zro2-pillared clay: an efficient catalyst for solventless synthesis of biologically active...

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Catalysis Communications 7 (2006) 571–578

ZrO2-pillared clay: An efficient catalyst for solventless synthesisof biologically active multifunctional dihydropyrimidinones

Vasundhara Singh *, Varinder Sapehiyia, Vivek Srivastava, Sukhbir Kaur

Basic and Applied Sciences, University College of Engineering, Punjabi University, Patiala 147002, India

Received 21 July 2005; received in revised form 9 December 2005; accepted 9 December 2005Available online 3 March 2006

Abstract

A novel protocol using ZrO2-pillared clay (Zr-PILC), prepared by us as a mild recyclable solid acid catalyst for multicomponent one-pot synthesis of dihydropyrimidinones under solvent free conditions both by thermal and microwave heating using the Bronsted andLewis acidity (proposed mechanism) of Zr-PILC is reported. The efficacy of the procedure is exemplified by the synthesis of biologicallyactive racemic mixture of monastrol and nitractin (a potent lead anti-cancer drug and antibacterial, antiviral drug, respectively).� 2006 Elsevier B.V. All rights reserved.

Keywords: ZrO2-pillared clay; Solventless dihydropyrimidinones; MW; monastrol; nitractin

1. Introduction

The design of promising Lewis acid catalysts hasattracted considerable interest in organic synthesisbecause of their unique catalytic performances in organicreactions [1]. Despite the advantages of homogeneousmetal complex catalysts [2a,2b] difficulties in recoveringthe expensive catalyst, metals and ligands from the reac-tion mixture severely limit their industrial applications.The use of heterogeneous inorganic solid acid catalystsfor fixed bed reactor technology and large-scale produc-tion in place of homogeneous catalysts has the advantagesof easy recovery, recyclability, increased yields and selec-tivity. Cation exchanged and pillared clays have beenextensively used in organic synthesis as both Bronstedand Lewis acids by fine-tuning their physico-chemicalproperties [2c,2d].

The multicomponent reactions (MCRs) [3a] are attract-ing the interest of organic chemists and other researchersdue to their significant potential for converting more than

1566-7367/$ - see front matter � 2006 Elsevier B.V. All rights reserved.

doi:10.1016/j.catcom.2005.12.021

* Corresponding author. Tel.: +91 175 239 3303/304 6327; fax: +91 175236 4498/304 6324.

E-mail address: [email protected] (V. Singh).

two adducts directly into respective products in quantita-tive yields in a one-pot reaction as compared to conven-tional strategies used in multi-step synthesis of variousbiologically active organic compounds. The three-compo-nent Biginelli reaction [3b] is particularly attractive, sincethe resulting dihydropyrimidinone (DHPM) scaffold dis-plays a wide range of biological activity as antiviral, antitu-mor, antibacterial, anti-inflammatory [4a,4b] calciumchannel blockers, antihypertensive agents [4c] and as a1a

andenoceptor-selective antagonists [5]. Furthermore, the2-oxodihydropyrimidine-5-carboxylate-core unit is foundin many marine natural products including batzelladinealkaloids, which have been found to be HIVgp-120-CD4

inhibitors [6].Several procedures have been reported for the synthesis

of 3,4-dihydropyrimidinones using Lewis as well as proticacids as promoters such as BF3 Æ OEt2 [7a], polyphosphateesters (PPE) [7b], Indium chloride [7c], FeCl3 Æ 6H2O [7d],LaCl3 [8a], lanthanide triflates [8b], Zn(OTf)2 [8c], CAN,NH2SO3H (under ultrasound irradiation) [9a,9b], ionic liq-uids [9c] and other recent reports in literature [10]. Few het-erogeneous catalysts used to promote Biginelli reaction areFeCl3 supported on Si-MCM-41 [11a], Yb(III)-resin [11b],KSF clay [11c] and heteropolyacid [11d]. A variety of

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Table 1One-pot Biginelli condensation of benzaldehyde, ethylacetoacetate andurea using ZrO2-PILC under different reaction conditions

Entry Mode of activation Solvent Time (min) Conversion (%)

1 D (100 �C) Methanol 60 932 D (100 �C) No solvent 40 943 )))) Methanol 150 554 MW (630 W) No solvent 5 95

Table 2Comparison of various catalysts for solventless, selective multicomponentone-pot Biginelli condensation

Entry Catalyst Yield (%)

1 Mont. K-10 clay 522 KSF 503 b-H Zeolite 554 Fe3+-Mont.K-10 clay 705 Zr-PILC 92

N

N H

H

X

Ar

H3C

O

RO

R = CH3, C2H5; X = O or S; Ar = Aromatic

Fig. 1. DHPM.

572 V. Singh et al. / Catalysis Communications 7 (2006) 571–578

different combinatorial protocols based on the classicalBiginelli [12] have been developed [4a,4b] e.g., solution-phase methods [13a,13b] flourous-phase conditions [13c]and several solid-phase protocols in which different resin-bound building blocks and linker combinations have beenutilized [14a,14b,14c]. However, some of the reportedmethods suffer from drawbacks such as longer reactiontime, higher temperatures, expensive catalysts and theirlong preparation methods, lower yields and cumbersomeproduct isolation procedures. Uemura et al. [14d] haveexploited the Lewis acidity of Zr4+ ion exchanged clayfor the carbonyl-ene reaction.

In continuation with our work [15] on use of hetero-geneous acid catalysts in conjunction with non-conven-tional energy sources viz; ultrasound and microwavesto promote reactions, we herein, introduce a novel proto-col for the selective, efficient and solventless synthesis ofvarious DHPM derivatives using recyclable ZrO2-pillaredclay (Zr-PILC) by microwave irradiation. The ZrO2-pil-lared clay has been prepared by us in 30 min and isreported in the literature [15d]. For the model reactionas shown in Scheme 1 the conversion, yields and thereaction time for the formation of corresponding dihy-dropyrimidinone under various reaction conditions andusing different catalysts is summarized in Tables 1 and2, respectively.

It is clear from the results that the method (Table 1,entry 4) under solventless conditions by microwave irradi-ation using Zr-PILC gave the best results with respect toyield, conversion and with the advantage of manifoldreduction in reaction times. The percentage conversion ofthe methods (Table 1, entries 1 and 2) when the reactionmixture was heated at 100 �C with and without solvent isalso good, however, the reaction time taken is much longer.Also by sonochemical irradiation (Table 1, entry 3) thereaction takes longer time and gives product in lower yield.

2. Experimental

2.1. General reaction

In a typical reaction, freshly distilled benzaldehyde(265 mg, 2.5 mmol), ethylacetoacetate (325 mg, 2.5 mmol)and urea (225 mg, 3.75 mmol) were mixed with activatedZr-pillared clay (250 mg) in a 50 ml borosil beaker. Thereaction mixture in the beaker was covered with watchglass and irradiated in a domestic microwave oven at

O

O

O O

C2H5

O

NH2H2N

+,

Solventle

Catalyst

Scheme

power level 630 W for 5 min. On complete conversion,monitored by TLC, the product was dissolved in methanol,followed by mere filtration to remove the catalyst. Afterevaporating methanol under vacuo, crushed ice was addedto it and the solid product was scratched from ice-coldwater, filtered and dried. The pure product for 1H and13C NMR, and IR analysis was obtained by recrystalliza-tion from hot 95% ethanol.

In a similar fashion a variety of aromatic aldehydesunderwent three-component condensation smoothly togive products with general formula as shown in Fig. 1 toafford a wide range of substituted dihydropyrimidinonesand are given in Table 3. The catalyst was recycled threetimes after washing it with acetone and then activating at100–110 �C without any loss of activity and selectivity ofthe products formed.

ss NH

NHO

O

O

C2H5

MW

1.

Table 3Synthesis of various dihydropyrimidinones catalyzed by ZrO2-pillared clay under microwave irradiation in dry media (see Fig. 1)

Entry Reactants Product MW irradiation M.pt. (�C) Found/Lit. [Ref.]

Aldehyde R X Time (min) Yield (%)

1 CHO C2H5 O

NH

NH

O

O

O

H3C

H3C

5 94 205-206/ 203-205 [11d]

2 CHO

OCH3

C2H5 O

NH

NH

O

O

O

H3C

OCH3

H3C

6 95 202-204/ 201-202 [11d]

3 CHO

OCH3

OCH3

C2H5 O

NH

NH

O

O

O

H3C

OCH3

H3CO

H3C

7 87 172-175/ 176-177 [9a]

4 CHO

OCH3

OCH3H3CO

C2H5 O

NH

NH

O

O

O

H3C

OCH3

H3CO OCH3

H3C

7 85 210-216/ 217-219 [11d]

5 CHO

Cl

C2H5 O

NH

NH

O

O

O

H3C

Cl

H3C

5 97 210-213/ 213-215 [11d]

6 CHO

NO2

C2H5 O

NH

NH

O

O

O

H3C

O2N

H3C

5 90 225-226/ 227-228 [8c]

7 CHO

NO2

C2H5 O

NH

NH

O

O

O

H3C

NO2

H3C

5 95 207-209/ 208-211 [11d]

8 CHO

OCH3OH

CH3 O

NH

NH

O

O

H3CO

H3C

H3CO

OH 5 92 230-231/ 232-233 [9b]

(continued on next page)

V. Singh et al. / Catalysis Communications 7 (2006) 571–578 573

Table 3 (continued)



9 CHO CH3 O

NH

NH

O

O

H3CO

H3C

5 94 210-212/ 209-216 [8c]

10CHO

OCH3

CH3 O

NH

NH

O

O

H3CO

H3C

OCH3 6 93 193-195/ 192-194 [9b]

11 CHO

OCH3

C2H5 S

NH

NH

S

O

O

H3C

OCH3

H3C

5 92 150-152/ 150-152 [11d]

12 CHO

Cl

C2H5 S

NH

NH

S

O

O

H3C

Cl

H3C

5 95 192-195/ 192-194 [11d]

13 CHO

Cl

CH3 O

NH

NH

O

O

H3CO

H3C

Cl 5 98 204-205/ 204-207 [9b]

14 CHO

NO2

CH3 O

NH

NH

O

O

H3CO

H3C

O2N 6 90 239-241/ 240-241 [8c]

15 CHO

NO2

CH3 O

NH

NH

O

O

H3CO

H3C

NO2 6 93 229-233/ 231-232 [8c]

16

O NO2OHC

CH3 O

NH

NH

O

O

H3CO

H3C

O

NO2 5 87 187-189/ –


Table 3 (continued)



17

HO

CHO C2H5 S

NH

NH

S

O

O

H3C

HO

H3C

5 90 180-183/183-185 [17b]


2.1.1. Synthesis of nitractin and monastrol

As early as the 1940s DHPMs (Fig. 1) were known topossess antiviral activity. Eventually, the nitrofuryl-substi-tuted analog nitractin (Fig. 2) was developed, which dis-played good activity against the viruses of the trachomagroup [16] in addition to showing modest antibacterialactivity. Mayer et al. have recently identified the structur-ally rather simple DHPM monastrol (Fig. 3) by screeninga 16,320-member library of diverse small molecules as anovel cell-permeable molecule that blocks normal bipolarmitotic spindle assembly in mammalian cells and thereforecauses cell cycle arrest [17]. Monastrol is the only moleculecurrently known to inhibit mitotic Kinesin Eg5 specificallyand can therefore be considered as a lead for the develop-ment of new anticancer drugs.

Using our developed methodology, we have synthesizedthe target molecules nitractin and monastrol in high yieldof 87% and 90% using Zr-PILC as solid acid catalystassisted by MW irradiation shown in Table 3 (entry num-ber 16 and 17), respectively.

2.1.1.1. Spectral data of nitractin. IR (KBr)/mmax cm � 1:3343, 3211, 2920, 1650, 1580, 1265, 1130.

1H NMR (CDCl3/[D6] DMSO) d: 9.30 (bs, 1H, –NH),7.82 (bs, 1H, –NH), 7.35 (d, J = 3.5 Hz, 1H, –Ar), 6.46 (d,1H, J = 3.5 Hz, –Ar), 5.45 (d, 1H, J = 3.19 Hz, –CH), 3.67(s, 3H, –COOCH3), 2.39 (s, 3H, –CH3).

NH

NH

O

O

H3CO

H3C

O

NO2

Fig. 2. Nitractin.

NH

NH

S

O

O

H3C

HO

H3C

Fig. 3. Monastrol.

13C NMR (CDCl3/[D6] DMSO) d: 164.59, 158.52,151.76, 150.27, 149.99, 112.35, 112.14, 108.49, 50.18,47.49, 17.22.

2.1.1.2. Spectral data of monastrol. IR (KBr)/mmax cm � 1 :3460, 3300, 3180, 2900-2600, 1675, 1650, 1620, 1575, 1215.

1H NMR (CDCl3/[D6] DMSO) d: 10.19 (bs, 1H, –NH),9.52 (bs, 1H, –NH), 9.33 (bs, 1H, –OH), 6.67–6.98 (m, 3H,–Ar), 7.06–7.11 (m, 1H, –Ar), 5.13 (d, 1H, J = 3.3 Hz, –CH–), 4.03 (q, 2H, J = 6.8 Hz, –OCH2–), 2.31 (s, 3H, –CH3), 1.15 (t, 3H, J = 6.9 Hz, –OCH2–CH3).

13C NMR (CDCl3/[D6] DMSO) d: 174.19, 165.11,157.36, 144.77, 144.52, 129.13, 117.02, 114.52, 113.31,100.88, 59.39, 54.05, 54.05, 17.14, 13.94.

2.2. Comparison of Zr-PILC with KSF, bH-HPZ, Mont.K-10 clay and Fe3+-Mont. K-10 clay for solventless one-pot

multicomponent condensation reaction under microwave

irradiation

The effect of different solid acid catalysts on this one-potcondensation reaction was studied using fresh distilledbenzaldehyde 265 mg (2.5 mmol), ethylacetoacetate 325mg (2.5 mmol) and urea 225 mg (3.75 mmol) as modelreaction and results are summarized as shown in Table 2.

2.3. General details

1H NMR was recorded in CDCl3/[d-DMSO] on a300 MHz Bruker instrument using TMS as the internalstandard reference. IR spectra were recorded on a Per-kin–Elmer 337 spectrometer. Microwave irradiation car-ried out in a domestic microwave oven, BPL BMO 700T,India operating at maximum power level of 9 (630 W).The ZrO2-pillared clay was prepared by pillaring of Na+-montmorillonite clay sample provided by Kunimine Co.Ltd. Japan. Montmorillonite K-10 clay and Montmorillon-ite KSF clay were purchased from Aldrich Chemical Com-pany, USA. b-H Zeolite (bH-HPZeolite type) waspurchased from KEMEFS VALUE ADDITIVES PVT.LMT., Mumbai (INDIA). b-H Zeolite has a surface areaof (BET) 700 m2/g and crystal size (SEM) 0.2–0.4 lm. Itis a crystalline alumino silicate, which can be used as ahighly acidic, shape selective catalyst, has high thermalstability, is acid resistant and regenerable. ZrOCl2 Æ 8H2Owas purchased from S.D. Fine Chemicals, India. For

O H

R

H2N

O

NH2

ZrO2-PILC

NH

O

NH2

OH

R

H2O

HN

O

NH2

H

R

ZrO2PILC

O

H3C

O

OC2H5

ZrO2

NH

OO

H2N

R

H3C

O

C2H5O

H2ONH

O

O

C2H5O

NH

R

H3C

Exploitation of Bronsted acidity

Exploitation of Lewis acidity

I

II

III

IV

VVI

VII

+

+ N

O:

NH2

H

R

H+

-H+

+

H

Fig. 4. Plausible mechanism.


sonochemical intercalation, model 3150 DTH (BransonCleaning Bath, USA) was used. XRD analysis was doneusing Rigaku D-Max IIIC using Ni-filtered Cu Ka radia-tion. X-ray fluorescence dispersive spectrophotometer wasused to find the zirconium content. BET equation was used

Table 4Comparison of different catalysts reported in literature for multicomponent o

S. No. Catalyst Mode ofactivation

Solvent

1 Mont. KSF D C6H5CH3 an2 NH2SO3H )))) C2H5OH3 Ag3PW12O40 D H2O4 Zn(OTf)2 D CH3CN5 LaCl3 Æ 7H2O D C2H5OH/H+

6 Ionic liquids: BMImBF4

and BMImPF6

D No solvent

7 FeCl3 over Si-MCM-41 MW No solvent8 Lanthanide triflates D H2O

CH3CNH2O-THFC6H5CH3

THFCH2Cl2No solvent

9 Mn(OAc)3 Æ 2H2O D CH3CN10 Yb(III)-resin and polymer scavengers D No solvent11 CAN (ceric ammonium nitrate) )))) CH3OH12 HCl and piperidine MW and

stirringC2H5OH

13 SnCl2 Æ 2H2O D CH3OH, CH14 ZrO2-pillared clay MW No solvent

to obtain the surface area from the nitrogen adsorption iso-therms done on Coulter SA3100 instrument. The averagepore diameter of PILMNT-MW10-US20 was calculatedusing the BJH method. The crystallite sizes were calculatedusing the Scherrer equation [15d].

ne-pot Biginelli condensation reaction

Temperature orPower level

Time Conversion(%) [Ref.]

d H2O 100 �C 10–48 h 70–88 [11c]25–30 �C 40–60 min 62–97 [9]80 �C 3–4.5 h 95–100 [11d]Refluxing 4.5–6 h 71–92 [8c]Refluxing 5 h 56–97 [8a]100 �C 0.5 h 56–97 [9c]

– 3–5 min 90 [11a]100 �C 20–40 min 24 [8b]

83 [8b]28 [8b]95 [8b]56 [8b]22 [8b]95–99 [8b]

Refluxing 2–4 h 75–96 [10e]120 �C 48 61–80 [11b]r.t. (room temperature) 3–9 h 84–92 [9]MW (HCl) 5 min 50–60 [10c]

24–36 h(product separation)

Stirring (r.t.) 4 h(piperidine) 24–36 h

(product separation)

3CN Refluxing 5–7 h 80 [10a,10b]630 W 4–7 min 85–98


3. Results and discussion

3.1. Plausible mechanism

We propose a plausible mechanism as shown in Fig. 4.The overall reaction cycle has been divided into two halves.In the first half of the cycle, Bronsted acidity of the catalysthas been exploited for formation of an acyl imine (IV) viaintermediate (III) by the reaction between aldehyde andurea as the key rate-limiting step. In the second half onthe cycle, it can be regarded as the addition of a p-nucleo-phile, ethyl acetoacetate enolate to the electron deficientN-acyliminium ion intermediate (IV), which are stabilizedby the Lewis acid site of ZrO2-pillars in Zr-PILC catalyst.Interception of the iminium ion (IV) by ethylacetoacetate,possibly through its enol tautomer, produces an open chainureide (VI), subsequently cyclizes to the desired 3,4-dihy-dropyrimidinone (VII). The mechanism suggests that thesynergistic action of the Bronsted and Lewis acid sites inZr-PILC promotes the Biginelli reaction. This observationis supported by the lower yields of the product obtained byreaction with K10 clay, KSF clay and b-H zeolite whichexhibit predominantly good Bronsted acidity. Low conver-sion level in case of Fe3+-K10 clay than Zr-PILC was unex-pected as it has both Bronsted and Lewis acid sites. Thiscan be accounted for likely due to the pore diffusion limita-tion in Fe3+-K10 clay, a cation exchanged clay, as com-pared to pillared clay catalyst having a large interlayerspacing of d0 0 1 = 22.1 A and surface area of 224.2 m2/g.The amount of the catalyst used was also studied rangingfrom 0.050 to 0.400 g. However, the best results wereobtained with 0.250 g Zr-pillared clay. Further increase inits quantity upto 0.400 g gave the similar results asachieved with 0.250 g Zr-PILC. It is also proposed thatsince the acidity is confined to the interlayer space in theZr-PILC catalyst with relatively large channels it providesa precisely defined, but flexible, microenvironment as aselective acid catalyst.

3.2. A Comparison with reported procedures is as given in

Table 4

A comparative study with the literature reported meth-ods and protocols for Biginelli reaction to synthesize vari-ous multifunctionalized dihydropyrimidinones is compiledin Table 4 to show the efficacy and efficiency of the catalystand is given in the supplementary information.

4. Conclusion

In conclusion, a simple, solventless and efficient method-ology for the synthesis of various biologically active dihy-dropyrimidinones using a recyclable Zr-PILC catalystaccelerated by microwave irradiation has been developed.The synthesis of monastrol and nitractin has also beenachieved. Enantioselective and diversity oriented synthesisof this class of compounds is underway.

Acknowledgements

The authors are grateful to CSIR New-Delhi for award-ing fellowship (V.S.). The corresponding author (V.S.)thanks All India Council for Technical Education (AICTE),New Delhi for the Young Teachers Career award for youngteachers (CAYT). We are thankful to Mr. Avtar Singh(RSIC, Chandigarh) for the NMR spectral analysis.

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zro2-pillared clay: an efficient catalyst for solventless synthesis of biologically active...

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