An efficient domino reaction in ionic liquid: Synthesis and biological evaluation of some pyrano- and thiopyrano-fused heterocycles

Bioorganic & Medicinal Chemistry Letters 23 (2013) 1656–1661

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An efficient domino reaction in ionic liquid: Synthesis and biological evaluation of some pyrano- and thiopyrano-fused heterocycles Narsidas J. Parmar ⇑, Rikin A. Patel, Bhagyashri D. Parmar, Navin P. Talpada Department of Chemistry, Sardar Patel University, Vallabh Vidyanagar, Dist. Anand, 388120 Gujarat, India

a r t i c l e

i n f o

Article history: Received 18 October 2012 Revised 5 January 2013 Accepted 17 January 2013 Available online 29 January 2013 Keywords: Thiopyranoquinoline Pyranocoumarin Triethylammonium acetate Domino/Knoevenagel-hetero-Diels–Alder Ionic liquid

a b s t r a c t An improved domino/Knoevenagel-hetero-Diels–Alder reaction of two new aldehyde substrates; 7-olefinoxy-coumarin-8-carbaldehyde and 2-alkensulfanyl-quinoline-3-carbaldehyde, with pyrazolones was studied in ionic liquid triethylammonium acetate (TEAA), affording a series of pyrazolopyran annulated-pyrano-fused coumarins, and thiopyrano-fused quinolones. Besides acting as catalyst, since no additional catalyst used, the ionic liquid TEAA also promised its easy recovery. In all new polyheterocycles, the cis-fusion of two pyranyl rings had been inferred from 2D NMR COSY and NOESY experiments. All are good antitubercular agents, as they are found active against Mycobacterium tuberculosis H37Rv, and antibacterial agents, as they are found active against three Gram-positive (Streptococcus pneumoniae, Clostridium tetani, Bacillus subtilis) and three Gram-negative (Salmonella typhi, Vibrio cholerae, Escherichia coli) bacteria. Ó 2013 Elsevier Ltd. All rights reserved.

As efficient green reaction media, ILs (ionic liquids) have attracted interest of many researchers due to their negligible vapor pressure and nonflammable nature1 that confer the reaction with many advantages like high thermal stability, polarity, and recyclability along with a good extracting power.2 Besides being alternative to organic solvents, ILs also act as efficient catalysts,3 which have solved both solvent emission and catalyst re-use problems.3b–e Today, ILs offer the organic synthesis with efficient green methodologies.4 Nucleophiles with compounds having electrondeficient double bonds like C@C or C@O showed excellent reactivity in ionic liquids.5 Wittig reaction,6a biginelli’s condensation,6b 1,3-dipolar cycloaddition,6c Michael addition,6d Diels–Alder reaction,6e benzoin condensation6f etc. have successfully been mediated by eco-friendly and environmentally benign solvents. Neverthless, these neoteric solvents and catalysts7 have seldom been employed in the domino/Knoevenagel-hetero-Diels–Alder (DKHDA) approach, a powerful tool to access diverse natural and unnatural bioactive polyheterocycles.8 Coumarins and quinolines, due to their much closer structural relationship with many bioactive natural and unnatural complex molecules, are useful templates for drug development.9 In recent past, a growing number of scaffolds, incorporating these moieties, have emerged as useful medicinal compounds. These heterocycles have been soured both synthetically as well as naturally.10 ⇑ Corresponding author. Tel.: +91 2692 226858; fax: +91 2692 236475. E-mail addresses: (N.J. Parmar).

[email protected],

Pyran-annulated heterocycles particularly have remarkable pharmacological potencies.11 Pyranocoumarin, for example, in which coumarin is fused to a pyran ring via its 7,8 positions, is an important subunit from bioactivity point of view. Non-nucleoside HIV-Ispecific reverse transcriptase inhibitors (+) calanolide A,12 30 ,40 -diO-(S)camphanoyl-(+)-cis-khellactone (DCK)13 analogs and anticancer agent seselin (Fig. 1) are the potential candidates this ring system exists in.14 Seselin also exhibited cytotoxic activity against Vero monkey cells.15 Besides being a significant cytotoxic against P-388 lymphocytic leukemia,16 it also possess an antiparasitic activity.17 Coumarin analogs quinolines, on the other hand, have been well recognized by synthetic and medicinal chemists.18 Pyran annulated quinolines constitute a basic framework of a large number of alkaloids19 like geibalasine, ribalinine, flindersine, etc. Metabotropic glutamate receptor antagonistic activity that is, mGlu 1 receptor activity of thiopyranoquinoline (Fig. 1),20 and velnacrine thia analogues, that act as potential agents for treating Alzheimer’s disease, are very useful medicinal applications of this class.21

O MeO

N

S

Thiopyranoquinoline

O

O

O

Seselin

[email protected]

0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmcl.2013.01.079

Figure 1. Biologically active thiopyranoquinolines and pyranocoumarins.

N. J. Parmar et al. / Bioorg. Med. Chem. Lett. 23 (2013) 1656–1661

In view of this, the development of class of these heterocycles is of a considerable interest. Moreover, a discloser of possibilities of combinatorial-based investigations certainly offers medicinal chemists a way to access new bio-molecules. Among the synthetic approaches, the domino/Knoevenagel-hetero-Diels–Alder (DKHDA) has overwhelmingly gained a vital importance to create complex molecules in organic synthesis. Olefin-ether-tethered aldehyde can be assembled with 1,3-diketones as well as other active methylene units like pyrazolones and isoxazolones,22 hydroxycoumarins and hydroxyquinolones.23 Many aromatic and hetero-aromatic aldehyde-based substrates have been tested. Surprisingly, no report on hydroxycoumarinsand hydroxyquinolone-based aldehyde substrates. 7-Hydroxy-4methyl-coumarin-8-carbaldehydes and 2-mercapto-quinoline-3carbaldehydes were therefore intended in the present work to construct new pyran and thiopyran annulated heterocyclic systems. Many ways to promote DKHDA reaction exist.24 Efficiency and selectivity however depend upon the nature of an active methylene unit, dienophile and aldehyde substrate. Prenyl-based aldehyde substrate undergoes this transformation easily even in a mild reaction condition.25 In contrast to this, allyl- or propargylbased substrates,26 require higher temperature, irrespective of whether the reaction is performed under efficient catalyst- and solvent-free or solvent-free catalyzed-one conditions, due to involving unactivated dienophile.27,28 Further, partial decomposition, toxic wastes also affect the yields, leaving the product isolation step a tedious work.29 Finally, the harsh condition may link with ecological issues such as more catalyst loading, and side reactions.30 Our recent interest is the green synthesis under conventional heating as well as microwave conditions.25a,31 To continue this, we envisioned the synthesis of biodynamic pyranocoumarins and thiopyranoquinolines in potentially recoverable medium-cum-catalyst triethylammonium acetate (TEAA) via DKHDA reaction. TEAA has mediated many organic reactions, and has emerged as a potential medium in the organic synthesis.32 We chose an assimilation of two new aldehyde substrates; 2-allyl/prenylsulfanyl-quinoline-3-carbaldehydes 3 and 7-allyloxy/ prenyloxy-4-methyl-coumarin-8-carbaldehydes 4, with corresponding less reactive pyrazolones via DKHDA reaction. Allylation/prenylation of 2-mercapto-quinoline-3-carbaldehyde 1 in the presence of anhydrous K2CO3-suspended DMF (dimethylformamide) solution, with stirring the reaction mass at room temperature, gave substrates 3 and that of 4-methyl-7-hydroxy-cumarin8-carbaldehyde 2 substrates 4 (Scheme 1). Yields of both the substrates were in the 94–96% range. Pyrazolones 5a–h were obtained from corresponding ethyl aceto acetates and phenyl hydrazines as reported in the Letter.33

CHO R'

N

SH

1 R R

Br

K 2CO 3 DMF rt

HO

CHO

O CHO

R'

O O

N

O CHO

2 R

S

3a-d

R

R' 3a; Me 3b; H R 3c; Me R 3d ;H

O

R H H Me Me

R 4a; H 4b; Me

4a-b

Scheme 1. Preparation of required coumarin and quinoline-based aldehyde substrates.

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For optimizing the reaction conditions, we have examined 2-allyl/prenylsulfanylquinolines 3a,c and 7-allyloxy/prenyloxycoumarins 4a–b each with pyrazolone 5a as four model substrates. The results are shown in Table 1. First, we examined the reaction in the absence of catalyst in acetonitrile at room temperature (entry 1) and then in the presence of catalyst tetrabutyl ammonium hydrogen sulphate (TBA-HS) (entry 2) in same solvent but at its reflux temperature. None of the substrates gave product after refluxing for a longer time. Similar results were found in catalyst SDS (sodium dodesyl sulfate) but in refluxing toluene (entry 3). Next, we tested TBA-HS in refluxing xylene (entry 4). We noticed that only prenyl-based substrates, 3c and 4b, yielded 20% of desired products, 6o and 7i respectively, leaving allyl-based substrates, 3a and 4a, unreacted. No improvement could be seen even replaced TBA-HS by ZnO (entry 5). Examining further TBA-HS-catalyzed protocol without solvent at 140 °C (entry 6) showed that although it reduced reaction time to 4 h, only moderate yields were recorded from both allyl- and prenyl-based substrates, 3a,c and 4a–b respectively, with 5a (entry 6). It may be due to partial decomposition, as TLC (thin layer chromatography) of reaction mass evidenced the association of other components with desired cyclized product. Mixture of burnt impurities and catalyst thus made the product isolation step difficult and tedious. We therefore attempted ionic liquid TEAA. Observing initially the reaction in the 30–70 °C temperature range showed no good results. We therefore omitted these results. But, since the temperature above 100 °C influenced the reaction, Table 1 displays results observed at 120 °C (entry 7). It improved the reaction in time and temperature both, taking 1.6 h in case of prenyl-based substrates 3c or 4b, and 2.5 h for allyl-based substrates 3a or 4a. No burnt impurities were formed and hence it made the product isolation step simple. Increasing the volume of TEAA however could not improve the results remarkably (entries 8–9). High yields, short reaction time, relatively less temperature, easy setup and work-up are the advantages of this new greener protocol. Other thiopyranoquinolines 6b as well 6d–r were obtained employing the optimal condition (Scheme 2).34 Orange–red Knoevenagel adducts that appeared after 20 min underwent cyclisation in 2–3 h as monitored by TLC. The yields of the products were in the 70–84 % range. Similarly, 7-allyl/prenyloxycoumarin-8-carbaldehydes 4a–b gave pyranocoumarins 7b–p with pyrazolones 5b–h in the 72–84% yields (Scheme 2). All are new compounds, and their chemistry characterizations are fully detailed in supplementary materials. In addition, the stereochemistry of these new heterocycles was confirmed by 2D NMR COSY and NOESY experiments, which suggests cis-fusion of two central pyran rings (Fig. 2). Allylsulfanylquinoline-3-carbaldehydes 3a–b relatively took more reaction time than the analogs prenylsulfanyle ones 3c–d due to the presence of unactivated dienophile. However this substrate with methyl at eight position of quinoline took relatively less reaction time to afford the desired products, favoring inverse electron demand hetero-Diels–Alder reaction. Same could be seen with the coumarin-based aldehyde substrates. Pyrazolones, particularly the one with the 4-nitrophenyl or 3, 4-dichlorophenyl at its N1 nitrogen required relatively less reaction time with a particular aldehyde substrate, indicating good reactivity. Pyrazolones are generally less reactive as there is no electron withdrawing group at 3-position in its Knoevenagel intermediate 1-oxa-1,3-butdiene with aldehyde. A mechanistic pathway is presented in Figure 3. It proceeds through the simultaneous generation of Knoevenagel adduct (v) along with a few portions of Michael adducts (iv) obtained from pyrazolonate (ii) and aldehyde substrate (iii), which are common in ionic liquid TEAA.31e Influence of catalyst-cum-medium TEAA in a long run however transformed these intermediates into exclusively DKHDA cyclized products (vi), indicating that Michael

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Table 1 Optimization of the DKHDA reaction conditions Entry

Catalyst

Solvent

Temp (°C)

Time (h) 6a/6o

Yield (%) 6a/6o

Time (h) 7a/7i

Yield (%) 7a/7i

1 2 3 4 5 6 7 8 9

— TBA-HS SDS TBA-HS ZnO TBA-HS — — —

Acetonitrile Acetonitrile Toluene Xylene Xylene — TEAA (2 mL) TEAA (3 mL) TEAA (5 mL)

rt 80 110 140 140 140 120 120 120

24 12 10 10 8 4 2.5/1.6 2.5/1.8 2.5/1.7

— — — 20 Trace 70/73 80/82 81/83 81/81

20 10 10 10 8 4 2.5/1.9 2.5/1.8 2.5/1.8

— — — 20 Trace 70/69 78/70 81/68 81/69

rt = room temperature.

CHO

R1 R2 5a; Me Ph 5b; Me 4-MePh 5c; Me 2-ClPh 5d; Me 3-ClPh 5e; Me 2,5-Cl2Ph 5f; Ph Ph 5g; Me 3,4-Cl2Ph 5h; Me 4-NO2Ph

R

3

N N 2 R

R

S

R1

TEAA 120 C O

O

O

O

R

3a-d

R1 O

N

R2 N N R R

N S R3 6a-r CHO

5a-h

R

O

R

O

R

4a-b

R

O O

O R1

N N R2

7a-p

Scheme 2. DKHDA reaction of 2-sulfanylquinoline 3 and 7-hydroxycoumarin-based aldehyde substrates 4 with pyrazolones 5.

CH3 HO H H H

Table 2 Synthesis of pyrazolopyran-annulated thiopyranoquiolones 6a–r

O O H CH3 N N

O

H

CH3 Figure 2. nOe’s of compound 7b.

AcOH Et3NH

R1

CHO R

N O NR 2

R1

(ii)

O NN (i) R 2

X

(iii)

R

1 Et 3NH O R N N XO R 2

Et3NHOAc

(iv)

R R

X

R1

R R O

N N

2 (vi) R

X

R1

R

N N

O R2 (v) R

a b

Entry

Product

R

R1

R2

R3

Time

Yielda

mpb

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

6a 6b 6c 6d 6e 6f 6g 6h 6i 6j 6k 6l 6m 6n 6o 6p 6q 6r

H H H H H H H H H H H H H H Me Me Me Me

Me Me Me Me Me Ph Me Me Me Me Me Me Me Ph Me Me Me Me

Ph 4-MePh 2-ClPh 3-ClPh 2,5-Cl2Ph Ph 3,4-Cl2Ph 4-NO2Ph Ph 4-MePh 2-ClPh 3-ClPh 2,5-Cl2Ph Ph Ph 4-MePh 2-ClPh 3-ClPh

Me Me Me Me Me Me Me Me H H H H H H Me Me Me Me

2.5 2.4 2.6 2.6 2.8 2.7 2.4 2.4 2.6 2.5 2.7 2.8 2.9 2.8 1.6 1.8 1.7 1.6

80 81 78 72 80 79 79 80 74 70 80 76 78 73 82 84 80 81

130–132 132–133 140–143 130–132 120–126 130–131 138–140 141–144 142–144 154–156 160–164 138–140 132–135 140–143 214–216 167–169 156–159 200–202

Of isolated compound. Uncorrected.

AcOH Et3NHOAc

HNEt3OAc R1 = Me, R2 = Ph, Ar = Ph, X = O, S

Figure 3. Proposed mechanism of DKHDA reaction.

adducts were ultimately converted into Knoevenagel intermediate to give cyclized products too. The endo- or exo-orientations of the dienophile,24g which decide the stereochemical outcome, leads to four transition states; exo-Eanti, endo-Z-anti, exo-E-syn and endo-Z-syn. The cis-product, which

is major yields and could be confirmed based on 1H NMR and 2D NMR experiments; nuclear Overhauser effect spectroscopy (nOe’s) and the double quantum filtered correlation spectroscopy (DQFCOSY), suggests that the reaction favored the endo-E-syn transition state 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, solidified on pouring a reaction mass into ice cold water, were isolated and purified by column chromatography using silica gel (Tables 2 and 3). The spectroscopic data35 are in good agreement with the proposed structures of the compounds. 1H NMR showed a doublet in the d 4.6–4.8 ppm range (J = 4–5 Hz) attributable to Hb proton, and multiplets in the d 3.0– 3.5 ppm range to Ha. A characteristic IR band that appeared in the

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efficiency of recovered TEAA remained unaltered. For every reaction, 2 mL (6.2 mmol) of ionic liquid was used. All newly synthesized polycyclic heterocycles were screened for their in vitro antimicrobial activity against Gram-positive (Streptococcus pneumoniae, Clostridium tetani, and Bacillus subtilis) and Gram-negative (Salmonella typhi, Vibrio chlolerae and Escherichia coli) bacteria-using macro-broth dilution method,36 antitubercular activity against Mycobacterium tuberculosis H37Rv bacteria-using L.J. Medium,37 and antioxidant property as a ferric reducing antioxidant power (FRAP)-using Benzie and Strain’s modified FRAP38 method. While ampicillin, norfloxacin, chloramphinicol, and ciprofloxacin were standard antibacterial reference drugs, griseofulvin and nystalin standard antifungal reference drugs. FRAP values are expressed as ascorbic acid equivalent (mmol/100 g). Percent growth inhibition of M. tuberculosis H37Rv bacteria was determined by running a test solution 250 lg/mL in DMSO. From the antimicrobial screening test results (Table 4), it reveals that a majority of pyrazolopyran-annulated thiopyranoquinolones 6a–r are rather more antibacterial with MIC values below 200 lg/mL than antifungal, as only two compounds 6a and 6d crossed this value against antifungal Aspergillus fumigates, and none of them against Candia albicans fungus. Among them, those which resemble standard reference drug chloramphenicol includes 6i—active against Clostridium tetani bacteria, 6g and 6j— active against Streptococcus pneumonia bacteria, 6e and 6l—active against Escherichia coli bacteria and 6h—active against Salmonella typhi bacteria. In addition, compound 6i resemble the standard drug Norfloxacin, and compounds 6g and 6i the standard reference drug Ciprofloxacin, also, in terms of their potencies against similar bacteria. Analysing Table 4 further, we noticed that a larger number of compounds have potency equal to the standard drug Ampicilin not Norfloxacin. Many compounds were also found

Table 3 Synthesis of pyrazolopyran-annulated pyranocoumarins 7a–p

a b

Entry

Product

R

R1

R2

Time

Yielda

mpb

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

7a 7b 7c 7d 7e 7f 7g 7h 7i 7j 7k 7l 7m 7n 7o 7p

H H H H H H H H Me Me Me Me Me Me Me Me

Me Me Me Me Me Ph Me Me Me Me Me Me Me Ph Me Me

Ph 4-MePh 2-ClPh 3-ClPh 2,5-Cl2Ph Ph 3,4-Cl2Ph 4-NO2Ph Ph 4-MePh 2-ClPh 3-ClPh 2,5-Cl2Ph Ph 3,4-Cl2Ph 4-NO2Ph

3.0 3.1 3.0 2.9 3.2 3.0 3.2 2.8 1.9 2.9 3.0 3.1 3.1 3.0 3.0 2.8

78 77 76 72 80 81 79 84 70 76 71 75 74 80 82 70

135–138 140–142 136–137 142–145 150–152 130–131 148–149 141–144 136–138 147–148 152–153 137–139 158–160 146–148 150–151 135–138

Of isolated compound. Uncorrected.

1210–1255 cm1 range indicates cyclic ether linkage of pyran ring. A band that appeared in the 1600–1750 cm1 range is due to m C@O, and around 1200 cm1 m C@S. Mass spectroscopy also confirmed the desired molecular weights of all domino products. Re-use of TEAA was also confirmed based on its recovery and recyclability studies. On simply heating aqueous filtrate, that was left after isolating solid products formed on pouring the reaction mass into ice water, under reduced pressure at 80 °C assured quantitative recovery of TEAA. The recovered TEAA was again used for the same reaction. In this way, the TEAA was recovered at least four-time after being used and tested for the reaction. The

Table 4 Biological screening test results; antimicrobial, antitubercular, and antioxidant activities of pyrazolopyran-annulated thiopyranoquinolones 6a–r (MIC, lg/mL) Antimicrobial activity (MIC, lgmL1)

Entry Gram-positive bacteria

6a 6b 6c 6d 6e 6f 6g 6h 6i 6j 6k 6l 6m 6n 6o 6p 6q 6r [A] [B] [C] [D] [E] [F] [G] [H]

Gram-negative bacteria

Fungi

B.s.

C.t.

S.p.

E.c.

S.t.

V.c.

A.f.

C.a.

100 200 125 250 100 200 200 250 200 200 125 200 100 200 250 100 250 200 1 250 50 50 100 — — —

200 250 125 200 100 125 250 200 62.5 200 250 125 200 250 100 200 100 1000 5 250 50 100 50 — — —

250 200 100 250 250 200 62.5 200 200 62.5 100 250 200 250 100 100 250 100 0.5 100 50 50 10 — — —

250 100 250 250 62.5 100 250 100 100 125 250 62.5 250 100 200 125 200 150 0.05 100 50 25 10 — — —

200 125 250 500 200 125 250 62.5 125 125 250 100 100 250 100 125 100 250 5 100 50 25 10 — — —

250 125 200 200 100 200 250 250 100 200 250 200 200 250 125 200 200 100 5 100 50 25 10 — — —

250 200 250 200 1000 >103 1000 >103 500 1000 >103 1000 >103 250 1000 500 500 500 — — — — — 100 100 —

1000 1000 500 1000 1000 >103 500 >103 500 1000 1000 >103 500 500 >103 250 250 500 — — — — — 100 500 —

Anti TBa

Antioxidant activityb

% Inhibition

FRAP valuec

38 63 29 82 49 9 38 20 87 33 52 61 93 40 49 91 50 91 — — — — — — — 99

160.39 112.40 146.55 125.16 129.31 101.15 61.70 49.75 126.02 121.26 90.94 127.87 158.00 105.01 83.50 160.60 115.26 18.18 — — — — — — — —

S.p.: Streptococcus pneumoniae, C.t.: Clostridium tetani, B.s.: Bacillus subtilis, S.t.: Salmonella typhi, V.c.: Vibrio cholerae, E.c.: Escherichia coli, A.f.: Aspergillus fumigatus, C.a.: Candida albicans, [A]: Gentamycin, [B]: Ampicillin, [C]: Chloramphenicol, [D]: Ciprofloxacin, [E]: Norfloxacin, [F]: Nystatin, [G]: Griseofulvin, [H]: Isoniazide. a Concentration of compounds used against M. tuberculosis H37Rv bacteria = 250 lg/mL, standard antimicrobials used: isoniazide (0.2 lg/mL). b Concentration of compounds = 200 lg/mL and standard: A.A. (ascorbic acid) = 176 lg/mL. c A.A. mm/100 g sample.

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Table 5 Biological screening test results; antimicrobial, antitubercular, and antioxidant activities of pyrazolopyran-annulated pyranocoumarins 7a–p (MIC, lg/mL) Antimicrobial activity (MIC, lgmL1)

Entry Gram-positive bacteria

7a 7b 7c 7d 7e 7f 7g 7h 7i 7j 7k 7l 7m 7n 7o 7p [A] [B] [C] [D] [E] [F] [G] [H]

Gram-negative bacteria

Fungi

B.s.

C.t.

S.p.

E.c.

S.t.

V.c.

A.f.

C.a.

500 250 62.5 200 200 125 250 200 200 250 100 200 100 200 250 200 1 250 50 50 100 — — —

250 200 200 62.5 250 100 100 250 500 250 250 200 200 100 250 200 5 250 50 100 50 — — —

250 250 100 62.5 200 100 250 250 200 100 250 62.5 100 125 250 200 0.5 100 50 50 10 — — —

250 200 125 100 125 62.5 250 125 250 100 125 200 100 125 200 200 0.05 100 50 25 10 — — —

200 250 100 200 250 125 250 200 250 250 125 200 125 100 250 125 5 100 50 25 10 — — —

250 200 250 250 100 100 125 250 250 500 250 250 100 125 125 200 5 100 50 25 10 — — —

>103 250 >103 250 >103 500 500 250 200 250 200 1000 500 >103 500 500 — — — — — 100 100 —

>103 1000 1000 1000 250 500 500 1000 1000 250 1000 500 500 1000 200 250 — — — — — 100 500 —

Anti TBa

Antioxidant activityb

% Inhibition

FRAP valuec

65 32 30 19 28 68 20 79 65 32 40 29 58 80 70 88 — — — — — — — 99

120.00 212.90 200.20 158.33 183.56 162.97 119.75 162.87 146.32 240.11 209.73 224.56 187.33 160.21 150.36 137.81 — — — — — — — —

S.p.: Streptococcus pneumoniae, C.t.: Clostridium tetani, B.s.: Bacillus subtilis, S.t.: Salmonella typhi, V.c.: Vibrio cholerae, E.c.: Escherichia coli, A.f.: Aspergillus fumigatus, C.a.: Candida albicans, [A]: Gentamycin, [B]: Ampicillin, [C]: Chloramphenicol, [D]: Ciprofloxacin, [E]: Norfloxacin, [F]: Nystatin, [G]: Griseofulvin, [H]: Isoniazide. a Concentration of compounds used against M. tuberculosis H37Rv bacteria = 250 lg/mL, standard antimicrobials used: isoniazide (0.2 lg/mL). b Concentration of compounds = 200 lg/mL and standard: A.A. (ascorbic acid) = 176 lg/mL. c A.A. mm/100 g sample.

active against multiple bacteria, which resemble Ampicilin. While compound 6c was found active against all three Gram-positive bacteria, 6b and 6i were against all three Gram-negative bacteria. Compounds which are active against both Gram-negative Escherichia coli and Salmonella typhi bacteria include 6f, 6j and 6o. Compound 6e was active against two Gram-positive Clostridium tetani and Streptococcus pneumonia bacteria. Surprisingly, 6p was active against Gram-positive Bacillus subtilis and Streptococcus pneumonia bacteria, as well as Gram-negative Escherichia coli and Salmonella typhi bacteria. A similar trend could be been seen for pyrazolopyran-annulated coumarin derivatives 7a–p (Table 5). Those which have potency comparable with that of standard Chloramphinicol include 7c—active against a Gram-positive Bacillus subtilis bacteria, 7d—against both Gram-positive Clostridium tetani and Streptococcus pneumonia bacteria, and 7f—against a Gram-negative Escherichia coli bacteria. Comparing antimicrobial screening test results with that of pyrazolopyran-annulated thiopyranoquinolones 6, we also noticed that some pyrazolopyran-annulated coumarins 7 are also active against multiple bacteria. For example, 7f, 7m and 7n are active against two Gram-positive (Streptococcus pneumoniae, and Bacillus subtilis), all three Gram-negative (Salmonella typhi, Vibrio chlolerae and Escherichia coli) bacteria. Compound 7f also active against one more Gram-positive Clostridium tetani bacteria. In conclusion, we have demonstrated the use of TEAA as an efficient green reaction medium for the synthesis of biologically active pyrano-fused coumarins and thiopyrano-fused quinolones via domino reaction. High yields, short reaction time and lower temperature (120 °C), particularly for an aldehyde-substrate containing unactivated allyl dienophile, are the main advantages of the present protocol. The so-called substrate generally needs reported higher temperature (150 °C) in the absence of catalyst. Compound 7f was active against most of the bacteria. Structurally, derivatives

that were derived from chlorophenylpyrazolones have a good antibacterial activity. Methyl in 2-mercapto-quinoline-based substrates has no great influence on biological activity. Generally, polyheterocycles from prenylated coumarins and allylated quinoline were good in bioactivities. Acknowledgments We sincerely express our thanks to Head, Department of Chemistry, Sardar Patel University for providing necessary research facility. Rikin, Bhagyashri are grateful to UGC, New Delhi, India for financial assistance under the UGC Scheme of RFSMS. A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.bmcl.2013.01. 079. These data include MOL files and InChiKeys of the most important 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. and references 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)

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Chem. Ber. 1883, 16, 2597. 34. Synthesis of pyranopyrazol derivatives (6a–r, 7a–p): in a round-bottom flask, aldehydes substrates 3a–d, 4a–b (3.7 mmol; 0.99 g of 3a, 0.85 g of 3b, 1.00 g of 3c, 0.95 g of 3d, 0.90 g of 4a, 1.00 g of 4b) and 5-pyrazolones 5a–f (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 were heated at 120 °C until the substrate disappeared as monitored by TLC. It gave products 6a–r, 7a–p in good yields. The crude products were purified by column chromatography. All the products were characterized based on their elemental, mass, UV–visible NMR and IR spectroscopy. 35. (5aS,13bR)-1,9-Dimethyl-3-phenyl-3,5a,6,13b-tetrahydro-5Hpyrazolo[400 ,300 :50 ,60 ]pyrano [40 ,30 :4,5]thiopyrano[2,3-b]quinoline (6a): isolated yield (0.89 g, 80%) as yellow crystals, mp 130–132 °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), 7.37–7.81 (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; ESIMS: 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. 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