNH) 1051 (s 1H ndashNH) ppm mass 119898119911 () 395 (M+2413) 379 (2113) 368 (4920) 352 (7697) 105 (8651) 55(1000) C


N 1771 O 809 S 811 found C 6073 H 536 N 1771O 808

2-(5-Acetyl-6-(4-methoxyphenyl)-4-methyl-16-dihydropyrim-idin-2-yl)hydrazinecarbothioamide (XIVb) Method (A)yield (64) method (B) yield (48) mp = 92∘C IR(KBr) ] = 3284 3145 2049 1604 1510 cmminus1 mass 119898119911() 333 (M+ 1218) 274 (1492) 233 (2731) 215 (8493) 178(9061) 136 (1000) 76 (650) 51 (2307) C

15H19N5O2S (333)


518 Synthesis of Compounds XVIIab Compound IVab(0005mol) was heated under reflux in (10mL) of methanolcontaining acetic acid (25mL) and water (25mL) Afterreflux for 25 hours methanol was distilled off and theremaining solution was treated portionwise with water untilprecipitation was completed After standing for severalhours at room temperature the solid product was removedby filteration to yield XVIIab which crystallized fromethanol

Ethyl 2-oxo-46-diphenyl-1234-tetrahydropyrimidine-5-car-boxylate (XVIIa) mp (found) = 160∘C mp (reported) =158∘C [48] yield (77)

5-Acetyl-4-(4-methoxyphenyl)-6-methyl-34-dihydropyrimi-din-2(1H)-one (XVIIb) mp (found) = 164ndash166∘C mp(reported) = 166-167∘C [48] yield (71)

References

[1] E W Hurst and R Hull ldquoTwo new synthetic substances activeagainst viruses of the psittacosis-lymphogranuloma- trachomagrouprdquo Journal ofMedicinal Chemistry vol 3 no 2 pp 215ndash2291961

[2] M Ashok B S Holla and N S Kumari ldquoConvenientone pot synthesis of some novel derivatives of thiazolo[23-b]dihydropyrimidinone possessing 4-methylthiophenyl moietyand evaluation of their antibacterial and antifungal activitiesrdquoEuropean Journal ofMedicinal Chemistry vol 42 no 3 pp 380ndash385 2007

[3] S S Bahekar and D B Shinde ldquoSynthesis and anti-inflamma-tory activity of some [46-(4-substituted aryl)-2-thioxo-1234-tetrahydro-pyrimidin-5-yl]-acetic acid derivativesrdquo BioorganicampMedicinal Chemistry Letters vol 14 no 7 pp 1733ndash1736 2004

[4] T U Mayer T M Kapoor S J Haggarty R W King SL Schreiber and T J Mitchison ldquoSmart molecule inhibitorof mitotic spindle bipolarity identified in a phenotype-basedscreenrdquo Science vol 286 no 5441 pp 971ndash974 1999

[5] C O Kappe ldquoRecent advances in the Biginelli dihydropy-rimidine synthesis New tricks from an old dogrdquo Accounts ofChemical Research vol 33 no 12 pp 879ndash888 2000

[6] A D Patil N V Kumar W C Kokke et al ldquoNovel alkaloidsfrom the sponge Batzella sp inhibitors of HIV gp120-humanCD4 bindingrdquo Journal of Organic Chemistry vol 60 no 5 pp1182ndash1188 1995

[7] 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

[8] P Biginelli ldquoDerivati aldeidureidici degli eteri acetil-edossalaceticordquo Gazzetta Chimica Italiana vol 23 pp 360ndash4161893

[9] PWipf and A Cunningham ldquoA solid phase protocol of the Big-inelli dihydropyrimidine synthesis suitable for combinatorialchemistryrdquo Tetrahedron Letters vol 36 no 43 pp 7819ndash78221995

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

[11] D Dallinger A Stadler and C O Kappe ldquoSolid- and solution-phase synthesis of bioactive dihydropyrimidinesrdquo Pure andApplied Chemistry vol 76 no 5 pp 1017ndash1024 2004

[12] C O Kappe ldquo4-aryldihydropyrimidines via the Biginelli con-densation aza-analogs of nifedipine-type calcium channelmodulatorsrdquoMolecules vol 3 no 1 pp 1ndash9 1998

[13] C O Kappe and A Stadler ldquoThe Biginelli dihydropyrimidinesynthesisrdquo Organic Reactions vol 63 pp 1ndash116 2004

[14] C Simon T Constantieux and J Rodriguez ldquoUtilisation of 13-dicarbonyl derivatives in multicomponent reactionsrdquo EuropeanJournal of Organic Chemistry no 24 pp 4957ndash4980 2004

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

[16] H E Zaugg and W B Martin ldquo120572-amidoalkylations at carbonrdquoinOrganic Reactions vol 14 pp 88ndash90 JohnWileyamp SonsNewYork NY USA 1965

[17] C O Kappe ldquoThe Biginelli reactionrdquo inMulticomponent Reac-tions pp 95ndash120 JohnWiley amp Sons NewYork NYUSA 2005


[18] L Z Gong X H Chen and X Y Xu ldquoAsymmetric organocat-alytic biginelli reactions a new approach to quickly access opti-cally active 34-dihydropyrimidin-2-(1H)-onesrdquo ChemistrymdashAEuropean Journal vol 13 no 32 pp 8920ndash8926 2007

[19] A Dondoni and A Massi ldquoParallel synthesis of dihydropy-rimidinones using Yb(III)-resin and polymer-supported scav-engers under solvent-free conditions A green chemistryapproach to the Biginelli reactionrdquo Tetrahedron Letters vol 42no 45 pp 7975ndash7978 2001

[20] A Shaabani and A Bazgir ldquoMicrowave-assisted efficient syn-thesis of spiro-fused heterocycles under solvent-free condi-tionsrdquo Tetrahedron Letters vol 45 no 12 pp 2575ndash2577 2004

[21] B J Ahn M S Gang K Chae Y Oh J Shin and W ChalgldquoA microwave-assisted synthesis of 34-dihydro-pyrimidin-2-(1H)-ones catalyzed by FeCl

3-supported Nanopore Silica under

solvent-free conditionsrdquo Journal of Industrial and EngineeringChemistry vol 14 no 3 pp 401ndash405 2008

[22] X Zhang Y Li C Liu and J Wang ldquoAn efficient syn-thesis of 4-substituted pyrazolyl-34-dihydropyrimidin-2(1H)-(thio)ones catalyzed by Mg(ClO

4)2under ultrasound irradia-

tionrdquo Journal of Molecular Catalysis A vol 253 no 1-2 pp 207ndash211 2006

[23] J T Li J F Han J H Yang and T S Li ldquoAn efficient synthesisof 34-dihydropyrimidin-2-ones catalyzed by NH

2SO3H under

ultrasound irradiationrdquo Ultrasonics Sonochemistry vol 10 no3 pp 119ndash122 2003

[24] N Foroughifar A Mobinikhaledi and H Fathinejad JirandehildquoSynthesis of some biginelli compounds in solvent mediumusing a photochemistrymethodrdquo Phosphorus Sulfur and Siliconand the Related Elements vol 178 no 3 pp 495ndash500 2003

[25] 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

[26] C V Reddy M Mahesh P V K Raju T R Babu and V V NReddy ldquoZirconium(IV) chloride catalyzed one-pot synthesis of34-dihydropyrimidin-2(1H)-onesrdquo Tetrahedron Letters vol 43no 14 pp 2657ndash2659 2002

[27] AKumar andRAMaurya ldquoAn efficient bakersrsquo yeast catalyzedsynthesis of 34-dihydropyrimidin-2-(1H)-onesrdquo TetrahedronLetters vol 48 no 26 pp 4569ndash4571 2007

[28] Y Q Zhang C Wang G S Li J C Li H M Liu and Q HWu ldquoOne-pot Synthesis of 34-Dihydropyrimidin-2(1H)-onesCatalyzed by Expandable Graphiterdquo Chinese Journal of OrganicChemistry vol 25 pp 1265ndash1267 2005

[29] R V Yarapathi S Kurva and S Tammishetti ldquoSynthesisof 34-dihydropyrimidin-2(1H)ones using reusable poly(4-vinylpyridine-co-divinylbenzene)-Cu(II)complexrdquo CatalysisCommunications vol 5 no 9 pp 511ndash513 2004

[30] J Azizian A A Mohammadi A R Karimi and M RMohammadizadeh ldquoKAl(SO

4)2sdot12H2O supported on silica gel

as a novel heterogeneous system catalyzed biginelli reactionone-pot synthesis of di-hydropyrimidinones under solvent-freeconditionsrdquoApplied Catalysis A vol 300 no 1 pp 85ndash88 2006

[31] NMizuno andMMisono ldquoHeterogeneous catalysisrdquoChemicalReviews vol 98 no 1 pp 199ndash217 1998

[32] A A Bakibaev and V D Filimonov ldquoSynthesis of hydro-genated acridine-18-diones amp 14-dihydropyrimidines by reac-tion of urea with 13-dicarbonyl compoundsrdquo Russian Journal ofOrganic Chemistry vol 27 pp 854ndash859 1991

[33] 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

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

reusable catalyst for high-yield synthesis of 34-dihydropyrim-idin-2(1H)-onesrdquo Tetrahedron Letters vol 44 no 16 pp 3305ndash3308 2003

[35] M Gohain D Prajapati and S Sandhub ldquoA novel Cu-catalysedthree-component one-pot synthesis of dihydropyrimidin-2(1H)-ones using microwaves under solvent free conditionsrdquoSynlett p 235 2004

[36] Y Ma C Qian L Wang and M Yang ldquoLanthanide triflatecatalyzed Biginelli reaction one-pot synthesis of dihydropyrim-idinones under solvent-free conditionsrdquoThe Journal of OrganicChemistry vol 65 no 12 pp 3864ndash3868 2000

[37] V T Kamble D B Muley S T Atkore and S D DakoreldquoThree component reaction an efficient synthesis of 34-dihydropyrimidin-2(1H)-ones and thiones using heteroge-neous catalystrdquo Chinese Journal of Chemistry vol 28 no 3 pp388ndash392 2010

[38] B Gangadasu S Palaniappan and V J Rao ldquoOne-pot syn-thesis of dihydropyrimidinones using polyaniline-bismoclitecomplexA facile and reusable catalyst for the biginelli reactionrdquoSynlett no 7 pp 1285ndash1287 2004

[39] A K Mitra and K Banerjee ldquoClay catalysed synthesis ofdihydropyrimidinones under solvent-free conditionsrdquo Synlettno 10 pp 1509ndash1511 2003

[40] J Mabry and B Ganem ldquoStudies on the Biginelli reaction amild and selective route to 34-dihydropyrimidin-2(1H)-onesvia enamine intermediatesrdquo Tetrahedron Letters vol 47 no 1pp 55ndash56 2006

[41] T Ghorge R Tahilramani and D V Mehta ldquoCondensed het-erocycles from 5-ethoxycarbonyl-6-methyltetrahydropyrimi-din-2-onesrdquo Communications pp 405ndash407 1975

[42] N-Y Fu Y-F Yuan Z Cao S-W Wang J-T Wang and CPeppe ldquoIndium(III) bromide-catalyzed preparation of dihy-dropyrimidinones improved protocol conditions for the Big-inelli reactionrdquoTetrahedron vol 58 no 24 pp 4801ndash4807 2002

[43] J S Yadav B V S Reddy P Sridhar et al ldquoGreen protocolfor the biginelli three-component reaction Ag 3PW

12O40as a

novel water-tolerant heteropolyacid for the synthesis of 34-dihydropyrimidinonesrdquo European Journal of Organic Chem-istry no 3 pp 552ndash557 2004

[44] K Folkers and T B Johnson ldquoResearches on pyrimidinesCXXXVI The mechanism of formation of tetrahydropyrim-idines by the Biginelli reactionrdquo Journal of the AmericanChemical Society vol 55 no 9 pp 3784ndash3791 1933

[45] R D Carlos D Bernardi and G Kirsch ldquoZrCl4or ZrOCl

2

under neat conditions optimized green alternatives for theBiginelli reactionrdquo Tetrahedron Letters vol 48 no 33 pp 5777ndash5780 2007

[46] N Foroughifar A Mobinikhaledi H F Jirandehi and SMemar ldquoMicrowave-assisted synthesis of some BI- and tricyclicpyrimidine derivativesrdquo Phosphorus Sulfur and Silicon and theRelated Elements vol 178 no 6 pp 1269ndash1276 2003

[47] B Ahmed R A Khan Habibullah and M Keshari ldquoAnimproved synthesis of Biginelli-type compounds via phase-transfer catalysisrdquo Tetrahedron Letters vol 50 no 24 pp 2889ndash2892 2009


[48] E Ramu V Kotra N Bansal R Varala and S R Adapa ldquoGreenapproach for the efficient synthesis of Biginelli compounds pro-moted by citric acid under solvent-free conditionsrdquo RASAYANJournal of Chemistry vol 1 no 1 pp 188ndash194 2008

Submit your manuscripts athttpwwwhindawicom

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Inorganic ChemistryInternational Journal of

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Advances in

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Analytical Methods in Chemistry

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Volume 2014

Bioinorganic Chemistry and ApplicationsHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

SpectroscopyInternational Journal of


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Medicinal ChemistryInternational Journal of


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Applied ChemistryJournal of



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Analytical ChemistryInternational Journal of


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ElectrochemistryInternational Journal of



CatalystsJournal of


Table 1 34-Dihydropyrimidin-2(1H)ones (I)

Entry R1 R2Time (h) MP [Reference] Yielda

Quartz Granite Found Reported Quartz GraniteIa C6H5 OEt 3 35 201-202 200ndash202 [33] 68 64Ib 2-(OH)-C6H4 OEt 35 5 202ndash204 200ndash202 [34] 62 60Ic 4-(OCH3)-C6H4 OEt 3 3 199-200 201-202 [35] 64 60Id Ph-CH=CH OEt 3 4 232ndash234 232ndash235 [36] 58 55Ie 25-(OCH3)-C6H3 OEt 4 5 210ndash212 212ndash214 [37] 61 58If 345-(OCH3)-C6H2 OEt 3 45 180-181 180ndash182 [25] 60 56Ig 2-furyl OEt 3 4 205-206 203ndash205 [38] 66 61Ih 2-(Cl)-C6H4 OEt 3 4 214-215 215-216 [39] 65 62Ii 4-(OCH3)-C6H4 CH3 3 4 165ndash167 166ndash168 [40] 69 65Ij 4-N(CH3)2-C6H4 OEt 3 4 233ndash235 230ndash232 [25] 62 58Ik 4-(CH3)-C6H4 OEt 2 3 210ndash212 214-215 [35] 65 62Il 26-(Cl)-C6H3 OEt 4 45 302-303 305 [41] 57 61Im 2-thienyl OEt 2 3 214ndash216 215ndash217 [42] 66 63In 4-(F)-C6H4 OEt 2 3 175ndash177 175ndash177 [43] 71 68Io 3-(OCH2Ph)-C6H4 OEt 3 35 178ndash180 New 65 62Ip 3-(OCH2Ph)-C6H4 CH3 35 4 192ndash194 New 40 63Iq 23-(OCH3)-C6H3 OEt 3 4 178ndash180 New 63 60aIsolated yield

H3CH3C

R2

O O++ H2N NH2

O

EtOH reflux

NH

NH

R1O

O

R2Granite or quartzR1minusCHO

Iandashq

Scheme 1

2 Result and Discussion

It is interesting to report that the one pot reaction of amixtureof benzaldehyde ethyl acetoacetate and urea in the presenceof granite or quartz as a catalyst in refluxing ethanol resultedin the formation of 4-phenyl-34-dihydropyrimidinone IaTable 1 in 64 or 68 yield according to the catalyst(Scheme 1) In a similar way urea was condensed smoothlywith variety of aromatic or heterocyclic aldehydes and varietyof 13-dicarbonyl compounds in the presence of granite orquartz in refluxing ethanol as one pot reaction to afford thecorresponding 34-dihydropyrimidines Ibndashq (Table 1) whosecomposition and structures were confirmed by elementalanalysis Mass IR and 1H NMR spectra of the isolatedproducts (cf experimental section)

On the other hand carrying out of the above reac-tion using of 3-benzyloxybenzaldehyde acetyl acetone andurea in refluxing ethanol using granite as catalyst the cor-responding 5-acetyl-4-(3-(benzyloxy)phenyl)-6-methyl-34-dihydropyrimidin-2(1H)-one Io was isolated However oncarrying the above reaction using quartz as a catalyst besidethe proposed 34-dihydropyrimidinone Io another productwith molecular formula (C

16H16N4O2) 119898119911 = 296 was

isolated from the reaction media in 25 yield This product

can be identified as 4-amino-6-(3-(benzyloxy)phenyl)-56-dihydro-135-triazin-2(1H)-one III based on the analyticaland the spectral data of the isolated product which revealedthe presence of characteristic stretching vibrations due toNH NH

2 and amidic CO at ] = 3450 3300 and 1640 cmminus1

regions respectively in the IR spectrum Also the 1H-NMRspectrum of the isolated product shows signals at 120575 = 507(s 2H ndashCH

2ndash) 543 (s 1H ndashCHndash) 568 (s 2H ndashNH

2)

670ndash746 (m 9H Ar) and 100 (s 1H NH) ppm The 13C-NMR spectrum of the isolated product shows signals at120575 = 512 (CH aliphatic) 6232 (CH

2aliphatic) 1653 (C

triazine ring) 1904 (C=O amidic) and 111ndash160 (Benzenerings) This expectation is based on the observation that the3-benzyloxybenzaldehyde condensed with two moles of ureato give the corresponding bis-ureide II as key intermediatewhich cyclized via elimination of H

2O to give the extremely

low yield triazine derivative III [44] (Scheme 2)In generality of this process various 13-diketones and

aldehydes were reacted with thiourea in refluxing ethanolusing granite or quartz as the reaction catalyst to give the cor-responding 34-dihydropyrimidin-2(1H)-thione derivativesIV (Table 2) which their structures were confirmed on thebases of the analytical and spectral data of the isolatedproducts (cf experimental section) (Scheme 3)


CHO

O Ph

H2N NH2

O

QuartizEtOHReflux

Me

O O

Me

+

NH

NHMe

O O

Me

O

Ph

H2N

NH

NH

O

O

PhH2N

O

Me

O

OMe NH

HNO

NH

Me

Me

O

O

Ph O

H2NH2N

NH

NH

O

OPh

H2N

O

HN NH

NH

HO

O Ph

HN

N

NH

O

O

Ph

H2N

minusH2O

minusNH2CONH2

II

IIIH2

N

O

Io

Scheme 2

+ R2 R3

O O+ H2N NH2

S

EtOH refluxNH

NH

R1

R2 S

O

R3Granite or quartz

IVandashh

R1minusCHO

Scheme 3


2in quartz This



3derivatives


3protons


18H22N2O5S







NH

NH

R

R1OC

S N

N

N

N

HNR

R1OC

S N

N

NH

RR

R

R1OC R1OC

R1OC

SCH3SCH3

SCH3

CH3

CH3

CH3

OO


CH3I dry acetone



AC2OReflux

AC2OReflux

DMF

R2 R2

R2

R2R2


(b) R = R1 = CH3 R2 = 4-OCH3

(c) R = CH3 R1 = OEt R2 =

Vandashc

VIandashc

VIIIa

23-OCH3

VIIab

Scheme 4










3protons (Scheme 4)






HN

N N

N

N

NR

R R

R

R

R1OCR1OC R1OC

SS S

S

NHNH

R2

R2 R2

XO

O

O

OH X = Cl or Br

ACONa anhy


BenzeneTEAOX

YX = Y = Cl or Br


CO2Et

XI R(a) = 4-Cl

(b) R =

(c) R = 4-NO2

CHO

EtO2C

IXabXab

23-(OCH3)

Scheme 5



2



17H20N2O3S The 1H


2










ClCH2COCH3

EtOHPip

SCH2COCH3

IV (b) R = R1 = CH3 R2 = 4-OCH3

HN

N

N

N

R

R

R

R1OC

R1OC

R1OC

S

S

NH

NH

R2

R2

R2 XII

XIII

CH3

Scheme 6

N

NN

NN

N N

N

N

R

RR

R

R1OC

R1OCR1OC

R1OC

NH

NH

NH

R2

R2

R2

R2


SCH3

NH2NHCSNH2

EtOH reflux

XV XVI

Or

XIVabNHNHCSNH2

HH

2N

N2H

Scheme 7

NH

NH

R S NH

NH

R O

MeOHACOHH2O reflux

XVIIab

R1OCR1OC

R2R2


Scheme 8






HN

N

NH

O

O Ph

III

H2N

12 12

NH

NHEtO2C

H3C S

O Ph

IVg 11 1275

NH

NHEtO2C

H3C S

ClCl

IVf 11 125

NH

NHEtO2C

H3C S

OCH3

H3CO

IVh 12 145

NH

NHEtO2C

H3C S

OCH3

OCH3

IVc 105 14



4 Conclusion











2ndash

CH3) 233 (s 3H CH


2ndashCH3) 503







3) 505 (s 2H







2ndash

CH3) 240 (s 3H CH


3) 392 (s 3H







2ndashCH3)


2ndashCH3) 505 (s






2ndashCH3) 242 (s



3) 405






2ndashCH3) 227 (s



3) 396






2ndash

CH3) 223 (s 3H CH


2ndashCH3) 628




2) 670ndash692









2ndash



2ndashCH3) 574





3) 223 (s



3)






3)


3) 406 (q 2H









3CH2Ondash


3) 367 (s 3H


3) 408 (q 2H CH

3CH2Ondash)


18H22N2O5S



21H20N2O3S (380)





3) 097 (t 119869 = 66Hz 3H CH



3) 402 (q 2H CH

3CH2Ondash)


22H22N2O3S (394)




() 332 (M+ 4322) 312 (3956) 278 (5128) 100 (1000) 67(5055) C


N 843 O 1444 S 965 found C 6143 H 604 N 846 O1445 S 966



2ndash



3) 401 (q 2H


ppm mass119898119911 () 366 (M+ 521) 350 (1000) 321 (2848)129 (3096) 77 (1587) C









3) 120575 = 085 (t 119869 =


2ndashCH3) 388


Ar) ppm mass 119898119911 () 378 (M+ 6003) 350 (1630) 301(1000) 273 (3562) 129 (2511) 77 (3557) C

21H18N2O3S




3) 370 (s 3H OCH

3)


4H Ar) ppm mass 119898119911 () 316 (M+ 3508) 301 (532)273 (1000) 245 (2808) 230 (472) 181 (1936) 115 (2514) 77(260) C


880 O 1508 S 1007 found C 6035 H 570 N 881 O1506 S 1008



3) 120575 = 087 (t 119869 = 69Hz 3H







3) 120575 = 087 (t


3) 385






3) 120575 = 084 (t


2ndashCH3)








3) 230 (s 3H



3) 644 (s






2CH3) 374


2) 526 (s ndashCH)



N 1771 O 809 S 811 found C 6073 H 536 N 1771O 808


15H19N5O2S (333)





References





























2SO3H under

























12O40as a




2















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


CHO

O Ph

H2N NH2

O

QuartizEtOHReflux

Me

O O

Me

+

NH

NHMe

O O

Me

O

Ph

H2N

NH

NH

O

O

PhH2N

O

Me

O

OMe NH

HNO

NH

Me

Me

O

O

Ph O

H2NH2N

NH

NH

O

OPh

H2N

O

HN NH

NH

HO

O Ph

HN

N

NH

O

O

Ph

H2N

minusH2O

minusNH2CONH2

II

IIIH2

N

O

Io

Scheme 2

+ R2 R3

O O+ H2N NH2

S

EtOH refluxNH

NH

R1

R2 S

O

R3Granite or quartz

IVandashh

R1minusCHO

Scheme 3


2in quartz This



3derivatives


3protons


18H22N2O5S







NH

NH

R

R1OC

S N

N

N

N

HNR

R1OC

S N

N

NH

RR

R

R1OC R1OC

R1OC

SCH3SCH3

SCH3

CH3

CH3

CH3

OO


CH3I dry acetone



AC2OReflux

AC2OReflux

DMF

R2 R2

R2

R2R2


(b) R = R1 = CH3 R2 = 4-OCH3

(c) R = CH3 R1 = OEt R2 =

Vandashc

VIandashc

VIIIa

23-OCH3

VIIab

Scheme 4










3protons (Scheme 4)






HN

N N

N

N

NR

R R

R

R

R1OCR1OC R1OC

SS S

S

NHNH

R2

R2 R2

XO

O

O

OH X = Cl or Br

ACONa anhy


BenzeneTEAOX

YX = Y = Cl or Br


CO2Et

XI R(a) = 4-Cl

(b) R =

(c) R = 4-NO2

CHO

EtO2C

IXabXab

23-(OCH3)

Scheme 5



2



17H20N2O3S The 1H


2










ClCH2COCH3

EtOHPip

SCH2COCH3

IV (b) R = R1 = CH3 R2 = 4-OCH3

HN

N

N

N

R

R

R

R1OC

R1OC

R1OC

S

S

NH

NH

R2

R2

R2 XII

XIII

CH3

Scheme 6

N

NN

NN

N N

N

N

R

RR

R

R1OC

R1OCR1OC

R1OC

NH

NH

NH

R2

R2

R2

R2


SCH3

NH2NHCSNH2

EtOH reflux

XV XVI

Or

XIVabNHNHCSNH2

HH

2N

N2H

Scheme 7

NH

NH

R S NH

NH

R O

MeOHACOHH2O reflux

XVIIab

R1OCR1OC

R2R2


Scheme 8






HN

N

NH

O

O Ph

III

H2N

12 12

NH

NHEtO2C

H3C S

O Ph

IVg 11 1275

NH

NHEtO2C

H3C S

ClCl

IVf 11 125

NH

NHEtO2C

H3C S

OCH3

H3CO

IVh 12 145

NH

NHEtO2C

H3C S

OCH3

OCH3

IVc 105 14



4 Conclusion











2ndash

CH3) 233 (s 3H CH


2ndashCH3) 503







3) 505 (s 2H







2ndash

CH3) 240 (s 3H CH


3) 392 (s 3H







2ndashCH3)


2ndashCH3) 505 (s






2ndashCH3) 242 (s



3) 405






2ndashCH3) 227 (s



3) 396






2ndash

CH3) 223 (s 3H CH


2ndashCH3) 628




2) 670ndash692









2ndash



2ndashCH3) 574





3) 223 (s



3)






3)


3) 406 (q 2H









3CH2Ondash


3) 367 (s 3H


3) 408 (q 2H CH

3CH2Ondash)


18H22N2O5S



21H20N2O3S (380)





3) 097 (t 119869 = 66Hz 3H CH



3) 402 (q 2H CH

3CH2Ondash)


22H22N2O3S (394)




() 332 (M+ 4322) 312 (3956) 278 (5128) 100 (1000) 67(5055) C


N 843 O 1444 S 965 found C 6143 H 604 N 846 O1445 S 966



2ndash



3) 401 (q 2H


ppm mass119898119911 () 366 (M+ 521) 350 (1000) 321 (2848)129 (3096) 77 (1587) C









3) 120575 = 085 (t 119869 =


2ndashCH3) 388


Ar) ppm mass 119898119911 () 378 (M+ 6003) 350 (1630) 301(1000) 273 (3562) 129 (2511) 77 (3557) C

21H18N2O3S




3) 370 (s 3H OCH

3)


4H Ar) ppm mass 119898119911 () 316 (M+ 3508) 301 (532)273 (1000) 245 (2808) 230 (472) 181 (1936) 115 (2514) 77(260) C


880 O 1508 S 1007 found C 6035 H 570 N 881 O1506 S 1008



3) 120575 = 087 (t 119869 = 69Hz 3H







3) 120575 = 087 (t


3) 385






3) 120575 = 084 (t


2ndashCH3)








3) 230 (s 3H



3) 644 (s






2CH3) 374


2) 526 (s ndashCH)



N 1771 O 809 S 811 found C 6073 H 536 N 1771O 808


15H19N5O2S (333)





References





























2SO3H under

























12O40as a




2















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


NH

NH

R

R1OC

S N

N

N

N

HNR

R1OC

S N

N

NH

RR

R

R1OC R1OC

R1OC

SCH3SCH3

SCH3

CH3

CH3

CH3

OO


CH3I dry acetone



AC2OReflux

AC2OReflux

DMF

R2 R2

R2

R2R2


(b) R = R1 = CH3 R2 = 4-OCH3

(c) R = CH3 R1 = OEt R2 =

Vandashc

VIandashc

VIIIa

23-OCH3

VIIab

Scheme 4










3protons (Scheme 4)






HN

N N

N

N

NR

R R

R

R

R1OCR1OC R1OC

SS S

S

NHNH

R2

R2 R2

XO

O

O

OH X = Cl or Br

ACONa anhy


BenzeneTEAOX

YX = Y = Cl or Br


CO2Et

XI R(a) = 4-Cl

(b) R =

(c) R = 4-NO2

CHO

EtO2C

IXabXab

23-(OCH3)

Scheme 5



2



17H20N2O3S The 1H


2










ClCH2COCH3

EtOHPip

SCH2COCH3

IV (b) R = R1 = CH3 R2 = 4-OCH3

HN

N

N

N

R

R

R

R1OC

R1OC

R1OC

S

S

NH

NH

R2

R2

R2 XII

XIII

CH3

Scheme 6

N

NN

NN

N N

N

N

R

RR

R

R1OC

R1OCR1OC

R1OC

NH

NH

NH

R2

R2

R2

R2


SCH3

NH2NHCSNH2

EtOH reflux

XV XVI

Or

XIVabNHNHCSNH2

HH

2N

N2H

Scheme 7

NH

NH

R S NH

NH

R O

MeOHACOHH2O reflux

XVIIab

R1OCR1OC

R2R2


Scheme 8






HN

N

NH

O

O Ph

III

H2N

12 12

NH

NHEtO2C

H3C S

O Ph

IVg 11 1275

NH

NHEtO2C

H3C S

ClCl

IVf 11 125

NH

NHEtO2C

H3C S

OCH3

H3CO

IVh 12 145

NH

NHEtO2C

H3C S

OCH3

OCH3

IVc 105 14



4 Conclusion











2ndash

CH3) 233 (s 3H CH


2ndashCH3) 503







3) 505 (s 2H







2ndash

CH3) 240 (s 3H CH


3) 392 (s 3H







2ndashCH3)


2ndashCH3) 505 (s






2ndashCH3) 242 (s



3) 405






2ndashCH3) 227 (s



3) 396






2ndash

CH3) 223 (s 3H CH


2ndashCH3) 628




2) 670ndash692









2ndash



2ndashCH3) 574





3) 223 (s



3)






3)


3) 406 (q 2H









3CH2Ondash


3) 367 (s 3H


3) 408 (q 2H CH

3CH2Ondash)


18H22N2O5S



21H20N2O3S (380)





3) 097 (t 119869 = 66Hz 3H CH



3) 402 (q 2H CH

3CH2Ondash)


22H22N2O3S (394)




() 332 (M+ 4322) 312 (3956) 278 (5128) 100 (1000) 67(5055) C


N 843 O 1444 S 965 found C 6143 H 604 N 846 O1445 S 966



2ndash



3) 401 (q 2H


ppm mass119898119911 () 366 (M+ 521) 350 (1000) 321 (2848)129 (3096) 77 (1587) C









3) 120575 = 085 (t 119869 =


2ndashCH3) 388


Ar) ppm mass 119898119911 () 378 (M+ 6003) 350 (1630) 301(1000) 273 (3562) 129 (2511) 77 (3557) C

21H18N2O3S




3) 370 (s 3H OCH

3)


4H Ar) ppm mass 119898119911 () 316 (M+ 3508) 301 (532)273 (1000) 245 (2808) 230 (472) 181 (1936) 115 (2514) 77(260) C


880 O 1508 S 1007 found C 6035 H 570 N 881 O1506 S 1008



3) 120575 = 087 (t 119869 = 69Hz 3H







3) 120575 = 087 (t


3) 385






3) 120575 = 084 (t


2ndashCH3)








3) 230 (s 3H



3) 644 (s






2CH3) 374


2) 526 (s ndashCH)



N 1771 O 809 S 811 found C 6073 H 536 N 1771O 808


15H19N5O2S (333)





References





























2SO3H under

























12O40as a




2















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


HN

N N

N

N

NR

R R

R

R

R1OCR1OC R1OC

SS S

S

NHNH

R2

R2 R2

XO

O

O

OH X = Cl or Br

ACONa anhy


BenzeneTEAOX

YX = Y = Cl or Br


CO2Et

XI R(a) = 4-Cl

(b) R =

(c) R = 4-NO2

CHO

EtO2C

IXabXab

23-(OCH3)

Scheme 5



2



17H20N2O3S The 1H


2










ClCH2COCH3

EtOHPip

SCH2COCH3

IV (b) R = R1 = CH3 R2 = 4-OCH3

HN

N

N

N

R

R

R

R1OC

R1OC

R1OC

S

S

NH

NH

R2

R2

R2 XII

XIII

CH3

Scheme 6

N

NN

NN

N N

N

N

R

RR

R

R1OC

R1OCR1OC

R1OC

NH

NH

NH

R2

R2

R2

R2


SCH3

NH2NHCSNH2

EtOH reflux

XV XVI

Or

XIVabNHNHCSNH2

HH

2N

N2H

Scheme 7

NH

NH

R S NH

NH

R O

MeOHACOHH2O reflux

XVIIab

R1OCR1OC

R2R2


Scheme 8






HN

N

NH

O

O Ph

III

H2N

12 12

NH

NHEtO2C

H3C S

O Ph

IVg 11 1275

NH

NHEtO2C

H3C S

ClCl

IVf 11 125

NH

NHEtO2C

H3C S

OCH3

H3CO

IVh 12 145

NH

NHEtO2C

H3C S

OCH3

OCH3

IVc 105 14



4 Conclusion











2ndash

CH3) 233 (s 3H CH


2ndashCH3) 503







3) 505 (s 2H







2ndash

CH3) 240 (s 3H CH


3) 392 (s 3H







2ndashCH3)


2ndashCH3) 505 (s






2ndashCH3) 242 (s



3) 405






2ndashCH3) 227 (s



3) 396






2ndash

CH3) 223 (s 3H CH


2ndashCH3) 628




2) 670ndash692









2ndash



2ndashCH3) 574





3) 223 (s



3)






3)


3) 406 (q 2H









3CH2Ondash


3) 367 (s 3H


3) 408 (q 2H CH

3CH2Ondash)


18H22N2O5S



21H20N2O3S (380)





3) 097 (t 119869 = 66Hz 3H CH



3) 402 (q 2H CH

3CH2Ondash)


22H22N2O3S (394)




() 332 (M+ 4322) 312 (3956) 278 (5128) 100 (1000) 67(5055) C


N 843 O 1444 S 965 found C 6143 H 604 N 846 O1445 S 966



2ndash



3) 401 (q 2H


ppm mass119898119911 () 366 (M+ 521) 350 (1000) 321 (2848)129 (3096) 77 (1587) C









3) 120575 = 085 (t 119869 =


2ndashCH3) 388


Ar) ppm mass 119898119911 () 378 (M+ 6003) 350 (1630) 301(1000) 273 (3562) 129 (2511) 77 (3557) C

21H18N2O3S




3) 370 (s 3H OCH

3)


4H Ar) ppm mass 119898119911 () 316 (M+ 3508) 301 (532)273 (1000) 245 (2808) 230 (472) 181 (1936) 115 (2514) 77(260) C


880 O 1508 S 1007 found C 6035 H 570 N 881 O1506 S 1008



3) 120575 = 087 (t 119869 = 69Hz 3H







3) 120575 = 087 (t


3) 385






3) 120575 = 084 (t


2ndashCH3)








3) 230 (s 3H



3) 644 (s






2CH3) 374


2) 526 (s ndashCH)



N 1771 O 809 S 811 found C 6073 H 536 N 1771O 808


15H19N5O2S (333)





References





























2SO3H under

























12O40as a




2















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


ClCH2COCH3

EtOHPip

SCH2COCH3

IV (b) R = R1 = CH3 R2 = 4-OCH3

HN

N

N

N

R

R

R

R1OC

R1OC

R1OC

S

S

NH

NH

R2

R2

R2 XII

XIII

CH3

Scheme 6

N

NN

NN

N N

N

N

R

RR

R

R1OC

R1OCR1OC

R1OC

NH

NH

NH

R2

R2

R2

R2


SCH3

NH2NHCSNH2

EtOH reflux

XV XVI

Or

XIVabNHNHCSNH2

HH

2N

N2H

Scheme 7

NH

NH

R S NH

NH

R O

MeOHACOHH2O reflux

XVIIab

R1OCR1OC

R2R2


Scheme 8






HN

N

NH

O

O Ph

III

H2N

12 12

NH

NHEtO2C

H3C S

O Ph

IVg 11 1275

NH

NHEtO2C

H3C S

ClCl

IVf 11 125

NH

NHEtO2C

H3C S

OCH3

H3CO

IVh 12 145

NH

NHEtO2C

H3C S

OCH3

OCH3

IVc 105 14



4 Conclusion











2ndash

CH3) 233 (s 3H CH


2ndashCH3) 503







3) 505 (s 2H







2ndash

CH3) 240 (s 3H CH


3) 392 (s 3H







2ndashCH3)


2ndashCH3) 505 (s






2ndashCH3) 242 (s



3) 405






2ndashCH3) 227 (s



3) 396






2ndash

CH3) 223 (s 3H CH


2ndashCH3) 628




2) 670ndash692









2ndash



2ndashCH3) 574





3) 223 (s



3)






3)


3) 406 (q 2H









3CH2Ondash


3) 367 (s 3H


3) 408 (q 2H CH

3CH2Ondash)


18H22N2O5S



21H20N2O3S (380)





3) 097 (t 119869 = 66Hz 3H CH



3) 402 (q 2H CH

3CH2Ondash)


22H22N2O3S (394)




() 332 (M+ 4322) 312 (3956) 278 (5128) 100 (1000) 67(5055) C


N 843 O 1444 S 965 found C 6143 H 604 N 846 O1445 S 966



2ndash



3) 401 (q 2H


ppm mass119898119911 () 366 (M+ 521) 350 (1000) 321 (2848)129 (3096) 77 (1587) C









3) 120575 = 085 (t 119869 =


2ndashCH3) 388


Ar) ppm mass 119898119911 () 378 (M+ 6003) 350 (1630) 301(1000) 273 (3562) 129 (2511) 77 (3557) C

21H18N2O3S




3) 370 (s 3H OCH

3)


4H Ar) ppm mass 119898119911 () 316 (M+ 3508) 301 (532)273 (1000) 245 (2808) 230 (472) 181 (1936) 115 (2514) 77(260) C


880 O 1508 S 1007 found C 6035 H 570 N 881 O1506 S 1008



3) 120575 = 087 (t 119869 = 69Hz 3H







3) 120575 = 087 (t


3) 385






3) 120575 = 084 (t


2ndashCH3)








3) 230 (s 3H



3) 644 (s






2CH3) 374


2) 526 (s ndashCH)



N 1771 O 809 S 811 found C 6073 H 536 N 1771O 808


15H19N5O2S (333)





References





























2SO3H under

























12O40as a




2















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of






HN

N

NH

O

O Ph

III

H2N

12 12

NH

NHEtO2C

H3C S

O Ph

IVg 11 1275

NH

NHEtO2C

H3C S

ClCl

IVf 11 125

NH

NHEtO2C

H3C S

OCH3

H3CO

IVh 12 145

NH

NHEtO2C

H3C S

OCH3

OCH3

IVc 105 14



4 Conclusion











2ndash

CH3) 233 (s 3H CH


2ndashCH3) 503







3) 505 (s 2H







2ndash

CH3) 240 (s 3H CH


3) 392 (s 3H







2ndashCH3)


2ndashCH3) 505 (s






2ndashCH3) 242 (s



3) 405






2ndashCH3) 227 (s



3) 396






2ndash

CH3) 223 (s 3H CH


2ndashCH3) 628




2) 670ndash692









2ndash



2ndashCH3) 574





3) 223 (s



3)






3)


3) 406 (q 2H









3CH2Ondash


3) 367 (s 3H


3) 408 (q 2H CH

3CH2Ondash)


18H22N2O5S



21H20N2O3S (380)





3) 097 (t 119869 = 66Hz 3H CH



3) 402 (q 2H CH

3CH2Ondash)


22H22N2O3S (394)




() 332 (M+ 4322) 312 (3956) 278 (5128) 100 (1000) 67(5055) C


N 843 O 1444 S 965 found C 6143 H 604 N 846 O1445 S 966



2ndash



3) 401 (q 2H


ppm mass119898119911 () 366 (M+ 521) 350 (1000) 321 (2848)129 (3096) 77 (1587) C









3) 120575 = 085 (t 119869 =


2ndashCH3) 388


Ar) ppm mass 119898119911 () 378 (M+ 6003) 350 (1630) 301(1000) 273 (3562) 129 (2511) 77 (3557) C

21H18N2O3S




3) 370 (s 3H OCH

3)


4H Ar) ppm mass 119898119911 () 316 (M+ 3508) 301 (532)273 (1000) 245 (2808) 230 (472) 181 (1936) 115 (2514) 77(260) C


880 O 1508 S 1007 found C 6035 H 570 N 881 O1506 S 1008



3) 120575 = 087 (t 119869 = 69Hz 3H







3) 120575 = 087 (t


3) 385






3) 120575 = 084 (t


2ndashCH3)








3) 230 (s 3H



3) 644 (s






2CH3) 374


2) 526 (s ndashCH)



N 1771 O 809 S 811 found C 6073 H 536 N 1771O 808


15H19N5O2S (333)





References





























2SO3H under

























12O40as a




2















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of






2ndash

CH3) 233 (s 3H CH


2ndashCH3) 503







3) 505 (s 2H







2ndash

CH3) 240 (s 3H CH


3) 392 (s 3H







2ndashCH3)


2ndashCH3) 505 (s






2ndashCH3) 242 (s



3) 405






2ndashCH3) 227 (s



3) 396






2ndash

CH3) 223 (s 3H CH


2ndashCH3) 628




2) 670ndash692









2ndash



2ndashCH3) 574





3) 223 (s



3)






3)


3) 406 (q 2H









3CH2Ondash


3) 367 (s 3H


3) 408 (q 2H CH

3CH2Ondash)


18H22N2O5S



21H20N2O3S (380)





3) 097 (t 119869 = 66Hz 3H CH



3) 402 (q 2H CH

3CH2Ondash)


22H22N2O3S (394)




() 332 (M+ 4322) 312 (3956) 278 (5128) 100 (1000) 67(5055) C


N 843 O 1444 S 965 found C 6143 H 604 N 846 O1445 S 966



2ndash



3) 401 (q 2H


ppm mass119898119911 () 366 (M+ 521) 350 (1000) 321 (2848)129 (3096) 77 (1587) C









3) 120575 = 085 (t 119869 =


2ndashCH3) 388


Ar) ppm mass 119898119911 () 378 (M+ 6003) 350 (1630) 301(1000) 273 (3562) 129 (2511) 77 (3557) C

21H18N2O3S




3) 370 (s 3H OCH

3)


4H Ar) ppm mass 119898119911 () 316 (M+ 3508) 301 (532)273 (1000) 245 (2808) 230 (472) 181 (1936) 115 (2514) 77(260) C


880 O 1508 S 1007 found C 6035 H 570 N 881 O1506 S 1008



3) 120575 = 087 (t 119869 = 69Hz 3H







3) 120575 = 087 (t


3) 385






3) 120575 = 084 (t


2ndashCH3)








3) 230 (s 3H



3) 644 (s






2CH3) 374


2) 526 (s ndashCH)



N 1771 O 809 S 811 found C 6073 H 536 N 1771O 808


15H19N5O2S (333)





References





























2SO3H under

























12O40as a




2















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of





2ndash



2ndashCH3) 574





3) 223 (s



3)






3)


3) 406 (q 2H









3CH2Ondash


3) 367 (s 3H


3) 408 (q 2H CH

3CH2Ondash)


18H22N2O5S



21H20N2O3S (380)





3) 097 (t 119869 = 66Hz 3H CH



3) 402 (q 2H CH

3CH2Ondash)


22H22N2O3S (394)




() 332 (M+ 4322) 312 (3956) 278 (5128) 100 (1000) 67(5055) C


N 843 O 1444 S 965 found C 6143 H 604 N 846 O1445 S 966



2ndash



3) 401 (q 2H


ppm mass119898119911 () 366 (M+ 521) 350 (1000) 321 (2848)129 (3096) 77 (1587) C









3) 120575 = 085 (t 119869 =


2ndashCH3) 388


Ar) ppm mass 119898119911 () 378 (M+ 6003) 350 (1630) 301(1000) 273 (3562) 129 (2511) 77 (3557) C

21H18N2O3S




3) 370 (s 3H OCH

3)


4H Ar) ppm mass 119898119911 () 316 (M+ 3508) 301 (532)273 (1000) 245 (2808) 230 (472) 181 (1936) 115 (2514) 77(260) C


880 O 1508 S 1007 found C 6035 H 570 N 881 O1506 S 1008



3) 120575 = 087 (t 119869 = 69Hz 3H







3) 120575 = 087 (t


3) 385






3) 120575 = 084 (t


2ndashCH3)








3) 230 (s 3H



3) 644 (s






2CH3) 374


2) 526 (s ndashCH)



N 1771 O 809 S 811 found C 6073 H 536 N 1771O 808


15H19N5O2S (333)





References





























2SO3H under

























12O40as a




2















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of


() 332 (M+ 4322) 312 (3956) 278 (5128) 100 (1000) 67(5055) C


N 843 O 1444 S 965 found C 6143 H 604 N 846 O1445 S 966



2ndash



3) 401 (q 2H


ppm mass119898119911 () 366 (M+ 521) 350 (1000) 321 (2848)129 (3096) 77 (1587) C









3) 120575 = 085 (t 119869 =


2ndashCH3) 388


Ar) ppm mass 119898119911 () 378 (M+ 6003) 350 (1630) 301(1000) 273 (3562) 129 (2511) 77 (3557) C

21H18N2O3S




3) 370 (s 3H OCH

3)


4H Ar) ppm mass 119898119911 () 316 (M+ 3508) 301 (532)273 (1000) 245 (2808) 230 (472) 181 (1936) 115 (2514) 77(260) C


880 O 1508 S 1007 found C 6035 H 570 N 881 O1506 S 1008



3) 120575 = 087 (t 119869 = 69Hz 3H







3) 120575 = 087 (t


3) 385






3) 120575 = 084 (t


2ndashCH3)








3) 230 (s 3H



3) 644 (s






2CH3) 374


2) 526 (s ndashCH)



N 1771 O 809 S 811 found C 6073 H 536 N 1771O 808


15H19N5O2S (333)





References





























2SO3H under

























12O40as a




2















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of




3) 230 (s 3H



3) 644 (s






2CH3) 374


2) 526 (s ndashCH)



N 1771 O 809 S 811 found C 6073 H 536 N 1771O 808


15H19N5O2S (333)





References





























2SO3H under

























12O40as a




2















Journal of

Chemistry


Advances in

Physical Chemistry



Journal of

Volume 2014














Journal of

Spectroscopy



Journal of


Quantum Chemistry






CatalystsJournal of












2SO3H under

























12O40as a




2















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 Three Component Reaction: An Efficient...

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