J. Serb. Chem. Soc. 83 (10) 1071–1097 (2018) UDC 547.7+547.78:544.275–128: JSCS–5134 615.9+542.9:57–188 Review 1071 REVIEW [Bmim]PF6: An efficient tool for the synthesis of diverse bioactive heterocycles GURPREET KAUR, ADITI SHARMA and BUBUN BANERJEE* Department of Chemistry, Indus International University, Village and Post Office Bathu, District Una. Himachal Pradesh-174301, India (Received 3 January, revised 3 July, accepted 16 July 2018) Abstract: Heterocycles are the privileged structural subunit of many marketed drug molecules. On the other hand, the last decade has seen tremendous applic- ations of the ionic liquid [bmim]PF6 (1-butyl-3-methyl-1H-imidazolium hexaflu- orophosphate) as an efficient, cheap, commercially available, low toxic reaction medium for various organic transformations. The present review summarizes recent reported applications of [bmim]PF6 as an efficient reaction medium for the synthesis of diverse biologically relevant heterocycles. Keywords: [Bmim]PF6; heterocycles; hexafluorophosphate; imidazolium; P-ionic liquid. CONTENTS 1. INTRODUCTION 2. SYNTHESIS OF N-HETEROCYCLES 2.1. Synthesis of aziridines 2.2. Synthesis of N-substituted phthalimides 2.3. Synthesis of spiro[azetidine-2,3′-(3H)indole] derivatives 2.4. Synthesis of 3-methylene-2,3-dihydro-1H-quinolin-4-ones 2.5. Synthesis of 1,3,5-triarylpyrazoles 2.6. Synthesis of spiro[indoline-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidine]triones 2.7. Synthesis of dispiropyrrolidine-bisoxindole derivatives 2.8. Synthesis of 2,3-dihydroquinazolin-4(1H)-ones 2.9. Synthesis of 2,4-diamino-6-aryl-1,3,5-triazines 2.10. Synthesis of 4-(1H-1,2,3-triazol-1-yl)-1,2,5-oxadiazol-3-amine derivatives 2.11. Synthesis of 3,4-dihydropyrimidin-2(1H)-ones 2.12. Synthesis of quinolines 2.13. Synthesis of anthraquinone fused N-heterocycles 2.14. Synthesis of novel N-heterocycles via ring-closing metathesis reaction * Corresponding author. E-mail: banerjeebubun@gmail.com Dedicated to Prof. Kamal Usaf Sadek, Mania University, Mania, Egypt. https://doi.org/10.2298/JSC180103052K ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ 1072 KAUR, SHARMA and BANERJEE 3. SYNTHESIS OF O-HETEROCYCLES 3.1. Synthesis of 2,3-disubstituted benzo[b]furans 3.2. Synthesis of coumarin derivatives 3.3. Synthesis of pyrano[4,3-b]pyran-5-one derivative 3.4. Synthesis of epoxyisobenzofuran-1,3-dione 3.5. Synthesis of xanthenes 3.6. Synthesis of 2-amino-3-cyano-benzochromenes 3.7. Synthesis of 1,3-dioxane derivatives 3.8. Synthesis of chromanone derivatives 3.9. Synthesis of lactone and lactam derivatives 4. SYNTHESIS OF N,O-HETEROCYCLES 4.1. Synthesis of spiro[chromeno[2,3-d]pyrimidine-5,3′-indoline]tetraones 4.2. Synthesis of pyrimidine containing isoxazolines 4.3. Synthesis of isoxazolidines 4.4. Synthesis of benzoxazine and quinazoline 5. SYNTHESIS OF S-HETEROCYCLES 5.1. Synthesis of 2-aminothiophenes 6. SYNTHESIS OF N,S-HETEROCYCLES 6.1. Synthesis of spiro[3H-indole-3,2′-thiazolidine]-2,4′(1H)-diones 6.2. Synthesis of 2-phenylthiazoles 6.3. Synthesis of benzothiazole derivatives 6.4. Synthesis of 1,5-benzothiazepine-4-ones 7. CONCLUSIONS 1. INTRODUCTION Heterocycles are the skeleton of the majority of hitherto known organic com- pounds.1,2 Many synthetic compounds containing heterocycles possess immense biological activities that include anti-microbial,3 anti-malarial,4 anti-cancer,5 cytotoxic,6 anti-inflammatory,7 anti-oxidant,8 anti-hyperglycemic and anti-dys- lipidemic,9 along with anti-neurodegenerative disorders such as Alzheimer’s and Parkinson disease and many more.10–12 Among the other significant parameters, screening of suitable reaction medium plays the key role during organic transformations.13,14 Worldwide, sci- entists are trying to modify the reaction media to increase the efficiency of the reaction and reduce their toxicity level as well. In recent times, a wide range of ionic liquids have been employed as reaction media due to their inherent features that include high thermal stability, ability to dissolve a large number of organic and inorganic compounds, non-volatility, low inflammability, easy reusability etc.15–29 The organic and ionic environment in ionic liquids renders almost all kinds of interactions with reactants. This may cause a reduction in activation energies, either by stabilizing the transition states or by destabilizing the react- ants.30,31 Moreover, both ionic and van der Waals interactions with solutes gen- erate internal pressure in an ionic liquid, which eventually accelerates the chem- ical reaction by promoting an accumulation of reactants in the cavities of the sol- vent.32–34 Recyclability of ionic liquid makes a protocol cost effective as well. ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ DIVERSE BIOACTIVE HETEROCYCLES 1073 Due to these above-mentioned advantages, ionic liquids are being used in many organic transformations as both reaction medium as well as promoter even in the absence of any other catalyst.35–40 Recently, among the others, ionic liquids based on imidazolium salts, have gained significant attention as efficient reaction media and have found immense applications in various organic synthesis that include hydrogenations,41 Friedel– –Crafts reactions,42 Heck reactions,43 Bishler–Napieralski reactions,44 Henry reaction45 and many more.46 Some of the ionic liquids based on the 1-butyl-3- -methylimidazolium cation are presented in Fig. 1. Among these, during few years, the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim]PF6) has shown tremendous applications in various organic transform- ations.47–50 N N BF4 [bmim]BF4 N N PF6 [bmim]PF6 N N X [bmim]X N N ClO4 [bmim]ClO4 N N OOCCF3 [bmim]CF3COO N N AlCl4 [bmim]AlCl4 N N N(SO2CF3)2 [bmim]NTf2 N N N3 [bmim]N3 X = Cl or Br N N OH [bmim]OH N N OOCCH3 [bmim]CH3COO + + + + + + + + + + Fig. 1. Some of the 1-butyl-3-methylimidazolium based ionic liquids. The present review deals with the applications of the ionic liquid [bmim]PF6 for the synthesis of diverse bioactive heterocycles, and when possible, gives a comparison of its efficiency with the rest of the hitherto reported congeners. 2. SYNTHESIS OF N-HETEROCYLCES 2.1. Synthesis of aziridines Aziridines are used as an important precursor for the synthesis of a wide range of nitrogen-containing heterocycles.51,52 A simple, efficient and stereo-sel- ective method was developed for the synthesis of aziridines (3) in the reaction between various imines (1) and ethyl diazoacetate (2) under catalyst-free con- ditions in the ionic liquid [bmim]PF6 at room temperature (Scheme 1).53 After completion of the reaction, the ionic liquid was recovered easily and reused five times without any loss in its activity. Mild reaction conditions, good yields and high product selectivity are some of the advantages of this protocol. In the same year, another method was reported for the synthesis of cis-dia- stereoselective aryl aziridines (3) via three-component reactions of aldehydes (4), various amines (5) and ethyl diazoacetate (2) using Bi(OTf)3 or Sc(OTf)3 as cat- alyst in the same ionic liquid at 27 °C (Scheme 2).54 The use of a catalyst red- ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ 1074 KAUR, SHARMA and BANERJEE uces the reaction time as compared to the catalyst-free conditions (Scheme 1). Ambient reaction condition, wide range of substrate tolerance, reusability of the media, high atom economy, good to excellent yields are some of the major bene- fits of this developed protocol. Scheme 1. [Bmim]PF6-mediated synthesis of aziridines at room temperature. Scheme 2. [Bmim]PF6-mediated triflate salts catalyzed three-component synthesis of aziridines. 2.2. Synthesis of N-substituted phthalimides The ionic liquid [bmim]PF6 was found to be an efficient alternative to clas- sical solvents for the synthesis of N-substituted phthalimides.55–57 A series of N-substituted phthalimides (7) was synthesized in good yields via the reaction of succinic anhydride (6) and various aryl amines (5) under catalyst-free conditions in [bmim]PF6 at 80 °C (Scheme 3).55 The ionic liquid was recovered and reused many times. In the next year, along with succinic anhydride, Le et al.56 also emp- loyed maleic and phthalic anhydride for the synthesis of N-aryl phthalimides in the ionic liquid [bmim]PF6 at 140 °C. Under these optimized conditions, react- ions with aliphatic amines also proceeded smoothly to produce the desired pro- ducts in high yields. ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ DIVERSE BIOACTIVE HETEROCYCLES 1075 Scheme 3. [Bmim]PF6-mediated synthesis of N-substituted phthalimides. 2.3. Synthesis of spiro[azetidine-2,3′-(3H)indole] derivatives Azetidinones are very common in many biologically active compounds having significant biological efficacies that include anti-bacterial, anti-fungal,58 and anti- -inflammatory59 activities. A series of novel spiro[azetidine-2,3′-(3H)indole] deri- vatives (11) was synthesized by the reactions of isatins (8), 4-amino-4H-1,2,4-tri- azole (9) and acetyl chloride (10) or chloroacetyl chloride (10a) in ionic liquid [bmim]PF6 using triethylamine as catalyst at 60–70 °C (Scheme 4).60 The ionic liquid was recovered easily and reused twice without any loss in its activity. The insecticidal activities of the synthesized compounds were tested against Peripla- neta americana and few were found to possess prominent efficacy. Scheme 4. [Bmim]PF6-mediated synthesis of spiro[azetidine-2,3′-(3H)indole derivatives. 2.4. Synthesis of 3-methylene-2,3-dihydro-1H-quinolin-4-ones The ionic liquid [bmim]PF6 was found to be an efficient medium for the pal- ladium-catalyzed cyclocarbonylation reaction of o-iodoanilines (12), various allenes (13) and carbon monoxide (14) to afford the corresponding 3-methylene- -2,3-dihydro-1H-quinolin-4-ones (15) in the presence of a catalytic amount of ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ 1076 KAUR, SHARMA and BANERJEE 1,4-bis(diphenylphosphino)butane (dppb) and diisopropylethylamine [(iPr)2NEt] as promoter at 90 °C (Scheme 5).61 The entire medium containing the catalyst as well as the promoter was successfully recovered and reused more than four times without significant loss in activities. Scheme 5. [Bmim]PF6-mediated synthesis of 3-methylene-2,3-dihydro-1H-quinolin-4-ones. 2.5. Synthesis of 1,3,5-triarylpyrazoles Heterocycles containing the pyrazole moiety have exhibited diverse bio- logical activities that include anti-depressant, anti-convulsant,62 anti-inflam- matory and anti-arthritic63 activities. A simple, efficient, and environmentally benign protocol was developed for the synthesis of 1,3,5-triarylpyrazoles (18) via the one-pot oxidative addition of chalcones (16) and arylhydrazines (17) using Cu(OTf)2 as catalyst in [bmim]PF6 at 130 °C (Scheme 6).64 During optimization, Scheme 6. [Bmim]PF6-mediated synthesis of 1,3,5-triarylpyrazoles. ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ DIVERSE BIOACTIVE HETEROCYCLES 1077 it was found that other metal triflates such as Sc(OTf)3, Ce(OTf)3, AgOTf, Zn(OTf)2 and Yb(OTf)3 as catalyst in [bmim]PF6 produced lower yields. On the other hand, Cu(OTf)2 yielded lower product in [bmim]BF4 and [bmim]Br compared to in [bmim]PF6. The catalyst along with the reaction media was successfully recovered and reused four times without loss in catalytic activity. The synthesized compounds were found to possess antiproliferative efficacies. 2.6. Synthesis of spiro[indoline-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidine]triones A simple, efficient and practical protocol was developed for the synthesis of a series of spiro[indoline-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidine]trione deri- vatives (21) via one-pot four-component reactions between isatins (8), barbituric acids (19), phenylhydrazines (17) and 3-oxo-3-phenylpropanenitrile (20) using alum KAl(SO4)2·12H2O as a reusable catalyst in [bmim]PF6 at 100 °C (Scheme 7).65 Scheme 7. [Bmim]PF6-mediated synthesis of spiro[indoline-pyrazolo[4′,3′:5,6]pyrido- [2,3-d]pyrimidine]triones. During optimization, other 1-butyl-3-methylimidazolium based ionic liquids such as [bmim]BF4, [bmim]CF3CO2, [bmim]Br, [bmim]Cl were also screened using alum as catalyst and among them, [bmim]PF6 came out to be superior in terms of both reaction time as well as product yields. Mild reaction conditions, short reaction time, excellent yields, varieties of substrates, high atom economy and reusability of medium are some of the major advantages in this protocol. In the same year, under the same reaction conditions Shirvan et al.66 also synthe- sized a variety of spiro[indoline-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrimidine]tri- ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ 1078 KAUR, SHARMA and BANERJEE ones staring from substituted isatins, barbituric acids, and 1,3-diphenyl-1H-py- razol-5-amines. 2.7. Synthesis of dispiropyrrolidine-bisoxindole derivatives Spiro-oxindoles are very common in pharmacologically important com- pounds.67 A simple, facile and efficient catalyst-free one-pot three-component protocol was reported for the synthesis of a series of novel dispiropyrrolidine-bis- oxindole derivatives (24) via the cycloaddition between isatins (8), sarcosine (22) and 3-(aroylmethylene)-1,3-dihydro-2H-indol-2-one (23) in [bmim]PF6 at 80 °C (Scheme 8).68 Ionic liquid was recovered successfully and reused three times without significant loss in its activity. Scheme 8. [Bmim]PF6-mediated catalyst-free synthesis of dispiropyrrolidine-bisoxindoles. 2.8. Synthesis of 2,3-dihydroquinazolin-4(1H)-ones Now-a-days, performing reactions in absence of any added catalysts is one of the thrusting areas.69–71 A series of 2,3-dihydroquinazolin-4(1H)-one deri- vatives (26) was synthesized in moderate to high yields via the condensation between anthranilamides (25) and various aldehydes (4) in [bmim]PF6 under cat- alyst-free conditions at 75 °C (Scheme 9).72 Mild reaction conditions, short Scheme 9. [Bmim]PF6-mediated catalyst-free synthesis of 2,3-dihydroquinazolin-4(1H)-ones. ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ DIVERSE BIOACTIVE HETEROCYCLES 1079 reaction times, good to excellent yields make this protocol attractive. A wide range of aldehydes that include electron donating as well as electron withdrawing substituent are well tolerated under the optimized reaction conditions affording the required products in good yields. During optimization, a number of other ionic liquids were also tested, whereby [bmim]PF6 was found to be superior for this transformation. After completion of the reaction, the ionic liquid [bmim]PF6 was successfully recovered and reused for the several runs without loss of its activity. 2.9. Synthesis of 2,4-diamino-6-aryl-1,3,5-triazines A simple, rapid and efficient microwave-assisted environmentally benign protocol was developed for the synthesis of 2,4-diamino-6-aryl-1,3,5-triazines (29) via the reaction of aromatic nitriles (27) and dicyanodiamide (28) using KOH as catalyst in [bmim]PF6 at 130 °C (Scheme 10).73 In the absence of microwave, i.e., under conventional heating at the same temperature, the reaction took more than 8 h to complete and yields of the corresponding products were also lower. [Bmim]PF6 was found to be superior to [bmim]BF4 for this conversion. After completion of the reaction, the ionic liquid was successfully recovered and recycled five times without significant loss in its activity. Scheme 10. [Bmim]PF6-mediated synthesis of 2,4-diamino-6-aryl-1,3,5-triazines under microwave conditions. 2.10. Synthesis of 4-(1H-1,2,3-triazol-1-yl)-1,2,5-oxadiazol-3-amine derivatives Seregin et al.74 synthesized 4-(1H-1,2,3-triazol-1-yl)-1,2,5-oxadiazol-3-ami- nes (32) via the 1,3-dipolar cycloaddition between 4-amino-3-azidofurazan (30) and butynediol (31) or propargyl alcohol (31a) in [bmim]PF6 under catalyst-free conditions at 80 °C (Scheme 11). The use of the ionic liquid [bmim]BF4 pro- duced lower yields. 2.11. Synthesis of 3,4-dihydropyrimidin-2(1H)-ones Dihydropyrimidinones possess significant biological efficacies that include anti-viral, anti-bacterial, anti-hypertensive and anti-tumour activity.75 A series of 3,4-dihydropyrimidin-2(1H)-ones (35) were synthesized in good yields via the one-pot, three-component Biginelli reaction76 of various aromatic aldehydes (4), ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ 1080 KAUR, SHARMA and BANERJEE urea (33) and ethyl acetoacetate (34) using a catalytic amount of ionic liquid [bmim]PF6 under solvent-free conditions at 100 °C (Scheme 12).77 For this transformation, the ionic liquid [bmim]BF4 was found to be as efficient as [bmim]PF6, whereas [bmim]Cl afforded lower yields. Scheme 11. [Bmim]PF6-mediated synthesis of 4-(1H-1,2,3-triazol-1-yl)-1,2,5-oxadiazol-3- -amines. Scheme 12. [Bmim]PF6-catalyzed synthesis of 3,4-dihydropyrimidin-2(1H)-ones. 2.12. Synthesis of quinolines A mild, simple and efficient protocol was developed for the synthesis of a variety of quinoline derivatives (38) by following the Friedländer annulation reaction78 of o-aminobenzophenone (36) and various ketones (34, 37a-e) using gadolinium triflate [Gd(OTf)3] as an inexpensive, moisture-stable Lewis acid catalyst in [bmim]PF6 at 60 °C (Scheme 13).79 After completion of the reaction, the catalyst containing ionic liquid was successfully recovered and reused several times without appreciable loss in product formation. Mild reaction conditions, operational simplicity, very short reaction time; high yields of products are some of the major advantages of this developed protocol. 2.13. Synthesis of anthraquinone fused N-heterocycles A number of anthraquinone fused N-heterocycles (41) were synthesized via the ring-closure metathesis reactions of 1,4-dihydroxyanthraquinone (39) and various diamines (40) in the presence of a catalytic amount of CuCl2 in the ionic liquid [bmim]PF6 at room temperature (Scheme 14).80 The reaction was also per- formed in conventional solvents, such as dimethylformamide and dichlorometh- ane, but lower yields were obtained. The ionic liquid containing catalyst was successfully recovered and reused five times without significant loss in its activity. ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ DIVERSE BIOACTIVE HETEROCYCLES 1081 Scheme 13. [Bmim]PF6-mediated synthesis of a variety of quinoline derivatives. Scheme 14. [Bmim]PF6-mediated synthesis of anthraquinone fused N-heterocycles. 2.14. Synthesis of novel N-heterocycles via ring-closing metathesis reactions The ionic liquid [bmim]PF6 was found to be an effective medium for ring- -closing metathesis using Grubbs catalysts.81,82 A simple and straightforward protocol was demonstrated for the ring-closing metathesis of 1,5-diallyl-3-ben- zyl-5-isobutylimidazolidine-2,4-dione (42) to afford the corresponding novel 2-benzyl-8a-isobutyl-8,8a-dihydroimidazo[1,5-a]pyridine-1,3(2H,5H)-dione (43) using ruthenium based Grubbs catalyst in [bmim]PF6 at 50 ºC (Scheme 15).83 Scheme 15. [Bmim]PF6-mediated ring-closing metathesis reaction using a ruthenium catalyst. ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ 1082 KAUR, SHARMA and BANERJEE After completion of reaction, the ionic liquid containing the ruthenium catalyst was successfully recovered and thrice reused for the same reaction. 3. SYNTHESIS OF O-HETEROCYCLES 3.1. Synthesis of 2,3-disubstituted benzo[b]furans Benzo[b]furan-containing heterocycles possess immense pharmaceutical efficacies that include anti-fungal84 and anti-tumor85 activity. A combination of CuI and 1-butyl-3-methylimidazolium acetate ([bmim]OAc) in [bmim]PF6 was shown to be an efficient catalytic system for the synthesis of a series of 2,3- -disubstituted benzo[b]furan derivatives (47) via one-pot three-component tan- dem reactions of salicylaldehyde (44), alkynes (45) and various aliphatic second- ary amines (46), such as morpholine, dibenzylamine, piperidine etc., at 80 °C (Scheme 16).86 Scheme 16. [Bmim]PF6-mediated synthesis of 2,3-disubstituted benzo[b]furans. Reactions with aromatic secondary amines, such as N-benzylaniline or N-methylaniline, and aromatic primary amines, such as aniline, instead of ali- phatic secondary amines did not afford the corresponding benzo[b]furan deriv- atives. In this reaction, it was also observed that aryl alkynes are more effective and produced higher yields than aliphatic alkynes. After completion of the react- ion, the ionic liquid containing CuI and [bmim]OAc was recovered and recycled five times without any significant loss in its catalytic activity. 3.2. Synthesis of coumarin derivatives Coumarins are very common in naturally occurring heterocycles possessing a wide range of pharmaceutical activities that include anti-bacterial, anti-HIV, anti-viral, anti-coagulant, anti-oxidant and anti-cancer activities.87–90 A variety of 3-substituted coumarins (49) were synthesized via the Knoevenagel conden- sation of salicylaldehyde (44) and dialkyl malonate (48 or 48a) using sodium methoxide as catalyst in the ionic liquid [bmim]PF6 at 95 °C (Scheme 17).91 ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ DIVERSE BIOACTIVE HETEROCYCLES 1083 Several other butylmethylimidazolium-based ionic liquids, such as [bmim]Cl, [bmim]BF4, [bmim]Br and [bmim]AlCl4, were also screened for the same transformation. Among them [bmim]PF6 was found to be superior in terms of both reaction time and product yield. Scheme 17. [Bmim]PF6-mediated synthesis of 3-substituted coumarin derivatives. 3.3. Synthesis of pyrano[4,3-b]pyran-5-one derivative 2-Isobutyl-3-isopropyl-7-phenyl-2H,5H-pyrano[4,3-b]pyran-5-one (52) was synthesized via the domino reaction between 3-isopropyl-6-methylhept-3-en-2- one (50) and 4-hydroxy-6-phenyl-2H-pyran-2-one (51) in the presence of a catalytic amount of β-alanine as catalyst in [bmim]PF6 under microwave irradiation at 110 °C (Scheme 18).92 Scheme 18. [Bmim]PF6-mediated synthesis of a pyrano[4,3-b]pyran-5-one derivative. 3.4. Synthesis of epoxyisobenzofuran-1,3-dione A simple and efficient method was developed for the synthesis of epoxyiso- benzofuran-1,3-dione 55 via the Diels–Alder reaction of furan (53) and furan- -2,5-dione (54) using ZnI2 as promoter in [bmim]PF6 at room temperature (Scheme 19).93 Scheme 19. [Bmim]PF6-mediated synthesis of an epoxyisobenzofuran-1,3-dione. ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ 1084 KAUR, SHARMA and BANERJEE 3.5. Synthesis of xanthenes Xanthenes, in particular, 1,8-dioxo-octahydroxanthene moieties, have gained significant attention due to their potent pharmacological efficacies, such as anti- -microbial, anti-cancer and enzyme inhibitory activity.94–96 A simple, rapid and efficient protocol was reported for the synthesis of 1,8-dioxo-octahydroxanthenes (56) via one-pot pseudo three-component reactions of aromatic aldehydes (4) and dimedone (37b) or 1,3-cyclohexanedione (37b′) in the presence of a catalytic amount of [bmim]PF6 under microwave irradiation and solvent-free conditions (Scheme 20).97 Using the same optimized reaction conditions, a series of benzo- xanthenes (59, Scheme 21) and chromene derivatives (60, Scheme 22) were also synthesized starting from various aromatic aldehydes (4), 1,3-cyclohexanediones (37b or 37b′) and β-naphthol (57) or 4-hydroxycoumarin (58), respectively. Very short reaction times, solvent-free conditions, high atom economy, reusability of the media and good to excellent yields are some of the major advantages of this protocol. A range of aldehydes that include electron donating and withdrawing Scheme 20. [Bmim]PF6-catalyzed synthesis of 1,8-dioxo-octahydroxanthenes under solvent-free conditions. Scheme 21. [Bmim]PF6-catalyzed synthesis of benzoxanthenes under solvent-free conditions. ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ DIVERSE BIOACTIVE HETEROCYCLES 1085 substituent are well tolerated under the optimized reaction conditions and excellent yields were attained. All the synthesized compounds were screened for their anti-oxidant properties and some of them were found to possess significant anti-oxidant efficacies. Scheme 22. [Bmim]PF6-catalyzed synthesis of chromenes under solvent-free conditions. Another efficient protocol was developed for the synthesis of 2,3-dihydro-1H- xanthen-1-one derivatives (61) via the cycloaddition of 1,3-cyclohexanediones (37b or 37b′) and salicylaldehyde (44) using glycine as promoter in [bmim]PF6 at 25 °C (Scheme 23).98 Conventional solvents, such as acetonitrile, DMF, DMSO, etc., were also screened for this reaction but lower yields were attained. Under the optimized conditions, other amino acids, such as L-histidine, L-lysine, L-alanine, as catalyst produced lower yields. The [Bmim]PF6 containing glycine was recovered and recycled four times without any loss in its catalytic activity. Scheme 23. [Bmim]PF6-mediated glycine-catalysed synthesis of 2,3-dihydro-1H-xanthen-1-ones. 3.6. Synthesis of 2-amino-3-cyano-benzochromenes 2-Amino-3-cyano-pyrans and related derivatives possess immense biological activities.99–101 A simple and facile protocol was developed for the efficient syn- thesis of 2-amino-3-cyano-benzochromenes (63) via one-pot three-component condensation between aromatic aldehydes (4), various substituted β-naphthols (57) and malononitrile (62) in [bmim]PF6 at 80 °C (Scheme 24).102 ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ 1086 KAUR, SHARMA and BANERJEE Scheme 24. [Bmim]PF6-mediated synthesis of 2-amino-3-cyano-benzochromenes. Other ionic liquids, such as [bmim]Br, [bmim]BF4, n-butylpyridinium bro- mide, cetylpyridinium chloride and n-butylpyridinium dodecyl sulphate, were also screened for this reaction but lower yields were attained. After completion of reaction, [bmim]PF6 was successfully recovered and recycled several times. Some of the synthesized compounds possess prominent anti-proliferative acti- vity. A range of aromatic aldehydes that include electron donating and withdraw- ing substituent are well tolerated under the optimized reaction conditions and produced excellent yields. Operational simplicity, high atom economy, excellent yields, catalyst-free reaction conditions are some of the major benefits of this developed protocol. 3.7. Synthesis of 1,3-dioxane derivatives A series of 1,3-dioxane derivatives (66) was synthesized in excellent yields via the condensation of olefins (64) and paraformaldehyde (65) in the presence of a catalytic amount of InBr3 in [bmim]PF6 at 25 °C (Scheme 25).103 The ionic liquid containing the catalyst was recovered and successfully recycled up to the fourth run with no appreciable loss in product formation. Scheme 25. [Bmim]PF6-mediated synthesis of 1,3-dioxane derivatives. 3.8. Synthesis of chromanone derivatives A simple and facile microwave-assisted intramolecular Stetter reaction104 was demonstrated with (E)-methyl 4-(2-formylphenoxy)but-2-enoate (67) to pre- ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ DIVERSE BIOACTIVE HETEROCYCLES 1087 pare the corresponding chromanone derivatives (68). The reaction was realized under the catalytic combination of thiazolium salt and [bmim]PF6 in basic medium at 80 °C (Scheme 26).105 The ionic liquid containing catalyst was rec- overed and recycled several times. Scheme 26. [Bmim]PF6-catalyzed microwave-assisted synthesis of chromanone derivatives. 3.9. Synthesis of lactone and lactam derivatives The ionic liquid [bmim]PF6 was found to be an efficient reaction medium for the palladium-catalyzed cyclocarbonylation of 2-allylphenols (69, Scheme 27), 2-vinylphenols (71, Scheme 28), and 2-aminostyrenes (73, Scheme 29) using Scheme 27. [Bmim]PF6-mediated synthesis of seven-membered lactones. Scheme 28. [Bmim]PF6-mediated synthesis of six membered-lactones. ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ 1088 KAUR, SHARMA and BANERJEE carbon monoxide (14) to afford the corresponding lactones (70 and 72) or lac- tams (74), respectively, in good yields in the presence of 1,4-bis(diphenylphos- phino)butane (dppb) as promoter at 90 °C. The ionic liquid containing the palla- dium catalyst and ligand was recovered and successfully recycled for several runs.106 Scheme 29. [Bmim]PF6-mediated synthesis of six membered-lactams. 4. SYNTHESIS OF N,O-HETEROCYCLES 4.1. Synthesis of spiro[chromeno[2,3-d]pyrimidine-5,3′-indoline]tetraones A simple and facile protocol was developed for the efficient synthesis of a series of spiro[chromeno[2,3-d]pyrimidine-5,3′-indoline]tetraones (75) via one-pot three-component reactions of substituted isatins (8), dimedone (37b) and barbituric acid derivatives (19) in the presence of a catalytic amount of montmorillonite K-10 in [bmim]PF6 at 100 °C (Scheme 30).107 During optimization, [bmim]PF6 was found to be superior to other butylmethyl- imidazolium-based ionic liquids, such as [bmim]BF4, [bmim]Br, [bmim]CF3COO and [bmim]Cl. Very short reaction times, a wide range of substrate tolerance, high atom economy, reusability of the media, excellent yields are some of the major advantages of this developed protocol. 4.2. Synthesis of pyrimidine containing isoxazolines A series of pyrimidine-containing isoxazoline derivatives (78) was synthesized via the reactions of 3,4-dihydropyrimidin-2(1H)-ones (76) or 3,4-dihydro- -2(1H)-pyrimidinethiones (76a) with hydroxylamine (77) using potassium hydro- xide as a promoter in water–[bmim]PF6 as a biphasic medium at ambient tempe- rature. The reaction medium was successfully recovered and recycled ten times with no appreciable loss in yields (Scheme 31).108 Short reaction times, a wide range of substrate tolerance, ambient conditions and good to excellent yields are some of the major benefits of this developed protocol. ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ DIVERSE BIOACTIVE HETEROCYCLES 1089 Scheme 30. [Bmim]PF6-mediated synthesis of spiro[chromeno[2,3-d]pyrimidine-5,3′-indo- line] derivatives. Scheme 31. [Bmim]PF6-mediated synthesis of pyrimidine-containing isoxazolines. 4.3. Synthesis of isoxazolidines The ionic liquid [bmim]PF6 was found to be an efficient medium for the 1,3- -dipolar intermolecular cycloaddition of aldehydes (4), phenylhydroxylamine (79) and various electron deficient olefins (80) to afford the corresponding ste- reospecific isoxazolidines (81) under catalyst-free conditions at room tempe- rature (Scheme 32).109 Under the same reaction conditions, [bmim]BF4 also afforded the same products with comparable yields. A catalyst-free reaction, a wide range of substrate tolerance, high atom economy, operational simplicity and good to excellent yields are some of the advantages of this protocol. ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ 1090 KAUR, SHARMA and BANERJEE Scheme 32. [Bmim]PF6-mediated synthesis of isoxazolidines at room temperature. 4.4. Synthesis of benzoxazine and quinazoline The ionic liquid [bmim]PF6 was found to be a safe and recyclable reaction medium for the efficient synthesis of 1,2,3,4-tetrahydro-2-phenylquinazoline (84) and 1,4-dihydro-2-phenyl-2H-3,1-benzoxazines (85) from the reaction of benzaldehyde (4) and 2-aminobenzyl amine (82) or 2-aminobenzyl alcohols (83), respectively, at room temperature (Scheme 33).110 Scheme 33. [Bmim]PF6-mediated synthesis of benzoxazine and quinazoline at room temperature. 5. SYNTHESIS OF S-HETEROCYCLES 5.1. Synthesis of 2-aminothiophenes Hu et al.111 demonstrated the ionic liquid [bmim]PF6-mediated Gewald synthesis112 to afford the corresponding 2-aminothiophenes (87 and 88) starting from various carbonyl compounds (37d and 86), malononitrile (62) and sulphur in the presence of a catalytic amount of ethylenediammonium diacetate (EDDA) at 50 °C. After completion of the reaction, the ionic liquid containing catalyst was recovered and reused several times without any loss in its activity (Scheme 34). ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ DIVERSE BIOACTIVE HETEROCYCLES 1091 [bmim]PF6, 50 oC O CN CN + S H3C CH3 O S S H3C H3C CN NH2 O NH2 CN 20 mol% EDDA 3 h, 87% [bmim]PF6, 50 oC 20 mol% EDDA 6 h, 69% 62 37d 86 8788 Scheme 34. [Bmim]PF6-mediated synthesis of 2-aminothiophenes. Scheme 35. [Bmim]PF6-mediated synthesis of spiro[3H-indole-3,2′-thiazolidine]-2,4′(1H)- -diones. 6. SYNTHESIS OF N,S-HETEROCYCLES 6.1. Synthesis of spiro[3H-indole-3,2′-thiazolidine]-2,4′(1H)-diones A simple, facile and environmentally sustainable protocol was developed for the synthesis of novel spiro[3H-indole-3,2′-thiazolidine]-2,4′(1H)-dione derivatives (90) via the one-pot three-component condensation of isatins (8), 4-amino-4H-1,2,4-triazole (9) and 2-sulfanylpropanoic acid (89) under catalyst- -free conditions in [bmim]PF6 at 80 °C (Scheme 35).113 Catalyst-free reaction conditions, high atom economy, good to excellent yields are some of the major benefits of this method. 6.2. Synthesis of 2-phenylthiazoles A series of 2-phenylthiazoles (93) was synthesized via the cycloaddition of α-tosyloxyketones (91) and thiobenzamide (92) in [bmim]PF6 as an efficient and reusable ionic liquid under catalyst-free conditions at room temperature (Scheme 36).114 Catalyst-free ambient reaction conditions, operational simplicity, good yields are some of the advantages of this method. After completion of the react- ion, the ionic liquid was successfully recovered and reused without any loss in its activity. ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ 1092 KAUR, SHARMA and BANERJEE [bmim]PF6, RT, 2 h 10 entries, 71-83% O R OTs R1 + S NH2 N S R R1 R1 = H; R = C6H5, 4-CH3C6H4, 4-OCH3C6H4, 4-ClC6H4, 4-BrC6H4, 3-furyl, 3-thienyl R1 = COOC2H5; R = C6H5, CH3, OC2H5 91 92 93 catalyst-free Scheme 36. [Bmim]PF6-mediated synthesis of 2-phenylthiazoles at room temperature. 6.3. Synthesis of benzothiazole derivatives [Bmim]PF6 efficiently catalyzed the reaction of various aldehydes (4) and 2-aminothiophenol (94) to afford the corresponding benzothiazoles (95) in aque- ous media under reflux conditions (Scheme 37).115 Scheme 37. [Bmim]PF6-catalyzed synthesis of benzothiazole derivatives. 6.4. Synthesis of 1,5-benzothiazepine-4-ones A facile and convenient protocol was developed for the regioselective synthesis of a series of 1,5-benzothiazepin-4-one derivatives (97) starting from substituted 2-aminobenzenethiol (94) and methyl (±)-trans-3-(4-methoxy/(benzyloxy)phenyl)- -glycidate (96) in [bmim]PF6 under catalyst-free conditions at 60 °C (Scheme 38).116 Scheme 38. [Bmim]PF6-mediated synthesis of 1,5-benzothiazepine-4-ones. ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ DIVERSE BIOACTIVE HETEROCYCLES 1093 Catalyst-free reaction conditions, operational simplicity, reusability of media and good to excellent yields are some of the major advantages of this developed protocol. 7. CONCLUSIONS The ionic liquid [bmim]PF6 (1-butyl-3-methyl-1H-imidazolium hexafluoro- phosphate) has been successfully employed as an efficient, commercially available, cheap, low toxicity and recyclable reaction medium for various organic transformations. During optimization, on many occasions, it was found that the efficiency of [bmim]PF6 was better than those of other imidazolium-based ionic liquids, such as [bmim]BF4, [bmim]OH, [bmim]Br, [bmim]Cl, [bmim]ClO4, [bmim]CH3COO, [bmim]NTf2, [bmim]N3, [bmim]AlCl4, etc. In many situ- ations, the addition of another catalyst was not required for the [bmim]PF6- -mediated transformations. The weak electrostatic interactions of hexafluoro- phosphate with the imidazolium cation provide good thermal and electrochemical stability of [bmim]PF6. Other favourable physical and chemical properties, such as mild properties, low volatility, lack of inflammability, commercial availability and excellent solubility with many organic compounds make this ionic liquid superior. After completion of the reaction, in the majority of cases, the ionic liquid was successfully recovered and recycled several times without significant loss in its efficacy. The present review summarizes the applications of [bmim]PF6 as an efficient, cheap, commercially available and reusable ionic liquid for the hitherto reported synthesis of structurally diverse bioactive heterocycles. Acknowledgements. The authors are grateful to Dr. Sudhir Kartha, Chancellor, Indus International University, Una, Himachal Pradesh, India, for his active support throughout and the Kartha Education Society, Mumbai, India, for the financial help. The authors are also grateful to Prof. Dr. György Keglevich, Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, Budapest, Hungary, for his wholehearted guidance throughout. И З В О Д [bmim]PF6: ЕФИКАСАН МЕДИЈУМ ЗА СИНТЕЗУ РАЗЛИЧИТИХ БИОАКТИВНИХ ХЕТЕРОЦИКЛИЧНИХ ЈЕДИЊЕЊА GURPREET KAUR, ADITI SHARMA и BUBUN BANERJEE Department of Chemistry, Indus International University, Village and Post Office Bathu, District Una. Himachal Pradesh-174301, India Хетероцикли су од изузетне важности због тога што чине важне структурне елементе многих лекова присутних на тржишту. Истовремено, у последњој деценији забележен је изузетан пораст у примени јонске течности [bmim]PF6 (1-бутил-3-метил-1H-имидазолијум хексафлуорофосфат) као ефикасног, јефтиног, комерцијално доступног и мање токсичног реакционог медијума за различите трансформације у органској хемији. Овај прегледни чланак даје приказ најновије примене [bmim]PF6 као ефикасног реакционог медијума за синтезу различитих биолошки важних хетероцикличних једињења. (Примљено 3. јануара, ревидирано 3. јула, прихваћено 16. јула 2018) ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ 1094 KAUR, SHARMA and BANERJEE REFERENCES 1. B. Banerjee, ChemistrySelect 2 (2017) 6744 2. B. Banerjee, Ultrason. Sonochem. 35 (2017) 15 3. A. H. F. A. El-Wahab, Pharmaceuticals 5 (2012) 745 4. V. F. De Andrade-Neto, M. O. Goulart, J. F. Da Silva Filho, M. J. Da Silva, M. D. C. Pinto, A. V. Pinto, M. G. Zalis, L. H. Carvalho, A. U. Krettli, Bioorg. Med. Chem. Lett. 14 (2004) 1145 5. J. Y. Wu, W. F. Fong, J. X. Zhang, C. H. Leung, H. L. Kwong, M. S. Yang, D. Li, H. Y. Cheung, Eur. J. Pharmacol. 473 (2003) 9 6. M. Kožurková, D. Sabolová, P. Kristian, J. Appl. Toxicol. 37 (2017) 1132 7. D. O. Moon, K. C. Kim, C. Y. Jin, M. H. Han, C. Park, K. J. Lee, Y. M. Park, Y. H. Choi, G. Y. Kim, Int. Immunopharmacol. 7 (2007) 222 8. P. Gurunanjappa, M. B Ningappa, A. K. Kariyappa, Chem. Data Collect. 5–6 (2016) 1 9. A. Kumar, R. A. Maurya, S. A. Sharma, P. Ahmad, A. B. Singh, G. Bhatia, A. K. Srivastava, Bioorg. Med. Chem. Lett. 19 (2009) 6447 10. B. Banerjee, Curr. Org. Chem. 22 (2018) 208 11. B. Banerjee, M. Koketsu, Coord. Chem. Rev. 339 (2017) 104 12. B. Banerjee, Aust. J. Chem. 70 (2017) 872 13. B. Banerjee, J. Nanostruct. Chem. 7 (2017) 389 14. B. Banerjee, J. Serb. Chem. Soc. 82 (2017) 755 15. P. Hapiot, C. Lagrost, Chem. Rev. 108 (2008) 2238 16. P. Wasserscheid, W. Keim, Angew Chem. Int. Ed. 39 (2000) 3772 17. M. Petkovic, K. R. Seddon, L. P. N. Rebelo, C. S. Pereira, Chem. Soc. Rev. 40 (2011) 1383 18. M. J. Earle, K. R. Seddon, Pure Appl. Chem. 72 (2000) 1391 19. S. Lee, Chem. Commun. 2006 (2006) 1049 20. D. R. Macfarlane, J. M. Pringle, K. M. Johansson, S. A. Forsyth, M. Forsyth, Chem. Commun. 2006 (2006) 1905 21. B. Liu, N. Jin, Curr. Org. Chem. 20 (2016) 2109 22. F. Guo, S. Zhang, J. Wang, B. Teng, T. Zhang, M. Fan, Curr. Org. Chem. 19 (2015) 455 23. K. V. Wagh, K. C. Badgujar, N. M. Patil, B. M. Bhanage, Curr. Org. Chem. 20 (2016) 736 24. D. E. Siyutkin, A. S. Kucherenko, S. G. Zlotin, in Comprehensive Enantioselective Organocatalysis, Vol. 2, P. I Dalko, Ed., Wiley–VCH Verlag, Weinheim, 2013, p. 617 25. A. A. Tietze, P. Heimer, A. Stark, D. Imhof, Molecules 17 (2012) 4158 26. S.-L. Chen, G.-L. Chua, S.-J. Ji, T.-P. Loh, ACS Symp. Ser. 950 (2007) 177 27. S. Mahato, S. Santra, R. Chatterjee, G. V. Zyryanov, A. Hajra, A. Majee, Green Chem. 19 (2017) 3282 28. B. C. Ranu, S. Banerjee, Org. Lett. 7 (2005) 3049 29. B. C. Ranu, R. Jana, Eur. J. Org. Chem. 2006 (2006) 3767 30. B. Banerjee, ChemistrySelect 2 (2017) 8362 31. T. Welton, Coord. Chem. Rev. 248 (2004) 2459 32. F. Shirini, K. Rad-Moghadam, S. Akbari-Dadamahaleh, in Green Solvents II: Properties and Applications of Ionic Liquids, 1st ed, A. Mohammad, Inamuddin, Eds., Springer, Dordrecht, 2012, p. 289 33. S. Zhang, X. Lu, Q. Zhou, X. Li, X. Zhang, S. Li, Ionic liquids: Physicochemical properties, Elsevier, Oxford, 2009 34. S. Zhang, Structures and interactions of ionic liquids, Springer, London, 2013 ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ DIVERSE BIOACTIVE HETEROCYCLES 1095 35. T. Welton, Chem. Rev. 99 (1999) 2071 36. J. P. Hallett, T. Welton, Chem. Rev. 111 (2011) 3508 37. C. Hubbard, P. Illner, R. Eldik, Chem. Soc. Rev. 40 (2011) 272 38. N. Isambert, M. M. S. Duque, J. Plaquevent, Y. Genisson, J. Rodriguez, T. Constantieux, Chem. Soc. Rev. 40 (2011) 1347 39. Q. Zhang, S. Zhang, Y. Deng, Green Chem. 13 (2011) 2619 40. C. Gordon, Appl. Catal., A 222 (2001) 101 41. P. J. Dyson, D. J. Ellis, D. G. Parker, T. Welton, Chem. Commun. 1999 (1999) 25 42. C. E. Song, W. H. Shim, E. J. Roh, J. H. Choi, Chem. Commun. 2000 (2000) 1695 43. V. P. W. Böhm, W. A. Herrmann, Chem. Eur. J. 6 (2000) 1017 44. Z. M. A. Judeh, B. C. Chi, B. Jie, A. McCluskey, Tetrahedron Lett. 43 (2002) 5089 45. W.-J. Xia, Z.-B. Xie, G.-F. Jiang, Z.-G. Le, Molecules 18 (2013) 13910 46. R. L. Vekariya, J. Mol. Liq. 227 (2017) 44 47. J. S. Jadav, B. V. S. Reddy, S. Sunitha, Adv. Synth. Catal. 345 (2003) 349 48. S. Jain, B. S. Keshwal, D. Rajguru, J. Serb. Chem. Soc. 77 (2012) 1345 49. J. S. Yadav, B. V. S. Reddy, G. Baishya, J. Org. Chem. 68 (2003) 7098 50. G. Keglevich, A. Grün, I. Hermecz, I. L. Odinets, Curr. Org. Chem. 15 (2011) 3824 51. D. Tanner, Angew. Chem., Int. Ed. 33 (1994) 599 52. T. Ibuka, Chem. Soc. Rev. 27 (1998) 145 53. W. Sun, C.-G. Xia, H.-W. Wang, Tetrahedron Lett. 44 (2003) 2409 54. Y. S. Yadav, B. V. S. Reddy, P. N. Reddy, M. S. Rao, Synthesis 2003 (2003) 1387 55. M.-Y. Zhou, Y.-Q. Li, X.-M. Xu, Synth. Commun. 33 (2003) 3777 56. Z.-G. Le, Z.-C. Chen, Y. Hu, Q.-G. Zheng, Synthesis 2004 (2004) 0995 57. Z.-G. Le, Z.-C. Chen, Y. Hu, Q.-G. Zheng, J. Heterocycl. Chem. 42 (2005) 735 58. A. Rajasekaran, M. Periasamy, S. Venkatesan, J. Dev. Biol. Tissue Eng. 2 (2010) 5 59. J. P. Suryavanshi, N. R. Pai, Indian J. Chem., B 45 (2006) 1227 60. R. Jain, K. Sharma, D. Kumar, J. Heterocycl. Chem. 50 (2013) 315 61. F. Ye, H. Alper, J. Org. Chem. 72 (2007) 3218 62. Z. Özdemir, H. B. Kandilci, B. Gümüsel, Ṻ. Çalis¸ A. A. Bilgin, Eur. J. Med. Chem. 42 (2007) 373 63. M. Ezawa, D. S. Garvey, D. R. Janero, S. P. Khanapure, L. G. Letts, A. Martino, R. R. Ranatunge, D. J. Schwalb, D. V. Young, Lett. Drug Des. Discov. 2 (2005) 40 64. V. K. Rao, R. Tiwari, B. S. Chhikara, A. N. Shirazi, K. Parang, A. Kumar, RSC Adv. 3 (2013) 15396 65. R. Ghahremanzadeh, M. M. Moghaddam, A. Bazgir, M. M. Akhondi, Chin. J. Chem. 30 (2012) 321 66. S. A. Shirvan, R. Ghahremanzadeh, M. M. Moghaddam, A. Bazgir, A. H. Zarnani, M. M. Akhondi, J. Heterocycl. Chem. 49 (2012) 951 67. G. Brahmachari, B. Banerjee, ACS Sustainable Chem. Eng. 2 (2014) 2802 68. R. Jain, K. Sharma, D. Kumar, Tetrahedron Lett. 53 (2012) 1993 69. B. Banerjee, Ultrason. Sonochem. 35 (2017) 1 70. G. Brahmachari, B. Banerjee, Asian J. Org. Chem. 1 (2012) 251 71. G. Brahmachari, B. Banerjee, Curr. Green Chem. 2 (2015) 274 72. J. Chen, W. Su, H. Wu, M. Liu, C. Jin, Green Chem. 9 (2007) 972 73. Y. Peng, G. Song, Tetrahedron Lett. 45 (2004) 5313 74. I. V. Seregin, L. V. Batog, N. N. Makhova, Mendeleev Commun. 12 (2002) 83 75. C. O. Kappe, Tetrahedron 49 (1993) 6937 76. P. Biginelli, Gazz. Chim. Ital. 23 (1893) 360 ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ 1096 KAUR, SHARMA and BANERJEE 77. J. Peng, Y. Deng, Tetrahedron Lett. 42 (2001) 5917 78. J. Marco-Contelles, E. Pérez-Mayoral, A. Samadi, M. C. Carreiras, E. Soriano, Chem. Rev. 109 (2009) 2652 79. J.-L. Wu, R.-S. Hou, H.-M. Wang, I.-J. Kang, L.-C. Chen, J. Chin. Chem. Soc. 56 (2009) 867 80. Z.-G. Le, Z.-B. Xie, M. Ying, Molecules 11 (2006) 464 81. Q. Yao, M. Sheets, J. Organomet. Chem. 690 (2005) 3577 82. N. Audic, H. Clavier, M. Mauduit, J.-C. Guillemin, J. Am. Chem. Soc. 125 (2003) 9248 83. R. C. Buijsman, E. V. Vuuren, J. G. Sterrenburg, Org. Lett. 3 (2001) 3785 84. N. Gundogdu-Karaburun, K. Benkli, Y. Tunali, U. Ucucu, Eur. J. Med. Chem. 41 (2006) 651 85. P. G. Baraldi, R. Romagnoli, I. Beria, P. Cozzi, C. Geroni, N. Mongelli, N. Bianchi, C. Mischiati, R. Gambari, J. Med. Chem. 43 (2000) 2675 86. X. Zhang, D. Li, X. Jia, J. Wang, X. Fan, Catal. Commun. 12 (2011) 839 87. S. Hesse, G. Kirsch, Tetrahedron Lett. 43 (2002) 1213 88. J.-C. Jung, Y.-J. Jung, O.-S. Park, Synth. Commun. 31 (2001) 1195 89. G. Melagraki, A. Afantitis, O. Igglessi-Markopoulou, A. Detsi, M. Koufaki, C. Kontogiorgis, D. J. Hadjipavlou-Litina, Eur. J. Med. Chem. 44 (2009) 3020 90. J.-C. Jung, J.-H. Lee, S. Oh, J.-G. Lee, O.-S. Park, Bioorg. Med. Chem. Lett. 14 (2004) 5527 91. H. Valizadeh, S. Vaghefi, Synth. Commun. 39 (2009) 1666 92. H. Leutbecher, S. Rieg, J. Conrad, S. Mika, I. Klaiber, U. Beifuss, Z. Naturforsch., B: J. Chem. Sci. 64 (2009) 935 93. I. Hemeon, C. DeAmicis, H. Jenkins, P. Scammells, R. D. Singer, Synlett 2002 (2002) 1815 94. N. Mulakayala, P. V. N. S. Murthy, D. Rambabu, M. Aeluri, R. Adepu, G. R. Krishna, C. M. Reddy, K. R. S. Prasad, M. Chaitanya, C. S. Kumar, M. V. B. Rao, M. Pal, Bioorg. Med. Chem. Lett. 22 (2012) 2186 95. A. Nakhi, M. S. Rahman, S. Archana, R. Kishore, G. P. K. Seerapu, K. L. Kumar, D. Haldar, M. Pal, Bioorg. Med. Chem. Lett. 23 (2013) 4195 96. B. Banerjee, G. Brahmachari, J. Chem. Res. 38 (2014) 745 97. P. Iniyavan, S. Sarveswari, V. Vijayakumar, Res. Chem. Intermed. 41 (2015) 7413 98. M. Kidwai, K. Singhal, S. Kukreja, Can. J. Chem. 86 (2008) 799 99. G. Brahmachari, B. Banerjee, ACS Sustainable Chem. Eng. 2 (2014) 411 100. G. Brahmachari, S. Laskar, B. Banerjee, J. Heterocycl. Chem. 51 (2014) E303 101. G. Brahmachari, B. Banerjee, Asian J. Org. Chem. 5 (2016) 271 102. M. S. Rao, B. S Chhikara, R. Tiwari, A. N. Shirazi, K. Parang, A. Kumar, Chem. Biol. Interface 2 (2012) 362 103. J. S. Yadav, B. V. S. Reddy, G. Bhaishya, Green Chem. 5 (2003) 264 104. M. Christmann, Angew. Chem., Int. Ed. 44 (2005) 2632 105. Z.-Z. Zhou, F.-Q. Ji, M. Cao, G.-F. Yang, Adv. Synth. Catal. 348 (2006) 1826 106. F. Yea , H. Alper, Adv. Synth. Catal. 348 (2006) 1855 107. M. M. Moghaddam, A. Bazgir, M. M. Akhondi, A. H. Zarnani, R. Ghahremanzadeh, Org. Chem. J. 2 (2010) 54 108. K. Lanjewar, A. Rahatgaonkar, M. Chorghade, B. Saraf, Synthesis 2011 (2011) 2644 109. J. S. Yadav, B. V. S. Reddy, P. Sreedhar, C. V. S. R. Murthy, G. Mahesh, G. Kondaji, K. Nagaiah, J. Mol. Catal. A: Chem. 270 (2007) 160 110. T. Kitazume, F. Zulfiqar, G. Tanaka, Green Chem. 2 (2000) 133 ________________________________________________________________________________________________________________________ (CC) 2018 SCS. Available on line at www.shd.org.rs/JSCS/ DIVERSE BIOACTIVE HETEROCYCLES 1097 111. Y. Hu, Z.-C. Chen, Z.-G. Le, Q.-G. Zheng, Synth. Commun. 34 (2004) 3801 112. R. W. Sabnis, D. W. Rangnekar, N. D. Sonawane, J. Heterocycl. Chem. 36 (1999) 333 113. R. Jain, K. Sharma, D. Kumar, Helv. Chim. Acta 96 (2013) 414 114. R.-S. Hou, H.-M. Wang, H.-H. Tsai, L.-C. Chen, J. Chin. Chem. Soc. 53 (2006) 863 115. A. Bhavsar, S. Makone, S. Shirodkar, IJARSET 3 (2016) 2485 116. R. Jain, T. Yadav, M. Kumar, A. K. Yadav, Synth. Commun. 41 (2011) 1889. ________________________________________________________________________________________________________________________ (CC) 2018 SCS. 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