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BrAnsted Acidic Ionic Liquids Catalyzed Three-Component Synthesis of 4,6-diarylpyrimidin-2(1H)-ones Under Solvent-Free Conditions.

Byline: Ebrahim Mollashahi and Asiyeh Biabangard

Summary:

4,6-Diarylpyrimidin-2(1H)-one derivatives have been synthesized from three-component reaction of aromatic aldehyde derivatives, acetophenone, and urea (thiourea) in the presence of BrAnsted acidic ionic liquids such as triethylammonium hydrogensulfate, N-methyl-2-pyrrolidonium dihydrogen phosphate, 3-methyl-1-sulfonic acid imidazolium chloride, N-methyl-2-pyrrolidonium hydrogensulfate, and 2-pyrrolidonium hydrogensulfate as catalyst under thermal solvent-free conditions in excellent yields. This new methodology presents five reusable ionic liquids as catalyst and their application in synthetic organic chemistry.

Keywords: Acetophenone; Urea; BrAnsted acidic ionic liquids; 4,6-diarylpyrimidin-2(1H)-one, Aldehyde

Introduction

Multicomponent reactions (MCRs) have been considered as a superior synthetic strategy for preparation of libraries of drug-like advanced compounds [1]. MCRs provide environmentally friendly processes by reducing the number of steps, energy consumption, and waste production [2]. Pyrimidin-2(1H)-ones and their derivatives show a wide range of biological, pharmaceutical and therapeutic activities [3]. In continuation of our research on MCRs [4-7], now, we would like to report mild reaction conditions, clean and high yielding approaches for the synthesis of 4,6- diarylpyrimidin-2(1H)-ones from three-component reaction of aromatic aldehyde derivatives, acetophenone, and urea (thiourea) in the presence of BrAnsted acidic ionic liquids such as triethylammonium hydrogensulfate [Et3NH][HSO4],

N-methyl-2-pyrrolidonium dihydrogen phosphate [NMP][H2PO4], 3-methyl-1-sulfonic acid imidazolium chloride {[Msim]Cl}, N-methyl-2- pyrrolidonium hydrogensulfate [NMP][HSO4], and 2- pyrrolidonium hydrogensulfate [Hnhp][HSO4] (Fig. 1) as catalyst under thermal solvent-free conditions (Scheme-1).

Ionic liquids (ILs) technology offers a new and environmentally benign approach toward modern synthetic chemistry [8]. ILs have been successfully employed as solvents and catalyst for a variety of reactions [9], which promise widespread applications in industry and organic syntheses [10]. [Et3NH][HSO4] was applied as dual solvent-catalysts in the hydrolytic reaction [11], and butylated hydroxytoluene [12]. [NMP][H2PO4] was used as dual solvent-catalyst for synthesis of AY-alkoxyketones by the oxa-Michael addition reactions [13].

{[Msim]Cl} can catalyzed the synthesis of N-sulfonyl imines[14], and the preparation of 1-amidoalkyl-2- naphthols [15]. [NMP][HSO4] was utilized in plasticizer ester synthesis [16], and 1,8-dioxo- octahydroxanthene [17]. [Hnhp][HSO4] was used for the esterification of acetic acid and butanol [18], and synthesis of 14-aryl-14H-dibenzoxanthene-8,13- dione, 3,4-dihydro-1H-benzoxanthene- 1,6,11(2H,12H)-trione, and aryl-5H- dibenzoxanthene-5,7,12,14(13H)-tetraone derivatives [19].

Equations

Experimental

All reagents were purchased from Merck and Aldrich and used without further purification. All yields refer to isolated pure products after purification. [Et3NH][HSO4] [11], [NMP][H2PO4] [13], {[Msim]Cl} [14], [NMP][HSO4] [16], [Hnhp][HSO4] [18] were prepared according to the literature procedure. The NMR spectra were recorded on a Bruker Avance DPX 500 MHz instrument. The spectra were measured in DMSO-d6 relative to TMS (0.00 ppm). IR spectra were recorded on a JASCO FT-IR 460 plus spectrophotometer. Melting points were determined in open capillaries with a BUCHI 510 melting point apparatus. TLC was performed on silica-gel Poly Gram SIL G/UV 254 plates.

General Procedure for the Synthesis of 4,6- diarylpyrimidin-2(1H)-ones

The mixture of arylaldehyde (1 mmol), acetophenone (1 mmol), urea (thiourea) (1.5 mmol), and A:{[Et3NH][HSO4] (5 mol%, 0.0099 g)}, B: {[NMP][H2PO4] (5 mol%, 0.0098 g)}, C: {{[Msim]Cl} (5 mol%, 0.0083 g)}, D: {[NMP][HSO4] (5 mol%, 0.009 g )}, E: {[Hnhp][HSO4] (5 mol%,0.0091 g)} as catalyst were mixed in an oil bath at 70 oC for the appropriated time. After completion of the reaction which was monitored by TLC, the mixture was cooled to room temperature and added water to dissolve ionic liquid. The solid product was separated and purified by recrystallization from ethanol. All of the desired product(s) were characterized by comparison of their physical data with those of known compounds. For recycling the catalysts, after washing solid products with water completely, the water containing ionic liquids (IL is soluble in water) was evaporated under reduced pressure and ionic liquids were recovered and reused.

The known products were characterized and compared for their physical properties (M.p, 1HNMR and IR) with authentic samples.

Selected spectroscopic data for two known compounds are given below: 4-(2-Chlorophenyl)-6-phenylpyrimidin-2(1H)-one (Table 2, entry 3)

Mp 220223 oC; IR (KBr, , cm-1): 3342, 3030, 2926, 1659, 1577, 1538, 1455, 1396, 1337, 1053, 994, 758, 689 cm-1; 1H NMR (500 MHz, DMSO-d6) (d, ppm): 7.24 (1H, s, C5-H), 7.547.57 (5H, m, ArH), 7.64 (2H, d, J=7.2 Hz, ArH), 8.14 (2H, d, J = 7.2 Hz, ArH), 12.24 (1H, s, NH).

4-(2,4-Dichlorophenyl)-6-phenylpyrimidin-2(1H)-one (Table 2. Entry 6)

Mp 223225 oC; IR (KBr, , cm-1): 3315, 3027, 2932, 1664, 1587, 1448, 1393, 1142, 1098, 995, 777, 689 cm-1, 1H NMR (500 MHz, DMSO-d6) (d, ppm): 7.557.69 (6H, m, ArH), 7.85 (1H, s, C5- H), 8.128.13 (2H, br, ArH), 12.26 (1H, s, NH).

Results and Discussion

Initial studies were carried out using the addition of acetophenone, 2-cholorobenzaldehyde and urea as model substrates to optimize the experimental conditions. The results are summarized in Table-1. First, the reaction was carried out by treating acetophenone (1 equiv), 2- cholorobenzaldehyde (1 equiv), and urea (1.5 equiv) in the presence of different catalytic amount of ionic liquids as catalyst (5 , 10, 15, 20 mol%) at different temperature ( 25, 40, 60, 70, 80 oC).The best results were obtained as A: [Et3NH][HSO4] (5 mol%, 70 oC), B: [NMP][H2PO4] (5 mol%, 70 oC), C: {[Msim]Cl}(5 mol%, 70 oC), D: [NMP][HSO4] (5 mol%, 70 oC), E: [Hnhp][HSO4] (5 mol%, 70 oC) under solvent-free conditions.

Table-1: Optimization conditions for the preparation of 4-(2-chlorophenyl)-6-phenylpyrimidin-2(1H)-one using acidic ionic liquids as catalyst such as A: [Et3NH][HSO4], B: [NMP][H2PO4], C: {[Msim]Cl}, D: [NMP][HSO4], E: [Hnhp][HSO4] under solvent-free conditions.

###Time (min)###Yield (%)a

###Entry###Catalyst (mol%)###Temp (oC)

###A###B###C###D###E###A###B###C###D###E

###1###5###80###6###5###7###4###4###88###94###87###97###96

###2###10###80###6###4###6###3###3###87###95###86###97###96

###3###15###80###5###4###6###3###3###88###95###87###98###97

###4###20###80###5###4###5###2###3###89###97###87###98###97

###5###5###25###_###_###_###_###_###Trace###Trace###Trace###Trace###Trace

###6###5###40###18###15###20###14###15###69###80###69###77###79

###7###5###60###10###8###12###5###7###77###87###78###88###88

###8###5###70###8###6###9###5###6###84###91###83###94###94

Table-2: Synthesis of 4,6-diarylpyrimidin-2(1H)-one derivatives in the presence of a catalytic amount of A: [Et3NH][HSO4], B: [NMP][H2PO4], C: {[Msim]Cl}, D: [NMP][HSO4], E: [Hnhp][HSO4] under solvent-free conditions

###Time (min)###Yield (%)a###Found m.p(C)

###Entry###Aldehyde###Lit. m.p (C) [Ref]

###X###A###B###C###D###E###A###B###C###D###E

###CHO

###232-238

###1###O###5###4###6###2###3###84###93###84###95###95

###233240 [20]

###CHO

###258

###2###O###5###4###6###3###3###89###95###88###97###97

###258260 [20]

###Cl

###CHO

###3

###Cl###O###6###5###7###4###4###88###94###87###96###96

###221

###220-223 [20]

###CHO

###209-211

###4###O###7###6###8###4###5###86###94###86###95###95

###210-212 [21]

###Cl

###CHO

###222

###5###O###6###5###8###3###4###86###93###86###96###97

###223-225 [21]

###Cl

###Cl

###CHO

###Cl

###293

###6###O###5###5###7###2###4###89###96###88###97###97

###greater than 290 [21]

###Cl

###CHO

###252-255

###7###O###6###4###7###2###3###82###91###83###94###93

###251254 [20]

###Br

###CHO

###258

###8###O###5###4###6###2###3###86###95###86###96###95

###258260 [21]

###OMe

###CHO

###287-291

###9###O###7###6###8###4###4###81###90###81###92###92

###287-290 [20]

###Me

###CHO

###287

###10###O###5###4###6###3###3###86###95###87###97###96

###287288 [20]

###CHO

###Cl

###224-226

###11###O###6###5###7###3###4###82###90###82###94###94

###223-225 [21]

###Cl

###CHO

###12

###Cl###S###9###8###11###9###10###72###82###71###84###83

###200-203

###200-205 [22]

###CHO

###219-228

###13###S###8###8###10###8###10###80###89###78###86###85

###220-230 [22]

###Cl

Next, a series of 4,6-diarylpyrimidin-2(1H)- ones were prepared using arylaldehydes, acetophenone, and urea (thiourea). Arylaldehydes carrying either electron-withdrawing or electron- donating groups afforded the corresponding 4,6- diarylpyrimidin-2(1H)-ones in high to excellent yields in short reaction times (Table-2).

According to the literatures [20, 22, 23], we propose a reaction mechanism for this transformation (Scheme-2).

The recovery of the catalyst is important via green organic synthesis. Thus, we also studied the recovery of the ionic liquids in the selected model. After completion of the reaction which was monitored by TLC, the mixture was cooled to room temperature and ionic liquids dissolved in water; the solid product was separated and purified by recrystallization from ethanol. For recycling the catalysts, after washing solid products with water completely, the water containing ionic liquids (ILs is soluble in water) was evaporated under reduced pressure and ionic liquids were recovered and reused. The reusable of ionic liquids acts well without any significant loss of their activities even after five run of recovery (Fig. 2).

In order to show the accessibility of the present work in comparison reported results in the literature such as sulfamic acid( H2NSO3H)/ trimethylsilyl chloride (TMSCl) [20], sodium hydroxide (NaOH) [21], Zeolite (H-BEA, H-Y) [22], (2,4,6-trichloro-1,3,5-triazine) (TCT)/ Zn(OTf)2 or Bi(OTf)3 [23], Bi(TFA)3 immobilized in [nbpy]FeCl4 {(Bi(TFA)3-[nbpy]FeCl4)}/ trimethylsilyl chloride (TMSCl) [24], trimethylsilyl chloride (TMSCl) / acetonitrile (CH3CN)/ (di methyl formaldehyde)DMF [25], H6P2W18O62 18H2O/ trimethylsilyl chloride (TMSCl) [26], iodine [27], H3PMo12O40 / trimethylsilyl chloride (TMSCl) [28], atomized sodium in THF under sonic condition [29], carbon- based solid acid (CBSA)/ trimethylsilyl chloride (TMSCl) [30], we summarized some of the results for the preparation of 4,6-diarylpyrimidin-2(1H)-ones in Table-3. Table-3 shows that A: [Et3NH][HSO4], B: [NMP][H2PO4], C: {[Msim]Cl}, D: [NMP][HSO4],

E: [Hnhp][HSO4] are efficient catalysts with respect to the reaction time and obtained yields relative to other catalysts reported in the literature.

Table-3: Comparison results of A: [Et3NH][HSO4], B: [NMP][H2PO4], C: {[Msim]Cl}, D: [NMP][HSO4], E: [Hnhp][HSO4] with H2NSO3H/ TMSCl, NaOH, Zeolite (H-BEA, H-Y), (TCT)/ Zn(OTf)2 or Bi(OTf)3, Bi(TFA)3-[nbpy]FeCl4 / TMSCl, TMSCl/ CH3CN/ DMF, H6P2W18O62 18H2O/ TMSCl , iodine, H3PMo12O40 / TMSCl, , atomized sodium /THF, carbon-based solid acid (CBSA)/ TMSCl, in the synthesis of 4,6- diarylpyrimidin-2(1H)-ones

Entry###Catalyst (mol%)###Conditions###Time (min)###Yield (%) [Ref]

1###H2NSO3H(5mol)/ TMSCl(1mmol)###solvent-free, 70 oC###15-60###90-98 [20]

2###NaOH(0.5mol %)###solvent-free, 70 oC###10-15###80-92 [21]

3###Zeolite (H-BEA, H-Y) (5 wt %)###Toluene (reflux)###20-30/60-70###71-88 [22]

###microwave irradiation

4###(TCT) (1mmol) / Zn(OTf)2 (10mol)or Bi(OTf)3 (1mol%)###10-15###79-94 [23]

###300W

5###Bi(TFA)3-[nbpy]FeCl4 (5 mol%)/ TMSCl(1mmol)###70 oC###1.30-2.40h###70-96 [24]

6###TMSCl(0.18 mol%)###CH3CN/DMF, 90 oC###12h###70-88 [25]

7###H6P2W18O6218H2O(1mol%)/ TMSCl(1mmol)###solvent-free, 70 oC###4-10###90-95 [26]

8###Iodine (5mol%)###solvent-free, 80 oC###5-15###90-96 [27]

9###H3PMo12O40(2 mol%)/ TMSCl(1mmol)###solvent-free, 70 oC###15-25###90-95 [28]

10###atomized sodium (2 mg atom)###THF , constant frequency/ 80 W###10-15###86-90 [29]

11###CBSA (0.03g) /TMSCl(1mmol)###solvent-free, 100 oC###25-40###90-95 [30]

###(81-86)

12###[Et3NH][HSO4] (5 mol%)###solvent-free, 70 C###5-7

###(Present work)

###(90-95)

13###[NMP][H2PO4] (5 mol%)###solvent- free, 70 C###4-6

###(Present work)

###(81-87)

14###{[Msim]Cl} (5 mol%)###solvent- free, 70 C###6-8

###(Present work)

###(92-97)

15###[NMP][HSO4] (5 mol%)###solvent- free, 70 C###2-4

###(Present work)

###(92-95)

16###[Hnhp][HSO4] (5 mol%)###solvent- free, 70 C###3-5

###(Present work)

Conclusion

In summary, We have developed an efficient, one-pot, three-component cyclocondensation of arylaldehydes, acetophenone, and urea (thiourea) in excellent yields under solvent- free and conventional heating conditions to get 4,6- diarylpyrimidin-2(1H)-ones using novel acidic ionic liquids A: [Et3NH][HSO4], B: [NMP][H2PO4], C: {[Msim]Cl}, D: [NMP][HSO4], E: [Hnhp][HSO4] as catalyst. The recovered ionic liquid was reused for five cycles without loss of its activities. This new methodology is accepted as green chemical processes in MCRs.

Acknowledgments

We are thankful to the University of Sistan and Baluchestan Research Council for the partial support of this research.

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