An efficient ultrasonic-assisted synthesis of ethyl-5 ... · motifs also show interesting biological activities (Overman et al., 1995). Substituted 3, 4-dihydropyrimidines a and 3,

Arabian Journal of Chemistry (2015) xxx, xxx–xxx

King Saud University

Arabian Journal of Chemistry

www.ksu.edu.sawww.sciencedirect.com

ORIGINAL ARTICLE

An efficient ultrasonic-assisted synthesisof ethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a]pyrimidine-6-carboxylate derivatives

* Corresponding author. Tel.: +98 391 3202430; fax: +98 391

3202429.

E-mail addresses: [email protected], [email protected].

ac.ir (A. Darehkordi).

Peer review under responsibility of King Saud University.

Production and hosting by Elsevier

http://dx.doi.org/10.1016/j.arabjc.2015.01.0101878-5352 ª 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University.This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Darehkordi, A., Ghazi, S. An efficient ultrasonic-assisted synthesis of ethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)- 7-methy3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate derivatives. Arabian Journal of Chemistry (2015), http://dx.doi.org/10.1016/j.arabjc.2015.01.010

Ali Darehkordi *, Somayeh Ghazi

Department of Chemistry, Faculty of Science, Vali-e-asr University of Rafsanjan, Rafsanjan 77176, Iran

Received 17 December 2011; accepted 10 January 2015

KEYWORDS

Thiazolo pyrimidine;

Dihydropyrimidinone

thiazine;

DMAD;

DEAD;

Montmorillonite;

Ultrasonic irradiation

Abstract Dihydropyrimidinone derivatives were prepared by tri-component reaction of ethyl

aceto acetate, aldehydes and thiourea in the presence of modified montmorillonite nanostructure

as a catalyst and used as key intermediates for the synthesis of ethyl-5-(aryl)-2-(2-alkokxy-2-oxoe-

thylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyri midine-6-carboxylate derivatives

with use of diethyl and dimethyl acetylene dicarboxylate by two methods: (a) in methanol as a sol-

vent under ultrasonic irradiation at ambient temperature (b) in methanol as a solvent at ambient

temperature (conventional magnetic stirring). Ultrasound-assisted synthesis provides excellent

yields in short reaction times (15–25 min) at room temperature.ª 2015 The Authors. Production and hosting by Elsevier B.V. on behalf of King Saud University. This isan open access article under the CCBY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction

Dihydropyrimidinone derivatives have attracted considerable

interest in recent years because of therapeutic and pharmaco-logical properties nowadays. For example, they can serve asthe integral backbones of several calcium channel blockers

(Rovnyak et al., 1995; Aswal et al., 1990), antihypertensiveagents (Atwal et al., 1991; Grover et al., 1995) anda-1a-antagonists (Kappe, 2000a,b). In addition, several marinealkaloids containing the dihydropyrimidinone-5-carboxylatemotifs also show interesting biological activities (Overmanet al., 1995). Substituted 3, 4-dihydropyrimidines a and 3,

4-dihydro-1, 3-oxazines b are regarded as promising synthonsin the design of new bioactive compounds (Scheme 1). Forinstance, structural scaffold a is represented by poly functional

3,4-dihydropyrimidines known as Biginelli compounds(Kappe, 1993, 2000a,b) which include a number of antiviral,anti-bacterial, anti-hypertensive, and anti-inflammatory agents

(Kappe, 2000a,b).Many pyrimidine derivatives have been reported to possess

useful medicinal and biological activities (Barton and Ollis,1974; Brown et al., 1984; Sasaki et al., 1980; Griengl et al.,

l-3-oxo-

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Scheme 1

2 A. Darehkordi, S. Ghazi

1987). In the last few years, various pyrimidinone and pyrimid-inone derivatives substituted either at C-5 or at C-6 positionshave emerged in the field of chemotherapy (Scheme 2)

(Parlato et al., 2004). Recently, the pyrimidinone derivatives2-methylthio-6-[(2-alkylamino) ethyl]-4(3H)-pyrimidinoneshave been shown to posses activity against positive strand

(vesicular stomatitis virus) RNA virus (Scheme 2) (Bottaet al., 1999).

A series of 1-(biphenylmethylamidoalkyl) pyrimidinoneshave also been designed as nano molar inhibitors of recombi-

nant lipoprotein-associated phospholipase A2 with highpotency in whole human plasma. Also, thienopyrimidinederivatives have been reported to possess useful molluscidal,

larvacidal activities against Biomphalaria alexandrina andSchistosoma mansoni, snails.

Scheme

Table 1 The effect of different solvent and temperature on the rea

NH

NH

SCH3

O

EtO

OMe

CO2MeMeO2CH

EtO+ solvent

temperature

Solvent Temperature (�C)

Dichloromethane 30

Dichloromethane Reflux

Dichloromethane Reflux

Ethyl acetate + H2O 30

Ethyl acetate 30

H2O 60

Ethanol 30

Methanol 30

Methanol 30

Please cite this article in press as: Darehkordi, A., Ghazi, S. An efficient ultrasonic-as3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate derivatives. Arabian Jour

Although the Claisen rearrangement is an excellent methodfor C–C bond formation and has been successfully employedfor the synthesis of a number of furo [3, 2-d] pyrimidines, pyr-

ano [3, 2-d] pyrimidines and dihydrofuro [2, 3-d] pyrimidinederivatives (Kawahara et al., 1985; Majumdar and Das,1997), there are hardly many reports in the pyrimidinone ser-

ies. Previously synthesis and characterization of pyrimidi-none-peptoid hybrid molecules that modulate Hsp70 activityin vitro and that, in some cases, prevent cancer cell prolifera-

tion have been reported (Wright et al., 2008; Fewell et al.,2004, 2001; Rodina et al., 2007). Recently we have reportedsynthesis a series of thiazoline compounds from reaction of thi-osemicarbazone derivatives of aldehydes and ketoses with

alkyl acetylenic esters (Darehkordi et al., 2007).The sonochemistry is a unique method in chemical reac-

tions, because of cavitations, a physical process that creates,

enlarges, and implodes gaseous and vaporous cavities in anirradiated liquid. Cavitations induce very high local tempera-tures and pressures inside the bubbles (cavities), leading to

turbulent flow of the liquid and enhanced mass transfer(Ranjbar-karimi et al., 2010).

Ultrasound irradiation has been considered as a clean and

useful protocol in organic synthesis in the last three decades(Xue and Li, 2008; Wang et al., 2008; Li et al., 2010), and

2

ction.

N

N

C3

O

S

O

OMe

CO2Me

NCH3

O

EtO N

S

O

OMe

CO2Me+

Time (h) Yield (%)

12 30

10 45

12 50

12 35

12 30

12 Trace

8 70

1 70

2 94

sisted synthesis of ethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)- 7-methyl-3-oxo-nal of Chemistry (2015), http://dx.doi.org/10.1016/j.arabjc.2015.01.010

http://dx.doi.org/10.1016/j.arabjc.2015.01.010

Table 2 UV–Vis absorption of 6a–6i in DMSO at 25 �C.

Entry Product kmax (nm)

1 6a 282.53, 377.20

2 6b 309.66, 402.02

3 6c 278.32, 376.62

4 6d 274.45, 380.66

5 6e 287.73, 378.35

6 6f 310.82, 395.67

7 6g 284.84, 376.6

8 6h 286.58, 384.70

9 6i 298.70, 386.43

An efficient ultrasonic-assisted synthesis 3

compared with traditional methods, the procedure is moreconvenient. A large number of organic reactions can be carried

out in higher yield, shorter reaction time or milder conditions

Table 3 Synthesis of ethyl 5-(4-Alkylphenyl)-2-(2-alkoxy-2-oxoeth

dine-6-carboxylate (6a–6i).

Entry R Acetylenic ester Product

1

NH

NH

CH3

O

EtO

S

Cl Me2O2C CO2Me

N

N

CH3

O

EtO

Cl

6a

2

NH

NH

CH3

O

EtO

S

Cl Et2O2C CO2Et

N

N

CH3

O

EtO

Cl

6b

3

NH

NH

CH3

O

EtO

S

OMe Me2O2C CO2Me

N

N

CH3

O

EtO

OMe

6c

4

NH

NH

CH3

O

EtO

S

OMe Et2O2C CO2Et

N

N

CH3

O

EtO

OMe

6d


under ultrasonic irradiation (Deshmukh et al., 2001;Rajagopal et al., 2002; Bravo et al., 2006).

The aim of this study was the synthesis of ethyl-5-(aryl)-2-

(2-alkokxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate derivatives fromreaction of dihydropyrimidinone derivatives with dimethyl

and diethyl acetylenedicarboxylate using both ultrasonic irra-diation method and a more conventional magnetic stirringmethod.

2. Results and discussion

The preparation of thiazoline compounds was developed in the

over years. In continuing our work in the synthesis of fivemembered S, N-heterocyclic thiazoline (Darehkordi et al.,2007), we wish to report other heterocyclic compounds from

ylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo[3, 2-a]pyrimi-

M.P (�C) Time (min) Yield

US R.T US R.T

S

OCO2Me

154–155 25 120 95 92

S

OCO2Et

167–169 23 120 97 95

S

OCO2Me

131–132 24 125 96 94

S

OCO2Et

170–173 25 128 95 93



Table 3 (continued)

Entry R Acetylenic ester Product M.P (�C) Time (min) Yield

US R.T US R.T

5

NH

NH

CH3

O

EtO

S

Me Me2O2C CO2Me

N

N

CH3

O

EtO

S

OCO2Me

Me

6e

196–197 22 123 94 93

6

NH

NH

CH3

O

EtO

S

Me Et2O2C CO2Et

N

N

CH3

O

EtO

S

O

Me

CO2Et

6f

172–173 20 130 97 95

7

NH

NH

CH3

O

EtO

S

OMeMeO

Me2O2C CO2Me

N

N

CH3

O

EtO

S

O

OMeMeO

CO2Me

6g

158–160 24 122 96 95

8

NH

NH

CH3

O

EtO

S

OMeMeO

Et2O2C CO2Et

N

N

CH3

O

EtO

S

OCO2Et

OMeMeO

6h

168–169 27 128 93 90

9

NH

NH

CH3

O

EtO

S

Me2O2C CO2Me

N

N

CH3

O

EtO

S

OCO2Me

6i

168–170 26 120 95 93


pyrimidinone derivatives. In our earlier studies, we havereported reaction of thiosemicarbazone derivatives with

DAMAD and DEAD at ambient temperature. Herein, wehave reacted DMAD and DEAD with different dihydropyrim-idine-2-(1H)-ones using both ultrasonic irradiation method

and a conventional method.Initially, we started the condensation of DMAD

(0.001 mol) with ethyl 4-(4-methoxyphenyl)-6-methyl-2-

thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (0.001 mol)in dichloromethane at room temperature for 12 h. This ledto poor yield (30%) of ethyl-5-(4-methoxyphenyl)-2-(2-meth-


oxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro- 2H-thiazol-o[3,2-a]pyrimidine-6-carboxylate(6c). To enhance the yield of

the reaction, temperature was increased to 60 �C but no appre-ciable increment was observed in the product yield. Choice ofsolvent is also very crucial factor for condensation reaction.

We also considered the solvent effect for this reaction. Thereaction was tested in a variety of solvents such as H2O,EtOAC, H2O-EtOAC and EtOH, but none of the above sol-

vents were found to be more effective than methanol (Table 1).Since water exhibits a unique reactivity and selectivity differentfrom conventional organic solvents, the reaction was also



Scheme 3 Suggested mechanism for the synthesis of ethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-

thiazolo [3, 2-a] pyrimidine-6-carboxylate derivatives.

Scheme 4 Synthesis of pyrimidine derivatives under solvent-free conditions.

Scheme 5 Synthesis of ethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3,2-a]pyrimidine-6-car-

boxylate derivatives.

Scheme 6 Synthesis of ethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo[3, 2-a]pyrimidine-6-car-

boxylate derivatives under ultrasonic irradiation.


Please cite this article in press as: Darehkordi, A., Ghazi, S. An efficient ultrasonic-assisted synthesis of ethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)- 7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate derivatives. Arabian Journal of Chemistry (2015), http://dx.doi.org/10.1016/j.arabjc.2015.01.010



carried out in water. Nevertheless, the reaction, at 60 �C, didnot give the desired product and the starting material wasrecovered, whereas after a prolonged reaction (12 h) at

100 �C, only trace of the desired products was identified byTLC. It was identified that methanol and ethanol, especiallymethanol were a choice for the reaction and the desired prod-

uct was obtained in methanol at 30 �C in excellent yield(Tables 1 and 3).

In this pursuit we first examined the reaction of pyrimidi-

none derivative 4a with dimethyl acetylenedicarboxylate inethanol at ambient temperature. This led to excellent yield(92%) of ethyl-5-(4-methoxyphenyl)-2-(2-methoxy-2-oxoethy-lidene)-7-methyl-3-oxo-3,5-dihydro- 2H-thiazolo[3,2-a]pyrimi-

dine-6-carboxylate 6c at 120 min. First of all, we studiedthe conventional magnetic stirring for the synthesis ofethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)-7-methyl-3-oxo-3,

5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate deriv-atives. In general, the desire products were isolated in excel-lent yields without purification (Scheme 5 Table 3).

To improve our studies, and in order to decrease the reac-tion times and increase the yield, the synthesis of the samecompounds 6a–6i was carried out using ultrasound irradia-

tion, at room temperature. In the first, we examined thereaction of pyrimidinone derivative 4a with dimethyl acety-lenedicarboxylate promoted by ultrasound in ethanol to givethe corresponding 5-(4-cholorophenyl)-2-(2-methoxy-2-oxoe-

thylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a]pyrimidine-6-carboxylate 6a in excellent yield (95%) only in25 min (Table 3, entry 1). Therefore all of the compounds

6a–6i were synthesized using ultrasound irradiation, at roomtemperature, shorter reaction times and excellent yields. Theultrasonic method was simpler and the products were isolated

without further purification (Scheme 6 Table 3).As therein revealed, using conventional magnetic stirring,

the resulting product was obtained with 92% yield after

120 min (Table 3, entry 1); however, under ultrasonic irradi-ation, with the power 360 W, irradiation frequency 47 kHzand the reaction temperature 27–30 �C, the excellent prod-ucts yield (95%) was obtained after only 20 min (Table 3,

entry 1). To establish the generality of the ultrasonic-assistedreaction, a series of dihydropyrimidinone derivatives wereemployed in this reaction, and the results are listed in

Table 3.The reaction is mainly condensation which fallowed by

cyclization. Initially the sulfur atom from dihydropyrimidi-

none attacks to the carbon triplet bond of acetylenic ester com-pound which is the prone to nucleophilic attack. Thencyclization proceeds on to the esoteric (CO2R) function to giveproducts 6 and 7 in excellent yield (Scheme 5). A plausible

mechanism has been proposed for the reactions ofpyrimidinone derivatives with DMAD and DEAD to yieldethyl-5-(aryl)-2-(2-alkoxy-2-oxoethylidene)-7-methyl-3-oxo-3,

5-dihydro-2H thiazolo [3,2a] pyrimidine-6-carboxylate deriv-atives as shown in Scheme 3.

Compounds 6a–6i are yellow or orange solid. The UV–Vis-

ible absorption of these products demonstrates major absorp-tion in wavelength ranges of 278.32–402.02 nm in DMSOsolvent at room temperature as indicated in Table 2.

Table 3 shows the stricture and yield of the ethyl 5-(4-Alkylphenyl)-2-(2-Alkoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate deriv-ative (6a–6i).


The structure of compound ethyl 5-(4-Alkylphenyl)-2-(2-Alkoxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate was deduced from

their 1H and 13C NMR, UV–Vis and elemental analysis.

3. Experimental section

3.1. Apparatus

A multiwave ultrasonic generator (Bandlin Sonopuls Gerate-Typ: UW 3200, Germany) equipped with a converter/trans-ducer and titanium oscillator (horn), 12.5 mm in diameter,

operating at 50 kHz with a maximum power output of780 W, was used for the ultrasonic irradiation. The ultrasonicgenerator automatically adjusted the power level. Melting

points were determined in open capillary tubes by an Electro-thermal IA 9000 melting point apparatus. IR spectra (KBr)were obtained on a Matson-1000 FT-IR spectrometer. Theproton and carbon-13 NMR spectra were recorded with a

BRUKER DRX-500 AVANCE spectrometer at 500 and125.7 MHz respectively with Me4Si as an internal standard(chemical shifts in d, ppm). Element analyses (C, H, and N)were performed with a Heracus CHN-O-Rapid analyzer.UV–Vis spectra were recorded with a CARY 100 CONC spec-trophotometer. Their results corresponded to the calculated

values within experimental error. TLC was performed on silicagel PolyGram SIL G/UV 254 plates. The starting materialswere purchased from Merck and used without further

purification. All yields refer to isolated products. Pyrimidinederivatives were synthesized by following procedure:

A mixture of ethyl acetoacetate or acetyl acetone 2(2 mmol), appropriate aldehyde 1 (2 mmol), thiourea 3

(3 mmol) and montmorillonite catalyst (0.6 g) was placed ina test tube and heated in a bathe oil under solvent free condi-tions, for 120 min (Scheme 4). After cooling the reaction mix-

ture, ethanol was added to that and catalyst was removed byfiltration. The filtrate was poured into the crushed ice waterand the resulting precipitate recrystallized from hot ethanol

to afford pure product. All of the compounds were character-ized by MP, FT-IR, 13C and 1H NMR, UV–Vis spectropho-tometer and elements analysis.

3.2. General procedure for synthesis of ethyl-5-(4-choloro-phenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3,

5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate (6a)

A solution of DMAD (0.001 mol, 0.140 g) or DEAD(0.001 mol, 0.172 g) in 3 ml methanol was added to a solutionof pyrimidinones derivatives (0.001 mol, 0.346 g) in methanol

(10 cc) in small portions. Mixture was stirred at ambient tem-perature for 2 h. The resulting yellow precipitate was filteredand washed with cold methanol or ethanol. The product was

obtained without purification as yellow powder (Scheme 5).

3.3. General procedure for synthesis of ethyl-5-(4-cholorophenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylateunder ultrasonic irradiation (6a)

A solution of DMAD (0.001 mol, 0.140 g) or DEAD

(0.001 mol, 0.172 g) in 3 ml methanol was added to a solution




of pyrimidinones derivatives (0.001 mol, 0.346 g) in methanol(4 cc) in small portions. This reaction mixture was sonicatedat 45 kHz. After the completion of reaction as indicated by

TLC, the reaction mixture was filtered. The resulting yellowprecipitate was filtered and washed with cold methanol or eth-anol. The product was obtained without purification as yellow

powder (Scheme 6).

3.4. Commentary and spectra

3.4.1. Ethyl-5-(4-cholorophenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo

[3, 2-a] pyrimidine-6-carboxylate (6a)

Yellow powder, m.p.: 150–155 �C, IR KBr ( , cm�1): 2978,2959 (CAH, aliphatic), 3057 (CAH, aromatic), 1728, 1711(C‚O), 1617, 1489 (C‚N, C‚C). 1H NMR (DMSO-d6,

500 MHz); d 1.09 (t, J = 7.0 H, 3H, CH3), 2.37 (s, 3H,CH3), 3.77 (s, 3H, OCH3), 4.03 (q, J = 7.0 Hz, 2H, OACH2),5.97 (s, 1H, CH), 6.83 (s,1H, CH), 7.30 (d, J = 5 Hz, 2H, arom

CH), 7.39 (d, J = 5 Hz, 2H, arom CH). 13C NMR (DMSO-d6,125.77 MHz): d = 13.71 (1C, CH3, CH3), 22.21 (1C, CH3,CH3), 52.73 (1C, CH, CH‚N), 54.53 (1C, CH3, OCH3),

60.30 (1C, CH2, OACH2), 117.48, 128.59, 129.60, 133.19,138.29, 139.18, 150.34, 155.41, 162.71, 164.44, 165.66. Anal.Calcd for C19H17 N2O5SCl: C, 54.22; H, 4.07; N, 6.66. Found:C, 54.49; H, 4.23; N, 6.87%.

3.4.2. Ethyl-5-(4-cholorophenyl)-2-(2-ethoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo

[3,2-a]pyrimidine-6-carboxylate (6b)

Yellow powder, m.p.: 144–147 �C, IR KBr ( , cm�1): 2908,2986 (CAH, aliphatic), 3070 (CAH, aromatic), 1729, 1708(C‚O), 1628, 1487 (C‚N, C‚C). 1H NMR (DMSO-d6,

500 MHZ): d = 1.1 (t, J= 7.0 Hz, 3H, CH3), 1.25 (t,J = 7.0 Hz, 3H, CH3), 2.39 (s, 3H, CH3), 4.05 (q,J = 7.0 Hz, 2H, OCH2), 4.23 (q, J = 7.0 Hz, 2H, OCH2),

5.99 (s, 1H, CH), 6.83 (s, 1H, CH), 7.32 (d, J = 7.0 Hz, aromCH) , 7.42(d, J = 7.0 Hz, arom CH). 13C NMR (DMSO-d6,125.77 MHz): d = 14.69 (1C, CH3), 14.80 (1C, CH3), 23.19(1C, CH3), 55.47 (1C, OACH2), 61.27 (1C, OACH2), 62.71(1C, OACH2), 118.72, 129.57, 130.58, 134.13, 139.29, 140.03,151.312, 156.46, 163.69, 165.41, 166.12. Anal. Calcd forC20H19N2O5SCl: C, 55.24; H, 4.40; N, 6.30%. Found; C,

55.36; H, 4.66; N, 6.42%.

3.4.3. Ethyl-5-(4-methoxyphenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6c)

Yellow powder, m.p.: 129–132 �C, IR KBr ( , cm�1): 2981(CAH, aliphatic), 3064 (CAH, aromatic), 1720, 1711 (C‚O),1611, 1464 (C‚N, C‚C). 1H NMR (DMSO-d6, 500 MHz):d = 1.1 (t, J = 7.0 Hz, 3H, CH3), 2.38 (s, 3H, CH3), 3.71 (s,3H, OCH3), 3.78 (s, 3H, OCH3) , 4.03 (q, J = 7.0 Hz, 2H,OACH2) , 5.95 (s, 1H, HCAN), 6.88 (s, 1H, CH‚C), 6.90(d, J = 8.6 Hz, arom CH), 7.2 (d, J= 8.6 Hz, arom CH).13C NMR (DMSO-d6, 125.77 MHz): d = 14.72 (1C, CH3),23.07 (1C, CH3), 53.71 (1C, CH3), 55.43 (1C, OACH3),55.96 (1C, CH), 61.18 (1C, CH2), 118.27, 129.88, 132.45,140.30, 150.67, 156.14, 160.18, 163.69, 165.59, 166.69. Anal.


Calcd for C20H20N2O6S: C, 57.68; H, 4.84; N, 6.73. Found;C, 57.98; H, 5.01; N, 6.79%.

3.4.4. Ethyl-5-(4-methoxyphenyl)-2-(2-ethoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6d)

Yellow powder, m.p.: 167–173 �C, IR KBr ( , cm�1): 2958(CAH, aliphatic), 3066 (CAH, aromatic), 1728, 1703 (C‚O),1612, 1463 (C‚N, C‚C). 1H NMR (DMSO-d6, 500 MHz):d = 1.12 (t, J = 7.1 Hz, 3H, CH3), 1.25 (t, J = 7.1 Hz, 3H,CH3), 2.39 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 4.04 (q,J= 7.1 Hz, 2H, OACH2), 4.25 (q, J = 7.1 Hz, 2H, OACH2),5.95 (s, 1H, CH, HCAN), 6.82 (s, 1H, CH), 6.90 (2H, aromCH), 7.20 (2H, arom CH). Anal. Calcd for C21H22 N2O6S:C, 58.59; H, 5.15; N, 6.51. Found; C, 58.77; H, 5.36; N, 6.67%.

3.4.5. Ethyl-5-(4-methylphenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6e)

Yellow powder, m.p.: 192–197 �C, IR KBr ( , cm�1): 2981,2957 (CAH, aliphatic), 3058 (CAH, aromatic), 1719, 1712(C‚O), 1615, 1437 (C‚N, C‚C); 13C NMR (DMSO-d6,125.77 MHz): d = 14.71 (1C, CH3), 21.55 (1C, CH3), 23.08(1C, OCH3), 53.70 (1C, OCH3), 55.75 (1C, CH), 61.20 (1C,OACH2), 118.31, 128.37, 130.11, 137.54, 139.01 , 150.73,156.25, 163.65, 165.58, 166.67. Anal. Calcd for C20H20N2O5S:C, 59.99; H, 5.03; N, 7.00. Found; C, 60.29; H, 5.26 N, 7.14%.

3.4.6. Ethyl-5-(4-methylphenyl)-2-(2-ethoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-

carboxylate (6f)

Yellow powder, m.p.: 169–174 �C, IR KBr ( , cm�1): 2985,2969 (CAH, aliphatic), 3067 (CAH, aromatic), 1727, 1708(C‚O), 1621, 1445 (C‚N, C‚C); 1H NMR (DMSO-d6,

500 MHz): d = 1.14 (t, J= 7.0 Hz, 3H, CH3) , 1.25 (t,J= 7.0 Hz, 3H, CH3) , 2.25 (s, 3H, CH3) , 2.38 (s, 3H, CH3), 4.04 (q, J = 7.1 Hz, 2H, OACH2), , 4.21 (q, J = 7.1 Hz,2H, OACH2), 5.96 (s, 1H, HCAN), 6.81 (s, 1H, CH‚C),7.13–7.17 (4H, arom CH). 13C NMR (DMSO-d6,125.77 MHz): d = 14.71 (1C, CH3), 14.80 (1C, CH3), 21.55(1C, CH3), 23.07(1C, CH3), 55.74 (1C, CH), 61.19 (1C,OACH2), 62.68 (1C, OACH2), 118.59, 128.36, 130.11,137.55, 138.99, 140.11, 150.74, 156.29, 163.66, 165.57, 166.11.Anal. Calcd for C21H22N2O5S: C, 60.85; H, 5.35; N, 6.76.

Found; C, 61.13; H, 5.72; N, 6.80%.

3.4.7. Ethyl-5-(3,4-dimethoxyphenyl)-2-(2-methoxy-2-

oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6g)

yellow powder, m.p.: 156–160 �C, IR KBr ( , cm�1): 2908,2986 (CAH, aliphatic), 3070 (CAH, aromatic), 1729, 1708(C‚O), 1628, 1487 (C‚N, C‚C); 1H NMR (DMSO-d6,500 MHz): d = 1.14 (t, J = 7.0 Hz, 3H, CH3), 2.39 (s, 3H,CH3), 3.72 (s, 6H, OCH3), 3.78 (s, 3H, OCH3), 4.06 (q,

J= 7.1 Hz , 2H, OACH2), 5.95 (s, 1H, HCAN), 6.76 (d,J= 8.4 Hz, 1H, CH), 6.83 (d, 2H, arom CH), 6.90 (d,J= 8.4 Hz, 1H, arom CH) 13C NMR (DMSO-d6,

125.77 MHz): d = 14.77 (1C, CH3), 23.03 (1C, CH3), 53.71(1C, CH3), 55.72 (1C, CH3), 56.32 (1C, CH3), 56.39 (1C,CH3), 61.17 (1C, OACH2), 112.45, 112.71, 118.28, 120.59,




132.85, 140.32, 149.24, 149.90, 150.60, 156.14, 163.74, 165.63,166.67. Anal. Calcd for C21H22N2O7S: C, 56.49; H, 4.97; N,6.27. Found; C, 56.67; H, 5.07; N, 6.13%.

3.4.8. Ethyl-5-(3,4-dimethoxyphenyl)-2-(2-ethoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-

a]pyrimidine-6-carboxylate (6h)

Yellow powder, mp.: 165–169 �C, IR KBr ( , cm�1): 2984,2936 (CAH, aliphatic), 3058 (CAH, aromatic), 1717, 1711(C‚O), 1622, 1464 (C‚N, C‚C); 1H-NMR (DMSO-d6,

500 MHz): d = 1.14 (t, J= 7.1 Hz, 3H, CH3), 1.25 (t,J= 7.0 Hz, 3H, CH3), 2.39 (s, 3H, OCH3), 3.72 (s, 6H,OCH3), 4.06 (q, J = 7.1 Hz, 2H, OACH2), 4.20 (q,J= 7.0 Hz, 2H, OACH2), 5.95 (s, 1H, HCAN), 6.70 (1H,arom CH), 6.83 (s, 2H, arom CH), 6.90 (1H, arom CH). Anal.Calcd for C22H24N2O7S: C, 57.38; H, 5.24; N, 6.08. Found; C,

57.64; H, 5.36; N, 6.12%.

3.4.9. Ethyl-5-(4-phenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-

carboxylate (6i)

Yellow powder, m.p.: 165–17 0 �C, IR KBr ( , cm�1): 2987,2949 (CA, aliphatic), 3062 (CAH, aromatic), 1722, 1708(C‚O), 1617, 1464 (C‚N, C‚C); 1H NMR (DMSO-d6,500 MHz): d = 1.11 (t, J= 7.0 Hz, 3H, CH3), 2.39 (s, 3H,CH3), 3.78 (s, 3H, OCH3), 4.04 (q, J = 7.0 Hz, 2H, OACH2),5.99 (s, 1H, HC-N), 6.85 (s, 1H, CH), 7.27–7.37(m, 5H, Arom

CH). 13C NMR (DMSO-d6, 125.77 MHz): d = 14.68 (1C,CH3), 23.11 (1C, CH3), 53.70 (1C, CH3), 56.04 (1C, CH),61.20 (1C, OACH2), 118.39, 128.47, 129.53, 129.58, 140.19,140.43, 150.88, 156.35, 163.04, 166.66, 167.14. Anal. Calcdfor C19H18 N2O5S: C, 59.06; H, 4.70; N, 7.25. Found; C,59.40; H, 4.86; N, 7.55%.

4. Conclusion

In conclusion, we have developed two different simple syn-

thetic methods to prepare ethyl-5-(aryl)-2-(2-alkokxy-2-oxoe-thylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a]pyrimidine-6-carboxylate derivatives, conventional magnetic

stirring and ultrasonic irradiation. Both of the methods ledto excellent yield. Ultrasonic irradiation displays dramaticallyreduced reaction time compared to conventional magneticstirring method, and also affords the desired products in high

yields and purity.

Acknowledgment

We gratefully acknowledge the financial support, for thisProject, of Vali-e-Asr University of Rafsanjan, Faculty

Research Grant.


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An efficient ultrasonic-assisted synthesis of ethyl-5-(aryl)-2-(2-alkokxy-2-oxoethylidene)- 7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate derivatives1 Introduction2 Results and discussion3 Experimental section3.1 Apparatus3.2 General procedure for synthesis of ethyl-5-(4-choloro-phenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate (6a)3.3 General procedure for synthesis of ethyl-5-4-cholorophenyl-2-2-methoxy-2-oxoethylidene-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate under ultrasonic irradiation 6a3.4 Commentary and spectra3.4.1 Ethyl-5-(4-cholorophenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3, 5-dihydro-2H-thiazolo [3, 2-a] pyrimidine-6-carboxylate (6a)3.4.2 Ethyl-5-(4-cholorophenyl)-2-(2-ethoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6b)

3.4.3 Ethyl-5-(4-methoxyphenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6c)3.4.4 Ethyl-5-(4-methoxyphenyl)-2-(2-ethoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6d)3.4.5 Ethyl-5-(4-methylphenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6e)3.4.6 Ethyl-5-(4-methylphenyl)-2-(2-ethoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6f)3.4.7 Ethyl-5-(3,4-dimethoxyphenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6g)3.4.8 Ethyl-5-(3,4-dimethoxyphenyl)-2-(2-ethoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6h)3.4.9 Ethyl-5-(4-phenyl)-2-(2-methoxy-2-oxoethylidene)-7-methyl-3-oxo-3,5-dihydro-2H-thiazolo[3,2-a]pyrimidine-6-carboxylate (6i)

4 ConclusionAcknowledgmentReferences

Documents

An efficient ultrasonic-assisted synthesis of ethyl-5 ... · motifs also show interesting biological activities (Overman et al., 1995). Substituted 3, 4-dihydropyrimidines a and 3,