ura

rm120

venehyethyrinse ioyraageey

a, ILs (due tthat ctabilitower.2

as efn andsynthe

Coumarins and quinolines, due to their much closer structuralrelationship with many bioactive natural and unnatural complexmolecules, are useful templates for drug development.9 In recentpast, a growing number of scaffolds, incorporating these moieties,have emerged as useful medicinal compounds. These heterocycleshave been soured both synthetically as well as naturally.10

ine, etc.c activity that is,Fig. 1),20 as for treati

heimers disease, are very useful medicinal applicationsclass.21

Corresponding author. Tel.: +91 2692 226858; fax: +91 2692 236475.E-mail addresses: njpchemdeptspu@yahoo.co.in, naroo26@yahoo.com

OO OSeselin

O

N SMeOThiopyranoquinoline

Figure 1. Biologically active thiopyranoquinolines and pyranocoumarins.

Bioorganic & Medicinal Chemistry Letters 23 (2013) 16561661

Contents lists available at SciVerse ScienceDirect

Bioorganic & Medicinal Chemistry Letters

.e lsevier .com/ locate/bmcl(N.J. Parmar).Neverthless, these neoteric solvents and catalysts7 have seldombeen employed in the domino/Knoevenagel-hetero-DielsAlder(DKHDA) approach, a powerful tool to access diverse natural andunnatural bioactive polyheterocycles.8

of alkaloids19 like geibalasine, ribalinine, indersMetabotropic glutamate receptor antagonisti

mGlu 1 receptor activity of thiopyranoquinoline (nacrine thia analogues, that act as potential agent0960-894X/$ - see front matter 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.bmcl.2013.01.079nd vel-ng Alz-of thismethodologies. Nucleophiles with compounds having electron-decient double bonds like C@C or C@O showed excellent reactiv-ity in ionic liquids.5 Wittig reaction,6a biginellis condensation,6b

1,3-dipolar cycloaddition,6c Michael addition,6d DielsAlder reac-tion,6e benzoin condensation6f etc. have successfully been medi-ated by eco-friendly and environmentally benign solvents.

Vero monkey cells. Besides being a signicant cytotoxic againstP-388 lymphocytic leukemia,16 it also possess an antiparasiticactivity.17

Coumarin analogs quinolines, on the other hand, have been wellrecognized by synthetic and medicinal chemists.18 Pyran annu-lated quinolines constitute a basic framework of a large numberAs efcient green reaction meditracted interest of many researcherspressure and nonammable nature1

many advantages like high thermal sbility along with a good extracting ptive to organic solvents, ILs also acthave solved both solvent emissiolems.3be Today, ILs offer the organic

4ionic liquids) have at-o their negligible vaporonfer the reaction withy, polarity, and recycla-Besides being alterna-cient catalysts,3 whichcatalyst re-use prob-sis with efcient green

Pyran-annulated heterocycles particularly have remarkable phar-macological potencies.11 Pyranocoumarin, for example, in whichcoumarin is fused to a pyran ring via its 7,8 positions, is an impor-tant subunit from bioactivity point of view. Non-nucleoside HIV-I-specic reverse transcriptase inhibitors (+) calanolide A,12 30,40-di-O-(S)camphanoyl-(+)-cis-khellactone (DCK)13 analogs and antican-cer agent seselin (Fig. 1) are the potential candidates this ring sys-tem exists in.14 Seselin also exhibited cytotoxic activity against

15PyranocoumarinTriethylammonium acetateDomino/Knoevenagel-hetero-DielsAlderIonic liquid

Clostridium tetani, Bacillus subtilis) and three Gram-negative (Salmonella typhi, Vibrio cholerae, Escherichiacoli) bacteria.

2013 Elsevier Ltd. All rights reserved.An efcient domino reaction in ionic liqevaluation of some pyrano- and thiopy

Narsidas J. Parmar , Rikin A. Patel, Bhagyashri D. PaDepartment of Chemistry, Sardar Patel University, Vallabh Vidyanagar, Dist. Anand, 388

a r t i c l e i n f o

Article history:Received 18 October 2012Revised 5 January 2013Accepted 17 January 2013Available online 29 January 2013

Keywords:Thiopyranoquinoline

a b s t r a c t

An improved domino/Knoenoxy-coumarin-8-carbaldstudied in ionic liquid trilated-pyrano-fused coumaadditional catalyst used, thcles, the cis-fusion of two pAll are good antitubercularantibacterial agents, as th

journal homepage: wwwid: Synthesis and biologicalno-fused heterocycles

ar, Navin P. TalpadaGujarat, India

agel-hetero-DielsAlder reaction of two new aldehyde substrates; 7-ole-de and 2-alkensulfanyl-quinoline-3-carbaldehyde, with pyrazolones waslammonium acetate (TEAA), affording a series of pyrazolopyran annu-, and thiopyrano-fused quinolones. Besides acting as catalyst, since nonic liquid TEAA also promised its easy recovery. In all new polyheterocy-nyl rings had been inferred from 2D NMR COSY and NOESY experiments.nts, as they are found active againstMycobacterium tuberculosis H37Rv, andare found active against three Gram-positive (Streptococcus pneumoniae,

In view of this, the development of class of these heterocycles isof a considerable interest. Moreover, a discloser of possibilities ofcombinatorial-based investigations certainly offers medicinalchemists a way to access new bio-molecules.

Among the synthetic approaches, the domino/Knoevenagel-het-ero-DielsAlder (DKHDA) has overwhelmingly gained a vitalimportance to create complex molecules in organic synthesis.Olen-ether-tethered aldehyde can be assembled with 1,3-dike-tones as well as other active methylene units like pyrazolonesand isoxazolones,22 hydroxycoumarins and hydroxyquinolones.23

Many aromatic and hetero-aromatic aldehyde-based substrateshave been tested. Surprisingly, no report on hydroxycoumarins-and hydroxyquinolone-based aldehyde substrates. 7-Hydroxy-4-methyl-coumarin-8-carbaldehydes and 2-mercapto-quinoline-3-

N. J. Parmar et al. / Bioorg. Med. Checarbaldehydes were therefore intended in the present work toconstruct new pyran and thiopyran annulated heterocyclicsystems.

Many ways to promote DKHDA reaction exist.24 Efciency andselectivity however depend upon the nature of an active methy-lene unit, dienophile and aldehyde substrate. Prenyl-based alde-hyde substrate undergoes this transformation easily even in amild reaction condition.25 In contrast to this, allyl- or propargyl-based substrates,26 require higher temperature, irrespective ofwhether the reaction is performed under efcient catalyst- and sol-vent-free or solvent-free catalyzed-one conditions, due to involv-ing unactivated dienophile.27,28 Further, partial decomposition,toxic wastes also affect the yields, leaving the product isolationstep a tedious work.29 Finally, the harsh condition may link withecological issues such as more catalyst loading, and sidereactions.30

Our recent interest is the green synthesis under conventionalheating as well as microwave conditions.25a,31 To continue this,we envisioned the synthesis of biodynamic pyranocoumarins andthiopyranoquinolines in potentially recoverable medium-cum-cat-alyst triethylammonium acetate (TEAA) via DKHDA reaction. TEAAhas mediated many organic reactions, and has emerged as a poten-tial medium in the organic synthesis.32

We chose an assimilation of two new aldehyde substrates; 2-al-lyl/prenylsulfanyl-quinoline-3-carbaldehydes 3 and 7-allyloxy/prenyloxy-4-methyl-coumarin-8-carbaldehydes 4, with corre-sponding less reactive pyrazolones via DKHDA reaction. Allyla-tion/prenylation of 2-mercapto-quinoline-3-carbaldehyde 1 inthe presence of anhydrous K2CO3-suspended DMF (dimethylform-amide) solution, with stirring the reaction mass at room tempera-ture, gave substrates 3 and that of 4-methyl-7-hydroxy-cumarin-8-carbaldehyde 2 substrates 4 (Scheme 1). Yields of both the sub-strates were in the 9496% range. Pyrazolones 5ahwere obtainedfrom corresponding ethyl aceto acetates and phenyl hydrazines asreported in the Letter.33

R

R Br

N

CHO

SHR'

O OCHO

HO

N

CHO

SR'

O OCHO

O

3a-d

4a-b

K2CO3DMFrt

RR

RR

1

2

3a; Me H3b; H H3c; Me Me3d; H Me

R' R

4a; H4b; Me

RScheme 1. Preparation of required coumarin and quinoline-based aldehydesubstrates.For optimizing the reaction conditions, we have examined 2-al-lyl/prenylsulfanylquinolines 3a,c and 7-allyloxy/prenyloxycouma-rins 4ab each with pyrazolone 5a as four model substrates. Theresults are shown in Table 1. First, we examined the reaction inthe absence of catalyst in acetonitrile at room temperature (entry1) and then in the presence of catalyst tetrabutyl ammoniumhydrogen sulphate (TBA-HS) (entry 2) in same solvent but at its re-ux temperature. None of the substrates gave product after reux-ing for a longer time. Similar results were found in catalyst SDS(sodium dodesyl sulfate) but in reuxing toluene (entry 3). Next,we tested TBA-HS in reuxing xylene (entry 4). We noticed thatonly prenyl-based substrates, 3c and 4b, yielded 20% of desiredproducts, 6o and 7i respectively, leaving allyl-based substrates,3a and 4a, unreacted. No improvement could be seen even re-placed TBA-HS by ZnO (entry 5).

Examining further TBA-HS-catalyzed protocol without solventat 140 C (entry 6) showed that although it reduced reaction timeto 4 h, only moderate yields were recorded from both allyl- andprenyl-based substrates, 3a,c and 4ab respectively, with 5a (entry6). It may be due to partial decomposition, as TLC (thin layer chro-matography) of reaction mass evidenced the association of othercomponents with desired cyclized product. Mixture of burnt impu-rities and catalyst thus made the product isolation step difcultand tedious. We therefore attempted ionic liquid TEAA. Observinginitially the reaction in the 3070 C temperature range showed nogood results. We therefore omitted these results. But, since thetemperature above 100 C inuenced the reaction, Table 1 displaysresults observed at 120 C (entry 7). It improved the reaction intime and temperature both, taking 1.6 h in case of prenyl-basedsubstrates 3c or 4b, and 2.5 h for allyl-based substrates 3a or 4a.No burnt impurities were formed and hence it made the productisolation step simple. Increasing the volume of TEAA howevercould not improve the results remarkably (entries 89). Highyields, short reaction time, relatively less temperature, easy set-up and work-up are the advantages of this new greener protocol.Other thiopyranoquinolines 6b as well 6dr were obtainedemploying the optimal condition (Scheme 2).34 Orangered Knoe-venagel adducts that appeared after 20 min underwent cyclisationin 23 h as monitored by TLC. The yields of the products were inthe 7084 % range. Similarly, 7-allyl/prenyloxycoumarin-8-carbal-dehydes 4ab gave pyranocoumarins 7bp with pyrazolones 5bhin the 7284% yields (Scheme 2). All are new compounds, and theirchemistry characterizations are fully detailed in supplementarymaterials. In addition, the stereochemistry of these new heterocy-cles was conrmed by 2D NMR COSY and NOESY experiments,which suggests cis-fusion of two central pyran rings (Fig. 2).

Allylsulfanylquinoline-3-carbaldehydes 3ab relatively tookmore reaction time than the analogs prenylsulfanyle ones 3cddue to the presence of unactivated dienophile. However this sub-strate with methyl at eight position of quinoline took relatively lessreaction time to afford the desired products, favoring inverse elec-tron demand hetero-DielsAlder reaction. Same could be seen withthe coumarin-based aldehyde substrates. Pyrazolones, particularlythe one with the 4-nitrophenyl or 3, 4-dichlorophenyl at its N1nitrogen required relatively less reaction time with a particularaldehyde substrate, indicating good reactivity. Pyrazolones aregenerally less reactive as there is no electron withdrawing groupat 3-position in its Knoevenagel intermediate 1-oxa-1,3-butdienewith aldehyde.

A mechanistic pathway is presented in Figure 3. It proceedsthrough the simultaneous generation of Knoevenagel adduct (v)along with a few portions of Michael adducts (iv) obtained frompyrazolonate (ii) and aldehyde substrate (iii), which are common

31e

m. Lett. 23 (2013) 16561661 1657in ionic liquid TEAA. Inuence of catalyst-cum-medium TEAAin a long run however transformed these intermediates into exclu-sively DKHDA cyclized products (vi), indicating that Michael

. CheTable 1Optimization of the DKHDA reaction conditions

1658 N. J. Parmar et al. / Bioorg. Medadducts were ultimately converted into Knoevenagel intermediateto give cyclized products too.

The endo- or exo-orientations of the dienophile,24g which decidethe stereochemical outcome, leads to four transition states; exo-E-anti, endo-Z-anti, exo-E-syn and endo-Z-syn. The cis-product, which

Entry Catalyst Solvent Temp (C) Time (h)

1 Acetonitrile rt 242 TBA-HS Acetonitrile 80 123 SDS Toluene 110 104 TBA-HS Xylene 140 105 ZnO Xylene 140 86 TBA-HS 140 47 TEAA (2 mL) 120 2.5/1.68 TEAA (3 mL) 120 2.5/1.89 TEAA (5 mL) 120 2.5/1.7

rt = room temperature.

R3

ONN

R2

R1

O

5a-h

TEAA

5a; Me Ph5b; Me 4-MePh5c; Me 2-ClPh5d; Me 3-ClPh5e; Me 2,5-Cl2Ph5f; Ph Ph5g; Me 3,4-Cl2Ph5h; Me 4-NO2Ph

120 C

R1 R2

O

Scheme 2. DKHDA reaction of 2-sulfanylquinoline 3 and 7-hydro

OO

O NNCH3

O

CH3

CH3

HH

H

HHH

Figure 2. nOes of compound 7b.

NNR2

O

R1 NNR2O

R1

Et3NH

O

NN

O

R1

R2X

AcOH

Et3NHOAc

NN

O

R1

R2

X

X

O NN

R2

R1

HNEt3OAc

CHO

X

R1 = Me, R2 = Ph, Ar = Ph, X = O, S

RR

R R

Et3NH

RR

RR

(i)

(ii)(iii)

(iv)

(v)

(vi)

AcOH

Et3NHOAc

Figure 3. Proposed mechanism of DKHDA reaction.6a/6o Yield (%) 6a/6o Time (h) 7a/7i Yield (%) 7a/7i

20 10 10 20 10 20Trace 8 Trace70/73 4 70/6980/82 2.5/1.9 78/7081/83 2.5/1.8 81/68

m. Lett. 23 (2013) 16561661is major yields and could be conrmed based on 1H NMR and 2DNMR experiments; nuclear Overhauser effect spectroscopy (nOes)and the double quantum ltered correlation spectroscopy (DQF-COSY), suggests that the reaction favored the endo-E-syn transitionstate although the another pathway (endo-Z-syn) is possible(Fig. 2). The exo-E-anti and endo-Z-anti favor the trans product.

All crude products, 6 and 7, solidied on pouring a reactionmass into ice cold water, were isolated and puried by columnchromatography using silica gel (Tables 2 and 3). The spectroscopicdata35 are in good agreement with the proposed structures of thecompounds. 1H NMR showed a doublet in the d 4.64.8 ppm range(J = 45 Hz) attributable to Hb proton, and multiplets in the d 3.03.5 ppm range to Ha. A characteristic IR band that appeared in the

81/81 2.5/1.8 81/69

OO

O NN

OR1

R2

N

CHO

S

O CHO

N SR3

ONNR2

R1

6a-r

7a-p

3a-d

4a-bRR

OR

R

R

R

RR

xycoumarin-based aldehyde substrates 4 with pyrazolones 5.

Table 2Synthesis of pyrazolopyran-annulated thiopyranoquiolones 6ar

Entry Product R R1 R2 R3 Time Yielda mpb

1 6a H Me Ph Me 2.5 80 1301322 6b H Me 4-MePh Me 2.4 81 1321333 6c H Me 2-ClPh Me 2.6 78 1401434 6d H Me 3-ClPh Me 2.6 72 1301325 6e H Me 2,5-Cl2Ph Me 2.8 80 1201266 6f H Ph Ph Me 2.7 79 1301317 6g H Me 3,4-Cl2Ph Me 2.4 79 1381408 6h H Me 4-NO2Ph Me 2.4 80 1411449 6i H Me Ph H 2.6 74 142144

10 6j H Me 4-MePh H 2.5 70 15415611 6k H Me 2-ClPh H 2.7 80 16016412 6l H Me 3-ClPh H 2.8 76 13814013 6m H Me 2,5-Cl2Ph H 2.9 78 13213514 6n H Ph Ph H 2.8 73 14014315 6o Me Me Ph Me 1.6 82 21421616 6p Me Me 4-MePh Me 1.8 84 16716917 6q Me Me 2-ClPh Me 1.7 80 15615918 6r Me Me 3-ClPh Me 1.6 81 200202

a Of isolated compound.b Uncorrected.

12101255 cm1 range indicates cyclic ether linkage of pyran ring.A band that appeared in the 16001750 cm1 range is due to mC@O, and around 1200 cm1 m C@S. Mass spectroscopy also con-rmed the desired molecular weights of all domino products.

Re-use of TEAA was also conrmed based on its recovery andrecyclability studies. On simply heating aqueous ltrate, that wasleft after isolating solid products formed on pouring the reactionmass into ice water, under reduced pressure at 80 C assured quan-titative recovery of TEAA. The recovered TEAA was again used forthe same reaction. In this way, the TEAA was recovered at least

efciency of recovered TEAA remained unaltered. For every reac-tion, 2 mL (6.2 mmol) of ionic liquid was used.

All newly synthesized polycyclic heterocycles were screened fortheir in vitro antimicrobial activity against Gram-positive (Strepto-coccus pneumoniae, Clostridium tetani, and Bacillus subtilis) andGram-negative (Salmonella typhi, Vibrio chlolerae and Escherichiacoli) bacteria-using macro-broth dilution method,36 antitubercularactivity against Mycobacterium tuberculosis H37Rv bacteria-usingL.J. Medium,37 and antioxidant property as a ferric reducing antiox-idant power (FRAP)-using Benzie and Strains modied FRAP38

method. While ampicillin, noroxacin, chloramphinicol, and cipro-oxacin were standard antibacterial reference drugs, griseofulvinand nystalin standard antifungal reference drugs. FRAP values areexpressed as ascorbic acid equivalent (mmol/100 g). Percentgrowth inhibition of M. tuberculosis H37Rv bacteria was deter-mined by running a test solution 250 lg/mL in DMSO.

From the antimicrobial screening test results (Table 4), it re-veals that a majority of pyrazolopyran-annulated thiopyranoqui-nolones 6ar are rather more antibacterial with MIC valuesbelow 200 lg/mL than antifungal, as only two compounds 6aand 6d crossed this value against antifungal Aspergillus fumigates,and none of them against Candia albicans fungus. Among them,those which resemble standard reference drug chloramphenicolincludes 6iactive against Clostridium tetani bacteria, 6g and 6jactive against Streptococcus pneumonia bacteria, 6e and 6lactiveagainst Escherichia coli bacteria and 6hactive against Salmonellatyphi bacteria. In addition, compound 6i resemble the standarddrug Noroxacin, and compounds 6g and 6i the standard referencedrug Ciprooxacin, also, in terms of their potencies against similarbacteria. Analysing Table 4 further, we noticed that a larger num-ber of compounds have potency equal to the standard drug

Table 3Synthesis of pyrazolopyran-annulated pyranocoumarins 7ap

Entry Product R R1 R2 Time Yielda mpb

1 7a H Me Ph 3.0 78 1351382 7b H Me 4-MePh 3.1 77 1401423 7c H Me 2-ClPh 3.0 76 1361374 7d H Me 3-ClPh 2.9 72 1421455 7e H Me 2,5-Cl2Ph 3.2 80 1501526 7f H Ph Ph 3.0 81 1301317 7g H Me 3,4-Cl2Ph 3.2 79 1481498 7h H Me 4-NO2Ph 2.8 84 1411449 7i Me Me Ph 1.9 70 136138

10 7j Me Me 4-MePh 2.9 76 14714811 7k Me Me 2-ClPh 3.0 71 15215312 7l Me Me 3-ClPh 3.1 75 13713913 7m Me Me 2,5-Cl2Ph 3.1 74 15816014 7n Me Ph Ph 3.0 80 14614815 7o Me Me 3,4-Cl2Ph 3.0 82 15015116 7p Me Me 4-NO2Ph 2.8 70 135138

a Of isolated compound.b Uncorrected.

ies o

1)

eria

V

212

N. J. Parmar et al. / Bioorg. Med. Chem. Lett. 23 (2013) 16561661 1659four-time after being used and tested for the reaction. The

Table 4Biological screening test results; antimicrobial, antitubercular, and antioxidant activit

Entry Antimicrobial activity (MIC, lgmL

Gram-positive bacteria Gram-negative bact

B.s. C.t. S.p. E.c. S.t.

6a 100 200 250 250 2006b 200 250 200 100 1256c 125 125 100 250 250

6d 250 200 250 250 500 26e 100 100 250 62.5 200 16f 200 125 200 100 125 26g 200 250 62.5 250 250 26h 250 200 200 100 62.5 26i 200 62.5 200 100 125 16j 200 200 62.5 125 125 26k 125 250 100 250 250 26l 200 125 250 62.5 100 26m 100 200 200 250 100 26n 200 250 250 100 250 26o 250 100 100 200 100 16p 100 200 100 125 125 26q 250 100 250 200 100 26r 200 1000 100 150 250 1[A] 1 5 0.5 0.05 5 5[B] 250 250 100 100 100 1[C] 50 50 50 50 50 5[D] 50 100 50 25 25 2[E] 100 50 10 10 10 1[F] [G] [H]

S.p.: Streptococcus pneumoniae, C.t.: Clostridium tetani, B.s.: Bacillus subtilis, S.t.: Salmonellaalbicans, [A]: Gentamycin, [B]: Ampicillin, [C]: Chloramphenicol, [D]: Ciprooxacin, [E]:

a Concentration of compounds used against M. tuberculosis H37Rv bacteria = 250 lg/mb Concentration of compounds = 200 lg/mL and standard: A.A. (ascorbic acid) = 176 lc A.A. mm/100 g sample.Ampicilin not Noroxacin. Many compounds were also found

f pyrazolopyran-annulated thiopyranoquinolones 6ar (MIC, lg/mL)

Anti TBa Antioxidant activityb

Fungi % Inhibition FRAP valuec

.c. A.f. C.a.

50 250 1000 38 160.3925 200 1000 63 112.4000 250 500 29 146.5500 200 1000 82 125.1600 1000 1000 49 129.3100 >103 >103 9 101.1550 1000 500 38 61.7050 >103 >103 20 49.7500 500 500 87 126.0200 1000 1000 33 121.2650 >103 1000 52 90.9400 1000 >103 61 127.8700 >103 500 93 158.0050 250 500 40 105.0125 1000 >103 49 83.5000 500 250 91 160.6000 500 250 50 115.2600 500 500 91 18.18

00 0 5 0

100 100 100 500 99

typhi, V.c.: Vibrio cholerae, E.c.: Escherichia coli, A.f.: Aspergillus fumigatus, C.a.: CandidaNoroxacin, [F]: Nystatin, [G]: Griseofulvin, [H]: Isoniazide.

L, standard antimicrobials used: isoniazide (0.2 lg/mL).g/mL.

ies o

1)

ria

V

222211122522111251521

ella[E]:g/m6 l

. CheTable 5Biological screening test results; antimicrobial, antitubercular, and antioxidant activit

Entry Antimicrobial activity (MIC, lgmL

Gram-positive bacteria Gram-negative bacte

B.s. C.t. S.p. E.c. S.t.

7a 500 250 250 250 2007b 250 200 250 200 2507c 62.5 200 100 125 1007d 200 62.5 62.5 100 2007e 200 250 200 125 2507f 125 100 100 62.5 1257g 250 100 250 250 2507h 200 250 250 125 2007i 200 500 200 250 2507j 250 250 100 100 2507k 100 250 250 125 1257l 200 200 62.5 200 2007m 100 200 100 100 1257n 200 100 125 125 1007o 250 250 250 200 2507p 200 200 200 200 125[A] 1 5 0.5 0.05 5[B] 250 250 100 100 100[C] 50 50 50 50 50[D] 50 100 50 25 25[E] 100 50 10 10 10[F] [G] [H]

S.p.: Streptococcus pneumoniae, C.t.: Clostridium tetani, B.s.: Bacillus subtilis, S.t.: Salmonalbicans, [A]: Gentamycin, [B]: Ampicillin, [C]: Chloramphenicol, [D]: Ciprooxacin,

a Concentration of compounds used against M. tuberculosis H37Rv bacteria = 250 lb Concentration of compounds = 200 lg/mL and standard: A.A. (ascorbic acid) = 17c A.A. mm/100 g sample.

1660 N. J. Parmar et al. / Bioorg. Medactive against multiple bacteria, which resemble Ampicilin. Whilecompound 6c was found active against all three Gram-positivebacteria, 6b and 6i were against all three Gram-negative bacteria.Compounds which are active against both Gram-negative Esche-richia coli and Salmonella typhi bacteria include 6f, 6j and 6o. Com-pound 6e was active against two Gram-positive Clostridium tetaniand Streptococcus pneumonia bacteria. Surprisingly, 6p was activeagainst Gram-positive Bacillus subtilis and Streptococcus pneumoniabacteria, as well as Gram-negative Escherichia coli and Salmonellatyphi bacteria.

A similar trend could be been seen for pyrazolopyran-annulatedcoumarin derivatives 7ap (Table 5). Those which have potencycomparable with that of standard Chloramphinicol include 7cac-tive against a Gram-positive Bacillus subtilis bacteria, 7dagainstboth Gram-positive Clostridium tetani and Streptococcus pneumoniabacteria, and 7fagainst a Gram-negative Escherichia coli bacteria.Comparing antimicrobial screening test results with that ofpyrazolopyran-annulated thiopyranoquinolones 6, we also noticedthat some pyrazolopyran-annulated coumarins 7 are also activeagainst multiple bacteria. For example, 7f, 7m and 7n are activeagainst two Gram-positive (Streptococcus pneumoniae, and Bacillussubtilis), all three Gram-negative (Salmonella typhi, Vibrio chloleraeand Escherichia coli) bacteria. Compound 7f also active againstone more Gram-positive Clostridium tetani bacteria.

In conclusion, we have demonstrated the use of TEAA as an ef-cient green reaction medium for the synthesis of biologically activepyrano-fused coumarins and thiopyrano-fused quinolones viadomino reaction. High yields, short reaction time and lower tem-perature (120 C), particularly for an aldehyde-substrate contain-ing unactivated allyl dienophile, are the main advantages of thepresent protocol. The so-called substrate generally needs reportedhigher temperature (150 C) in the absence of catalyst. Compound7f was active against most of the bacteria. Structurally, derivativesf pyrazolopyran-annulated pyranocoumarins 7ap (MIC, lg/mL)

Anti TBa Antioxidant activityb

Fungi % Inhibition FRAP valuec

.c. A.f. C.a.

50 >103 >103 65 120.0000 250 1000 32 212.9050 >103 1000 30 200.2050 250 1000 19 158.3300 >103 250 28 183.5600 500 500 68 162.9725 500 500 20 119.7550 250 1000 79 162.8750 200 1000 65 146.3200 250 250 32 240.1150 200 1000 40 209.7350 1000 500 29 224.5600 500 500 58 187.3325 >103 1000 80 160.2125 500 200 70 150.3600 500 250 88 137.81

00 0 5 0

100 100 100 500 99

typhi, V.c.: Vibrio cholerae, E.c.: Escherichia coli, A.f.: Aspergillus fumigatus, C.a.: CandidaNoroxacin, [F]: Nystatin, [G]: Griseofulvin, [H]: Isoniazide.L, standard antimicrobials used: isoniazide (0.2 lg/mL).g/mL.

m. Lett. 23 (2013) 16561661that were derived from chlorophenylpyrazolones have a good anti-bacterial activity. Methyl in 2-mercapto-quinoline-based sub-strates has no great inuence on biological activity. Generally,polyheterocycles from prenylated coumarins and allylated quino-line were good in bioactivities.

Acknowledgments

We sincerely express our thanks to Head, Department of Chem-istry, Sardar Patel University for providing necessary research facil-ity. Rikin, Bhagyashri are grateful to UGC, New Delhi, India fornancial assistance under the UGC Scheme of RFSMS.

A. Supplementary data

Supplementary data associated with this article can be found, inthe online version, at http://dx.doi.org/10.1016/j.bmcl.2013.01.079. These data include MOL les and InChiKeys of the mostimportant compounds described in this article.

References and notes

1. (a) Freemantle, M. An Introduction to Ionic Liquids; RSC Publishing: Cambridge,2010; (b) Plechkova, N. V.; Seddon, K. R. Chem. Soc. Rev. 2008, 37, 123. andreferences cited therein; (c) Zhao, H. Chem. Eng. Commun. 2006, 193, 1660; (d)Isambert, N.; Sanchez, M. D. M.; Plaquevent, J. C.; Genisson, Y.; Rodriguez, J.;Constantieux, T. Chem. Soc. Rev. 2011, 40, 1347.

2. (a)Ionic Liquids in Synthesis; Wasserscheid, P., Welton, T., Eds.; Wiley-VCH:Weinheim, 2002; (b) Welton, T. Chem. Rev. 1999, 99, 2071; (c) Meshram, H. M.;Reddy, P. N.; Vishnu, P.; Sedashir, K.; Yadav, J. S. Tetrahedron Lett. 2006, 47, 991;(d) Gong, H.; Cai, C.; Yang, N.; Yang, L.; Fan, Q. J. Mol. Catal. A: Chem. 2006, 249,236; (e) Wasserscheid, P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39, 3773.

3. (a) Shahoo, S.; Joseph, T.; Halligudi, S. B. J. Mol. Catal. A: Chem. 2006, 244, 179;(b) Liu, F. C.; Abrams, M. B.; Baker, R. T.; Tumas, W. Chem. Commun. 2001, 433;(c) Bates, E. D.; Mayton, R. D.; Ntai, I. J.; Davis, H. J. Am. Chem. Soc. 2002, 124,926; (d) Earle, M. J.; McCormac, P. B.; Seddon, K. R. Green Chem. 2000, 2, 261; (e)

N. J. Parmar et al. / Bioorg. Med. Chem. Lett. 23 (2013) 16561661 1661Olah, G. A.; Mathew, T.; Goeppert, A.; Torok, B.; Bucsi, I.; Li, X. Y.; Wang, Q.;Marinez, E. R.; Batamack, P.; Aniszfeld, R.; Prakash, G. K. S. J. Am. Chem. Soc.2005, 127, 5964.

4. (a) Khurana, J. M.; Magoo, D. Tetrahedron Lett. 2009, 50, 7300; (b) Chaturvedi, D.Curr. Org. Synth. 2011, 8, 438; (c) Harjani, J. R.; Nara, S. J.; Salunkhe, M. M.Tetrahedron Lett. 2002, 43, 1127; (d) Namboodiri, V. V.; Varma, R. S. Chem.Commun. 2002, 342; (e) Sheldon, R. Chem. Commun. 2001, 2399.

5. (a) Zhang, F.; Xu, D. Q.; Luo, S. P.; Liu, B. Y.; Du, X. H.; Xu, Z. Y. Chem. Res. 2004,24, 773; (b) Kamal, A.; Chouhan, G. Adv. Synth. Catal. 2004, 346, 579; (c)Nguyen, H. P.; Znifeche, S.; Baboulene, M. Synth. Commun. 2004, 34, 2085.

6. (a) Valizadeh, H.; Vaghe, S. Synth. Commun. 2009, 39, 1666; (b) Jawale, D. V.;Pratap, U. R.; Mulay, A. A.; Ramrao, J. R. M.; Mane, A. J. Chem. Sci. 2011, 123, 645;(c) Dubreuil, J. F.; Bazureau, J. P. Tetrahedron Lett. 2000, 41, 7351; (d) Ranu, B. R.;Banerjee, S. Org. Lett. 2005, 7, 3049; (e) Hikaru, Y.; Hiroshi, O.; Takeo, T. Org.Biomol. Chem. 2009, 7, 3657; (f) Fang, S.; Hua, Y.; Ge, G.; Gang, R. Chin. Chem.Lett. 2005, 16, 321.

7. (a)Ionic Liquids in Synthesis; Wasserscheid, P., Welton, T., Eds.; Wiley-VCH:Weinheim, 2008; Vol. 1, (b)Ionic Liquids in Synthesis; Wasserscheid, P., Welton,T., Eds.; Wiley-VCH: Weinheim, 2008; Vol. 2, (c) Parvulescu, I.; Hardacre, C.Chem. Rev. 2007, 107; (d) Durand, J.; Teuma, E.; Gmez, M. C. R. Chimie 2007, 10,152; (e) Zlotin, S. G.; Makhova, N. N. Mendeleev Commun. 2010, 20, 63; (f)Zlotin, S. G.; Makhova, N. N. Usp. Khim. 2010, 79, 603.

8. (a) Tietze, L. F. Chem. Rev. 1996, 96, 115; (b) Tietze, L. F.; Zhou, Y. F. Angew.Chem., Int. Ed. 1999, 38, 2045; (c) Pellissier, H. Tetrahedron 2006, 62, 1619; (d)Dat, N. T.; Lee, J.; Lee, K.; Hong, Y.; Kim, Y. H.; Lee, J. J. J. Nat. Prod. 2008, 71,1696; (e) Kwok, D. J.; Farr, R. N.; Daves, D. J. J. Org. Chem. 1991, 56, 3711; (f)Sinder, B. B.; Lu, Q. J. J. Org. Chem. 1996, 61, 2839; (g) Borah, H. N.; Deb, M. L.;Boruach, R. C.; Bhuyan, P. Tetrahedron Lett. 2005, 46, 3391; (h) Majumdar, K. C.;Taher, A.; Ray, K. Tetrahedron Lett. 2009, 50, 3889.

9. (a) Murray, R. D.; Mendez, J.; Brown, S. A. The Natural Coumarins: Occurrence,Chemistry and Biochemistry; John Wiley and Sons: New York, NY, 1982. 227; (b)Maity, S.; Khan, S. A.; Ahmad, S. Int. J. Pharm. Sci. 2012, 2, 87; (c) Wen, Y. L.; Xu,Q. X.; Dong, M. Z.; Yu, F. S.; Zhi, H. Y. Molecules 2012, 17, 5497; (d) Megbas, A.G.; Abdullah, H. F.; Abd, E. W.; Mostafa, A. M. Lett. Drug Des. & Discovery 2012, 9,459; (e) Kini, S. G.; Choudhary, S.; Mubeen, M. J. Comput. Methods Mol. Des.2012, 2, 51; (f) Marco, J. L.; Carreiras, M. C. J. Med. Chem. 2003, 6, 518; (g)Argotle, R.; Ramirez, A.; Rodriquez, G.; Rodriguez, M. H.; Gonzalez, C. J. Nat.Prod. 2006, 69, 1442.

10. (a) Seleem, H. S.; El-Inany, G. A.; El-Shetary, B. A.; Mousa, M. A. Chem. Cent. J.2011, 5, 2; (b) Bhat, M. A.; Al-Omar, M. A. Acta Pol. Pharm. Drug Res. 2011, 68,889; (c) Mustafa, M. S.; El-Abadelah, M. M.; Zihlif, M. A.; Naffa, R. G. Molecules2011, 16, 4305; d Kontogiorgis C.; Desti A.; Hadjipavlou-Litina D. Coumarin-Based Drug: a Patent Review (2008present); Expert Opin. Ther. Pat. 2012, 22,437. http://dx.doi.org/10.1517/13543776, 2012, 678835.; (e) Solomon, V. R.;Lee, H. Curr. Med. Chem. 2011, 18, 1488.

11. (a) Wang, J. L.; Liu, D.; Zhang, Z. J.; Shan, S.; Han, X.; Srinivasula, S. M.; Croce, C.M.; Alnemri, E. S.; Huang, Z. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 7124; (b) Zaki,M. E. A.; Soliman, H. A.; Hiekal, O. A.; Rashad, A. E. Z. Naturforsch C 2006, 61, 1;(c) Ismail, Z. H.; Aly, G. M.; El-Degwi, M. S.; Heiba, H. I.; Ghorab, M. M. Egypt. J.Biotech. 2003, 13, 73; (d) Abdelrazek, F. M.; Metz, P.; Metwally, N. H.; El-Mahrouky, S. F. Arch. Pharm. 2006, 339, 456.

12. (a) Eiznhamer, D. A.; Creagh, T.; Tolbert, D. T.; Giltner, J.; Dutta, B. HIV Clin.Trials 2002, 6, 435; (b) Saklani, A.; Kutty, S. K. Drug Discovery Today 2008, 13,161.

13. (a) Suzuki, M.; Li, Y.; Smith, P. C. Drug Metab. Dispos. 2005, 33, 1588; (b) Chun,H. Z.; Ting, Z.; Lan, X.; Jing, Y. Chin. Chem. Lett. 2005, 16, 1297; (c) Shi, Q. X.; Xin,Y.; Ying, C.; Peng, X.; Keduo, Q. Bioorg. Med. Chem. 2010, 18, 7203.

14. Eleni, M.; Prokopios, M.; Mitaku, S.; Leandros, S.; Chinou, E. J. Nat. Prod. 2005,68, 78.

15. Gunatilaka, A.; Kingston, D. J. Nat. Prod. 1994, 57, 518.16. (a) Duh, C. Y.; Wang, S. K.; Wu, Y. C. Phytochemistry 1991, 30, 2812; (b) Duh, C.

Y.; Wang, S. K.; Wu, Y. C. Phytochemistry 1829, 1992, 31.17. Damien, L.; Prado, D. K.; Kasenene, J. J. Nat. Prod. 2011, 74, 2286.18. (a) Kalluraya, B.; Nayak, J.; Adhikari, A.; Sujith, K. V.; Sucheta, N.; Shetty, M. W.

Phosphorus, Sulfur Silicon 1870, 2008, 183; (b) Charris, J. E.; Domnguez, J. N.;Gamboa, N.; Rodrigues, J. R.; Angel, J. E. Eur. J. Med. Chem. 2005, 40, 875; (c)Bhovi, V. K.; Bodke, Y. D.; Biradar, S.; Kumar, B. E.; Umesh, S. Phosphorus, SulfurSilicon 2010, 185, 110; (d) Xie, Z.; Chai, K.; Piao, H.; Kwak, K.; Quan, Z. Bioorg.Med. Chem. Lett. 2005, 15, 4803; (e) Nawaz Khan, F. R.; Roopan, S. M. Arkivoc2009, 13, 161.

19. (a) Corral, R. A.; Orazi, O. Tetrahedron Lett. 1967, 7, 583; (b) Puricelli, L.;Innocenti, G.; Delle, M. G.; Caniato, R.; Filippini, R.; Cappelletti, E. M. Nat. Prod.Lett. 2002, 16, 95.

20. Lesage, A. S. J.; Bischoff, F. P.; Janseen, C. G. M.; Lavreysen, H. WO 03082350;2003.

21. Tabarrini, O.; Cecchetti, V.; Temperini, A.; Filipponi, E. Bioorg. Med. Chem. 2001,9, 2921.

22. (a) Khoshkholgh, M. J.; Hosseindokht, M. R.; Balalaie, S. Helv. Chim. Acta 2012,95, 52; (b) Ghoshal, A.; Sarkar, A. R.; kumaran, R. S.; Hegde, S. Tetrahedron Lett.2012, 53, 1748; (c) Majumder, S.; Bhuyan, P. J. Tetrahedron Lett. 2012, 53, 137;(d) Mishra, A.; Rastogi, N.; Batra, S. Tetrahedron 2012, 68, 2146; (e) Reddy, B. V.S.; Divya, B.; Swain, M.; Rao, T. P.; Yadav, J. S. Bioorg. Med. Chem. Lett. 1995,2012, 22.23. (a) Maiti, S.; Panja, S. K.; Bandyopadhyay, C. Tetrahedron 2010, 66, 7625; (b)Yadav, J. S.; Reddy, B. V. S.; Narsimhaswamy, D.; Lakshmi, P. N. Tetrahedron Lett.2004, 45, 3493.

24. (a) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. 1993, 32, 131; (b) Pellissier, H.Tetrahedron 2006, 62, 2143; (c) Tietze, L. F.; Rackelmann, N. Pure Appl. Chem.1967, 2004, 76; (d) Tietze, L. F.; Kinzel, T.; Brazel, C. C. Acc. Chem. Res. 2009, 42,367; (e) Enders, D.; Wang, C.; Bats, J. W. Angew. Chem., Int. Ed. 2008, 47, 7539;(f) Zhang, Z.; Zhang, Q.; Sun, S.; Xiong, T.; Liu, Q. Angew. Chem., Int. Ed. 2007, 46,1726; (g) Enders, D.; Grondal, C.; Hutt, M. R. M. Angew. Chem., Int. Ed. 2007, 46,1570; (h) Yadav, A. K.; Peruncheralathan, S.; Ila, H.; Junjappa, H. J. Org. Chem.2007, 72, 1388.

25. (a) Parmar, N. J.; Teraiya, S. B.; Patel, R. A.; Talpada, N. P. Tetrahedron Lett. 2011,52, 2853; (b) Jayashankaran, J.; Manian, R. S.; Rghavachary, R. Tetrahedron Lett.2006, 47, 2265.

26. Parmar, N. J.; Patel, R. A.; Teraiya, S. B.; Sharma, D.; Gupta, V. K. RSC Adv. 2012,2, 3069.

27. Bakthadoss, M.; Sivakumar, G.; Kannan, D. Org. Lett. 2009, 11, 4466.28. (a) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025; (b) Choudhary, V. R.; Dhar,

A.; Jana, P.; Jha, R.; Uphade, B. S. Green Chem. 2005, 7, 768; (c) Deka, N.;Mariotte, A. M. Green Chem. 2001, 3, 263.

29. Yanlong, G.; Juan, Z.; Zhiying, D.; Youquan, D. Adv. Synth. Catal. 2005, 347, 512.30. (a) Movassagh, B.; Shaygan, P. Arkivoc 2006, 7, 130; (b) Rao, H. S.; Jothilingam,

S. J. Chem. Sci. 2005, 117, 323.31. (a) Parmar, N. J.; Pansuriya, B. R.; Barad, H. A.; Rajni, K.; Gupta, V. K. Bioorg. Med.

Chem. Lett. 2012, 22, 4075; (b) Parmar, N. J.; Barad, H. A.; Teraiya, S. B.;Pansuriya, B. R.; Rajni, K.; Gupta, V. K. Bioorg. Med. Chem. Lett. 2012, 22, 3816;(c) Parmar, N. J.; Teraiya, S. B.; Barad, H. A.; Sharma, D.; Gupta, V. K. Synth.Commun. 2012 http://dx.doi.org/10.1080/00397911.2011.652755 (publishedonline 17 may 2012).; (d) Parmar, N. J.; Pansuriya, B. R.; Labana, B. M.; Sutariya,T. R.; Kant, R.; Gupta, V. K. Eur. J. Org. Chem. 2012, 5953; (e) Parmar, N. J.;Pansuriya, B. R.; Barad, H. A.; Parmar, B. D., Kant, R.; Gupta, V. K.Monatsh Chem.http://dx.doi.org/10.1007/s00706-012-0873-7 (published online).

32. (a) Verma, A. K.; Attri, P.; Chopra, V.; Tiwari, R. K.; Chandra, R. Monatsh Chem.2008, 139, 1041; (b) Balaskar, R.; Gavade, S.; Mane, M.; Pabrekar, P.; Shingare,M.; Mane, D. Lett. Org. Chem. 2011, 8, 282; (c) Kumar, D.; Sandhu, J. S. Rasayan J.2009, 2, 937; (d) Mamoru, H.; Morimura, M.; Hayakawa, Y. NucleosidesNucleotides Nucleic Acids 2005, 24, 585; (e) Xiaoke, H.; Liangfang, Z.; Xueqin,W.; Bin, G.; Jiaquan, X.; Guiying, L.; Changwei, H. J. Mol. Catal. A: Chem. 2011,342, 41; (f) Balaskar, R.; Gavade, S.; Mane, M.; Pabrekar, P.; Shingare, M.; Mane,D. Chin. Chem. Lett. 2010, 21, 1175.

33. Knorr, L. Chem. Ber. 1883, 16, 2597.34. Synthesis of pyranopyrazol derivatives (6ar, 7ap): in a round-bottom ask,

aldehydes substrates 3ad, 4ab (3.7 mmol; 0.99 g of 3a, 0.85 g of 3b, 1.00 g of3c, 0.95 g of 3d, 0.90 g of 4a, 1.00 g of 4b) and 5-pyrazolones 5af (3.7 mmol;0.64 g of 5a, 0.70 g of 5b, 0.87 g of 5c, 0.77 g of 5d, 0.77 g of 5e, 0.90 g of 5f,0.70 g of 5g, 0.77 g of 5h) in the presence of 2 mL of TEAA as ionic liquid wereheated at 120 C until the substrate disappeared as monitored by TLC. It gaveproducts 6ar, 7ap in good yields. The crude products were puried bycolumn chromatography. All the products were characterized based on theirelemental, mass, UVvisible NMR and IR spectroscopy.

35. (5aS,13bR)-1,9-Dimethyl-3-phenyl-3,5a,6,13b-tetrahydro-5H-pyrazolo[400 ,300:50 ,60]pyrano [40 ,30:4,5]thiopyrano[2,3-b]quinoline (6a): isolatedyield (0.89 g, 80%) as yellow crystals, mp 130132 C; IR (KBr): mmax cm1

3010, 2920, 1620, 1510, 1380, 1045, 745; 1H NMR (CDCl3, 400 MHz): d 2.22 (s,3H, Me), 2.40 (s, 1H, CH), 2.59 (m,1H, CH), 2.81(s, 3H, Me), 3.41 (m, 1H, CH),3.88 (t, 1H, J = 10.8 Hz, CH), 4.11 (d, 1H, J = 5.6 Hz, CH), 4.31 (dd, J = 10.7 Hz, 1H,CH), 7.377.81 (m, 9H ArH); 13C NMR (CDCl3, 100 MHz): d 13.41, 17.94, 28.87,34.73, 34.98, 69.54, 96.36, 120.28, 125.48, 125.76, 126.03, 126.89, 129.05,129.96, 131.07, 136.06, 136.86, 138.54, 145.92, 147.36, 156.20, 157.80; ESI-MS: m/z: 399.2 ; C24H21N3OS (399.14 g/mol): calcd C 72.15, H 5.30, N 10.52;found C 72.15, H 5.25, N 10.48.(2aR,10cS)-7,11-Dimethyl-13-phenyl-2a,3,10c,13-tetrahydro-2H,9H-pyrano-[200 ,300:50 ,60]chromeno[40 ,30:4,5]pyrano[2,3-c]pyrazol-9-one (7a): isolated yield(0.76 g, 78%) as white crystals, mp 135138 C; IR (KBr): mmax cm1 3050, 2990,1670, 1600, 1380, 1250, 1000, 840, 650; 1H NMR (CDCl3, 400 MHz): d 1.86(s, 3H, Me), 2.35(s, 3H, Me), 4.36 (d, 2H, J = 8.7 Hz, CH2), 4.49 (m, 2H, CH2), 4.69(d, 1H, J = 5.1 Hz, CH), 6.697.80 (m, 8H ArH); 13C NMR (CDCl3, 100 MHz):d 13.86, 18.69, 25.70, 29.15, 64.49, 69.21, 95.49, 110.43, 111.65, 112.84, 113.86,124.89, 127.62, 129.43, 129.93, 131.86, 147.92, 148.36, 153.15, 153.46, 156.86,160.79; ESI-MS: m/z: 400.1; C24H20N2O4 (400.43 g/mol): calcd C 71.99, H 5.03,N 7.00; found C 71.92, H 5.10, N 7.06.

36. (a) Shadomy, S.; Pfaller, M. A. Laboratory Studies with Antifungal Agents:Susceptibility Tests and Quantitation in Body Fluids. In Manual of ClinicalMicrobiology, 5th ed.; Balows, A., Hausler, W. J., Hermann, K. L., Isenberg, H. D.,Shadomy H. J., Eds.; Washington DC, 1991; Chapter 117, p 1173.; (b) NationalCommittee for Clinical Laboratory Standards. Methods forDilutionantimicrobial Susceptibility Tests for Bacteria that Grow Aerobically,5th ed.; Approved Standard (M7A5); National Committee for ClinicalLaboratory Standards: Wayne, PA, 2000.

37. Rattan, A. Antimicrobials in Laboratory Medicine; Churchill BI Livingstone: NewDelhi, 2000. p 85.

38. Benzie, I. F. F.; Strain, J. J. Anal. Biochem. 1996, 239, 70.

An efficient domino reaction in ionic liquid: Synthesis and biological evaluation of some pyrano- and thiopyrano-fused heterocyclesAcknowledgmentsA. Supplementary dataReferences and notes