Mpi

ISL

a

ARRAA

KBMPCS

1

npradat[tpnhdcCaepm

1h

Journal of Molecular Catalysis A: Chemical 382 (2014) 126– 135

Contents lists available at ScienceDirect

Journal of Molecular Catalysis A: Chemical

j ourna l ho me pa g e: www.elsev ier .com/ locate /molcata

icrowave accelerated facile and efficient synthesis ofiperido[3′,4′:5,6]pyrano[2,3-d] pyrimidinones catalyzed by basic

onic liquid [BMIM]OH

.R. Siddiqui ∗, Arjita Srivastava, Shayna Shamim, Anjali Srivastava, Malik A. Waseem,hireen, Rahila, Afaf A.H. Abumhdi, Anushree Srivastava, Pragati Rai

aboratory of Green Synthesis, Department of Chemistry, University of Allahabad, Allahabad 211002, India

r t i c l e i n f o

rticle history:eceived 14 March 2013eceived in revised form 15 October 2013ccepted 20 October 2013vailable online 9 November 2013

a b s t r a c t

A basic ionic liquid [BMIM]OH could very efficiently catalyze the synthesis ofpiperido[3′,4′:5,6]pyrano[2,3-d]pyrimidinone derivatives from pyrano[3,2-c]piperidine analoguesand carbonyl compounds. [BMIM]OH acted as a catalyst as well as the reaction medium and could beused for the reactions for five times without any appreciable loss of its catalytic efficiency. The synergiccouple of microwave and ionic liquid provided high yields of the product in very short reaction times

eywords:asic ionic liquidicrowave

yrimidinoneatalyst

and allowed easy workup.© 2013 Elsevier B.V. All rights reserved.

ynthesis

. Introduction

Fused pyrimidinones, specially tricyclic condensed pyrimidi-one derivatives represent structural architectures of remarkablehysiological efficiency and are found in a number of natu-al products and clinical drugs [1]. Pyrano[2,3-d]pyrimidinonesnd their fused variants, in particular, exhibit a wide range ofiverse biological properties such as antitumor [2], antibacterial [3],ntihypertensive [4], hepatoprotective [4], cardiotonic [4], antihis-aminic [5], vasodilatory [6], bronchodilatory [6] and antiallergic7] activities. Most of these pharmacological activities are due tohe presence of the annulated uracil species. Nevertheless, theharmacological properties of polycyclic derivatives of pyrimidi-ones have been less well explored so far. Although few protocolsave been reported for the synthesis of pyrano[2,3-d]pyrimidinoneerivatives, most of them make use of conventional and hazardousatalysts and bases [8] such as p-TsCl, ZnCl2, YbCl3, and bases likea(OH)2, NaOH and Et3N. Most of these catalysts and bases areccompanied with drawbacks like highly toxic and corrosive prop-

rties, environmentally hazardous nature, etc. and they also do notrovide for recyclability and reuse. Further, most of the reportedethods use organic solvents such as DCM, DMF, CH3CN, etc. which

∗ Corresponding author.E-mail address: dr.irsiddiqui@gmail.com (I.R. Siddiqui).

381-1169/$ – see front matter © 2013 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.molcata.2013.10.026

are known to have hazardous effect on the environment [9]. Thereaction reported by Pandey et al. [9b] uses l-proline for the syn-thesis of pyrimidinone derivatives but a very long reaction time isrequired.

As part of eco-compatible organic transformations, ionic liquids(IL) have received substantial interest from the synthetic com-munity [10,11] owing to their properties like negligible vapourpressure, lack of flammability, wide solvation ability, high stabil-ity, ability to synergistically interact with microwave irradiation,etc. [12,13]. Today, ionic liquids offer their potential in controllinga reaction as a catalyst as well as playing a role in rate enhancementof a reaction [14]. The association of reactant molecules in solventcavities due to the internal pressure created by ionic environmentof the ionic liquid is probably responsible for the rate enhance-ment. Basic ionic liquids have attracted huge interest for a longtime by virtue of their catalytic efficiency and their easy recov-ery and reuse as compared to the combination of a base and ILfor a base-catalysed process [15]. A basic ionic liquid [BMIM]OH(1-butyl-3-methylimidazolium hydroxide) has been successfullyemployed as a catalyst for Michael addition [16], Knoevenagelcondensation [17], Markovnikov addition, and a number of otherreactions [18]. It has very successfully replaced conventional bases

as it is flexible, non-volatile and non-corrosive. In continuationof our program to develop simple, efficient, atom economicaland eco-compatible protocols for the synthesis of novel poten-tially bioactive heterocycles [19], we report herein an efficient,

I.R. Siddiqui et al. / Journal of Molecular Catal

NH3C

R1

O

R1

NH2

CN [BMIM] OHNH3C

R1O

R1

NH

HN

O

R2 R3

O

(6)R2R3

5

MW(10 -18 min)

S

fod[t

hal

2

2

hlmbutd(teSctAtpta

2

a

2

C31

7 and 8

cheme 1. Synthesis of novel piperido[3′;4′:5,6]pyrano[2,3-d]pyrimidinone.

acile, microwave-assisted and [BMIM]OH catalyzed synthesisf novel substituted piperido[3′,4′:5,6]pyrano[2,3-d]pyrimidinoneerivatives from pyrano[3,2-c]piperidine analogues (Scheme 1).BMIM]OH plays the dual role of a solvent as well as a catalyst inhe reaction.

The starting material pyrano[3,2-c]piperidine analogues (5)ave been obtained by the reaction of N-methyl piperidone (1),romatic aldehyde (2) and malononitrile (4) using the basic ioniciquid [BMIM]OH (Scheme 2).

. Experimental

.1. Materials and Instruments

The starting material N-methyl piperidone (1), aromatic alde-ydes (2a-f and 6k-o), ketones (6a-j), malononitrile (4), ionic

iquids [BMIM]Br and [BMIM]Cl are commercially available. Theonomode microwave reactor “Monowave 300” (manufactured

y Anton-paar Pvt. Ltd.) was used in all reactions. The instrumentses a maximum of 850 W magnetron output power (2.45 GHz). Theemperature was recorded using IR temperature sensor. The irra-iation experiments were performed in temperature control mode“as-fast-as-possible”, ramp mode). The reaction times reported arehe ‘hold times’. Care was taken to ensure efficient stirring in allxperiments. All the pH values were measured on Eutech’s Cyber-can pH 510 meter. Melting points were determined by open glassapillary method (uncorrected). 1H and 13C NMR spectra of the syn-hesized compounds 5a-f, 7a-o and 8a-e were recorded on a Brukervance II (400 MHz) FT spectrometer at 400 and 100 MHz, respec-

ively, with CDCl3 as solvent. Chemical shifts are reported in partser million relative to TMS as internal reference. Mass (EI) spec-ra were recorded on JEOL D-300 mass spectrometer. Elementalnalysis was performed on an Elementar vario EL.

.2. Preparation of catalytic basic ionic liquid [BMIM]OH

The basic ionic liquid [BMIM]OH was synthesized according to reported procedure [16].

.3. Characterisation of [BMIM]OH

IR (neat) 3435, 3060, 1569, 1168 cm−1; 1H NMR (400 MHz,DCl3) ı = 0.81 (t, 3H), 1.17–1.35 (m, 2H), 1.73–1.85 (m, 2H),.20–3.27 (bs, 1H), 4.02 (s, 3H), 4.24 (t, 2H), 7.46 (d, 1H), 7.59 (d,H), 10.17 (s, 1H); 13C NMR (100 MHz) ı = 13.3, 19.0, 31.6, 36.4, 49.3,

NCH3

O

NCH3

OR 1-CHO

(2) R1 R1

1 3

[BMIM]OH rt (10) min

Scheme 2. Synthesis of the starting materia

ysis A: Chemical 382 (2014) 126– 135 127

122.1, 123.6, 136.8; HRMS calcd for C8H16N2O (M+−OH) 139.2182,found 139.2355.

2.4. Preparation of solid supported ionic liquid

The basic ionic liquid [BMIM]OH was also used on polystyreneresin as a solid support in order to examine its efficiency. This solidsupported ionic liquid was synthesized according to a reportedprocedure [20].

2.5. Preparation of other basic ionic liquids

The basic ionic liquids 1-butyl-2,3-dimethylimidazoliumhydroxide [BMMIM]OH has been synthesized from [BMMIM]Brusing the same procedure as used for [BMIM]OH. [BMMIM]Br hasin turn, been synthesized following a reported procedure [21]. Theother basic ionic liquids, [BMIM]Im (1-butyl-3-methylimidazoliumimdazolide), [DBU]Ac (1,8-diazabicyclo[5.4.0] undec-7-eniumacetate), [C8DABCO]NTf2 (1-octyl-1,4-diaza[2.2.2]bicyclooctan-iumbis(trifluoromethylsulfonyl)imide, and 2-[2-(dimethylamino)ethoxy]ethyl-N,N-diisopropylammonium bis(trifluoromethane-sulfonyl)imide (Fig. 1) have been synthesized according to reportedprocedures [22–24].

2.6. General procedure for the synthesis of2-amino-3-cyano-5,6,7,8-tetrahydro-4H-pyrano[3.2-c]piperidine 5a

A mixture of 1-methyl-4-piperidone 1 (0.01 mol) and the appro-priate aldehyde 2a (0.02 mol) in basic ionic liquid [BMIM]OH wasstirred at room temperature for 10 min. The separated solid was fil-tered and recrystallized from the suitable solvents. The separatedsolid (0.01 mol) and malononitrile (0.01 mol) in [BMIM]OH wasstirred at room temperature for 1.5 h. The precipitated product wasfiltered off and recrystallized to yield 2-amino-3-cyano-5,6,7,8-tetrahydro-4H-pyrano[3.2-c]piperidine 5a in good to excellentyields.

2.6.1. 5a:(E)-2-amino-3-cyano-4-(4-chlorophenyl)-6-methyl-8-(4-chlorobenzylidene)-5,6,7,8-tetrahydro-4H-pyrano[3,2-c]pyridine

Yield 80%; m.p. = 216–219 ◦C; 1H NMR (400 MHz, CDCl3): ı = 2.27(s, 3H), 3.06 (s, 4H), 3.94 (s, 1H), 6.42 (s, 1H, NH), 6.57 (s, 1H),7.00–7.15 (m, 4H), 7.22–7.24 (m, 4H). 13C NMR (100 MHz, CDCl3):ı = 40.9, 44.2, 52.2, 52.4, 58.1, 106.5, 117.3, 124.3, 127.8, 128.8,130.5, 131.3, 133.3, 133.5, 136.9, 140.3, 146.6, 159.3. Anal. Found:C, 65.13; H, 4.49; N, 9.92 C23H19Cl2N3O requires C, 65.10; H, 4.52;N, 9.90.

2.7. General procedure for the preparation ofpiperido[3′,4′:5,6]pyrano[2,3-d]pyrimidinone 7b catalyzed by

basic ionic liquid [BMIM]OH

A solution of corresponding 2-amino-3-cyano-5,6,7,8-tetra-hydro-4H-pyrano[3.2-c]piperidine 5a (1.0 mmol); cyclohexanone

[BMIM] OHrt (1.5 h)

NH3C

R1

O

R1

NH2

CN

H2C

CN

CN(4)

5

l pyrano[3,2-c]piperidine derivative.

128 I.R. Siddiqui et al. / Journal of Molecular Catalysis A: Chemical 382 (2014) 126– 135

N N

OH[BMIM]OH

N N

OH[BMMIM]OH

N N

N N

[BMIM]Im

N

N

H

CH3COO

[DBU]Ac

N N

N(SO2CF 3)2

[C8DABCO]NTf 2

N(SO2CF 3)2

2-[2-(dimethylamino)ethoxy]ethyl-N,N-diisopropylammonium lfonyl)imide

NO

N

c Liquids synthesized.

6vpapp

2c[

(111415

2

Eaoatiim

2ps

i

bis(trifluoromethanesu

Fig. 1. Basic Ioni

b (1.3 mmol) and [BMIM]OH (2 mL) was added in a 10 mL reactionial, sealed and irradiated at 90 ◦C for 10 min (hold time). After com-letion of the reaction as monitored by TLC, the mixture was coolednd the resulting precipitate was filtered, washed with brine, andurified by column chromatography (7:3 EtOAc:hexane) to yieldure target product 7b.

.7.1. 7b: 8′-(4-chlorobenzylidene)-1′-methyl-5′-(4-hlorophenyl)spiro[cyclohexane-1,2′-piperido3′,4′:5,6]pyrano[2,3-d]pyrimidine]-4′(1′H)-one

Reddish brown powder. Yield 93%; m.p. = 305–307 ◦C; 1H NMR400 MHz, CDCl3): ı = 1.12–1.23 (m, 2H), 1.37–1.49 (m, 4H),.60–1.77 (m, 4H), 2.29 (s, 3H), 3.03 (s, 4H), 3.97 (s, 1H), 6.46 (s,H, NH), 6.58 (s, 1H), 7.03–7.18 (m, 4H), 7.23–7.25 (m, 4H), 8.13 (s,H, NH). 13C NMR (100 MHz, CDCl3): ı = 19.2, 28.0, 29.7, 36.3, 44.0,9.7, 52.4, 52.5, 82.0, 106.5, 124.3, 127.6, 128.7, 130.5, 131.5, 133.4,33.7, 136.9, 140.4, 146.6, 166.7, 168.3. Anal. Found: C, 66.62; H,.55; N, 8.01 C29H29Cl2N3O2 requires C, 66.67; H, 5.55; N, 8.03.

.8. Recycling of [BMIM]OH

The filtrate containing ionic liquid was extracted with 1:1tOAc–Et2O solution using a seperatory funnel, dried in vacuumt 90 ◦C for 2 h to eliminate any water trapped from moisture tobtain the pure ionic liquid (confirmed from spectroscopy data)nd reused for subsequent reactions (Fig. 2). This could be used forhe reactions for up to five times without any appreciable loss ofts catalytic efficiency. After five runs, about 50% freshly preparedonic liquid was added and the mixture proved very efficient for

any more reactions.

.9. General procedure for the preparation ofiperido[3′,4′:5,6]pyrano[2,3-d]pyrimidinone 7b catalyzed by

olid supported basic ionic liquid

For a typical reaction process, the solid supported basiconic liquid (75 mg-optimized), 2-amino-3-cyano-5,6,7,

Fig. 2. aIsolated yields of the product.

8-tetrahydro-4H-pyrano[3.2-c]piperidine 5a (5.0 mmol); cyclo-hexanone 6b (6.5 mmol) were charged into a 30 mL reaction vial,sealed and irradiated at 90 ◦C for 10 min (hold time). After comple-tion of the reaction as monitored by TLC, the mixture was cooledand the resulting precipitate was filtered, washed with brine, andpurified by column chromatography (7:3 EtOAc:hexane) to yieldpure target product 7b.

3. Results and discussion

N-Methyl piperidone (1), 4-chlorobenzaldehyde 2a and mal-ononitrile (4) were chosen as model substrates for the synthesisof the starting material 5a. The formation of 5a was achieved atroom temperature by a two step reaction sequence catalyzed by[BMIM]OH. The reaction between model substrates pyrano[3,2-c]piperidine derivative 5a and cyclohexanone 6b was then carriedout smoothly and provided the best yields (93%) under microwave

irradiation in the presence of basic ionic liquid [BMIM]OH as thesolvent-basic catalyst system.

Catal

3c

ml1wyTu(etp2Ct[daoyb2brwrsaboaf

TS

C

a

I.R. Siddiqui et al. / Journal of Molecular

.1. Solvent, base and temperature screening for the synthesis ofompound 7b

In order to explore the effects of other ionic liquids on thisicrowave accelerated reaction, different combinations of ionic

iquids such as 1-butyl-3-methylimidazolium chloride ([BMIM]Cl),-butyl-3-methylimidazolium bromide ([BMIM]Br), and a baseas used. Surprisingly, both the combinations resulted in very low

ields of the product. The results have been summarized in Table 1.he combination of [BMIM]Br with DBU (1,8-diazabicyclo[5.4.0]ndec-7-ene) gave only 40% yield in 20 min of irradiation time,Table 1, entry 4) and that of [BMIM]Cl gave 44% yield (Table 1,ntry 5). As a comparison, the reaction was also carried out inhe common molecular solvents such as MeOH and DMF whichrovided 24% and 37% yields respectively (Table 1, entries 1 and) whereas the reaction could not proceed in the presence ofH3CN (Table 1, entry 3). Several other basic ionic liquids knowno act as a basic catalyst such as [BMIM]Im [22], [DBU]Ac [23],C8DABCO]NTf2 [24], 2-[2-(dimethylamino)ethoxy]ethyl-N,N-iisopropylammonium bis(trifluoromethanesulfonyl)imide [24]nd [BMMIM]OH [25] were also synthesized and their effectsn the reaction were studied. [BMMIM]OH although gave betterields (80%) (Table 1, entry 9) but the best yields were obtainedy [BMIM]OH (93%) (Table 1, entry 6). [BMIM]Im, [DBU]Ac and-[2-(dimethylamino)ethoxy]ethyl-N,N-diisopropylammoniumis(trifluoromethanesulfonyl)imide gave 54%, 41% and 15% yieldsespectively (Table 1, entry 10, 11 and 13). No product formationas observed in case of [C8DABCO]NTf2 (Table 1, entry 12). The

esults clearly indicate that [BMIM]OH was the most effectiveolvent-catalyst system for the transformation and it effectivelyvoided the use of any other base or solvent in the reaction. This

asic ionic liquid provided excellent yields of the product undernly 10 min of microwave irradiation (Table 1, entry 6) and causedn increase in the reaction rate as well. The irradiation time wasound to have a significant impact on the yield. When the reaction

able 1olvent, base and temperature screening for the synthesis of compound 7b under microw

N

O

CN

NH2

l

Cl

H3CN

O

H3C

Cl

Cl

NH

HN

O

7b

(6a)

O

5a

Solvent/BaseMW

Entry Solvent Base

1 MeOH DBU

2 CH3CN DBU

3 DMF DBU

4 [BMIM]Br DBU

5 [BMIM]Cl DBU

6 [BMIM]OH –

7 [BMIM]OH –

8 [BMIM]OH –

9 [BMMIM]OH –

10 [BMIM]Im –

11 [DBU]Ac –

12 [C8DABCO]NTf2 –

13 2-[2(dimethylamino)ethoxy]ethyl-N,N-diisopropylammoniumbis(trifluoromethanesulfonyl)imide

–

Reaction conditions: pyrano[3,2-c]piperidine derivative 5a (1.0 mmol), cyclohexanone 6b Isolated yields after filtration and purification.

ysis A: Chemical 382 (2014) 126– 135 129

time was shortened to 5 min, only 72% yield was obtained (Table 1,entry 7). The increase in reaction time, however, did not affect theyield of the product (Table 1, entry 8).

3.2. Probable reaction mechanism

The increase in the reaction rate and yields in the presenceof [BMIM]OH and the fact that it remained intact (1HNMR) andwas recycled and reused easily, clearly indicate that [BMIM]OHplayed a major part in the reaction as a catalyst as well as thereaction medium. Studies have shown that ionic liquids owing totheir ionic nature are capable of many types of interactions withthe solute species and transition states, which effectively reducesthe activation energies, thus catalyzing the reaction [26]. In thecase of [BMIM]OH, it has also been reported that the C2-H of theimidazolium group is capable of forming hydrogen bond and thusinfluences the reaction [27] and the hydroxy group of [BMIM]OHis well known to assist the formation of nucleophilic anions [28].Buoyed from the above facts, a reaction mechanism has been pos-tulated in which it has been assumed that the hydroxyl group ofthe basic ionic liquid activates the intermediate I by abstractingits proton and thus making it a better nucleophile in the reactionand the proton of the imidazolium group (C2-H) forms hydrogenbonding with the nitrogen of the nitrile group and thus increasesits electrophilicity for the intramolecular nucleophilic attack. Forfurther insight into its catalytic activity, we designed another ionicliquid [BMMIM]OH, and as expected, it provided only 80% yieldof the product in 15 min of irradiation time (Table 1, entry 9).There remains a possibility of weaker hydrogen bonds involvingany other hydrogen of [BMMIM]OH. This proves that the C2-H of[BMIM]OH plays a significant role in the reaction. The possible role

of [BMIM]OH is shown in the proposed mechanism (Scheme 3).

The amino group of the pyrano[3,2-c]piperidine derivativereacts with the carbonyl of cyclohexanone to give key interme-diate I. [BMIM]OH catalyzes the intramolecular Pinner reaction by

ave irradiation.a

Amount of base (equiv.) Time (min) Yieldb (%)

1.5 25 241.5 25 -1.5 25 371.5 20 401.5 25 44– 10 93– 5 72– 15 93– 15 80– 17 54– 23 41– 25 –– 21 15

b (1.3 mmol), solvent (2 mL).

130 I.R. Siddiqui et al. / Journal of Molecular Catalysis A: Chemical 382 (2014) 126– 135

N

O

H3C

Cl

Cl

NH2

CN

O

N

O

H3C

Cl

Cl

HN

N

O

N NH3C C4H9

OH

H2O

N

O

H3C

Cl

Cl

HN

N

O

N NH3C C4H9

H

N

O

H3C

Cl

Cl

O

HN

N

HO

H

N

O

H3C

Cl

Cl

O

HN

NH

N

O

H3C

Cl

Cl

NH

HN

O

Dimroth Rearrangement

N NH3C C4H9OH

H

I5a

6b

aqIropeptn

3

mT(t

TE

Table 3Comparison of solid supported ionic liquid with non-supported ionic liquids.

Entry Ionic liquid Product yield (%)

1 Polystyrene bound [BMIM]OH 802 [BMIM]OH 933 [BMIM]Im 544 [DBU]Ac 415 [C8DABCO]NTf2 –6 2-[2-(Dimethylamino)ethoxy]ethyl- 15

II7b

Scheme 3. Postulated mechanism of the reaction.

bstracting the proton of the hydroxyl group from I which subse-uently attacks the nitrile group to give the cyclised intermediate II.

ntermediate II under the reaction conditions undergoes Dimrothearrangement to furnish the final product. The smooth conversionf pyrano[3,2-c]piperidine derivative 5a and cyclohexanone intoiperido[3′,4′:5,6]pyrano[2,3-d]pyrimidinone 7b with high atomconomy via Pinner reaction and Dimroth rearrangement in theresence of [BMIM]OH and absence of any other base suggests thathe BIL (basic ionic liquid) activates the hydroxyl group for theucleophilic attack and thus, expedites the reaction.

.3. Effect of pH of basic compounds as catalyst in the reaction

The effect of pH of basic compounds as catalyst in the reaction

edium was studied. The results have been summarized in Table 2.

he basic ionic liquid [BMIM]OH with pH 9.37 gave the best yieldsTable 2, entry 6). The other basic ionic liquids with pH comparableo [BMIM]OH also did not prove very satisfactory for the reaction.

able 2ffect of pH of basic catalysts on the reaction.a

Entry Base + solvent pH Product yield

1 DBU + MeOH 12.24 242 DBU + CH3CN >14 –3 DBU + DMF 13.92 374 DBU + [BMIM]Br 13.33 405 DBU + [BMIM]Cl 12.67 44

Ionic liquidsb

6 [BMIM]OH 9.37 937 [BMIM]Im 10.11 548 [DBU]Ac 10.50 419 [C8DABCO]NTf2 9.09 –

10 2-[2-(Dimethylamino)ethoxy]ethyl-N,N-diisopropylammoniumbis(trifluoromethanesulfonyl)imide

11.24 15

a Temperature = 34 ◦C.b Solvent–water, concentration of base = 10%.

N,N-diisopropylammoniumbis(trifluoromethanesulfonyl)imide

3.4. Synthesis of compound 7b in the presence of solid supportedbasic ionic liquid and its comparison with the reaction innon-supported basic ionic liquid

The model reaction was also carried out under microwave irra-diation in the presence of polystyrene resin supported basic ionicliquid [BMIM]OH. The results obtained were not very satisfactorywith a substantial decrease in the yield of the product in the samereaction time (80%). This might be due to the less stability of thesolid support under the reaction conditions. Further, side productswere also observed. A table showing its comparison with non-supported basic ionic liquids has been presented (Table 3). Theresults of Table 3 clearly indicate that the best yields are obtainedwith [BMIM]OH (Table 3, entry 2). The solid supported ionic liquidalthough provides good yields (Table 3, entry 1), but the best yieldsare obtained by using [BMIM]OH as solvent as well as a catalyst.

3.5. Synthesis of various derivatives ofpiperido[3′,4′:5,6]pyrano[2,3-d]pyrimidinone 7a–7o and 8a–8e

Under optimized conditions, we tried to survey the feasibil-ity and scope of the strategy for which we synthesised a varietyof substituted pyrano[3,2-c]piperidine derivatives (5a-f) by usingvariants of the aromatic aldehydes (2a-f), and we got very satisfac-tory results with all variants (Table 4, entries 1–6). The aldehydeswith electron-withdrawing groups exerted a very positive responsetowards the yield as well as the rate of the target product for-mation (Table 4, entry 1–4), 4-chlorobenzaldehyde being the bestsubstituent (Table 4, entry 1). Identities of all the synthesised com-pounds were confirmed by 1HNMR, 13CNMR, mass spectral dataand elemental analysis.

In an attempt to further analyse and extend the scope of thestrategy, we subjected a series of ketones to react with substrate,i.e., pyrano[3,2-c]piperidine derivative 5a. The reaction proceededwell in nearly all the ketones although the yields did vary because ofthe steric strain imposed by some ketones (Table 5, entries 1–10).The best yield was obtained with cyclohexanone (Table 5, entry2). Encouraged by the results, we probed the reaction of 5a with arange of aromatic aldehydes with electron-donating and electron-withdrawing groups. All of these aldehydes performed well in thereaction and furnished the pyrimidinone variants in good yields(Table 5, entries 11–15).

3.6. Synthesis of piperido[3′,4′:5,6]pyrano[2,3-d]pyrimidinone (7and 8) derivatives using oil bath heating and its comparison withmicrowave-assisted reaction

For comparison purposes, all the reactions were also carried outin a thermostated oil-bath at the same temperature for optimizedperiod of time. The results have been summarised in Table 6. The

results in Table 6 clearly show a significant reduction in the yieldsof the product in case of reactions carried out in oil bath. Further,the time required for the reactions to reach the reported yield wasquite high. This observation clearly indicates the existence of a non

I.R. Siddiqui et al. / Journal of Molecular Catalysis A: Chemical 382 (2014) 126– 135 131

Table 4Synthesis of piperido[3′ ,4′:5,6]pyrano[2,3-d]pyrimidinone derivatives using cyclohexanone (6b) and various substituted pyrano[3,2-c] piperidine analogues (5a-g).

[BMIM]OHrt (1.5 h)

[BMIM]OHrt (10) minN

CH3

O

NH3C

R1

O

R1

NH2

CN [BMIM] OHN

CH3

O

R1-CHO(2) R1 R1

H2C

CN

CN(4)

1 3 5 7 and 8

O

N

O

H3CR1

R1

NH

HN

O

(6b)

MW

Entry R1CHO Pyrano-piperidines Product Time (min) Yielda (%)

1

CHO

Cl 2a

N

O

CN

NH2

Cl

Cl

H3C

5a

NO

NH

HN

O

Cl

Cl

H3C

7b

10 93

2

CHO

NO2 2b

N

O

CN

NH2

O2N

NO2

H3C

5b

NO

NH

HN

O

O2N

NO2

H3C

8a

10 91

3 SO

2c N

O

CN

NH2

H3C

S

S 5c

N

O

NH

HN

OH3C

S

S 8b

10 83

4N

CHO

2d

N

O

CN

NH2

H3C

N

N 5d

N

O

NH

HN

OH3C

N

N8c

10 87

5

CHO

2e

N

O

CN

NH2

H3C

5e

N

O

NH

HN

OH3C

8d

10 80

6

CHO

CH3

2f

NO

CN

NH2

H3C

H3C

CH35f

N

O

NH

HN

O

H3C

CH 3

H3C

8e

15 70

a Isolated yields after purification.

132 I.R. Siddiqui et al. / Journal of Molecular Catalysis A: Chemical 382 (2014) 126– 135

Table 5Basic ionic liquid catalyzed synthesis of piperido[3′ ,4′: 5,6]pyrano[2,3-d]pyrimidinone derivatives using 5a and various carbonyl compounds.a

NH3C

R1

O

R1

NH2

CN [BMIM] OHNH3C

R1O

R1

NH

HN

O

R2 R3

O

(6)R2R3

5 7 and 8

MW(10-18 min)

Entry Ketone/aldehyde Product Time (min) Yieldb (%)

1

O

6a

N

O

NH

HN

O

Cl

H3C

Cl

7a

18 70

2

O

6b

NO

NH

HN

O

Cl

H3C

Cl

7b

10 93

3

O

6c

N

O

NH

HN

O

Cl

H3C

Cl

7c

15 85

4

O

6dN

O

NH

HN

O

Cl

H3C

Cl

7d

15 84

5

O

6eN

O

NH

HN

O

Cl

H3C

Cl

7e

15 82

6

O

6fN

O

NH

HN

O

Cl

H3C

Cl

7f

15 82

I.R. Siddiqui et al. / Journal of Molecular Catalysis A: Chemical 382 (2014) 126– 135 133

Table 5 (Continued )

Entry Ketone/aldehyde Product Time (min) Yieldb (%)

7

O

6gN

O

NH

HN

O

Cl

H3C

Cl

7g

12 89

8

O

6hN

O

NH

HN

O

Cl

H3C

Cl

7h

15 80

9O

6i

N

O

NH

HN

O

Cl

H3C

Cl

7i

15 83

10N

O

6j

N

O

NH

HN

O

Cl

H3C

N

Cl

7j

15 90

11

O

6k

N

O

NH

HN

O

Cl

H3C

Cl

7k

15 91

12

O

Cl6l

N

O

NH

HN

O

Cl

H3C

Cl

Cl

7l

15 88

134 I.R. Siddiqui et al. / Journal of Molecular Catalysis A: Chemical 382 (2014) 126– 135

Table 5 (Continued )

Entry Ketone/aldehyde Product Time (min) Yieldb (%)

13

O

F6m

N

O

NH

HN

O

Cl

H3C

F

Cl

7m

15 85

14O

H3C 6nN

O

NH

HN

O

Cl

H3C

CH3

Cl

7n

15 90

15O

H3CO 6oN

O

NH

HN

O

Cl

H3C

OCH3

Cl

7o

15 90

a Reaction conditions:pyrano[3,2-c]piperidine derivative 5a (1.0 mmol), carbonyl compb Isolated yields after filtration and purification.

Table 6Conventional vs. microwave conditions.

Product Classical conditionsa

(thermo stated oilbath)

Microwave irradiationa

Time (h) Yieldb (%) Time (min) Yieldb (%)

7a 6 42 15 707b 5 60 10 93

7c 6 47 15 857d 5 43 15 847e 6 40 15 827f 7 40 15 827g 6 48 12 897h 7 41 15 807i 6 44 15 837j 6 48 15 907k 7 50 15 917l 7 42 15 887m 6 46 15 857n 6 49 15 907o 7 47 15 908a 5 52 10 918b 6 48 10 838c 5 49 10 878d 5 44 10 808e 6 40 15 70

a

c

ticmse

Reaction conditions: pyrano[3,2-c]piperidine derivative 5a (1.0 mmol), carbonylompound 6a-o (1.3 mmol), [BMIM]OH (2 mL).

b Isolated yields after filtration and purification.

hermal microwave effect. It is thus assumed that the microwave-onic liquid synergy plays a significant role in the reaction and it

ombines with the specific effect of the electromagnetic field of theicrowaves in decreasing the activation energy of the reaction by

tabilising the polar activated complex of the reaction, to providexcellent yields in short reaction times.

ound 6a-o (1.3 mmol), [BMIM]OH (2 mL).

4. Conclusions

In conclusion, our strategy using a BIL presents an efficaciousand convenient procedure for the synthesis of novel substitutedpyrimidinone ring systems having piperidine, pyran and pyrimidi-none rings fused together without the need of any toxic catalystor solvent. We report for the first time the synthesis of this novelpotentially bioactive heterocyclic scaffold. The synthetic strategyoffers marked improvements with regards to reaction rate, reac-tion time, yields of the product, greenness of procedure, avoidanceof the use of toxic bases and thus, it offers an effective methodologyfor the synthesis of novel fused pyrimidinone derivatives. How-ever, most conspicuously, this strategy demonstrates the catalyticeffect of basic IL [BMIM]OH on the intramolecular Pinner reactionbetween hydroxyl group and nitrile group. Discernibly, this pro-cedure can be used effectively for the synthesis of diverse fusedpyrimidinone libraries.

Acknowledgements

Authors gratefully acknowledge the financial support by CSIR,New Delhi, UGC, New Delhi and are thankful to SAIF, Chandigarhfor spectral analysis.

Appendix A. Supplementary data

Supplementary data associated with this article can befound, in the online version, at http://dx.doi.org/10.1016/j.molcata.2013.10.026.

References

[1] (a) K.S. Atwal, G.C. Rovnyak, B.C. O’Reillu, J. Schwartz, J. Org. Chem. 54 (1989)5898–5907;

Catal

[

[

[

[[

[

[[[

[

[[[

[

[

[[

I.R. Siddiqui et al. / Journal of Molecular

(b) C.O. Kappe, W.M.F. Fabian, M.A. Semones, Tetrahedron 53 (1997)2803–2816;(c) Y. Zhu, S. Huang, Y. Pan, Eur. J. Org. Chem. (2005) 2354–2367;(d) H.M. Gaber, M.C. Bagley, S.M. Sheriff, U.M. Abdul-Raouf, J. Het. Chem. 47(2012) 1162–1170.

[2] (a) G.L. Anderson, J.L. Shim, A.D. Broom, J. Org. Chem. 41 (1976) 1095;(b) E.M. Griva, S. Lee, C.W. Siyal, D.S. Duch, C.A. Nichol, J. Med. Chem. 23 (1980)327–329.

[3] M.M. Ghorab, A.A. Hassan, Y. Phosphorus, Sulfur Silicon Relat. Elem. 141 (1998)257–261.

[4] (a) D. Heber, C. Heers, U. Ravons, Pharmazie 48 (1993) 537;(b) S. Furuya, T. Ohtaki, Eur. Pat. Appl. EP. 608565, Chem. Abstr. 121 (1994)205395.

[5] C.J. Shishoo, V.S. Shirsath, I.S. Rathod, V.P. Yande, Eur. J. Med. Chem. 35 (2000)351–358.

[6] W.J. Coater, Eur. Pat. 351058, Chem. Abstr. 113 (1990) 40711.[7] N. Kitamura, A. Onishi, Eur. Pat. 163599, Chem. Abstr. 104 (1984) 186439.[8] (a) C. Mohan, V. Kumar, P.M. Mahajan, Tetrahedron Lett. 45 (2004) 6075–6077;

(b) Z. Li-Jun, Y. Xi-quan, L. Jia-Rong, S. Da-Xin, Z. Ling, F. Yan-Qiu, Chin. J. Str.Chem. 27 (2008) 1469–1474;(c) H. Zhang, Z. Zhou, Z. Yao, F. Xu, Q. Shen, Tetrahedron Lett. 50 (2009)1622–1624;(d) R.N. Bhattacharya, K. Pradip, M. Gourhari, Tetrahedron Lett. 52 (2011)26–28.

[9] (a) S. Mashkouri, M.R. Naimi-Jamal, Molecules 14 (2009) 474–479;(b) J. Pandey, N. Anand, R.P. Tripathi, Tetrahedron 65 (2009) 9350–9356;(c) M.C. Parlato, C. Mugnaini, M.L. Renzulli, F. Corell, M. Botta, Arkivoc V (2004)349–363.

10] (a) L. Perreux, A. Loupy, Tetrahedron 57 (2001) 9199–9283;(b) P. Lidstrom, J. Tierney, B. Wathey, J. Westman, Tetrahedron 57 (2001)9225–9283;(c) C.O. Kappe, Angew. Chem. Int. Ed. 43 (2004) 6250–6284;(d) M. Larhed, Microwaves in Organic Synthesis, 2nd ed., Wiley-VCH, GmbH &KGaA, Weinheim, 2006;(e) E. Gershonov, E. Katz, Y. Karton, Y. Zafrani, Tetrahedron 63 (2007)3762–3767;(f) S. Caddick, R. Fitzmaurice, Tetrahedron 65 (2009) 3325–3355.

11] (a) T. Welton, Chem. Rev. 99 (1999) 2071–2083;(b) L.A. Blanchard, D. Hancu, E.J. Becman, J.F. Brennecke, Nature 399 (1999)28–29;(c) P.J. Wasserscheid, W. Keim, Angew. Chem. Int. Ed. 39 (2000) 3772–3789;

(d) R.A. Brown, P. Pollet, E. Mckoon, C.A. Eckert, C.L. Liotta, D.G. Jessop, J. Am.Chem. Soc. 123 (2001) 1254–1255;(e) X.F. Yang, M.W. Wang, C.J. Li, Org. Lett. 5 (2003) 657–660;(f) W. Leitner, Nature 423 (2003) 930–931;(g) A. Kumar, S.S. Pawar, J. Org. Chem. 69 (2004) 1419–1420.

[

[

ysis A: Chemical 382 (2014) 126– 135 135

12] H. Hoffmann, M. Nuchter, B. Ondruschka, P. Wasserscheid, Green Chem. 5(2003) 296–299.

13] J.M. Levenque, G. Cravotto, Chimia (Aarau) 60 (2006) 613–620.14] (a) J.A. Boon, S.A. Levinsky, J.L. Pflig, J.S. Wilker, J. Org. Chem. 51 (1986) 480–483;

(b) R. Sheldon, Chem. Commun. (2001) 2399–2407;(c) A.L. Zhu, T. Jiang, D. Wang, B.X. Han, L. Liu, J. Huang, Z.C. Zhang, D.H. Sun,Green Chem. 7 (2005) 514–517;(d) Y.S. Kim, R.S. Varma, Tetrahedron Lett. 46 (2005) 7447–7449;(e) B.C. Ranu, R. Jana, J. Org. Chem. 70 (2005) 8621–8624.

15] (a) P. Formentin, H. Garcia, A. Levya, J. Mol. Catal. A: Chem. 214 (2004) 237;(b) H. Chen, D.R. Justes, R.G. Cooks, Org. Lett. 7 (2005) 3949–3952.

16] B.C. Ranu, S. Banerjee, Org. Lett. 7 (2005) 3049–3052.17] C.R. Brindaban, R. Jana, S.J. Sowmiah, Org. Chem. 72 (2007) 3152–3154.18] (a) J.M. Xu, B.K. Liu, W.B. Wu, C. Qian, Q. Wu, X.F. Lin, J. Org. Chem. 71 (2006)

3991–3993;(b) L.D.S. Yadav, S. Singh, V.K. Rai, Tetrahedron Lett. 50 (2009) 2208–2212.

19] (a) I.R. Siddiqui, P.K. Singh, J. Singh, J. Singh, J. Agric. Food Chem. 51 (2003)7062–7065;(b) I.R. Siddiqui, S.A. Singh, P.K. Singh, V. Srivastava, J. Singh, Arkivoc XII (2008)277–285;(c) I.R. Siddiqui, A. Singh, S. Shamim, S. Srivastava, P.K. Singh, S. Yadav, R.K.P.Singh, Synthesis 10 (2010) 1613–1616;(d) I.R. Siddiqui, S. Shamim, A. Singh, V. Srivastava, S. Yadav, Arkivoc XI (2010)232–241;(d) I.R. Siddiqui, S. Shamim, D. Kumar, Shireen, M.A. Waseem, New J. Chem. 36(2012) 2209–2214;(e) I.R. Siddiqui, Shireen, S. Shamim, A.H. Abumhdi, M.A. Waseem, A. Srivas-tava, Rahila, A. Srivastava, New J. Chem. (2013), http://dx.doi.org/10.1039/C3NJ41070F.

20] L.F. Xiao, Q.F. Yue, C.G. Xia, L.W. Xu, J. Mol. Catal. A: Chem. 279 (2008) 230–234.21] J. Shen, H. Wang, H. Liu, Y. Sun, Z. Liu, J. Mol. Catal. A: Chem. 280 (2008) 24–28.22] C. Xuewei, L. Xuehui, S. Hongbing, L. Yangxiao, W. Furong, H. Aixi, Chin. J. Catal.

29 (2008) 957–959.23] A.G. Ying, L. Liu, G.F. Wu, G. Chen, X.Z. Chen, W.D. Ye, Tetrahedron Lett. 50

(2009) 1653–1657.24] (a) M. Hut’ka, S. Toma, Monatsh Chem. 140 (2009) 1189–1194;

(b) C. Paun, J. Barklie, P. Goodrich, H.Q.N. Gunaratne, A. McKeowna, V.I.Pârvulescu, C. Hardacre, J. Mol. Catal. A: Chem. 269 (2007) 64–71.

25] J.M. Xu, C. Qian, B.K. Liu, Q. Wu, X.F. Lin, Tetrahedron 63 (2007) 986–990.26] M.A.P. Martins, E.A. Guarda, C.P. Frizzo, E. Scapin, P. Beck, A.C. da Costa, N.

Zanatta, H.G. Bonacorso, J. Mol. Catal. Chem. 266 (2007) 100–103.

27] (a) A. Aggarwal, N.L. Lancaster, A.R. Sethi, T. Welton, Green Chem. 4 (2002)

517–520;(b) J. Ross, J.L. Xiao, Chem. Eur. J. 9 (2003) 4900–4906.

28] (a) J.M. Xu, C. Qian, B.-K. Liu, Q. Wu, X.F. Lin, Tetrahedron 63 (2007) 986–990;(b) H. Sun, D. Zhang, F. Wang, C. Liu, J. Phys. Chem. 111 (2007) 4535–4541.