RSC Advances

This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication.

Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. This Accepted Manuscript will be replaced by the edited, formatted and paginated article as soon as this is available.

You can find more information about Accepted Manuscripts in the Information for Authors.

Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.

www.rsc.org/advances Page 1 of 35RSC Advances RSC Advances Dynamic Article Links ►

Cite this: DOI: 10.1039/c0xx00000x www.rs c.org/xxxxxx REVIEW

Metal-free domino one-pot protocols for quinoline synthesis †

Jaideep B. Bharate, ab Ram A. Vishwakarma, ab * Sandip B. Bharate ab * Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x

5 Quinoline is one of the most widely investigated scaffold by camptothecin analogues namely topotecan and irinotecan have synthetic chemists because of its medicinal importance. The been approved for clinical use for cancer chemotherapy, 34 and wide range of metal-catalyzed, metal-free, multi-step or another analog exatecan is under clinical studies. A fused domino one-pot protocols are reported in literature for quinoline natural product mappicine ketone is an antiviral lead construction of this scaffold. Several reviews appeared on 45 compound with selective activities against herpes viruses HSV1 and HSV2 and human cytomegalovirus (HCMV). 35 A fused 10 synthetic aspects of this scaffold, however there is no focused review on metal-free domino one-pot protocols. Domino one- quinoline alkaloid cryptolepine isolated from Cryptolepis sp. is 36 pot protocols offer an opportunity to access highly an antimalarial natural product possessing cytotoxic properties. Its structural isomers isocrytolepine and neocryptolepine also functionalized final products from simple starting materials. 37 50 possesses antimalarial activity. The chemical structures of Because of this unique feature of domino protocols, in recent Manuscript quinoline class of natural products are shown in Figure 1. 15 years their utility for generation of molecular libraries has been widely appreciated. In this review, all contributions till N O March 2015 are surveyed with particular emphasis on metal- HO N HO N N HO O H H O N N free domino reactions for quinoline ring construction and are O O N discussed herein along with mechanistic aspects. N O N OH O Quinine Quinidine Camptothecin Topotecan OH O NH 1 2 O 20 1. Introduction O N N N O O N Quinoline (1azanapthalene or benzo[ b]pyridine) is a weak N O N O HO O O F

tertiary base. It was first extracted from coal tar in 1834 by Irinotecan OH Exatecan Accepted Friedlieb Ferdinand Runge and this source still remains the O N N principal source of commercial quinoline. This scaffold has found N O N N 25 many applications in diverse chemical domains. This scaffold has N N N 1 wide occurrence among natural products (alkaloids) and is a key Isocryptolepine Neocryptolepine Mappicine ketone Cryptolepine structural component of several pharmaceuticals, agrochemicals, Figure 1 . Structures of quinoline ring containing natural products dyestuffs, and materials. In coordination chemistry, quinolines and their analogs 2 are used to chelate metallic ions as Ndonor ligands. The 55 30 quinoline scaffold has been reported to possess diverse range of 314 1520 Quinoline is also part of several clinically used drugs, where their pharmacological activities including antiprotozoal, major occurrence is among antimalarial drugs. The antitubercular, 21, 22 anticancer, 4, 23, 24 antipsychotics, 25 aminoquinoline scaffold has been a backbone of antimalarial 26, 27 3 28 29 Advances antiinflammatory, antioxidant, antiHIV, antifungal, as drugs since 1940s. In this class, chloroquine was the first drug 30 efflux pump inhibitors, and for treatment of neurodegenerative 60 discovered in 1934 by Hans Andersag and coworkers at the Bayer 19 31 38 35 diseases, and treatment of lupus, etc. laboratories. With the emergence of resistance to chloroquine, a series of its analogs (e.g. amodiaquine, primaquine, mefloquine, The well known antimalarial natural products quinine and tafenoquine, bulaquine, NPC1161B, AQ13, IAAQ) were

quinidine alkaloids isolated from Cinchona bark comprises discovered. Other antimalarial quinolines include piperaquine and RSC 32, 33 quinoline scaffold. Camptothecin is a quinoline alkaloid 65 pyronaridine. Quinoline has also been a part of drugs used for discovered in 1966 by Wall and Wani through systematic other diseases. This includes fluoroquinolone antibiotic 40 screening of natural products for anticancer drugs. Two ciprofloxacin (and its analogs), pitavastatin (cholesterol lowering agent), lenvatinib (kinase inhibitor for cancer) and its other structural analogs (such as carbozantinib, bosutinib), tipifarnib a Medicinal Chemistry Division, CSIR-Indian Institute of Integrative 70 (farnesyl transferase inhibitor for leukemia), Medicine , Canal Road, Jammu-180001, India. saquinavir (antiretroviral), bedaquiline (antiTB), etc. The 2(2 bAcademy of Scientific & Innovative Research (AcSIR), CSIR-Indian fluorophenyl)6,7methylenedioxy quinolin4one monosodium Institute of Integrative Medicine, Canal Road, Jammu-180001, India. phosphate (CHM1PNa) is a preclinical anticancer agent, *E-mail: [email protected] ; [email protected] † showing excellent antitumor activity in a SKOV3 xenograft nude IIIM Publication number IIIM/xxxxx/2015 39, 40 Fax: +91-191- 2586333 ; Tel: +91-191- 2585006 75 mice model. The chemical structures of above discussed

This journal is © The Royal Society of Chemistry [year] [journal] , [year], [vol] , 00–00 | 1 RSC Advances Page 2 of 35

representative quinoline based drugs are shown in Figure 2a. multicomponent reactions (MCRs) for quinolines and related Several quinoline based compounds showed inhibition of kinases fused skeletons. involved in cancer progression. 4 The chemical structures of representative kinase inhibitors are shown in Figure 2b. 2. Classical methods for quinoline synthesis

40 There exist several classical methods (name reactions) for (a) N N N synthesis of quinolines. Most of the methods involve simple N N OH N HN N arylamines as starting materials. The ‘name reactions’ involving N N HN N OMe arylamines as one of the starting material includes: (a) Combes Cl N Cl Cl Cl N quinoline synthesis (from anilines and βdiketones); (b) Skraup Chloroquine Piperaquine F Pyronaridine 45 synthesis (from ferrous sulfate, glycerol, aniline, nitrobenzene, Cl Cl O O H N and sulfuric acid); (c) ConradLimpach synthesis (from anilines N NH F N OH OH OH O O H2N and βketoesters); (d) Povarov reaction (from aniline, O O N N OH benzaldehyde and an activated alkene); (e) Doebner reaction HN N H2N O N Cl MeO N (from anilines, aldehyde and pyruvic acid); (f) DoebnerMiller Ciprofloxacin Pitavastatin Lenvatinib Tipifarnib 50 reaction (from anilines and α,βunsaturated carbonyl O compounds); (g) GouldJacobs reaction (from aniline and ethyl P OH H Me O CONH2 ONa O OH N ethoxymethylene malonate); and (h) Reihm synthesis (from H H Me O N N F N aniline and acetone). H Br O O N Ph O N H N OMe A number of other name reactions exists, which require Saquinavir Bedaquiline CHEM-1-P-Na 55 specifically substituted anilines or related substrates. These N N (b) N includes: (i) Knorr quinoline synthesis (from βketoanilide and O HN Br O O2 sulfuric acid); (j) Pfitzinger reaction (from an isatin with base and S MeO CN N HN H S a carbonyl compound); (k) Friedländer synthesis (from 2 N F F N MeO N O EKB1 aminobenzaldehyde and carbonyl compounds); (l) Niementowski

PI3K inhibitor PI3K inhibitor Manuscript EGFR inhibitor 60 Cl quinoline synthesis (from anthranilic acid and carbonyl S N compounds); (m) MethCohn synthesis (from acylanilides and N N N NH HN MeO N DMF/POCl 3); and (n) Camps quinoline synthesis (from an o O CN acylaminoacetophenone and hydroxide). The synthetic schemes MeO N N O N of these classical methods are summarized in Figure 3. N N ALK5 inhibitor PDGFR kinase inhibitor 5 MEK inhibitor 65 Despite of the availability of several classical methods for Figure 2 . Chemical structures of (a) quinoline containing drugs quinoline synthesis, extensive efforts have been made on the and clinical candidates; and (b) quinolinebased kinase inhibitors development of new metalfree domino protocols for preparation of quinolines, which are described in this review.

As a consequence of their tremendous biological importance, Accepted 10 chemists have developed a plethora of methods to elaborate this 70 3. Metal-free domino one-pot or multicomponent structure, and most of them have been compiled in a series of reviews. 4147 Recently, Patel’s group (2014) 41 have reviewed protocols for synthesis of quinolines and related advances in the synthesis of quinolines, which covered very quinoline fused heterocycles broadly various reports on quinoline synthesis and cited 57 42 Development of domino reactions for the concise construction of 15 references. Koorbanally’s group (2014) have reviewed diverse heterocyclic architectures is of a tremendous importance synthesis and anticancer activity of 2substituted quinolines. 48 45 75 in synthetic organic and medicinal chemistry. Extensive amount Nammalwar and Bunce (2014) have reviewed recent syntheses of efforts have been made in this area towards development of of 1,2,3,4tetrahydroquinolines, 2,3dihydro4(1H)quinolinones domino onepot protocols or multicomponent reactions (MCRs) and 4(1H)quinolinones using domino reactions. Alam’s group 4958 47 for construction of heterocycles. Few specific reviews on 20 (2013) have briefly discussed various synthetic and biological multicomponent synthesis of particular heterocycles such as aspects of this scaffold and cited total of 75 references. Hussanin 50, 59 60 61 Advances 80 pyrroles, indoles, and pyridines have been published. et al (2012) 44 reviewed synthesis and chemical reactivity of 46 Such domino reactions achieve high level of atomefficiency, and pyrano[3,2c]quinolinones. Mekheimer et al (2012) reviewed avoids timeconsuming isolation and purification of recent developments in the chemistry of pyrazolo[4,3 43 intermediates. Reduction in number of steps is the major 25 c]quinolines. Barluenga et al (2009) reviewed advances in the advantage with these protocols, thus reduces manpower and synthesis of indole and quinoline derivatives through cascade 62 85 avoids waste production. This section discusses all reported RSC reactions and cited total of 46 references. metalfree onepot protocols for quinoline synthesis. Most of the Despite of the fact that large number of metalfree domino one metalfree protocols discussed herein, comprises simple acid pot protocols for quinoline synthesis have been published; this catalysts, bases, molecular iodine, ionic liquids or 30 has never been reviewed. The metalfree domino protocols organocatalysts, and few methods are catalystfree. In this provide rapid access to structural diversity, and metalfree nature 90 section, these protocols have been discussed according to the use of the reaction makes these protocols environmentally friendly. of different nonmetal reagents/ catalysts: (a) acid catalyzed Therefore, a critical review on such protocols for synthesis of this protocols; (b) base catalyzed protocols; (c) molecular iodine medicinally important scaffold is highly desirable. The present catalyzed protocols; (d) ionic liquid mediated quinoline synthesis; 35 review provides a comprehensive compilation of synthetic (e) organocatalysis for quinoline synthesis; (f) catalystfree approaches involving specifically metalfree onepot domino and 95 reactions; and (g) miscellaneous reactions.

2 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 3 of 35 RSC Advances O R R1 R Riehm H2SO4, reflux Knorr quinoline Synthesis synthesis N O N O (i) (h) N R H H R1 O OH O OH O O AlCl3 R R1 R2 R2 O OEt R1 O O Pfitzinger reaction N R R N KOH H O OEt N O H N R1 (j) Combes 2 SO x O flu Gould– (a) quinoline 4 , r OEt re H ef R , (g) Jacobs R1 synthesis lu 1 O 4 x S O reaction R OH H 2 O 2 R1 Friedländer synthesis (k) HO OH TFA , reflux N R2 R H NH2 H SO p-TSA, reflux 2 4 , PhNO2 OH O OH N (b) Skraup Reaction NH2 Doebner–Miller(f) reaction N R R1 O O R2 R Niementowski R- O 1 O OR3 CH quinoline synthesis D O NH R o OH 2 N 2 (l) r e + R R ea bn 1 2 ux ct e O R OH refl ch io r COOH 2 R2 , pa n DMF, POCl 2 SO 4 im Ar-CHO (e) 3 Meth-Cohn R H 2 –L O rad BF OEt Synthesis on sis 3 N O N Cl C the H (m) 1 yn (c) N R s N R R1 NaOH R2 O Camps quinoline N Ar Synthesis N R (n) (d) Povarov reaction NH 3 A: R1= OH, R2 = H, R3 = Et O B: R1= Me, R2 = Me, R3= OH Figure 3 . Classical methods (“Name Reactions”) for quinoline synthesis

R2 R2 3.1. Acid catalyzed protocols H 10% HCOOH in water R1 OEt + O R1 Manuscript Acids have been widely used as simple and ecofriendly catalysts NH rt, 45 min OEt 2 O 20 examples N and promoters for various organic reactions. Acid catalysts which 1 2 3 78-92% 4 O Imine formation 5 are routinely used in various organic transformations include H Protonation [O] trifluroacetic acid (TFA), formic acid, acetic acid, triflic acid, and

pTSA. Acetic acid and formic acid are the two most common R2 R2 R2 reagents available in most of the chemistry laboratories and their aza-Diels- H use for quinoline synthesis has been well documented. Among Alder reaction R R1 R1 10 various starting materials, arylamines are among most widely 1 OEt OEt OEt N N N H H used precursors for quinoline synthesis. O O O I II III Many acid catalyzed protocols are based on the traditional name Cl

reactions. Pavarov reaction is one of the most widely investigated Accepted reaction for quinoline synthesis, comprising the aza DielsAlder 63 O O MeO 15 cycloaddition as the key step. Recently our group have OEt O OEt OEt developed an efficient formic acid catalyzed onepot synthesis of O N N MeO N O 4arylquinoline 2carboxylates 4 in water via threecomponent 4a, 92% O 4a, 85% 4c, 78% O Pavarov reaction of arylamines 1, glyoxylates 2 and phenylacetylenes 3 (Scheme 1). The reaction mechanism involves Scheme 1 . Formic acidcatalyzed synthesis of quinoline2 carboxylates 4; some representative examples are shown. 20 a cascade of reactions involving initial condensation of arylamine 64 1 and ethyl glyoxylate 2 to form imine intermediate I. Next, there 30 Zhang et al reported a threecomponent Pavarov reaction is a protonation of the nitrogen of the imine which facilitates the between aryl aldehydes 5, arylamines 1, and alkynes 3 in attack by phenylacetylene, resulting in cyclization to produce presence of triflic acid leading to formation of 2,4disubstituted dihydroquinoline III , which on oxidation produces 4 quinolines 6 (Path A of Scheme 2). Interestingly, the use of Advances 25 arylquinoline 2carboxylates 4. These compounds displayed alkenes 3 instead of alkynes 7 with the increase in reaction time neuroprotective, antioxidant and Pgpinduction activities. 35 (from 4 h to 8 h) produced same quinoline products 6 (Path B of Scheme 2).

NH2 NH2 R2 R R 1 RSC 1 N 1 1 A B CHO CHO + + 5 mol% TfOH R 5 mol% TfOH Toluene, 4 h, 1 Toluene, 8 h, R R2 R2 100 oC 3 100 oC 5 5 18 examples 6 9 examples + + 54-95% yield 42-78% yield R3 R3 3 Me 7 Me Me N N N N

Me Me MeO O2N Pr COOEt

6a, 54% 6b, 95% 6c, 42% 6d, 78%

This journal is © The Royal Society of Chemistry [year] Journal Name , [year], [vol] , 00–00 | 3 RSC Advances Page 4 of 35

Scheme 2 . TfOHcatalyzed synthesis of 2,4disubstituted 30 An interesting utility of Pavarov reaction for construction of quinolines 6; some representative examples are shown. pentacyclic quinoline based fused heterocycles has been recently reported by Khadem et al. 68 This protocol implies the three component reaction between arylamine 1, 2carboxy Mujumdar et al 65 reported another Pavarovtype threecomponent benzaldehyde 12 and cyclopentadiene 13 in presence of TFA to 5 domino reaction of heterocyclic amines 8, aldehydes 5, and 35 furnish isoindolo[2,1a]quinoline 14 (Scheme 5). The Schiffs terminal alkynes 3 in the presence of BF 3.OEt 2, which led to base I undergoes a stepwise aza Diels–Alder reaction with formation of pyrano[3,2f]quinolines 9a and phenanthrolines 9b . cyclopentadiene 13 to produce isoindolo[2,1a]quinolines 14 . The imine intermediate I undergoes intermolecular concerted Authors mentioned that the concerted [4+2] cycloaddition route type azaDiels–Alder reaction with an alkyne 3 leading to would afford a mixture of regioisomeric products due to free N– 10 formation of quinoline skeleton II , which on aromatization 40 Ar bond rotation prior to addition. produces 9 (Scheme 3). O COOH H R Ph R1 2 equiv.TFA N R NH2 CHO NH CH3CN 2 N + + H 10 mol% BF OEt 40 h, + R1-CHO + 3 2 EtO C EtO2C 78-79% 2 H O X Ph toluene, reflux, 12 h R1 = C6H5OMe, O X 2 examples R = H, Me 14 examples 1 12 13 14 C6H5Br X = O, N-Me, N-Et 53-87% 9a: X = O; 8 5 3 9b: X = N-Me or N-Et Imine formation Aromatization HOOC HOOC HOOC H R1 N H H R Ph R1 Ph Cyclization R N N N H N EtO2C EtO2C EtO2C O X H O X I II I II III Br O Ph O Me Ph S Ph H N H N N Manuscript N H H

O O N O N H EtO2C O N H Me OMe Me 9a1, 53% 9b , 80% 9b , 87% 1 2 14a, 78% 14b, 79% Scheme 3 . BF 3.OEt 2catalyzed synthesis of pyrano[3,2 Scheme 5 . TFA catalyzed synthesis of pentacyclic f]quinolines 9a and phenanthrolines 9b ; some representative isoindoloquinolines 14 ; some representative examples are shown. 15 examples are shown.

Ketenedithioacetals have been used as important building blocks 66 69 for construction of heterocycles. EthynylS,Sacetals 10 are 45 Borel et al reported a threecomponent Povarov reaction of highly reactive electronrich dienophiles which undergo pyridine aldehydes 15 and arylamines 1 with ethyl vinyl ether 16 regiospecific azaDielsAlder (Povarov) reaction with arylimines in presence of boron trifluoride methyl etherate producing 2(2 Accepted 20 to produce quinoline skeleton. A triflic acid mediated three pyridyl)quinolines 17 (Scheme 6).

component reaction between ethynylS,Sacetals 10 , arylamines 1 O NH2 and aldehydes 5 produced quinoline skeleton 11 via consecutive N 20 mol% BF3.OMe2 H R1 R R2 + O o N arylimine I formation, regiospecific azaDielsAlder reaction, and 1 + ACN, 82 C N 67 15 examples R reductive amination (Scheme 4). 17 2 1 15 16 31-76% OMe S R R O S NH2 N MeO N N N O N N SS 1 equiv. CF3SO3H +R + R -CHO R OMe 1 2 CH Cl , rt 1 2 2 N R2 17a, 31% 17b, 48% 17c, 76% 10 1 5 27 examples 11 53-72% yield 50 Scheme 6 . BF .OMe catalyzed synthesis 2(2pyridyl)quinolines 3 2 Advances Imine 17 ; some representative examples are shown. formation aza-Diels-Alder reaction CF3SO3 N Reductive amination H R2 70 I Shindoh et al reported triflic imide and triflic acid catalyzed S O PovarovHydrogenTransfer cascade reaction to produce S O S O S OEt 55 quinolines 20 . The reaction between electronrich olefins 19 and RSC Me S OEt S OEt excess amount of imines 18 in the presence of triflic imide in

N DCM at 60 °C afforded substituted quinolines 20 in onepot N N 11a, 53% (Scheme 7). 11b, 63% 11c, 72% F OMe 25 Scheme 4 . Triflic acidcatalyzed synthesis of 2,4disubstituted quinolines 11 via threecomponent aza DielsAlder reaction; some representative examples are shown.

4 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 5 of 35 RSC Advances

R3 O EDG R3 R1 NH2 + 0.5-1.0 equiv. BF3OEt2 R N R2 + R 4 4 R2 R2 EtO DCM, rt, 6-12 h N 18 19 R1 24 29 examples 23 R 15 examples 1 43-97% 1 19-64% Povarov Tf2NH (10 mol%) Imine formation Aromatization reaction 60 oC, 24 h H R3 R3 N R3 N Cyclization EDG BF3OEt2 R EDG 4 R Hydrogen N 2 R2 R2 transfer EtO R1 EtO R R1 R1 Oxidative R1 1 N aromatization N I II III R2 Me H R2 20 Me I Br O2N

TIPS Bn N Pr TIPS N N Me N Pr O N Me 2 MeO 23a, 43% 23b, 70% 23c, 82% 23d, 97% F3C N N N Scheme 9 . BF 3.OEt 2catalyzed synthesis of alkyl quinolines 23 20a, 19% 20b, 31% 20c, 64% from 3ethoxycyclobutanones 24 and aromatic amines 1; some 30 representative examples are shown. Scheme 7 . Triflic imidecatalyzed synthesis of imidazopyrrolo quinolines 20 ; some representative examples are shown. Apart from the Pavarov reaction, arylamines are also one of the key precursors in several other protocols. There are several 5 Paratoluene sulfonic acid (pTSA) catalyzed condensation of reports on the threecomponent reaction of arylamines, aryl aromatic amines 1 with δ,εunsaturated aldehydes 21 , followed 35 aldehydes and active methylene compounds leading to formation by intramolecular formal hetero DielsAlder reaction produced 73 71 of a quinoline skeleton. Mirza and Samiei reported Doebner cyclopenta[b]quinolines 22 . Mechanistically, reaction proceeds type multicomponent reaction of arylamine 1, acetone 25 and through the iminium ion transition state I which further benzaldehyde 5 without any solvent under microwave irradiation Manuscript 10 undergoes ring closure via intramolecular Diels−Alder reaction to on the surface of alumina impregnated with hydrochloric acid to produce II with a transarrangement of allylic cation and an 40 produce substituted quinolines 26 (Scheme 10). amine. The electrophilic aromatic substitution reaction between NH2 allylic cation and aniline moiety then leads to formation of stable 2.2 equiv. HCl R R1 cyclopenta[b]quinoline 22 (Scheme 8). 3 O MW, 3-5 min + Ph-CHO + 10 examples R N Ph R2 70-98% 2 R R1 3 1 H 5 25 26 + 5 mol% TsOH MeO OHC MeO Benzene Me Scheme 10 . HClcatalyzed synthesis of 4methyl quinolines 26 . NH2 Me Me N 5 examples H H Accepted R = OMe 60-79% Me 1 21 22 Imine formation Cyclization Tu’s group 74 established a sequential threecomponent reaction 45 between 2aminoanthracene 27 , aromatic aldehyde 5 and cyclic H H 1,3dicarbonyl compounds 28 (such as tetronic acid 28d , 5,5 Cyclization Me R Me R H dimethyl,3cyclohexanedione 28e , 1,3indanedione 28c , 3H N H N H H H chromene2,4dione 28f , quinoline2,4(1H, 3H)dione 28b and I II barbituric acid 28a ) in acidic medium under microwave 50 irradiation to produce a series of unusual fused heterocyclic compounds, naphtho[2,3f]quinoline derivatives 29 (Scheme 11). H H H MeO This scaffold exhibited good luminescent properties with emission wavelengths in the blue region. MeO N Me MeO N Me MeO N Advances H H H H H Me Me H Me 22a, 71% 22b, 75% 22c, 76% 15 Scheme 8 . pTSA catalyzed synthesis of cyclopenta[b]quinolines 22 from δ, εunsaturated aldehydes 21 ; some representative

examples are shown. RSC

20 Boron trifluoride etherate is a widely used lewis acid catalyst in various reactions. Shan et al 72 reported boron trifluoride etherate catalyzed singlestep approach toward the regioselective synthesis of 2alkylquinolines 23 from 3ethoxycyclobutanones 24 and aromatic amines 1. The imine intermediate I formed from 25 two substrates undergoes intramolecular cyclization followed by aromatization to produce quinoline product 23 (Scheme 9).

This journal is © The Royal Society of Chemistry [year] Journal Name , [year], [vol] , 00–00 | 5 RSC Advances Page 6 of 35

O O O R O O O HN + R-CHO O AcOH (1 ml) 5 O N O O Ar R MW, 120 oC R1 H 1 O Ar 19 examples N O 28a HN + ArH2N R R1 85-93% Ar 1 28d 6 examples O O 90-93% O N N 32a 33 13 examples H H 34a N 90-94% H 29a O O R O O O 29d O ArCHO + + R-CHO 5 AcOH (1 ml) R2 5 o R1 MW, 120 C R NH2 O Ar + 1 O Ar N O ArHN 6 examples R2 N O H O R1 R1 28b HN 89-95% Ar 28e 27 6 examples 32b 33 34b 7 examples N N O 3 mol% 89-92% H H 86-91% AcOH O R O 29b 29e + R-CHO NC + + CN AcOH (1 ml) 5 o R1 MW, 120 C R1 28 O O CN O Ar + ArHN 6 examples H2N N O Ar O R1 R 85-92% Ar 1 O 32c 33 O O O 34c N 28c N H 28f 5 examples H 90-93% 29c 29f 6 examples 30 Scheme 13 . AcOHcatalyzed synthesis of imidazopyrrolo 91-95% quinolines 34a-c. Scheme 11 . AcOHcatalyzed synthesis of naphtho[2,3

f]quinoline derivatives 29a-f. Azizian et al 77 also utilized enaminones as amine precursors for

quinoline synthesis. A threecomponent reaction between 2 75 5 Khan and Das utilized 3aminocoumarins 30 as the arylamine 35 hydroxynaphthalene1,4dione 35 , 6aminouracils 36 , and precursor for synthesis of chromeno[3,4b]quinolines 31 . The aromatic aldehydes 5 in presence of pTSA in aqueous media pTSA catalyzed onepot three component reaction between aryl produced pyrimido[4,5b]quinolinetetraones 37 . This reaction

aldehydes 5, 3aminocoumarins 30 , and cyclic 1,3diketones 28e has been proposed to proceed by first condensation of 2 Manuscript (Scheme 12) produced chromeno[3,4b]quinolines 31 . The hydroxynaphthalene1,4dione 35 and aldehyde 5 followed by 10 reaction proceeds through the key intermediate I which on 40 coupling with 6aminouracil 36 and then cyclization of II to cyclization produces chromeno[3,4b]quinoline 31 . yield 37 (Scheme 14).

R1 O O O Ar O CHO X NH2 X R NR 1 + 20 mol% pTSA O + Ar-CHO + 30 mol% pTSA NR O O H2N N O H2O, Reflux, 6 h R1 = Me, OMe, NO2 Ethanol, reflux OH N N O X= H, Br, NO2 R 5 O 20 examples 13 examples H R O R3 O R = H, Me O 30 72-82% ( ) 83-91% yield N n 35 5 36 37 H R2 + R2 R1 O ( )n O 31 R1 X n = 0, R = R = H O 2 3 Ar O Accepted O O Ar n = 1, R2 = R3 = H Me 28e H + 36 NR R3 O O ( ) O N n R2 O R NH O O H2N O 2 O I I OMe II NO2 Me Me NO2

O Me O O O O O O O O

Me NH NR O Me Me NH N O O H Me N N N N O O H Me H Me N N O N N O O O H R H R H R O O O 31a, 72% 31b, 77% 31c, 82% 37a, 83% 37b, 87% 37c, 91% Advances Scheme 12 . pTSAcatalyzed synthesis of chromeno[3,4 Scheme 14 . pTSAcatalyzed synthesis pyrimido[4,5b]quinoline b]quinolines 31 ; some representative examples are shown. tetraones 37 ; some representative examples are shown.

15 45 76 Tu and coworkers employed the use of enaminones 33 as the The fourcomponent reaction between naphthylamines 41 , RSC amine precursor and 1,3indanedione 32a as an active methylene phenylhydrazine 39 , isatins 40 and 3ketoesters 38 in presence of precursor for preparation of quinoline skeleton. The three pTSA under solventfree conditions afforded spiro[1H component onepot protocol involving treatment of aldehydes 5, pyrazolo[3,4b]benzo[h]dihydroquinolin4,3indolin2ones] 42a- 20 1,3indanedione 32a and enaminone 33 in presence of acetic acid 50 b (Scheme 15). Authors also employed this 4CR protocol for produced indeno[1,2b]quinoline9,11(6H,10H)diones 34a . anilines instead of naphthylamines, which produced 4substituted Authors also used other active methylene compounds such as 5 pyrazolo[3,4b]quinoline derivatives. 78 substitutedcyclohexane1,3dione 32b or malononitrile 32c in this protocol to produce acridine1,8(2 H,5 H)diones 34b or 25 multisubstituted quinolines 34c (Scheme 13). The reaction mechanism involves Michael addition as the key step; and the protocol was found to work both by microwave irradiation and conventional heating.

6 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 7 of 35 RSC Advances

Ph N N Scheme 16 . AcOH catalyzed synthesis of R benzo[f]thiopyrano[3,4b]quinolin11(8H)ones 43 ; some 41a or 41b Ph O representative examples are shown. N N O O N 15 R H I II 80 Ph Narasimhulu et al used silica supported perchloric acid as a NH2 N N heterogeneous recyclable catalyst for synthesis of various poly R H O N substituted quinolines 45 using Friedlander condensation of 2 O O + 41a aminoarylketones 46 with carbonyl compounds 47 and αketo R OEt + O N 20 esters at ambient temperature (Scheme 17). 38 N 20 mol% p-TSA H O 8 examples 40 H 42a + 53-92% R1 R Ph 1 N N R H O O HClO4 - SiO2 3 R N NH2 H + R o Ph NH N 3 CH3CN, 60 C 2 NH R2 2 2-3 h N R2 39 18 examples 41b 46 47 45 N O 90-96% 20 mol% p-TSA H 2 examples Ph O 78-81% OMe 42b Ph N Ph N N N N N N Ph N N Ph 45a, 90% Me Pr H 45b, 94% 45c, 96% H O N H N N 2 N Scheme 17 . Silica supported perchloric acidcatalyzed synthesis N O N N H of polysubstituted quinolines 45 ; some representative examples H O H O are shown.

42a1, 79% 42a2, 92% 42b1, 78% 25 Manuscript Scheme 15 . pTSAcatalyzed synthesis of spiro[1 Hpyrazolo[3,4 The quinoline synthesis through condensation of b]benzo[h]dihydroquinolin4,3indolin2ones] 42 using 4CR; benzylideneanilines with active methylene compounds has been some representative examples are shown. reported by two groups. Tanaka et al 81 reported the condensation

5 of benzylideneanilines 48 with carbonyl compounds (aldehydes 30 or ketones or diketones) 47 in presence of catalytic HCl leading 79 Yu et al reported acetic acid catalyzed threecomponent reaction to formation of quinolines 49 . The enol form of carbonyl between aryl aldehyde 5, βnaphthylamine 41b , and 2H compound reacts with imine to form quinoline ring II via thiopyran3,5(4H,6H)dione 44 in the presence of acetic acid intramolecular cyclization, which further on aromatization leading to formation of benzo[f]thiopyrano[3,4b]quinolin produces 49 (Scheme 18). 10 11(8H)ones 43 (Scheme 16). Ph H R2 O Ar Accepted O air Ph R3 N HCl (5 mol%) NH2 R 10 ml HOAc R + R 3 N ArCHO + + 1 2 DMSO o S R1 S 25 C, 6-10 h N O 19 examples O 14 examples H 48 47 43-82% 5 41b 44 73-85% 43 49 R3 = H, Ph, COOMe Aromatization O HCl OH O Ar R R2 H 2 N Ph O Ph R3 Ar O O Cyclization S S O HN R3 -H2O HN NH2 R R I II 44 V 1 1 I II Ph N Advances S Ph N Ph N O O O O H S Me NH COOMe Ph HN 2 Ar NH Ar + 49a, 43% 49b, 69% 49c, 82% S 35 Ar O O

Scheme 18 . HClcatalyzed synthesis of substituted quinolines 49 ; RSC III IV 41b V some representative examples are shown.

NO2 Br OMe 82 MeO OMe Bojinov and Grabchev reported cyclization of 3(arylidene 40 amino)benzo[de]anthracen7ones 50 , with 3oxobutyric acid O O O ethyl ester 38 in presence of catalytic amount of HCl to produce fluorescent ethyl 3aryl1methyl8oxo8Hanthra[9,1 S N S S gh]quinoline2carboxylates 51 in 4043% yields (Scheme 19). H N N H H The reaction proceeds through key amine intermediate I, which 43a, 73% 43c, 85% 43b, 82% 45 on cyclization produces 51 .

This journal is © The Royal Society of Chemistry [year] Journal Name , [year], [vol] , 00–00 | 7 RSC Advances Page 8 of 35

R dimethylamine to a carbocation intermediate VIII to produce C2H5O O R 30 structurally diverse pyrrolo[3,4c]quinoline1ones 54 (Scheme H3C N 21). N C2H5O O + H3C 0.25 mL HCl O R2 2 examples O O N O O 40-43% o 50 38 O 51 p-xylene, 130 C R1 N + R2 NH2 + O C2H5O O R N TFA, 20 min H 35 examples N R1 55 60-82% H3C 1 40 54

O R2 -H N NH N R1 R H HO O 2 O N N O H N O H I N R1 I VIII tautomerization imine-enamine R -H2O Scheme 19 . HClcatalyzed synthesis of anthra[9,1gh ]quinoline 2 R2 2carboxylates 51 by cyclization of 3(arylideneamino) HN R1 N HO O R O 1 benzo[ de ]anthracen7ones 50 . H2O O N N 5 H II VII Apart from the above discussed protocols involving either H R -H2O R 1 R2 R arylamine, enaminone or benzylimine as one of the key O 1 O 2 N N O HO HO OH precursor, several groups have established protocols involving R2 O R N O N 2 HO R HO precursors other than those involved in conventional name 1 R1 O H O 83 N NH2 NH2 10 reactions. Yu et al ., established a domino onepot protocol for N H H H H2 Manuscript the synthesis of highly substituted imidazopyrroloquinolines 52 III IV V VI by simply refluxing a reaction mixture of different types of isatins MeO OMe 40 and heterocyclic ketene aminals 53 in presence of acetic acid. OMe The reaction mechanism involves cascade of reaction involving O O O N N N 15 first addition of ketene N,Nacetals to the carbonyl group of isatin 40 . This was followed by imineinamine tautomerization, intramolecular cyclization, dehydration and ring opening to N N N produce amino intermediate II . This intermediate on protonation OMe OMe Cl 54a, 60% 54b, 70% followed by cyclization leads to the formation of 54c, 82% 20 imidazopyrroloquinoline 52 (Scheme 20). Scheme 21 . TFAcatalyzed synthesis of pyrrolo[3,4c]quinoline 35 1ones 54 ; some representative examples are shown. O Accepted R n 2 NH R1 O N 0.4 mL AcOH N O H toluene, reflux HO Quiroga et al ., 85 showed that microwaveassisted intramolecular 40 1. Addition + R1 O cyclization of N4substituted 6chloropyrimidine5 H O N N R3 H carbaldehydes 57 in acetic acid leads to formation of n R3 I 40 pyrimido[4,5b]quinolines 56 (deazaflavin analogs), which N R2 H 2. Tautomerization exhibited excellent fluorescence properties (Scheme 22). The 53 27 examples 3. Cyclization reaction process involves removal of the both Cl and NH groups 78-94% 4. Ring opening 2 of the starting material, as these groups are not present in the final ( )n O R2 R2 N n products. N R O N NH 5. Protonation 1 Cl O R1 6. Cyclization O Advances N N OH R3 NH O R2 1.5 mL AcOH HN R3 2 R1 52 H2N N N o II MW,15 min 300 O N N 9 examples, O R N O O R1 60-80% 2 N N N Br N F N 57 56 O O RSC N O N N HN Me HN HN 52a, 78% 52b, 86% 52c, 94% Cl O N N O N N O N N Et Me Scheme 20 . AcOHcatalyzed synthesis of imidazopyrrolo Ph 56a, 60% 56b, 70% 56c, 80% quinolines 52 via cascade of reactions; some representative 45 examples are shown. Scheme 22 . Synthesis of pyrimido[4,5b]quinolines 56 via 25 intramolecular cyclization of N4substituted 6chloropyrimidine 5carbaldehydes 57 ; some representative examples are shown. Yu et al 84 described a threecomponent reaction of enaminones 55 , amines 1, and isatin 40 under acidic condition. The reaction proceeds through an unusual hydride transfer from in situ formed

8 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 9 of 35 RSC Advances

The reaction of NmethylNphenylcinnamamides 59 with transitionmetal catalyst. This transformation consisted of a phenyliodine bis(trifluoroacetate) (PIFA) in the presence of TFA cascade reaction of the arylisothiocyanate 65 with alkyltriflate 67 produced 3arylquinolin2one compounds 58 . First, the 35 to form alkylthiosubstituted carbenium ion I, which followed the nucleophilic attack on the iodine center by the carbonyl oxygen reaction with alkyne 66 to form intermediate II and subsequent 89 5 of the amide moiety in 59 affords 3azatriene I which undergoes electrophilic annulation to give quinoline 64 (Scheme 25). an electrocyclic ring closure and the subsequent proton S R1 C + R3OTF N SR elimination to give intermediate III . Next, the 1,2aryl shift N 67 3 R followed by the breakage of the OI bond gives 3phenylquinolin R + o 86 DCE, 130 C R1 2one 58 (Scheme 23). R2 24 examples 65 R2 66 24-82% Ar R R = Me, OMe 64 R 3 R = H, Me, OMe, Et, Ph, Cl, Br 3 10 equiv. TFA, 1 Ar R2 = OMe, Et, C6H5F, N-hex, Ph L 1equiv. BF3.OEt2 R3OTf -HOTf R1 R1 R3 = Me, Et, ClCH2CH2Cl I Ph o N O DCE, 0 C-rt N O L 19 examples OTf R2 R PIFA 30-90% 2 59 58 N C SR3 N SR L = OCOCF3 3 60 R R 1,2-Ar shift I R R R 1 2 1 OTf R Ar 66 2 R Ar Ar II 3 Ring closure H R R3 3 + R L -H 1 I R L R L N SMe N SMe N SMe N O Ph 1 I 1 I N O Ph N O R2 Ph R2 R2 Ph Br Ph MeO Ph I II III OMe Ph Ph OMe Ph 64a, 24% 64b, 68% 64c, 82% Ph Ph S Scheme 25 . Alkyl triflate triggered synthesis of quinolines 64 N O N O N O N O 40 from arylisothiocyanates 65 ; some representative examples are

Me Manuscript Me shown. 58a, 30% 58b, 63% 58c, 71% 58d, 45% 10

Scheme 23 . TFA catalyzed synthesis of 3arylquinolin2ones 58 from NmethylNphenylcinnamamides 59 ; some representative The reaction between pyridinesubstituted oalkynylanilines 70 examples are shown. and βketo esters 38 in presence of pTSA in ethanol produced 45 quinolinebased tetracyclic scaffold 69 . Reaction proceeds

through sequential hydrationcondensationdouble cyclization 15 Arylmethyl azides 62 undergo rearrangement to produce Naryl reactions. Interestingly, in the absence of βketo esters, iminium ion intermediate I which can be trapped with a variety of multisubstituted quinolines 68 were formed via condensation of nucleophiles. 87 Tummatorn et al 88 utilized arylmethyl azides as two molecules of oalkynylanilines 70 in reasonable yields 90 the precursors to give an Naryl iminium ion intermediate. 50 (Scheme 26). Accepted Following the addition of ethyl 3ethoxyacrylate 63 , the 2 N R2 20 substituted quinoline products 61 were obtained in moderate to R2 pTSA, EtOH, reflux N excellent yields (Scheme 24), via a cascade of reactions including R 24 h 2 R N 7 examples 1 intramolecular electrophilic aromatic substitution, elimination R1 31-70% R NH2 70 and subsequent oxidation. N 3 O pTSA, EtOH, reflux H N N 2 COOEt 15-60 h N 1 equiv.TfOH, toluene, rt, 3h 68 R3 18 examples R 3 R DDQ, EtOAC, rt, 5 min OEt 38 96% yield 17 examples 62 61 O 14-83% O R2 N H EtO OEt N O 63 R R 1 Rearrangement Intramolecular electrophilic N R

3 Advances aromatic substitution 69 Iminium ion I OMe Scheme 26 . pTSAcatalyzed synthesis of quinolinebased N N N tetracyclic scaffolds 69 and multisubstituted quinolines 68 from OEt OEt OEt oalkynylanilines. O2N O O O 55 RSC 61a, 14% 61b, 70% 61c, 83% A cascade reaction of (E)5(arylamino)pent3en1ols 72a and 25 Scheme 24 . Triflic acid catalyzed domino synthesis of quinolines thiols 72b with various aldehydes 5 in the presence of 30 mol% 57 from arylmethyl azides 62 ; some representative examples are BF 3·OEt 2 in 1,2dichloroethane at 80 °C afforded transfused shown. hexahydro1Hpyrano[3,4c]quinolines 71a and hexahydro1H 60 thiopyrano[3,4c]quinolines 71b in good yields with high

selectivity. 91 The reaction proceeds via formation of an A threecomponent reaction between arylisothiocyanate 65 oxocarbenium ion I from the hemiacetal that is formed in situ 30 alkyltriflate 67 , and alkynes 66 led to the formation of substituted from the aldehyde and a homoallylic alcohol likely after quinolines 64 in high yields. The reaction undergoes alkyltriflate activation with BF 3·OEt 2. The oxocarbenium ion is attacked by triggered domino electrophilic activation and avoids the use of a 65 an internal olefin resulting in the formation of a carbocation that

This journal is © The Royal Society of Chemistry [year] Journal Name , [year], [vol] , 00–00 | 9 RSC Advances Page 10 of 35

is simultaneously trapped by a tethered aryl group, leading to the enamine II . RetroDielsAlder reaction followed by migration of formation of hexahydro1Hpyrano[3,2c]quinolines 71 (Scheme acyl group from aniline to the more nucleophilic imine nitrogen 27). produces IV , followed by the nucleophilic attack by the aniline at the acyliminium moiety in IV affords aminoquinoline V, which Ts Ts BF3 OEt2 N 35 further on hydrolytic cleavage produces 3aryl2quinolones 75 N O R + BF3OEt2 (30 mol%) R H (Scheme 29). R1 R H EDC 80 oC 1 H 25 examples R2 OH NH XH X HO 70-95% Ph + NO2 80% PPA + P 72a: X = O 5 71a: X = O N R2 o O Ph 72b: X = S 71b: X = S 100-110 C N O O H 76 R1 77 16 examples Ts PPA 62-92% yield 75 N H O R R R2 O R 2 OH 1 P OH NHOH O X N I Ph N O Ts N R1 Ts Ts V Ph N R1 N Cl N Cl I H O H H PPA OH R OP(O)(OH) P H Me Me 2 2 R2 O OH O H H R2 OP(O)(OH)2 O S O Ph NH N NH 71a , 70% 71a , 95% 71b , 90% Ph 1 2 1 O N O N R1 N Ph R1 H 5 Scheme 27 . BF 3.OEt 2catalyzed synthesis of hexahydro1H R1 II III IV pyrano[3,4c]quinolines 71a-b; some representative examples are OMe Me shown. nPr Me N O N O H H N O N O H H Zhang et al 92 developed an efficient synthesis of pyrano[2,3 75a, 62% 75b, 74% 75c, 88% 75d, 92% Manuscript 10 b]quinolines 74 via the H 2SO 4mediated domino cyclization/ring Scheme 29 . PPAcatalyzed synthesis of 3aryl2quinolones 75 opening/recyclization reaction of readily available activated from 2substituted indoles 76 and nitroalkenes 77 ; some cyclopentanes 73 . This transformation commences from a H 2SO 4 40 representative examples are shown. mediated Combestype annulation of cyclopentane to provide an alcohol intermediate I, which on elimination of water, produces a 15 tertiary benzylic cation intermediate II . The elimination of a Aksenov et al 93 also reported a threecomponent condensation of proton from intermediate II directly provide a terminal alkene arylhydrazines 39 , 2nitroalkenes 77 and acetophenone 78 to intermediate III , which undergoes an intramolecular produce 3aryl 2quinolones 75 (Scheme 30). 93 Markovnikov addition to produce pyrano[2,3b]quinoline 74 (Scheme 28). Ar

R Ph Me 80% PPA R + Ph NH2 Accepted + o NHNH2 100-110 C N O O O O O H 0.5 mL H2SO4 39 4 examples R o 78 75 50 C R NO 79-87% yield N + Ar 2 H 12 examples O N 67-96% 74 77 73 Intramolecular Markovnikov Me H2SO4 Combes-type MeO annulation addition H N O H H O N N O H O N O N N O H H H R H R R 75a, 79% 75b, 82% 75c, 87% -H2O 45 OH Scheme 30 . PPAcatalyzed synthesis of 3aryl2quinolones 75 IH II III from arylhydrazines 39 ; some representative examples are shown. Advances Cl Me 94 O N O N O N Yamaoka et al reported a Brønsted acidpromoted Me Me 50 arene−ynamide cyclization reaction to construct 3Hpyrrolo[2,3 74a, 67% 74b, 85% 74c, 90% 20 c]quinolines 79 . This reaction involves generation of a highly

reactive keteniminium intermediate IV from arene−ynamide RSC Scheme 28 . H 2SO 4mediated synthesis of pyrano[2,3 activated by a Brønsted acid and electrophilic aromatic b]quinolines 74 ; some representative examples are shown. substitution reaction to give arenefused quinolines 79 in high 55 yields (Scheme 31). Aksenov et al 93 reported synthesis of 3aryl2quinolones 75 from 25 indoles 76 via a metalfree transannulation reaction of 2 substituted indoles 76 with 2nitroalkenes 77 in polyphosphoric acid. The conjugation of nitroalkene with indole in presence of PPA produces hydroxamic acid intermediate I. Next the intramolecular nucleophilic attack by the Nhydroxyl moiety at 30 the C2 of indole followed by tautomerization affords cyclized

10 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 11 of 35 RSC Advances

96 20 Zhi and Cai reported similar protocol for synthesis of quinolines Ar 1.2 equiv. TfOH Ar R CH Cl rt 86 using Nheterocyclic carbene as a catalyst. The reaction R 1 2 2, 2 9 examples R2 between 2aminobenzyl alcohol 83 and ketones 84 proceeds via N 52-92% N Boc 79 R two tandem reactions alphaalkylation and indirect Friedländer 80 1 annulation. The base deprotonates Nheterocyclic carbene salt I Work-up H NTf2 25 to generate a free carbine II . A cross aldol reaction between keto Ar Ar intermediate IV and deprotonated ketone V, followed by a R1 R2 R2 NTf2 cyclization leads to formation of quinoline 86 (Scheme 33). N N Boc Boc R1 I IV N KOH N H NTf2 N N III Ar R Ar R 1 Ar 2 NHC N O O R2 H OH H H R2 + R1 N N Ar O R2 NH2 N NH2 Boc R1 83 84 Boc R1 III II III 1 equiv.NHC 23 examples, 62-95% KOH, toluene NH O R2 O R2 HO R2 R1 O N N Ar O N + R1 R Ar TIPS Ph TIPS N Ar 1 NH 79a, 52% NH2 2 79b, 74% 79c, 92% 86 VI IV V Scheme 31 . TfOH catalyzed synthesis of 3Hpyrrolo[2,3 c]quinolines 79 ; some representative examples are shown.

N Manuscript N N 5 3.2. Base catalyzed protocols 86a, 62% 86b, 70% 86c, 95% Like acids, various simple and commonly used bases have been Scheme 33 . Nheterocyclic carbene and KOH catalyzed synthesis employed to catalyze several important organic transformations. 30 of quinolines 86 ; some representative examples are shown. This has opened up a way to greener routes for synthesis of heterocyclic structures. Wu et al 95 reported synthesis of 10 substituted quinolines 81 via direct reaction between the Using similar starting materials (aminobenzylalcohol 83 and corresponding aminoalcohol 83 and ketone 84 using PEG400 as ketones 47 or 84 ), Mierde et al 97 have accomplished the synthesis reaction medium in the presence of a base (Scheme 32). This of 2,3disubstituted quinolines 87 in the presence of potassium method was also effective for cyclic ketones 85 such as 35 tertbutoxide (Scheme 34). In the same year, Yus and cyclopentanone, cyclohexanone and cycloheptanone producing coworkers 98 have reported exactly same protocol, with the Accepted 15 corresponding substituted quinolines 82 . inclusion of 100 mol% benzophenone as an additive. O OH O 1.5 equiv. KOtBu R2 R1 + R 1,4 Dioxane Ar NH 2 R 2 1 80 oC, 1 h 84 N R1 Ph 83 11 examples R = H, Me, Ph Ph 47 or 84 87 R 1 15-99% OH R R 0.5 equiv. KOH 1 OH O o NH2 PEG-400, 80 C, 1h Cyclization N Ar Cross aldol R1 R = H, Cl 16 examples reaction R2 83 81-92% NH2 O 81 I

(CH )n 2 OMe Advances Ph n = 1, 2, 3 R N N N Ph N 85 87a, 15% 87b, 51% 87c, 83% 87d, 99% 0.5 equiv. KOH, PEG-400 N (CH2)n 80 oC,1h, 3 examples, 84-90% Scheme 34 . KOtBucatalyzed synthesis of quinolines 86 from 82 40 amino benzyl alcohols 83 ; some representative examples are shown. RSC Yan et al 99 employed the use of alkyl or aryl nitro olefins 77 and Cl 2aminobenzaldehydes 90 in the presence of DABCO for N N synthesis of 2substituted3nitro1,2dihydroquinolines 89 . The F N 45 amino group of 90 attacks the aryl nitro olefin 77 to form 1,4 NO2 addition intermediate I, which on cyclization followed by 81a, 81% 81b, 92% 82a, 84% dehydration gives product 88. After oxidation with DDQ, high Scheme 32 . KOHcatalyzed synthesis of quinolines 81-82 ; some yields of 2alkyl3nitroquinolines 88 were obtained (Scheme representative examples are shown. 34).

This journal is © The Royal Society of Chemistry [year] Journal Name , [year], [vol] , 00–00 | 11 RSC Advances Page 12 of 35

CHO NO R2 R3 2 NC CO Me N NO 0.4 equiv. DABCO 2 + R 2 Benzene, reflux CHO 0.2 equiv. NaOH 102 EtOH O NH2 DDQ N R + R H 1 40 examples R1 90 77 13 examples 88 + N NH 2 59-98% N NH2 25-97% R2 R3 90 DDQ [O] 103 101 OH CHO NO 2 NO NO2 DABCO 2 N R N R N R NH NH Br NH H H H2O H MeO O I II 89 O O O O NO2 MeO N NH2 N NH2 N NH2 NO2 NO2 Br N 101a, 59% 101b, 76% 101, 98% N N 88a, 25% 25 Scheme 36 . Base catalyzed onepot threecomponent synthesis of 88b, 3% 88c, 97% 2aminoquinoline3carboxamides 101 ; some representative Scheme 34 . DABCOcatalyzed synthesis of 3nitro quinolines examples are shown. 88 ; some representative examples are shown.

Cameron et al 102 described an efficient onepot procedure for the 5 Basecatalysed cyclization of β(2aminophenyl)α,βynones 30 fourstep preparation of 7hydroxyquinoline 104 from 3N 92 led to formation of 2,4disubstituted quinolines 91 through tosylaminophenol 105 in presence of diisopropylethylamine in 100 tandem nucleophic addition annulations reactions. 60% isolated yield. This onepot procedure has reduced the risk Interestingly, the exposure of the β(2malonylamidophenyl)α,β of exposure to acrolein. The 3Ntosylaminophenol 105 on ynone 94 to K 2CO 3 accomplished the synthesis of fused condensation with acrolein 106 produces intermediate I. In 10 quinolones 93 through an intramolecular Michael addition 35 ethanol, this intermediate I is readily converted to the stable /tautomerisation and transesterification cascade reaction. acetal II , which further on intramolecular FriedelCraft reaction, Manuscript Similarly, other fused quinolines 95-97 were also obtained followed by dehydration, oxidation and detosylation produces 7 (Scheme 35) from β(2aminophenyl)α,βynones. hydroxyquinoline 104 (Scheme 37).

O O Nu OMe iPr NEt, EtOH R H , + 2 5 equiv. NaOMe H HO NHTs 2 equiv. HCl warm 10 examples COR KOH reflux HO N NH NH2 32-98% 2 N R 105 106 pH 7, 60% 104 92 I 91 Oxidation O Ar Ar Ar -H O 4equiv. 2 Detosylation R K CO O O 2 3 O O OEt OH O DMF, 60 oC H COOEt O 0.5 h, 80% COOEt H OEt

N EtOH Accepted H N O N O N O COOEt H H H HO N HO N HO N 94 II III 93 Ts Ts Ts O I II III H CF3 N dry toluene N + 40 Scheme 37 . Diisopropylethylamine catalyzed synthesis of 7 110 oC, Overnight CF NH 3 2 41% N hydroxyquinoline 104 from 3Ntosylaminophenol 105 . 92a 98 95

O N2 N N N 1,1,2,2,-tetrachloroethane NO2 + The reaction of aminochalcones 108 with tosylmethyl isocyanide reflux, 6h N 63% 109 in presence of NaOH produced tricyclic pyrrolo[3,4 NH2 NO2 92b 99 96 45 c]quinolines 107 . In this domino process, three new bonds and 103 O two rings are successively formed at ambient conditions. The

O N Advances Cl OH 1,1,2,2,-tetrachloroethane overall reaction process involves (i) Michael addition of 109 to + Cl N Et3N, reflux, 6 h aminochalcone 108 under basic conditions that provides the Ph 61% N NH2 carbanion intermediate I; (ii) intramolecular cyclization of the 92c 100 97 Cl 50 resulting anion I to form the imidoyl anion intermediate II 15 Scheme 35 . Basecatalyzed synthesis of 2,4disubstituted followed by hydrogen shift and elimination of tosylic acid to give quinolines 91 and fused quinolines 93 , 95-97 from β(2 the pyrrole intermediate III ; and finally (iii) intramolecular RSC aminophenyl)α,βnones condensation of ketone with amine to furnish pyrrolo[3,4 c]quinoline 107 (Scheme 38). Wang and coworkers 101 reported a threecomponent reaction 20 between cyanoacetic acid methyl ester 102 , substituted secondary amine 103 and 2aminobenzalehyde 90 in the presence of NaOH in ethanol as a solvent produced 2aminoquinoline3 carboxamides 101 in good yields (Scheme 36).

12 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 13 of 35 RSC Advances

R O NH 20 quinolines 112 . This transformation involves a threestep reaction R 1.2 equiv. NaOH cascade of Michael addition, aldol condensation, and 1,3N → C R2 105 R1 + EtOH, rt Tos CN R1 rearrangement (Scheme 40). NH2 20-40 min N R2 R CO Et K CO R1 108 109 23 examples 107 CHO 2 2 2 3 DMSO, 100 oC 83-97% + CO Et N 2 Michael addition Cyclization NH 35 examples R -H2O 21-97% 2 Boc R1 O OtBu 112 R Tos R 113 114 Tos CN N NH O R Cyclization H shift Michael R -H+ 2 R R addition 1,3-N C R1 1 COPh 1 COPh NH NH2 acyl shift NH2 2 I II III O R R1 NH 1 R1 NH NH NH MeO R2 R2 R N N 2 N CO2Et O N Boc CO2Et Boc CO Et N N N 2 O OtBu I II III 107a, 83% 107b, 90% 107c, 94% 107d, 97% Scheme 38 . Synthesis of pyrrolo[3,4c]quinolines 107 in CO Et CO Et CO2Et 2 presence of base in ethanol; some representative examples are N 2 N N shown. O O OtBu O Ph 5 112a, 21% 112b, 69% 112c, 97% Rehan et al 104 reported synthesis of 2aryl 4substituted quinolines 110 from Ocinnamylanilines 111 ( which are prepared 25 Scheme 40 . K 2CO 3 catalyzed synthesis of 2,3disubstituted from anilines and cinnamylalcohols). The reaction occurs via a quinolines 112 ; some representative examples are shown. Manuscript regioselective 6endotrig intramolecular oxidative cyclization 10 using KOtBu as a mediator and DMSO as an oxidant at room temperature (Scheme 39). The treatment of 3(2bromophenyl)3oxopropanals 115 with amines 1 in presence of K 2CO 3 in dimethylsulfoxide led to FG R R 1 106 1 0.5-1.0 equiv. KOtBu 30 formation of 3substituted 4quinolones 114 . Reaction cascade R2 DMSO, rt involves base promoted enamine I imine II transformation R FG 2 33 examples NH followed by dehydrobromination leading to cyclization to yield 2 61-89% N G G quinolone 114 (Scheme 41). In this reaction, weaker bases failed 111 110 to function in either of the processes and stronger base triggered Ar G = Ar, 35 aldol condensation, however K CO was proved to be the most DMSO 2 3 R1 = aryl, alkyl, H; suitable base. Accepted FG R2 = alkyl, H O R1 O O O R R S 2 1 equiv. K2CO3, 2 N R DMSO 100 oC, 0.5 h, FG 1 R NH R1 H R2 + 3 2 N G Br 130 oC, 8 h N R 23 examples, 40-97% 1 H 115 R3 G IV 1 114 R2 I Imine formation Cyclization electrocyclization O FG O FG R2 R2 OH SMe2 R1 R1 S NH Br N N Br NH I R3 II Advances H R3 R1 G R1 O O G R2 O O R2 O II III Ph N O N Ph N N Br MeS N RSC N N Ph N Ph 114a, 40% 114b, 70% 114c, 84% 114d, 97% 110a, 61% 110b, 73% 110c, 89% Scheme 39 . Potassium tertbutoxide catalyzed synthesis of 2aryl Scheme 41 . K 2CO 3catalyzed synthesis of 3substituted 4 4substituted quinolines 110 ; some representative examples are quinolones 114 in DMSO; some representative examples are 40 shown. 15 shown.

107 The Nprotected Oaminobenzaldehydes 113 in presence of Fu et al have constructed another quinoline ring in the 2 chloroquinoline3carbaldehyde structure 117 by treatment with K2CO 3 in DMSO smoothly react with α,γdialkylallenoates 114 under brønsted basic conditions to yield 2,3disubstituted enaminones 33 in presence of Cs 2CO 3 catalyst, producing 1,8 45 naphthyridines 116 . Initially, the azaene addition of enaminones

This journal is © The Royal Society of Chemistry [year] Journal Name , [year], [vol] , 00–00 | 13 RSC Advances Page 14 of 35

O CO R 33 to 2chloroquinoline3carbaldehyde 117 catalyzed by base 2 CO2R1 CO R CO2R1 2 leads to the formation intermediate I. The intermediate I then O + + Cl 1 equiv. Et3N N O H O, 70 oC undergo an intramolecular cyclization to give intermediate II , H CO2R 2 N CO R 5 examples 2 which on elimination of water produces 1,8naphthyridines 116 40 122 123 78-87% 121 5 R = Me,Et, tBu Cyclization (Scheme 42). Et N 3 R1 = Me, Et Aromatization O O O O O COOH H 2 equiv. Cs2CO3 O R1 R1 COOR + toluene, reflux, 0.7 h N 1 N Cl H N N N N 30 examples Cl R R2 117 2 33 75-87% 116 ROOC Base COOR ROOC I COOR Dehydration V Aza-ene addition OH O 1. Imine-enamine O O O O tautomerization O 2. Cyclization O OH O O COOR1 R1 COOR1 N N N COOR N N O N Cl N O 1 Cl Cl R2 H I II R2 ROOC Cl ROOC COOR ROOC COOR O COOR O O II III IV MeO CO2Et CO Me CO2Et CO2Et 2 CO2tBu CO Me N N N N N N CO2Et CO2Me 2

N CO2tBu N CO Me N CO2Et N CO2Me 2 121a, 78% 121b, 83% 121c, 85% 121d, 87% Cl 116a, 78% 116b, 84% 116c, 87% Scheme 44 . Et 3N catalyzed synthesis of substituted quinolines 121 from isatins 40 ; some representative examples are shown. Scheme 42 . Cs CO catalyzed synthesis of 1,8naphthyridines 2 3 Manuscript 116 ; some representative examples are shown. 110 30 Alizadeh et al reported three component reaction of isatins 10 40 , 1aryl2(1,1,1triphenylλ5phosphanylidene)1ethanone Zhu and coworkers established a facile and efficient method 125 and hydrazonoyl chlorides 126 in the presence of Et 3N as a for the preparation of 2nonsubstituted quinoline4carboxylic catalyst to produce pyrazolo[4,3c]quinoline 124 (Scheme 45). acids 118 via the Pfitzinger reaction of isatins 40 with sodium Ph O N N pyruvate 120 following consequent decarboxylation under Cl Ar2 108 O Et N, DMF, r.t. 15 X O + Ph P 3 X microwave irradiation (Scheme 43). 3 + Ar2 N Ph N Ar 7 examples H 1 70-85% N Ar1 R1 O R1 COOH R1 COOH 40 125 126 124 + CH3-CO-COONa MW, R R R2 2 110 2 190-200 oC -HCO2H O O 20% NaOH/ H2O, MW H2O Accepted R N R N COOH R N Ph 3 H o 3 3 110 C, 10 min Ar N N R R R4 1 HO2C 4 11 examples 4 Cl Ar X O TEA 2 40 82-95% 119 118 X N Ar2 N N Ph Ar2 N Ph H -HCl COOH N Ar1 I H COOH F COOH V EtO COOH N COOH N COOH OMe N COOH Ar Br N COOH N 2 N Ar2 Ph N N 119a, 82% 119b, 84% 119c, 87% 119d, 95% Ph N Ph N Ar2 Ar COAr1 1 X O HO X O X O O Ar1 N N Scheme 43 . Synthesis of quinoline4carboxylic acids 118-119 H H NH2 under basic condition; some representative examples are shown. II III IV Ph Ph Ph Advances 109 N N N N N 20 Rineh and coworkers have established triethylamine mediated N Br Br protocol for synthesis of quinolines 121 via reaction between Cl Cl Cl ethyl chloropyruvate 123 and activated acetylenic compounds N N N 122 in the presence of nucleophilic form of isatin in water as the Br 124a, 70% 124b, 80% 124c, 85% solvent. Nucleophilic form of isatin is produced from the reaction 35 25 of isatin 40 and triethylamine (Scheme 44). RSC Scheme 45 . Et 3N catalyzed synthesis of pyrazolo[4,3 c]quinolines 124 from isatins 40 ; some representative examples are shown.

111 40 Kato et al developed a domino protocol for synthesis of pyrazolo[1,5a]quinolines 127 starting from 2 fluorobenzaldehydes 128 and substituted 3,5dimethyl1H pyrazoles 129 . In this cascade reaction, the inactivated methyl group of the pyrazoles 129 participates in the Knoevenagel 45 cyclization upon arylating at the nitrogen of the pyrazoles

14 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 15 of 35 RSC Advances

through the SNAr substitution (Scheme 46). F O N R1 3 equiv. Cs2CO3, N R1 H o R CHO CH R + R DMF, 120 C 3 2.5 equiv. K2CO3 2 N o N 24 examples R + HN 120 C, DMF R H X R = H, Br, 4-Me R = Me, OMe, CF , 29-98% F N 22 examples N X 2 3 R1 = H, Me F, Br, CN R = F, Cl, Br, CN, 12-71% R N 133 128 132 2 Me, OMe, CF3 X = F, Cl N 128 129 127 R S Ar reaction Knoevenagel F N N CHO cyclization MeO base F F3C base I N CO2Et N CO Et R 2 N CO2Et N CO2Et 1 N N N N N N N S N N 127a, 12% 127b, 63% 127c, 64% 127d, 71% N N N N N MeO Scheme 46 . Base catalyzed synthesis of pyrazolo[1,5 OMe CF3 5 a]quinolines 127 ; some representative examples are shown. 132a, 29% 132b, 69% 132c, 80% 132d, 88% 132e, 98% 25

Scheme 48 . CS CO catalyzed synthesis of benzimidazo[1,2 Kato et al 112 reported another similar protocol for synthesis of 2 3 a]quinolines 132 ; some representative examples are shown. pyrazolo[1,5a]quinolines 130 from 2fluoro aryl aldehydes 128 and pyrazole3carboxylic acid ester 131 using cesium carbonate 10 base. This cascade reaction involves a sequential intermolecular 114 aromatic nucleophilic substitution (SNAr) and intramolecular Kapoor and coworkers have reported synthesis of Knoevenagel condensation (Scheme 47). 30 polyhydroquinolines 134-135 via a fourcomponent onepot reaction of aldehydes 5, dimedone 28e , active methylene CHO compounds 38 and ammonium acetate 136 under solventfree

HN 3 equiv. Cs2CO3 Manuscript R R + N DMF,120 oC, 16 h conditions at room temperature via grinding. The products of this F CO2Et CO Et 6 examples N 2 protocol were obtained simply by recrystallization from ethanol 31-78% N 128 131 130 35 (Scheme 49).

O O CHO O O R O R + R1 SNAr reaction Knoevenagel O R1 N O CO2Et Cyclization + 38 N R CHO + NH4OAc O Grinding, rt, solvent-free N I 12-45 min H 28e 5 136 F C 18 examples 134 3 56-95% yield + NC EWG N N CO2Et N CO2Et O R MeO N CO2Et N CO2Et 32c: EWG = CN N N EWG N N 137: EWG = COOR1 Accepted 130a, 31% 130b, 45% 130c, 55% 130d, 78% Grinding, rt, solvent-free 15-25 min N NH2 14 examples, 65-88% yield H 135 Cl 15 Scheme 47 . Cs CO catalyzed cascade synthesis of pyrazolo[1,5 2 3 Br a]quinolines 130 ; some representative examples are shown. O O O O O O O OEt CN OMe OEt N H N The reaction of 2methyl benzimidazole 133 with 2 N NH2 N NH2 H H H 134a, 56% fluorobenzaldehydes 128 in presence of cesium carbonate in 134b, 95% 134a, 65% 134b, 88% 20 DMF produces benzimidazo[1,2a]quinolines 132 via a cascade reactions involving sequential aromatic nucleophilic substitution and intramolecular Knoevenagel condensation reactions (Scheme Scheme 49 . Catalyst and solvent free synthesis of 48). 113 polyhydroquinolines 134-135 using a one pot four component Advances 40 reaction; some representative examples are shown.

Zhu and coworkers 115 have developed a transitionmetalfree

method for the synthesis of C6 phenanthridine derivatives 138 by RSC arylative cyclization of 2isocyanobiphenyls 139 with arylamines 45 1 in presence of tertbutyl nitrite (tBuONO) and using benzoyl peroxide as a promoter and sodium acetate as a base (Scheme 45). Initially, the anilines 1 reacts with tBuONO to produce aryldiazonium ion which then gets decomposed (releasing N 2 and tBuO•) in presence of benzoyl peroxide to produce aryl radical. 50 The resulting aryl radical gets added to the terminal divalent carbon of 2isocyanobiphenyl 139 , to produce the Nbiphenyl2 yl imidoyl radical intermediate I. Next, the intramolecular hemolytic aromatic substitution of the imidoyl radical on the pending phenyl ring, forms the cyclohexadienyl radical

This journal is © The Royal Society of Chemistry [year] Journal Name , [year], [vol] , 00–00 | 15 RSC Advances Page 16 of 35

intermediate III . Finally, deprotonation of the intermediate III Boc Boc R3 R produces 138 , as depicted in Scheme 50. R1 3 0.3 equiv. DBU, MeCN, r.t. R N 12 examples, 1 R2 Benzoyl peroxide, DMEDA, R2 65-92% N R2 1.1 equiv. NaOAC R2 R1 + 143 + Ar-NH2 t-BuONO O R1 144 CN PhCF3, 70 C, 3h 31 examples N Ar 139 1 140 Boc R3 26-99% 138 propargyl-allenyl R1 aza-electrocyclization Ar isomerization + -H N

R R R 2 R2 + 2 2 I O SET SEAr R R H 1 C R1 + 1 Cl N Ar N Ar N Ar I II III N N OMe N N O O O I MeO N N N N N N N CF 143a, 65% 143c, 92% 138a, 26% 138b 63% 3 138c, 70% 138d, 99% 143b, 87% Scheme 50 . Sodium acetate and benzoyl peroxide mediated 25 Scheme 52 . DBU promoted synthesis of polyfunctionalized 5 synthesis of phenanthridine derivatives 138 ; some representative quinolines 143 ; some representative examples are shown. examples are shown. 3.3. Molecular iodine catalyzed protocols BerteinaRaboin and Guillaumet 116 described DBU catalyzed

Iodine has been very extensively used in organic chemistry to Manuscript synthesis of pyrido[2´,1´:2,3]imidazo[4,5b]quinolines 141 from 30 catalyze diverse range of organic transformations including 10 (ethynyl)Himidazo[1,2a]pyridin3amines 142 . The electron multicomponent reactions. 118 Gao et al 119 developed a highly rich secondary amine 142 assists in the hydroarylation of the efficient molecular iodine mediated formal [3+2+1] cycloaddition triple bond after deprotonation by DBU. Next, aromatization reaction for the direct synthesis of substituted 2acyl quinolines leads to formation of pyrido[2´,1´:2,3]imidazo[4,5b]quinoline 145 from methyl ketones 78 , arylamines 1, and styrenes 7. Initial 141 (Scheme 51). 35 reaction of molecular iodine with acetophenone 78 leads to

R1 formation of the αiodo ketone I, which gets converted to R1 phenylglyoxal II by a subsequent Kornblum oxidation. The NH N 2 equiv. DBU, 1,4-dioxane reaction of ptoluidine 1 with the aldehyde group of II then gives N 5 min, 220 oC (MW) N R R2 R the Cacyl imine III , which reacts with HI to give the activated Y 21 examples Y N R2 N 40 65-97% Cacyl imine ion IV . This activated Cacylimine species IV then Accepted R = CHO, 142 2 141 undergoes cycloadition reaction with styrene (Povarovtype pMe-Ph-NC Y = N, C reaction) to give intermediate V in the presence of excess or H R1 R1 regenerated iodine. Intermediate V then undergoes sequential N N oxidation and aromatization reactions to give 145 (Scheme 53). N N H R R Y N R2 R2 Y N R2 II I Ar R2 R 2 equiv. I2 DMSO R + + 1 1 Ar F OMe H N Formal [3+2+1] N N OMe O 2 N N 26 examples Cl Br 78 7 1 145 O N N N 42-90% [O] N Ph N N Ph Ph N I HI 2 R2 141a, 65% 141b, 81% 141c, 97% 15 O R Advances I 2 Ar Scheme 51 . DBUcatalyzed synthesis of Ar N I H O pyrido[2´,1´:2,3]imidazo[4,5b]quinolines 141 ; some VI representative examples are shown. DMSO R1 HI R1 R2 NH2 R2 O R1 Ar Ar O N N 117 Ar -H2O R1 HI Ar RSC 20 Zhou et al. described synthesis of polyfunctionalized O O N I2 H quinolines 143 via the sequence of propargyl−allenyl II III IV V O

isomerization and azaelectrocyclization from but2yn1yl Ph Ph Ph Me MeO phenylimines 144 (Scheme 52). S Ph Ph N N N O O O 145a, 42% 145b, 81% 45 145c, 90% Scheme 53 . Molecular iodinecatalyzed synthesis of 2acyl quinolines 145 from a threecomponent reaction between methyl ketones 78 , arylamines 1 and styrenes 7; some representative examples are shown.

16 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 17 of 35 RSC Advances

Scheme 55 . Synthesis of 2,4disubstituted quinolines 146d and 147a-c. Recently Deshidi et al 120 reported molecular iodine catalyzed tandem reaction between styrenes 7 and anilines 1 producing 2,4 disubstituted quinolines 146 . Styrene 7 first gets oxidized to Lin’s group have developed molecular iodine catalysed synthesis 5 aldehyde I which on condensation with arylamine 1 produces 25 of quinolines 150-151 from aldehydes, amines, and alkynes at imine II. Imine intermediate II then on coupling with iodine 121 forms iminium ion intermediate III which undergoes azaDiels mild reaction conditions . The method was also applicable for Alder cycloaddition reaction with styrene 7 to form IV . construction of benzo[f] quinolines 151a (70% yield) and Intermediate IV on oxidation leads to formation of quinoline 146 ellipticine 151b (68% yield) (Scheme 56). 10 (Scheme 54). O H N NH2 OEt R OEt I2, MeNO2, air, rt 1 + O + Ph 1 example O MeO o MeO 82% yield R I2 / DMSO, 80 C Ph + R R 1 2 3 150 NH 1 2 15 examples N R1 1 7 64-83% 146 N CHO NH2 I , MeNO , air, rt R [O] 2 2 1 [O] R1 + + R3 17 examples R2 32-83% yield R R R3 1 O 1 1 5 3 151 I R R N N R1 N R1 N II H IV N R Ph + [4+ 2] N R1 Ph III R1 I2 benzo[f] quinoline isomeric ellipticine O Cl 151a 151b O

30 Scheme 56 . Molecular iodine catalyzed synthesis of 2,4 Manuscript disubstituted quinolines 150-151 ; some representative examples F CO 3 are shown. N O N N O Cl 146a, 64% 146b, 71% 146c, 83% Wang’s group 122124 have developed a mild and efficient method Scheme 54 . Synthesis of 2,4disubstituted quinolines 146 ; some 35 for the synthesis of pyranoquinoline 152 , thiopyranoquinoline representative examples are shown. 153 , thienoquinoline 154 , chromanoquinolines 155 and naphtho[2,7]naphthyridine 156 derivatives via threecomponent reaction of aromatic aldehyde 5, naphthalene2amines 41b , and 120 heterocycloketones 149 and 161-168 including tetrahydropyran 15 Deshidi et al also reported molecular iodine catalyzed three component reaction between arylamines 1, styrenes 7 and 40 4one 161 , tetrahydrothiopyran4one 162 , dihydrothiophen Accepted 3(2H)one 163 , chroman4one 164 and NBoc 4piperidinone carbonyl compound 5, 78, 148-149 leading to formation of 122 substituted quinolines 146a , 1147a-c (Scheme 55). 165 , using iodine as catalyst (routes AE). On the use of 2 halogenated acetophenones 149 in the place of cyclic ketones, 1,3diarylbenzo[f]quinolines 157 were obtained (route F). 123 45 Further same group explored the utility of this method for Br construction of several other fused quinolines viz. N benzo[f]furo[3,2c]quinoline 158 (route G), benzo[f]pyrano[3,2 147c, 63% O O c]quinoline 159 (route H), and benzo[f]quinolines 160 (route I) Br using dihydrofuran 166 , dihydropyran 167 and nbutylvinyl ether H I O 124 O 149 50 168 as third coupling partners (Scheme 57). I2 / DMSO O 80 oC, 10 h H Advances Ph Br MeO NH 5 Br 148 2 1 I2 / DMSO I2 / DMSO o N o + 80 C, 10 h N 80 C, 10 h Ph OMe O 7 147b, 68% 146d, 53% O I / DMSO 2 Br RSC 80 oC, 10 h 78

Br

N 147a, 57%O 20

This journal is © The Royal Society of Chemistry [year] Journal Name , [year], [vol] , 00–00 | 17 RSC Advances Page 18 of 35

O O ArCHO + X O X 5 ( )n NH I2 ( )n Air N Ar 2 H + ( ) THF N Ar N Ar 159 n N Ar H X IV H 158 12 examples N Ar 41b 152-156 160 X = O, S, N 15 examples 78-89% yield n = 5, 6 -H2O I2 I 78-93% yield 2 X 9 examples X O-nBu N CH Ar I2 HO O ( )n ( ) H 82-92% yield O n Ar 166 168 O 1 O G O OH 167 I N O O I Ar N Ar Ar1 CH2X H H 149 II III Ar-CHO N Ar ( )n N Ar + 161 X 5 NH 152 157 F 2 A 1 example, 86% 26 examples Boc 78-90% yield N S O ArCHO O 41b + + 5 mol% I in THF S 5 OBu O 2 162 NH 165 2 168 Air Boc E B N I2 O N Ar N Ar O D S 147 164 N Ar 41a VIII C 163 153 14 examples -BuOH N Ar I2 78-90% yield I2 156 Bu O N Ar O I2 Bu 6 examples S O 79-89% yield

N Ar N Ar V 154 N Ar N Ar 155 OBu H H 4 examples 9 examples 168 VI VII 76-86% yield 68-76% yield Scheme 57 . Molecular iodine catalyzed synthesis of pyranoquinoline 152 , thiopyranoquinoline 153 , thienoquinoline 154 , chromanoquinolines 155 and naphtho[2,7]naphthyridine 156 derivatives. Wang’s group 125 further investigated this reaction, wherein a form I of tetrahydropyran4one 161 to produce cyclized threecomponent reaction of aromatic aldehyde 5, naphthalene2 20 intermediate IV , which on dehydration produces V. Finally air amine 41b and tetrahydro2,5dimethoxyfuran 170 in methanol oxidation of V produces naphthoquinoline 174 (Scheme 60). catalyzed by iodine, produced 3aryl2(3arylbenzo[f]quinolin2

5 yl)benzo[f]quinoline derivatives 169 via ring opening of furan Manuscript (Scheme 58). O Ar N O 166 + OCH H3CO O 3 NH2 A + Ar-CHO 170 9 examples + 5 mol% I2 in MeOH N Ar 78-87% yield N Ar 41b 5 H 16 examples 169 171 64-82% yield I2 1 -CH3OH 2 Air

I2 Ar OCH O 3 H CO OCH N O 3 O 3 Ar-CHO + O I 170 N 5 167 Accepted I2 Ar Ar O NH2 B II H C 6 examples N Ar 3 H VI 78-84% yield 172 27

+ 5 mol% I2 in THF I2 I2 O O-nBu OCH3 O OCH 3 Air OCH3 168 I , -H O N 2 2 C N N Ar 10 examples H Ar Ar III V 87-92% yield N Ar IV 173 F O2N N N O Advances O N N O 161 F NO2 N Ar 169a, 64% 169b, 78% D 174 H 12 examples Scheme 58 . Molecular iodine catalyzed synthesis of bis 82-93% yield RSC benzoquinolines 169 ; some representative examples are shown. Scheme 59 . Molecular iodine catalyzed synthesis of 25 naphthoquinolines 171-174 from anthracenyl amines. 10 These authors 124, 126 also investigated the utility of this method for preparation of naphtho[2,3f]furo[3,2c]quinolines 171 (route A),124 naphtho[2,3f]pyrano[3,2c]quinolines 172 (route B) 124 and naphtho[2,3f]quinolines 173 (route C) 124 and naphtho[2,3 15 f]pyrano[3,4c]quinolines 174 (route D) (Scheme 59) from anthracen2amine 27 .126 The mechanism involves the formation of imine II which undergoes covalent bond formation with iodine to produce intermediate III . This intermediate reacts with enol

18 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 19 of 35 RSC Advances

NH2 Ph Ar Ar I2 (10 mol%) N Ar O + N NH O O O H2O, SDS, NH o + + 2 8 70-80 C,2 h O O I2 O O O O + + Ph ArCHO A: 25-72% yield 178 179 180 O THF Ar-CHO + 12 examples 55% 20% 10% N Ar 5 27 5 161 174 7 Hydrogen -H O O OH I2, H2O, SDS 2 Ar transfer O Ph Ar H I2 N Air Ph N Ar O 7 NH + O O Povarov reaction O O 161 I Ar N O O Ph II I OH II III OMe Cl I2 I Ph Ph Ar O N Ph N -H2O I OH N N N O O I O O 2 N O O O O O N O Ph Ph Ar 178a, 53% 178b, 54% 179a, 20% 179b, 40% Ar III IV V Scheme 60 . Reaction mechanism for molecular iodine catalyzed Scheme 62 . Molecular iodine catalyzed synthesis of synthesis of synthesis of naphthoquinolines 174 . pyrano[3.2f]quinolin3ones 178 and pyrano[2.3g]quinolin2 30 ones 179 ; some representative examples are shown.

5 Molecular iodine catalyzed threecomponent imino Diels– Alder reaction of aromatic aldehyde 5, anthracene2amine 27 or Wu and coworkers 130 reported a mild and efficient route for the 1Hindazol5amine 177 and cyclopentanone 85 produced synthesis of quinolines 181 and polycyclic quinolines 182-183 cyclopenta[c]naphtho[2,3f]quinoline 175 and cyclopenta[c] via Friedlander annulation utilizing molecular iodine (1 mol%). 127

pyrazolo[4,3f ]quinoline 176 (Scheme 61). 35 Treatment of 2aminoaryl ketone 46 with αmethylene ketones 38 Manuscript in ethanol in presence of molecular iodine produced quinolines H2N H2N N 181 . Cyclic ketones such as cyclopentanone 85 and O N N H 177 HN cyclohexadione 28e also underwent smooth condensation with 2 27 ArCHO + aminoaryl ketones to afford the respective tricyclic quinolines 0.05 mmol, I , THF 0.1 mmol, I2, THF 2 N Ar N Ar 12 examples 12 examples 40 182-183 (Scheme 63). The synthesis of 181 from 2aminoaryl 175 79-90% 5 85 82-92% 176 ketone 46 with αmethylene ketones 38 has also been reported 131 N N using (bromodimethyl)sulfonium bromide or cyanuric HN HN chloride 132 as a catalyst. N N N O O N Ph OMe Cl R = OEt, Me 175a 175b Br 176a 176b 1 Cl R1 COR 10 Br 38 Accepted Scheme 61 . Molecular iodine catalyzed synthesis of R 1 mol% I2 N cyclopenta[c]naphtho[2,3f]quinoline 175 and cyclopenta[c] rt, air 181 pyrazolo[4,3f ]quinolines 176 . 8 examples 53-98% yield O O Ph O Ph 15 Anionic surfactant sodium dodecyl sulfate has also been 128 employed in heterocycle synthesis. Recently Ganguly and O 28e R 129 R 1 mol% I N Chandra have employed the use of molecular iodine and NH 2 sodium dodecyl sulfate for the construction of quinoline skeleton 2 EtOH 182 46 O 2 examples using a threecomponent reaction. A threecomponent coupling of 83-88% yield 20 6aminocoumarin 8, aromatic aldehyde 5 and an excess of styrene

Ph Advances 7 in water in presence of molecular iodine and sodium dodecyl 85 sulfate produced pyrano[3.2f]quinolin3ones 178 and R pyrano[2.3g]quinolin2ones 179 . The reaction mechanism 1 mol% I2 N EtOH involves a cascade of two key transformations viz. Povarov 183 25 reaction and hydrogen transfer (Scheme 62). 2 examples 71-73% yield

Ph RSC Ph O COOEt COCH3

N N N 181a, 96% 181b, 53% 182a, 88%

45 Scheme 63 . Molecular iodinecatalyzed synthesis of 2,3,4 trisubstituted quinolines 181-183 ; some representative examples are shown.

This journal is © The Royal Society of Chemistry [year] Journal Name , [year], [vol] , 00–00 | 19 RSC Advances Page 20 of 35

Zeng and Cai 133 reported a domino protocol for synthesis of The oxidative cyclization of phenylN(oalkynylphenyl)imines benzo[f]quinolinyl acetamides 184 and benzo[h]quinolinyl 190 in presence of molecular iodine produced furanoquinolines acetamides 185 from diketene 186 , benzyl amines 187 , aromatic 189 (Scheme 66). 135 The iodide cation on coupling with imine aldehydes 5 and naphthalene amines 41b using molecular iodine 190 generated iminium ion I which further undergoes 5 as a catalyst (Scheme 64). 30 intramolecular cyclization to produce quinoline II , which in

O elimination of HI produces 189 .

O Ph N Nu 20 mol% I H + NH2 + 2 O (CH )n Ph NH2 MeCN, rt, reflux 2 Nu 41b I , CH CN 186 187 2 3 (CH )n 9 examples R2 N K CO 2 + R2 CHO 50-72% 2 3 R1 in-situ 184 6 examples 5 N O O 46-80% N R O n = 1, 2 R1 190 R 189 N H Ph N H I+ O 20 mol% I2 -HI NH2 Nu +Ph + MeCN, rt, reflux O R2 N 41b NH 2 examples 2 36-45% (CH )n 186 187 2 Nu + R2 CHO 185 (CH2)n 5 O R O O 1 R1 H N R N N N N H R H H I I I II

N N N O O O MeO O2N Cl 184a, 50% 184b, 72% 185a, 45% N N N Manuscript Me Scheme 64 . Molecular iodine catalyzed synthesis of 189a, 59% 189b, 61% 189c, 80% benzo[f]quinolinyl and benzo[h]quinolinyl acetamides 184-185 ; 10 some representative examples are shown. Scheme 66 . I 2catalyzed synthesis of furanoquinolines 189 ; some representative examples are shown.

35 Fotie et al 134 reported synthesis of a series of unusual 2,3,4,5 136 tetrahydro4,4tetramethylene1H cyclopenta[c] quinolines 188 Batra’s group reported molecular iodine catalyzed synthesis of through the SkraupDoebner−Von Miller quinoline synthesis. 2substituted quinolines 191 from substituted primary 15 The reaction mechanism involves three basic sequences: (a) the allylamines 192 . Iodine initially activates the carbonyl group, formation of a Schiff base I through a reaction between the which is then followed by electrophilic cyclization to produce Accepted ketone 85 and the aniline 1 in the first step, followed by (b) a 40 dihydroquinoline II . The intermediate II on the subsequent cycloalkenylation at the orthoposition to the amine functional elmination of two protons in the form of 2 HI molcules produces group of the aniline, and (c) an annulations in the final step to intermeidate V, which finally oxidizes to the quinoline 191 20 close the quinoline ring, leading to a dihydroquinoline derivative (Scheme 67). 188 as described in Scheme 65. CO Me CO2Me 2 3 equiv. I2, K2CO3, R R (CH2)n CHCl , 30 min 3 N O R NH2 20 examples, R 192 28-84% 191 I2 (5 mol%) + N (CH2)n 160 oC, 72h, Neat H I NH2 (CH2)n 2 4 examples O [O] O 1 46-59% 85 (CH )n 188 2 OMe OMe Imine formation R R Aza-Diels-Alder reaction Advances O Aromatization H N N 2 H I V R (CH2)n R (CH2)n I (CH2)n 85 O H -HI (CH )n I O O N 2 I N OMe R OMe OMe I R R II RSC N -HI N (CH2)n H H N 2 H H H H Cl EtO II III IV

N N CO2Me CO Me H N CO2Me 2 H H

N O2N N N 188a, 46% 188b, 58% 188c, 53% 191a, 28% 191b, 79% 191c, 84%

Scheme 65 . I2catalyzed synthesis of cyclopenta[c]quinolines 45 Scheme 67 . Iodinecatalyzed synthesis of 2substituted 188 ; some representative examples are shown. quinolones 191 from allylamines 192 ; some representative examples are shown. 25

20 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 21 of 35 RSC Advances

O R4 R R R1 1 + 4 R 2 equiv. I 2Tosylaminophenylprop1yn3ols 194 in the presence of N 3 2 R3 2 equiv Cs CO R2 HN 2 3 molecular iodine undergoes 6endodig iodocyclization leading to MeCN, 90oC, N N 137 Ts 23 examples R2 formation of substituted 3iodoquinolines 193 (Scheme 68). 196 197 195 32-99% 5 The mechanism involves antiattack of the iodide cation and the nitrogen of the tosylated amino group on the alkyne moiety of I -TsCl Cl I 178 to produce an intermediate II , which further undergoes a R4 R TsHN 1 R proton removal by the iodide producing intermediate III . The R1 3 N R3 + R4 N intermediate III then loses hydroxyl ion to give cation IV , which R N 2 Ts O R IV 10 finally on elimination of tosyl group leads to formation of I 197 2 quinoline 193 . -H O O 2 R R2 4 R4 O R2 OH R Ts I I 3 B 2 equiv. I2 R N R1 1 N IH R1 R3 o R NHTs MeOH, 60 C N R 1 Ts N 17 examples, 3 H 193 N R 194 40-96% R2 3 R2 II I+ -Ts+ III OMe R R OH 2 2 I I

R1 R1 R3 NH N R3 Ts Ts I V N N N N N N 195a, 32% 195b, 81% 195c, 99% R2 OH R2 R2 OH 30 Scheme 69 . I catalyzed synthesis of indolo(2,3b)quinolines I + I 2 Manuscript -H I - R1 -HO R1 R1 195 ; some representative examples are shown. N R3 Ts H N R3 N R3 Ts Ts IIIIIIV Isocyanides are one of the promising precursors for the preparation of Nheterocycles such as pyrroles, indoles, and 139141 142 I I I 35 quinolines. Tu and coworkers have established a iodine promoted domino reaction of 2aminochromene3carbonitriles N Cl N N 199 with various isocyanates 200 for synthesis of 193a, 40% 193b, 88% 193c, 96% OMe polyfunctionalized Nsubstituted 2aminoquinoline3 carbonitriles 198 with high regioselectivity under microwave Scheme 68 . Molecular iodine catalyzed synthesis of 2aryl3 40 heating. The reaction of phenyl isocyanate 200 with 2 Accepted iodoquinolines 193 ; some representative examples are shown. aminochromene3carbonitrile 199 underwent [2+2] cyclization to produce βlactam intermediate I, which then gets hydrolyzed 15 forming a ringopened intermediate II . Next, the intermediate II Activation of C2 and C3 of indoles 196 by molecular iodine and releases CO 2 to give intermediate III, which undergoes base followed by in situ reaction with 1(2 45 intramolecular cyclization to afford the 1,4dihydropyridine IV . tosylaminophenyl)ketones 197 or 2tosylaminobenzaldehyde Finally, the aromarization of IV led to formation of 198 (Scheme afforded highly substituted indolo(2,3b)quinolines 195 in 70). 138 20 moderate to excellent yields. This is a domino onepot protocol involving cascade of three reactions – amination, alkylation and aromatization. The mechanism of this reaction involves electrophilic addition of iodonium to the 3position of indole 196

to give cation I, which undergoes 2amination with 197 to afford Advances 25 II . The intermediate II eliminates a molecule of HI in the presence of base to give III . Alkylation and subsequent detosylation of III in the prescence of HCl gives 195 (Scheme 69). RSC

This journal is © The Royal Society of Chemistry [year] Journal Name , [year], [vol] , 00–00 | 21 RSC Advances Page 22 of 35

O Ar O Ar intermediate. The C2 benzyl moiety gets cleaved through radical CN 1 equiv. I2 CN mechanism by release of benzaldehyde, producing 3substituted DMF, MW + R N C O 30 quinoline 204 (Scheme 72). 19 examples N NH O NH2 62-85% R 200 198 Ph C-C bond 199 R C-C/ C-N bond Ph formation cleavage R R I NH2 [2+2] 2 1 [Bmim]BF4, N N 150 °C, 4 h O Ar + R CHO 203 Ph 204 9 examples (18-80%) O Ar I CN 205 20 examples (60-80%) CN 2 O Imine formation PhCHO H O N NH N 2 H O Ph Ph NH R R R Dimerization 2 IV R H I N Cyclization R N OOH Ph N -I2 H -I2 Ph Ar I II III Ph O O Ar CN CN O MeO I2 O H H2N NH Ph O -CO2 O O NH R MeO N I Me N Ph O NH2 R 2 N II III OMe OMe Cl 203a, 18% 203b, 80% 204a, 80% Scheme 72 . Synthesis of 2,3disubstituted 203 and 3substituted O O O quinolines 204 in ionic liquid; some representative examples are CN CN CN shown.

N NH N NH N NH 35

Another ionic liquid mediated synthesis of quinolines is reported, Manuscript involving a fourcomponent, onepot reaction of aromatic 198a, 62% 198b, 74% 198c, 85% aldehyde 5, cyclohexanone 85 , malononitrile 33c , and amines 1 Scheme 70 . I 2catalyzed synthesis of aminoquinoline3 or 205 in basic ionic liquid [Bmim]OH to produce 145 carbonitriles 198 ; some representative examples are shown. 40 tetrahydroquinoline3carbonitriles 206 (Scheme 73). O Ar CN [Bmim]OH CN 143 Ar-CHO + R-NH 5 Mitamura and Ogawa found that upon photoirradiation of + + 2 CN 48 examples Oalkynylaryl isocyanides 202 in the presence of molecular 67-87% yield N NHR 5 33c 85 1 or 205 iodine, it undergoes intramolecular cyclization to afford the 206 corresponding 2,4diiodoquinolines 201 in good yields. This -H2O Ar Ar reaction does not took place in the dark, indicating that the Accepted NC 10 reaction requires photoirradiation (Scheme 71). NC

I N O R R2 N NH2 O H R2 I 1 equiv. I2, hv V R1 R1 [Bmim]OH CHCl3, 4 h CN N I 11 examples Ar 10-86% Ar Ar 202 201 N N Cl NC C [Bmim]OH C I I I TMS F3C H N HN O 2 O H2N O NH II N I N I N I R-NH2 III R IV OMe OMe 201a, 10% 201b, 71% 201c, 85% MeO

Scheme 71 . Synthesis of 2,4diiodoquinolines 201 via the Advances MeO CN photochemical cyclization of oalkynylaryl isocyanides 202 with CN CN CN molecular iodine; some representative examples are shown. N NH N NH N NH N NH 15

206a, 67% 206b,83% 3.4. Ionic liquid mediated quinoline synthesis Cl 206c, 85% 206d, 87% RSC Ionic liquid have been considered as a green reaction media with OMe recyclability and this has been used as catalyst as well as reaction Scheme 73 . Synthesis of tetrahydroquinoline3carbonitriles 206 55 144 media. Our group have developed an expedient and metal in ionic liquid; some representative examples are shown. 20 free synthetic protocol for construction of substituted quinolines 203-204 from anilines 1 and phenylacetaldehydes 205 using imidazolium cationbased ionic liquids as the reaction medium. 45 A twophase microwaveassisted cascade reaction between isatins [Bmim]BF 4 activates the aldehyde electrophile by interaction 40 and βketoamides 208 in [Bmim]BF 4/toluene led to the with the carbonyl oxygen. The ionic liquid [Bmim]BF4 also formation of pyrrolo[3,4c]quinoline1,3diones 207 (Scheme 25 enhances the nucleophilicity of the amine through interaction of 74). 146 The recyclability of the ionic liquid for 6 cycles was tetrafluoroborate with NH bond. The resulting imine intermediate I undergo selfcondensation to generate II as a key

22 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 23 of 35 RSC Advances

shown. The prepared pyrrolo[3,4c]quinoline1,3diones O COOH O R2 0.5 equiv.[Bmim]OH displayed antibacterial activity. O R + R 2 N 1 H2O N R H 1 O R4 40 47 Ultrasonication 210 N 23 examples O [bmim] OH 34-96% R1 O O R1 O 0.1 mL [Bmim]BF4 O O O R4 O O + R N COOH N 3 toluene, MWI H 47 examples N R3 R H O [Bmim]OH 2 R 48-90% R O O 2 2 H 40 208 N OMe 207 N N R1 NO2 R R2 [bmim] R 2 R1 1 III I II O O COOH O N O COOH COOH N N N O OMe O O O NO2 N N N N N N N 210a, 34% 210b, 80% 30 210c, 96% 207a, 48% 207b,66% 207c, 88% 207d, 90% Scheme 76 . Synthesis of quinoline4carboxylates 210 in ionic liquid; some representative examples are shown. 5 Scheme 74 . Synthesis of pyrrolo[3,4c]quinoline1,3diones 207 in ionic liquid; some representative examples are shown. A threecomponent reaction of aryl aldehyde 5, (E)3aminobut

35 2enenitrile 212 and 2hydroxynaphthalene1,4dione 35 in ionic The condensation reaction involving an Oaminoaryl ketones 46 liquid produced polysubstituted benzo[h]quinolines 211 (Scheme 77). Another threecomponent reaction involving concensation of with αmethylene ketones 47 in ionic liquid [Hbim][BF 4] as a 10 solvent with methanol as cosolvent at room temperature under aryl aldehyde 5, (E)3aminobut2enenitrile 212 and dimedone ultrasound irradiation afforded the corresponding quinolines 28e in ionic liquid produced 1,4,5,6,7,8hexahydro2,7,7 40 trimethyl5oxo4arylquinoline3carbonitriles 213 (Scheme Manuscript derivatives 209 in excellent yields, via tandem 149 addition/annulation reactions. 147 The reaction was also applicable 78). The reaction mechanism involves subsequent to cyclic ketones producing tricyclic compounds (Scheme 75). Knoevenagel condensation, Michael addition, intramolecular cyclization, and dehydration reaction. O R1 R R R O 2 4 2 2 mL HbimBF R1 4 R + R4 O R3 MeOH, Ultrasound N R O NH 3 HO CN 2 rt, 10-35 min 209 CHO [Bmim]Br, 50 oC NC O 46 47 14 examples + R + 11 examples 64-92% H2N 82-90% N O H 5 35 212 211

Cl

Cl Accepted Cl CO2Me Cl O R R N O N N N NC O Br 209a, 64% 209d, 92% 15 209b, 70% 209c, 83% OH O N I H OH IV Scheme 75 . Synthesis of substituted quinolines 209 in ionic + 212 liquid under ultrasound irradiation; some representative R R examples are shown. O O NC O NC O 20 O Kowsari and Mallakmohammadi 148 described synthesis of NH O NH2 II quinoline4carboxylates 210 by condensation of isatins 40 α III Advances Cl methylene ketones 47 in presence of 0.5 equiv [Bmim]OH ionic CN MeO OMe liquid and ultrasonication (Scheme 76). The mechanism of this O 25 reaction involves the reaction of isatin 40 with a [Bmim]OH that Cl O O NC O hydrolyses the amide bond to produce the ketoacid I. The NC O NC O enamine II form on cyclization produces quinoline III which N N N H RSC finally on dehydration result in the formation of desired quinoline H H product 210 . 211a, 82% 211b, 86% 211c, 90%

45 Scheme 77 . Synthesis of polysubstituted benzo[h]quinolines 211 in ionic liquid; some representative examples are shown.

This journal is © The Royal Society of Chemistry [year] Journal Name , [year], [vol] , 00–00 | 23 RSC Advances Page 24 of 35

154 25 dr and 97% ee. The 2 hydroxystyrene 217 is structurally R O O similar to an dienol species, which participate in a vinylogous CHO CN o [Bmim]Br, 50 C CN Mannich reaction with an aldimine II generated from an aryl R + + 11 examples H2N 86-93% aldehyde 5 or aliphatic aldehyde 205 and aniline 1 under the O N 5 28e 212 213 H catalysis of a chiral phosphoric acid, forming a transient 30 intermediate III , which principally undergoes an intramolecular O Friedel−Crafts reaction (the 1,4addition of aniline to the enone R functionality) to afford enantioenriched multiply substituted O R CN tetrahydroquinolines 216 (Scheme 80). O

I SiPh3 N HO + 212 H IV O O P OH R NH2 10 mol% 2 O OH R1 OH R R + R R R1 2 3 SiPh3 O O o o 5 A MS, toluene, 25 C R1 217 1 CN CN + R CHO 27 examples N R 72-97% H 5 or 205 216 O HN O H2N RO OR Intramolecular III P II F-C reaction O OH RO OR CN P RO Cl OMe O O OR R P Cl MeO H 1 O O H N H R Vinylogous H 1 O R2 Mannich reaction O R2 N O O O R II CN CN R CN R3 R3 I Dienol-type substrate III N N N H H H 213a, 86% 213b, 88% 213c, 93% Manuscript OH OH OH Scheme 78 . Synthesis of 2,7,7trimethyl5oxo4arylquinoline MeO MeO MeO 3carbonitriles 213 in ionic liquid; some representative examples N Ph N N are shown. H H H Br NO 216a, 72% 216b, 90% 216c, 97% 2 5 A series of 7aryl11,12dihydrobenzo[h]pyrimido[4,5 b]quinoline8,10(7H,9H)diones 214 were synthesized via three 35 Scheme 80 . Chiral phosphoric acidcatalyzed synthesis of cis component reaction of aryl aldehydes 5, 1naphthylamine 41a disubstituted tetrahydroquinolines 216 ; some representative and barbituric acid 215 in ionic liquid (Scheme 79). 150 examples are shown.

R NH O 2 O A series of 4azapodophyllotoxin derivatives 218 have been Accepted CHO 2 mL [Bmim]BF4 , HN NH o 40 R + + 90 C NH synthesized regioselectively via the threecomponent reaction of O O 12 examples N N O aldehydes 5, aromatic amines 1, and tetronic acid 28d catalyzed 76-92% H H by Lproline. 155 Lproline catalyzes the formation of iminium ion 5 41a 215 214 II in a reversible reaction with tetronic acid 28d . The higher OH NO2 reactivity of the iminium ion II compared with the carbonyl MeO 45 species facilitates the addition of aniline 1, via intermediate III , Cl O O O producing intermediate IV . The intermediate IV on elimination NH NH NH of Lproline produces V. The product 218 was then formed by N N O tautomerization of intermediate V (Scheme 81). N N O H H N N O H H H H

214a, 76% 214b, 89% 214c, 91% Advances 10 Scheme 79 . Synthesis of pyrimido[4,5b]quinoline 8,10(7H,9H)diones 214 ; some representative examples are shown.

3.5. Organocatalysis for quinoline synthesis RSC

15 The use of small chiral organic molecules as catalysts, has proven to be a valuable and attractive tool for synthesis of enantiomerically enriched molecules and thus it finds wide applications in drug discovery. 151 Furthermore, organocatalysis finds tremendous utility in asymmetric CC bond formation 152, 153 20 reactions. The utility of these catalysts in quinoline synthesis has also been well reported. An organocatalytic asymmetric threecomponent Povarov reaction involving 2 hydroxystyrenes produced structurally diverse cisdisubstituted tetrahydroquinolines 216 in high stereoselectivities of up to >99:1

24 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 25 of 35 RSC Advances

R2 O O Ar O O 10 mol% L-Proline HN L-proline (20 mol%) NH EtOH, 80 oC R O R + CHO + R O + 1 R2-CHO + R1 Ar X N O H2O, reflux 24 examples N NH2 N N X O NH H H 10 examples H H 2 89-95% 82-92% 28d 5 1 218 1 5 215: X = O 219 220: X = S OH L-proline HN H X N O O R O COO X N O 2 O R2 H H HN N O O O L-Proline Ar OH Ar-CHO N II O R1 O Ar COOH COO O 5 III N N COOH N I O OOC OOC 28d L-Proline V H + X 1 H II I N N X N N H L-proline 219 L-Proline X N O -H2O -L-proline HN HN L-Proline HN O O O Ar O Ar R2 R O Ar 2 H2N O O VI V IV R HOOC 1 COO + N N H2N N H S R1 O OHC O O III 1 IV MeO NH MeO NH NH N N S Cl OMe N N O H H N N S NO2 H H OMe MeO OMe H H 219a, 82% 219b, 92% 219c, 91% O O O Scheme 82 . LProlinecatalyzed synthesis of arylpyrimido[4,5 O 20 b]quinolinediones 219 ; some representative examples are shown. O O O

O Manuscript N N N H H H 218c, 95% 218a, 89% 218b, 91% KhalafiNezhad et al. 156 also described a Lproline mediated Scheme 81 . LProlinecatalyzed synthesis of dihydrofuro[3,4 synthesis of 2amino4arylquinoline3carbonitriles 221 using a b]quinolin 1(3 H)ones 218 ; some representative examples are similar threecomponent reaction between anilines 1, aldehydes 5 shown. 25 and malanonitrile 33c under aqueous conditions (Scheme 83). Ar 5 CN L-proline (20 mol%) CN R + CHO + R 156 Ar H2O, reflux KhalafiNezhad et al. have described a Lproline mediated NH2 CN 9 examples N NH2 33c 83-92% synthesis of 5arylpyrimido[4,5b]quinolinediones 219 via a 1 5 221 threecomponent reaction between anilines 1, aldehydes 5 and NO Accepted barbituric acids 215 (or 220 ) under aqueous conditions. Lproline 2 NH 10 activates the aldehyde to produce intermediate I. Similarly, L proline assists in enolization of the barbituric acid 215 (or 220 ) to MeO produce II . Coupling of I and II produces adduct III , which CN MeO CN CN further loses a Lproline molecule to generate orthoquinone N NH2 N NH MeO N NH methide IV . Lproline further activates this adduct IV , followed 2 2 221a, 89% 221b, 84% 221c, 83% 15 by coupling of aniline produces VI . Intermediate VI subsequently undergoes an intramolecular reaction to give the desired product Scheme 83 . LProlinecatalyzed synthesis of 2amino4 219 (Scheme 82). arylquinoline3carbonitriles 221 ; some representative examples are shown.

30

Advances A series of 2Hbenzo[g]pyrazolo[3,4b]quinoline5,10(4H,11H) diones 222 were synthesized using three component reaction of 2hydroxy1,4naphthoquinone 35 , aldehydes 5, and aminopyrazoles 223 in the presence of a catalytic amount of L 157

35 proline. Reaction proceeeds via domino Aldol reaction– RSC Michael addition–Ncyclization–tautomerism sequence to give fused quinoline product regioselectively (Scheme 84).

This journal is © The Royal Society of Chemistry [year] Journal Name , [year], [vol] , 00–00 | 25 RSC Advances Page 26 of 35

O O NO2 H OH NH 2 N N L-proline (20 mol%) R2 + L-proline (20 mol%) NH Et3N, DCM, rt + R1-CHO N R + R1COCH2R2 R R2 Ethanol, reflux 15examples 1 N N N R O H 16 examples R 3 65-94% 52-88% yield O R1 2 225 47 224 35 5 223 222 Ph3P (100mol%) -CH3NO2 NO O 2 NO2 O NO2 O 2 N R R2 N R2 OH NH R 1 R -Ph PO COR 1 3 R N COR H 3 N 1 O R1 N R O R R2 I 1 PPh3 IV I III -H2O II -H2O NO2 O O O L-proline (20 mol%) NH O H2N 2 Et N, DCM, rt O N 3 + R ( ) + R ( ) 5examples n N Michael type addition NH n N N R2 N3 80-94% O R1 H 225 85 226 O R1 R2

II 223 III O N 2 O O O H L-proline H O Ph3P N N H N N R N Et N, rt ( ) NH N NH 3 n NH N3 IV O O O O O O OEt NO2 Cl N N N N 222a, 52% 222b, 71% 222c, 88% 224a, 86% 224b, 65% 226a, 87% 226b, 82% Scheme 84 . LProlinecatalyzed synthesis of Manuscript benzo[g]pyrazolo[3,4b]quinoline diones 222 ; some Scheme 85 . LProlinecatalyzed synthesis of 2,3disubstituted representative examples are shown. quinolines 224 , 226 ; some representative examples are shown.

5 A cascade reaction of orthoazidoβnitrostyrenes 225 with 20 3.6. Catalyst-free quinoline synthesis various carbonyl compounds 45 furnished substituted quinolines Apart from the use of above discussed simple nonmetal 158 224 (Scheme 85). The Michael reaction of ketone 47 to β catalysts, several reactions proceeds efficiently in suitable nitroolefins 225 followed by coupling of PPh 3 led to formation of solvents without use of any catalyst. Reaction of 2 10 iminophosphorane intermediate II via Staudinger reaction. This (aminomethyl)aniline 228 with ketones 47 in presence of oxygen 159 iminophosphorane II undergoes the intramolecular ringclosure 25

atmosphere produced quinoline products 207 . Reaction Accepted via the azaWittig reaction at room temperature to produce involved condensation of aniline 211 with ketone 47 to form quinoline III which on elimination of nitromethane moiety imine I which gets oxidized to aldehyde II by oxygen and high produces 224 . The cyclic ketones 85 produced corresponding temperature. This was followed by cyclization and dehydration to 15 tricyclic products 226 via intermediate IV . produce quinolines 227 (Scheme 86).

O NH2 N R1 R + O2 (balloon) R 2 1 9 examples R 52-88% 2 47 228NH2 227

-H2O

N R N R Advances N R1 1 1 O 2 R R R2 2 2 O OH NH2 I II III

Cl RSC N N N

227a, 52% 227b, 88% 227c, 75% 30 Scheme 86 . Catalystfree synthesis of 2substituted quinolines 227 by treatment of 2(aminomethyl)aniline 228 with ketones 47 ; some representative examples are shown.

35 The condensation and cyclization of two molecules of ortho haloacetophenones 230 with primary amines 1 produced halogen

26 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 27 of 35 RSC Advances

160 O Ar substituted 2aryl quinolines 229 . The mechanism involves NH first the formation of ketimine I by dehydration of 230 with amine 1. This was then followed by the intermolecular N 234 nucleophilic attack of 1 by enamine carbon of II followed by O 5 dehydration to give α,βunsaturated imine III . Next the DMF electrocyclic reaction of III leads to formation of the intermediate O Reflux O 28c O IV . Finally the elimination and subsequent SN 2 reaction of IV O Ar produces 229 (Scheme 87). Ar NH2 O O O NH NH 28g 28e Ar-CHO + N EtOH H EtOH X O 235 N X N Reflux 5 Reflux H NH2 o H 45 examples (68-93%) + toluene, 120 C, 48 h 232 R R1 231 7 examples N O 63-75% DMF 230 1 229 Reflux

SN2 28g O R O Ar R1 NH R1 X N X N N Cl R 233 OMe I R Cl V Cl Cl O O O NH NH NH R R1 R1 1 X R N X HN R N N X N X N H X 231a, 90% 232a, 89% 234a, 87% R R R

II III IV Manuscript 20 Scheme 88 . Catalyst free synthesis of pyrrolo[3,2f]quinoline 231-233 and pyrrolo[3,2a]acridines 234 ; some representative Br Cl Br Cl Cl examples are shown. N N N Cl

Cl Br 229a, 63% Cl 229b, 68% 229c, 69% Fayol and Zhu 162 have reported synthesis of polysubstituted 25 furo[2,3c]quinoline 236 , simply by mixing an ortho alkynyl 10 Scheme 87 . Catalystfree synthesis of 2aryl quinolines 229 ; aniline 237 , an aldehyde 5, and ammonium chloride in toluene at some representative examples are shown. room temperature, followed by addition of an isocyanoacetamide 238 under heating condition (Scheme 89). The proposed reaction mechanism involves the formation of A threecomponent reaction of aromatic aldehyde 5, 1Hindol5 Accepted 30 oxazole III as a key intermediate. Next the intramolecular amine 235 , and 1,3dicarbonyl compounds 28c , 28e , 28g cycloaddition reaction of an oxazole III as an azadiene with the 15 produced pyrrolo[3,2f]quinoline 231-233 and pyrrolo[3,2 properly predisposed triple bond produce an furo[2,3 a]acridine 234 derivatives under catalystfree conditions (Scheme c]quinolines 236 . 88). 161 NR R R2 4 5 R2 O NH4Cl O NC Toluene, reflux, rt R + NR R R1 1 4 5 9 examples N R NH2 R6 42-75% 3 237 238 236 + R3-CHO 5 [O] NR R R2 4 5 R2 O Advances R R 1 + H 1 N I N R3 V R3 R R CN R 2 6 2 NR4R6 R R R1 2 6 R1 O RSC NH NH N R O R1 R O 3 3 N R3 N H + N NR4R5 NR4R5 III R5 IV II R5 O O O

N N MeOOC MeOOC N MeOOC

O O O

N N N 236a, 75% 236b, 60% 236c, 43% F

This journal is © The Royal Society of Chemistry [year] Journal Name , [year], [vol] , 00–00 | 27 RSC Advances Page 28 of 35

Scheme 89 . Catalystfree synthesis of furo[2,3c]quinolines 236 ; R1 NH O some representative examples are shown. O O O O MW, 700W R O + + 1 N 10 Min N N O NH2 H 20 examples O R N R3 3 83-95% H The condensation of Ophenylaniline 241 and its homologues 40 28e 246 245 5 with cyclic ketones 85 under hydrothermal conditions led to -H2O R1 O -H2O 163 R1 formation of phenanthridines 239-240 . The mechanism R1 O O R3 N R3 proposed for this transformation involves azatrienetype R 3 H N O HN 2 O electrocyclization, followed by irreversible cycloalkane ring OH HN HN O O fission as crucial steps (Scheme 90). O O NH N 2 O NH2 N O O ( )n O ( )n I II III 79 o 79 H2O, 250-300 C o H2O, 250-300 C Cl NH NH ( )n NH N 4 examples + 6 examples NH Cl N ( )n O O O 33-67% 3 28-84% 240 241 239 O O O N N N O O N O N N H H H 245a, 83% 245b, 87% 245c, 95% N ( )n N ( ) H n II I Scheme 92 . Catalyst free MW assisted synthesis of oxazolo[5,4 b]quinolinefused spirooxindoles 245 ; some representative 35 examples are shown. N C H N N 3 7 N C5H11 10 240a, 50% 240b, 67% 239a, 28% 239b, 84% Scheme 90 . Catalyst free synthesis of phenanthridines 239-240 ; The fourcomponent domino reaction of 2hydroxy1,4 some representative examples are shown. naphthaquinone 35 , aromatic aldehydes 5, methyl/ethyl Manuscript acetoacetate 38 and ammonium acetate in ethanol under

40 microwave irradiation at 100 ºC afforded These authors 163 further extended this protocol to the reaction of tetrahydrobenzo[g]quinoline5,10diones 247 regioselectively in 15 2isopropenylanilines HCl 244 to obtain quinoline derivatives good yields. The mechanism involved first the Mannich reaction 242-243 . The reaction pathway has been depicted in Scheme 91. between 2hydroxy1,4naphthaquinone 35 with aromatic aldehydes 5 to produce intermediate I which further on release of ( ) 45 ammonia produces II . The condensation of II with amine + n H3O + O ( )n + O intermediate III leads to formation of a cyclized intermediate IV , NH + 3 Cl NH2 which finally on dehydration generated product 247 (Scheme 244 85 I 93). 165

+

C H H O Ar O Accepted 2 5 ( ) O ( )n O n R O O + Ar-CHO EtOH, reflux, 4 h OR or N OH 5 + N MW, 120 W, 100 oC, 10 min H N ( )n ( )n O O 242 O 16 examples III H 35 38 247 + NH4OAc 71-80% yield (thermal) 82-89% yield (MW) N ( )n Mannich 136 - H2O reaction NH3 ( )n II + O Ar O Ar O H NH3 O Ar O R R NH2 O N C4H9 N ( )n O Cyclization H OH O N 243 IV H2N H O O O OH I II III Cl IV Cl Michael addition Scheme 91 . Catalystfree synthesis of quinolines 242-243 . Br S O O Cl O O Advances O O O O OEt OMe 164 OMe OMe 20 Yuvaraj et al described a microwaveassisted, chemoselective N N N H H N synthesis of oxazolo[5,4b]quinoline fused spirooxindoles 245 O O H H O O via threecomponent tandem Knoevenagel/Michael addition 247a, 71% 247b, 80% 247c, 82% 247c, 89% reaction of 5amino3methylisoxazole 246 , βdiketones 28e and 50 Scheme 93 . Catalyst free synthesis of

isatins 40 in good to excellent yields under catalyst and solvent RSC tetrahydrobenzo[g]quinolines 247 ; some representative examples 25 free conditions. A possible mechanism for the established 3CC are shown. reaction indicated that the βdiketone 28e initially reacts with isatin 40 to give the Knoevenagel condensation product I which Alizadeh and Rezvanian 166 reported onepot, catalystfree, four undergoes a Michaeltype addition with 5amino3 component synthesis of octahydroimidazo[1,2a]quinolin6ones methylisoxazole 246 followed by the cyclocondensation of the 55 248 from aromatic aldehydes 5, cyclic 1,3diones 28e , diamines 30 intermediate adduct II to give corresponding quinolines 245 250 , and nitro ketene dithioacetal 249 under catalyst and solvent (Scheme 92). free conditions. Mechanism involves first Knoevenagel condensation between the aldehyde 5 and the cyclic 1,3dione 28e , resulting in the adduct I. Then the reaction between 60 intermediate I and the ketene aminal II (which is derived from the addition of diamine 250 to nitro ketene dithioacetal 249 ) gives

28 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 29 of 35 RSC Advances

the Michael adduct III . The Michael adduct III undergoes a benzaldehyde 5 under reflux condition to produce 7,8 cyclocondensation reaction through amino and carbonyl to afford 20 dihydroquinolin5(1H,4H,6H)ones 254 (Scheme 96). compound 248 (Scheme 94). O O

Me S NO2 O Ar H H NO2 R + R + Me S H Ar O 110 oC, 2 h O DMSO O 249 5 9 examples R' N 5 28e Sealed tube O O R' NH O H2N R'' 71-91% yield 120-130 oC + 248 R'' 11 examples 72-92% N R' R' H2N + NH4OAc H 28e 250 Ring closure 255 136 254 OH OMe Cl R'' R'' R'' O Ar Michael O Ar N O Ar HN H N reaction HO + N N O R' NH R' H R' H O O NO NO O O 2 O 2 R' NO2 R' R' I II III IV Cl NO2 N N N H H H

O O 254a, 72% 254b, 86% 254c, 92% NO O 2 NO NO2 2 Scheme 96 . Catalyst free synthesis of substituted 7,8 N NH N N NH NH dihydroquinolin5(1H,4H,6H)ones 254 ; some representative examples are shown. 248a, 71% 248b, 73% 248c, 91%

5 25 Scheme 94 . Catalystfree synthesis of octahydroimidazo[1,2 3.7. Miscellaneous protocols

a]quinolin6ones 248 ; some representative examples are shown. Manuscript GhorbaniVaghei and Malaekehpoor 169 reported the use of N bromosuccinimide as a catalyst for synthesis of polycyclic indolo[2,3b]quinolines 256 from aryl amines 1 with indole3 Chidurala et al 167 reported onepot multicomponent atom 30 carbaldehyde 257 at room temperature. Initially, N 10 efficient, catalystfree reaction between resorcinol 252 , aromatic bromosuccinimide catalyzed the formation of an imine I and then aldehyde 5, acetoacetanilide 253 and ammonium acetate 136 to a 3bromoindolinium cation as intermediate II . After produce substituted 1,4dihydroquinolines 251 (Scheme 95). nucleophilic attack by a second mole of aniline, intramolecular OH OH Ar O cyclization and oxidation lead to indoloquinolines 256 . Reaction + Ar-CHO O EtOH 5 35 is shown in scheme 97. + Reflux, 4-6 h or N + NH4OAC N H H MW, 8-10 min CHO OH 136 10 examples N O H 88-96% NBS, rt R 252 253 251 R + Accepted 9 examples N N NH N H 2 95-50% Knoveenagel H 1 257 256 condensation HN -H O Ar [O] 2 N O HN O HN R Ar + Ar N H N N I H H H2N O OH OH IV VII I NBS Michael Ar -H2O addition Br N Br HN R HN N N N HN H HN O R H O Intramolecular HO II VI O H2N H condensation Ar H Advances H O Ar Ar Ar H OH III NH NH Br N Br H Br II N OMe R R R N N N N N N O H H H H H OH O OH O V OH O III IV H

N N O RSC H H N H N N H H N N N N N N N O H H H H 251a, 88% 251b, 93% 251c, 96% 256a, 90% 256b, 56% 256c, 60% Scheme 95 . Catalystfree synthesis of substituted 1,4 Scheme 97 . NBS catalyzed synthesis of polycyclic indolo[2,3 15 dihydroquinolines 251 ; some representative examples are shown b]quinolines 256 ; some representative examples are shown.

168 170 Findik et al reported onepot fourcomponent condensation of 40 Plaskon et al . described synthesis of 7Hchromeno[3,2 dimedon 28e , αionone 255 , ammonium acetate 136 and c]quinolin7ones 258 using TMSClmediated recyclization of 3 formylchromone 259 with various anilines 1 (Scheme 98).

This journal is © The Royal Society of Chemistry [year] Journal Name , [year], [vol] , 00–00 | 29 RSC Advances Page 30 of 35

O O O R2 O O PPh3(10 mol%) N O 1.5 equiv. TMSCl, DMF R MeCN, rt R3 + R 2 + R O R1 R 1 O NH 15 examples 3 HCl work up 2 39-67% NHTs N 259 1 258 21 examples 260 R 261 262 30-99% TMSCl PPh3 SiMe3 HCl O O O O O O NH NH R2 OH R R3 O O 3 R R1 R2 R1 I R V N O N 2TMSCl Ts V Ts I -2HCl R3 262 Me Si SiMe O O 3 O O 3 SiMe3 PPh SiMe N NH 3 N 3 H2O O O O -(TMS)2O R2 O O -(TMS)2O O R O R R 2 O R R3 R IV 3 R II III R1 1 + Ph3P R3 O N N O O Ts Ts N II III IV N N O O O O O O O S S

CF3 S O N N N N N 258a, 39% 258b, 57% SMe 258c, 67% 260a, 30% 260b, 86% 260c, 99% 20 Scheme 99 . Phosphinecatalyzed synthesis of dihydroquinolines Scheme 98 . TMSClmediated synthesis of quinolines 258 from

260 ; some representative examples are shown. Manuscript 3formyl chromones 259 ; some representative examples are 5 shown. An efficient and facile onestep synthesis of pyrrolo[3,4 25 c]quinolinedione derivatives 263 has been developed using Khong and Kwon 171 reported phosphinecatalyzed efficient one ethylenediamine diacetate (EDDA)catalyzed cascade reactions pot procedure for preparation of 3substituted and 3,4 of isatins 40 and βketoamides 208 .172 The carbonyl group of disubstituted quinolines 260 from stable starting materials isatin 40 gets protonated by EDDA, which facilitates a 10 (activated acetylenes 262 and Otosylamidobenzaldehydes/ O nucleophilic attack of the enol form of βketoamide 208 followed tosylamidophenones 261 , respectively) under mild conditions. 30 by dehydration and proton transfer to give I. Intermediate I then Mechanism involves a general base catalysis. Coupling of 261 undergoes intramolecular cyclization by N1 nucleophilic attack and 262 in presence of PPh 3 produces anion intermediate II .

of the βketoamide group followed by proton transfer to form Accepted Nucleophilic addition of the free phosphine to the activated intermediate II . Ring opening of intermediate II followed by 15 alkyne 262 generated phosphonium allenolate III , which acts as proton transfer gives the free aromatic amine III . Subsequently, a base to activate the pronucleophile II through deprotonation, 35 the NH2 group of III attacks a carbonyl group by intramolecular resulting in a subsequent general basecatalyzed Michael/aldol cyclization to form intermediate IV , which on elimination of reaction to produce IV (Scheme 99). Intermediate IV on water and deprotonation results in formation of 263 (Scheme aromatozation produces 260 . 100). Advances RSC

30 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 31 of 35 RSC Advances

R O 4 25 species that tautomerizes to yield I (Scheme 102). This O N R1 O O intermediate I undergoes intramolecular cyclization to form the + 0.1 equiv. EDDA R1 O O R4 R3 N Toluene, reflux, 6h intermediate II , which is immediately converted to a more N H H 41 examples N R3 reactive and unstable intermediate III via ringopening of R2 35-86% 40 208 R2 263 indoline2,3dione. After that, due to the high reactivity, EDDA 30 intermediate III instantly undergoes further nucleophilic addition -H2O -H O 2 with the other molecule of indane1,3dione 28c to produce O R O O 4 another imine intermediate IV , which tautomerizes to yield V. R3 N R O N 4 R1 Finally, the intramolecular cyclisation of V results in the ultimate R1 H OH OH spiro compound 267 . N N R H H2 3 H R R2 2 I IV N O O O cyclization 15 mol% CTAB, X X O H2O (10 ml) O O + O + R3 R4 R1 reflux, 5h, 100 oC O N N O O N O H H 51 examples N 75-96% R1 O R1 N R1 28c40 33 267 R4 N O -H2O H OH X H R3 R2 NH2 H R2 II III N OMe HO X Cl O NH OH O O O N O O O O N N N O NH R1 O Cl O R1 V I N N O N X 263a, 35% 263b, 63% 263c, 86% X R1 O N HO O O HO N O Manuscript Scheme 100 . Ethylenediamine diacetatecatalyzed synthesis of X 28c O NH O H pyrrolo[3,4c]quinolinediones 263 ; some representative examples OH N O H O N -H2O NH2 are shown. R R1 II 1 III IV H H N H N 5 1,1Cyclopropane aminoketones 265 on reaction with diethyl N azodicarboxylate 266 (DEAD, 2.0 equiv.) in toluene at 80 °C for Cl O O O 8 h produced 2benzoyl quinolines 264 via oxidation, ring O O O O opening and cyclization. 173 The reaction is proposed to proceed O O N N via a cascade procedure. 1,1Cyclopropane aminoketone 265 is NH 10 first oxidized with DEAD to give cyclopropene intermediate II . 267a, 75% 267b, 85% 267c, 96% Then, ringopening of II gives Nazadiene intermediate III , 35

which undergoes an intramolecular [4+2] reaction, followed by Scheme 102 . Cetyltrimethyl ammonium bromide (CTAB) Accepted dehydrogenation to form 264 (Scheme 101). catalyzed synthesis of spiro[indolo3,100indeno[1,2b]quinolin] O 2,4,11’triones 267 ; some representative examples are shown. H N COOEt Ar + NN Toluene R R o Ar EtOOC 80 C, 8 h N 9 examples 175 265 266 47-84% 264 O 40 Fang et al reported metalfree cyclization reaction of 2 isocyanobiphenyls 269 with amides 270 by using tertbutyl DEAD Cyclization Aromatization peroxybenzoate (TBPB) as oxidant, which provided an access to O H O O 6amidophenanthridine 268 . The reactions proceeds through a N H N Ar N Ar R Ar R sequence of functionalization of the C(sp3)−H bond adjacent to N COOEt R 45 the nitrogen atom and intramolecular radical aromatic cyclization HN COOEt with good yields (Scheme 103). I II III Advances

MeO Cl

N N N O O O 264a, 47% 264b, 77% 264c, 84%

RSC

15 Scheme 101 . Catalyst free synthesis of 2benzoyl quinolines 264 from 1,1cyclopropane aminoketones 265 ; some representative examples are shown.

The synthesis of highly substituted spiro[indolo3,10'indeno[1,2 20 b]quinolin]2,4,11'triones 267 has been developed under CTAB/H 2O system to provide spiroproducts with excellent yields. 174 At first, the nucleophilic addition reaction occurs between the enaminone 33 with the more electrophilic carbonyl centre of isatin 40 in ecofriendly water medium to give an imine

This journal is © The Royal Society of Chemistry [year] Journal Name , [year], [vol] , 00–00 | 31 RSC Advances Page 32 of 35

R 2 R2 3 equiv. TBPB o R1 + 120 C, N2, 24 h H N R1 N 19 example N C O 16-87% 269 270 O 268 O O O O

O N O N II I R2 R R2 2 Jaideep B. Bharate obtained M.Sc. degree in Organic Chemistry from the University of Pune in 2009. Currently he is pursuing Ph.D. in Chemical R1 C N R1 H R1 Sciences, at Academy of Scientific and Innovative Research, CSIR-Indian N N N N N 40 Institute of Integrative Medicine, Jammu under the supervision of Dr. O III IV O V O Ram A. Vishwakarma. His current research interests are in the field of OMe OMe development of new tandem one-pot or multicomponent approaches for synthesis of medicinally important scaffolds and metal catalyzed C-H activation. N N N N N O N O 268a, 16% 268b, 59% O 268c, 87%

Scheme 103 . Synthesis of 6amidophenanthridines 268 ; some representative examples are shown. Manuscript

5 45 4. Summary and future prospects Ram Vishwakarma studied chemistry at the Central Drug Research Institute (CDRI), Lucknow and completed Ph.D. in 1986 under joint As illustrated through the comprehensive compilation of role of supervision of Drs. SP Popli and RS Kapil. After working for few years as metalfree domino onepot reactions for quinoline synthesis, it is research scientist at CIMAP, Lucknow, he moved to the Cambridge 50 University in 1991 to work with Sir Alan Battersby on biosynthesis of clear that these protocols has numerous advantages such as high cyanocobalamin (vitamin B 12 ) and related porphyrins/corrins. In the end 10 yields, shorter reaction times, environmentally benign milder of 1993, he joined as staff-scientist at the National Institute of reactions and safe operations. Immunology at New Delhi and initiated a research program on chemical biology of Glycosyl Phosphatidyl Inositol (GPI) anchors of parasitic Many metalfree domino onepot protocols have been developed 55 protozoa (Leishmania and Malaria). In 2005, he moved to Piramal Life

by using inorganic/ organic acids, bases, organocatalysts, ionic Sciences (Mumbai) as vice-president and head of medicinal chemistry & Accepted liquids or molecular iodine. Use of these nonmetal reagents natural product groups. During this period, he worked on the clinically 15 certainly makes these protocols an environmentally friendly. validated disease targets relevant to cancer (PI3K/mTOR, IGFR1), Thus, these reagents and solvents have an indispensable role in diabetes (DGAT1) and infection (VRE/MRSA), learnt the “intricacies” of the development of many new domino onepot protocols for 60 drug-discovery under guidance of Dr. Somesh Sharma, and realized the several other heterocycles. An appropriate use of solvent or potential of marine natural products. In 2009, he joined as Director of reagents as catalysts in such protocols avoids the use of metal Indian Institute of Integrative Medicine (Council of Scientific and Industrial Research) at Jammu, where his primary focus remain natural- 20 catalyst and allows development of new metalfree products driven drug discovery for cancer and infection. His scientific methodologies for the efficient synthesis of quinolines. With the 65 work has been published in over 200 papers and >40 patent applications great importance of quinoline scaffold in drug discovery, these filed. Ram Vishwakarma is an elected Fellow of the National Academy of protocols will have great impact in rapid development of Sciences, India. molecular libraries and structureactivity relationship generation.

Advances 25 In summary, metalfree domino onepot strategies toward quinoline synthesis encompass the vast majority of green chemistry criteria and represent a solid, efficient, experimentally simple, and somehow elegant alternative to other methods. Based on the progress summarized in this review, we feel certain that

30 combined strategy of domino onepot protocols and metalfree RSC cabability of the reaction will find broad applications and will continue to attract much attention in organic synthesis applications.

70 Sandip B. Bharate obtained B. Pharm. degree from the University of 35 Author biographies Pune in 2001 and received a M.S. (Pharm.) degree from the National Institute of Pharmaceutical Education and Research (NIPER), Mohali (India), in 2002. In 2003, he worked in the discovery research unit of Dr Reddy’s Laboratories, Hyderabad, for six months before commencing his 75 Ph.D., which he completed under the supervision of Dr. Inder Pal Singh at NIPER Mohali in January 2007. Subsequently, he worked as a

32 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 33 of 35 RSC Advances

Research Scientist in the Department of Medicinal Chemistry, Piramal 70 29. R. Musiol, M. Serda, S. HenselBielowka and J. Polanski, Curr. Life Sciences Ltd, Mumbai (formerly, Nicholas Piramal Research Med. Chem. , 2010, 17 , 19601973. Center), for 1.5 years. He subsequently pursued postdoctoral studies 30. A. Mahamoud, J. Chevalier, A. DavinRegli, J. Barbe and J. M. (2008-2010) at the University of Montana (USA) with Professor Charles Pagès, Curr. Drug Targets , 2006, 7, 843847. 5 M. Thompson in the area of neuroscience. Presently, he is working as a 31. N. CostedoatChalumeau, B. Dunogué, N. Morel, V. Le Guern and Senior Scientist in the Medicinal Chemistry Division of the Indian 75 G. GuettrotImbert, Presse. Med. , 2014, 43 , e167180. Institute of Integrative Medicine (Council of Scientific and Industrial 32. H. BF, Chem. News , 1931, 142 , 129133. Research), Jammu, India. His current research interests are in the field of 33. J. Achan, A. O. Talisuna, A. Erhart, A. Yeka, J. K. Tibenderana, F. development of new tandem one-pot protocols for construction of N. Baliraine, P. J. Rosenthal and U. D'Alessandro, Malaria J. , 2011, 10 medicinally important scaffolds and medicinal chemistry of marine 10 , 144. natural products. He is recipient of several innocentive awards in the 80 34. M. E. Wall, M.C.Wani, C. E. Cook, K.H.Palmer, A. I. McPhail and area of new drug discovery. G.A.Sim, J. Am. Chem. Soc. , 1966, 88 , 3888–3890. 35. I. Pendrak, S. Barney, R. Wittrock, D. M. Lambert and W. D. Kingsbury, J. Org. Chem. , 1994, 59 , 26232625. 36. C. W. Wright, J. AddaeKyereme, A. G. Breen, J. E. Brown, M. F. 15 Acknowledgements 85 Cox, S. L. Croft, Y. Gökçek, H. Kendrick, R. M. Phillips and P. L. JBB is thankful to CSIR Innovation Center project ITR001 for Pollet, J. Med. Chem. , 2001, 44 , 3187–3194. fellowship. The financial support from DSTSERB is gratefully 37. P. Grellier, L. Ramiaramanana, V. Millerioux, E. Deharo, J. acknowledged (grant no. SR/FT/CS168/2011). Schrével, F. Frappier, F. Trigalo, B. Bodo and J.L. Pousset, Phytother. Res. , 1996, 10 , 317321. 90 38. K. Krafts, E. Hempelmann and A. SkórskaStania, Parasitol. Res. , References and notes 2012, 11 , 1–6. 39. L. C. Chou, C. T. Chen, J. C. Lee, T. D. Way, C. H. Huang, S. M. 20 1. J. P. Michael, Nat. Prod. Rep. , 2008, 25 , 166187. Huang, C. M. Teng, T. Yamori, T. S. Wu, C. M. Sun, D. S. Chien, 2. A. Marson, J. E. Ernsting, M. Lutz, A. L. Spek, P. W. N. M. van K. Qian, S. L. MorrisNatschke, K. H. Lee, L. J. Huang and S. C. Leeuwena and P. C. J. Kamer, Dalton Trans. , 2009, 621633. 95 Kuo, J. Med. Chem. , 2010, 53 , 16161626. 3. M. Orhan Püsküllü, B. Tekiner and S. Suzen, Mini-Rev. Med. 40. L. C. Chou, M. T. Tsai, M. H. Hsu, S. H. Wang, T. D. Way, C. H. Chem. , 2013, 13 , 365372. Huang, H. Y. Lin, K. Qian, Y. Dong, K. H. Lee, L. J. Huang and S. 25 4. V. R. Solomon and H. Lee, Curr. Med. Chem. , 2011, 18 , 1488 C. Kuo, J. Med. Chem. , 2010, 53 , 80478058. Manuscript 1508. 41. S. M. Prajapati, K. D. Patel, R. H. Vekariya, S. N. Panchal and H. 5. J. Lavrado, R. Moreira and A. Paulo, Curr. Med. Chem. , 2010, 17 , 100 D. Patel, RSC Adv. , 2014, 4, 2446324476. 23482370. 42. K. Gopaul, S. A. Shintre and N. A. Koorbanally, Anticancer Agents 6. S. Kumar, S. Bawa and H. Gupta, Mini-Rev. Med. Chem. , 2009, 9, Med Chem. , 2014, PMID: 25511516. 30 16481654. 43. J. Barluenga, F. Rodríguez and F. J. Fañanás, Chem. Asian J. , 2009, 7. J. P. Michael, Nat. Prod. Rep. , 2002, 19 , 742–760. 4, 10361048. 8. J. P. Michael, Nat. Prod. Rep. , 1997, 14 , 605618. 105 44. H. M. Hassanin, M. A. Ibrahim, Y. A. Gabr and Y. A. Alnamer, J. 9. R. N. Kharwar, A. Mishra, S. K. Gond, A. Stierle, D. Stierle and S. Heterocyclic Chem. , 2012, 49 , 12691289. Bawa, Nat. Prod. Rep. , 2011, 28 , 12081228. 45. B. Nammalwar and R. A. Bunce, Molecules , 2014, 19 , 204232. 35 10. I. P. Singh and H. S. Bodiwala, Nat. Prod. Rep. , 2010, 27 , 1781 46. R. A. Mekheimer, E. A. Ahmed and K. U. Sadek, Tetrahedron , 1800. 2012, 68 , 16371667. 11. P. Williams, A. Sorribas and M.J. R. Howes, Nat. Prod. Rep. , 110 47. A. Marella, O. P. Tanwar, R. Saha, M. R. Ali, S. Srivastava, M. Accepted 2011, 28 , 4877. Akhter, M. Shaquiquzzaman and M. M. Alam, Saudi Pharm. J. , 12. P. M. S. Chauhan and S. K. Srivastava, Curr. Med. Chem. , 2001, 8, 2013, 21 , 112. 40 1535. 48. L. Q. Lu, J. R. Chen and W. J. Xiao, Acc. Chem. Res. , 2012, 45 , 13. Y.L. Chen, K.G. Fang, J.Y. Sheu, S.L. Hsu and C.C. Tzeng, J. 12781293. Med. Chem. , 2001, 44 , 2374. 115 49. B. H. Rotstein, S. Zaretsky, V. Rai and A. K. Yudin, Chem. Rev. , 14. G. Roma, M. D. Braccio, G. Grossi, F. Mattioli and M. Ghia, Eur. J. 2014, 114 , 83238359. Med. Chem. , 2000, 35 , 10211035. 50. V. Estevez, M. Villacampa and J. C. Menendez, Chem. Soc. Rev. , 45 15. S. Bawa, S. Kumar, S. Drabu and R. Kumar, J. Pharm. Bioallied 2014, 43 , 46334657. Sci. , 2010, 2, 6471. 51. A. Domling, W. Wang and K. Wang, Chem. Rev. , 2012, 112 , 3083 16. B. Gryzło and K. Kulig, Mini-Rev. Med. Chem. , 2014, 14 , 332344. 120 3135. 17. K. Kaur, M. Jain, R. P.Reddy and R. Jain, Eur. J. Med. Chem. , 52. M. S. Singh and S. Chowdhury, RSC Adv. , 2012, 2, 45474592. 2010, 45 , 32453264. 53. B. B. Toure and D. G. Hall, Chem. Rev. , 2009, 109 , 44394486. 50 18. A. P. Gorka, A. d. Dios and P. D. Roepe, J. Med. Chem. , 2013, 56 , 54. C. de Graaff, E. Ruijter and R. V. A. Orru, Chem. Soc. Rev. , 2012, 5231−5246. 41 , 39694009. Advances 19. S. Bongarzone and M. L. Bolognesi, Expert Opin. Drug Discov. , 125 55. N. Isambert, M. d. M. S. Duque, J.C. Plaquevent, Y. Genisson, J. 2011, 6, 251268. Rodriguez and T. Constantieux, Chem. Soc. Rev. , 2011, 40 , 1347 20. K. A. Reynolds, W. A. Loughlin and D. J. Young, Mini-Rev. Med. 1357. 55 Chem. , 2013, 13 , 730743. 56. K. C. Nicolaou, D. J. Edmonds and P. G. Bulger, Angew. Chem. Int. 21. R. S. Keri and S. A. Patil, Biomed. Pharmacother. , 2014, 68 , 1161 Ed. , 2006, 45 , 71347186.

1175. RSC 130 57. J. D. Sunderhaus and S. F. Martin, Chem. Eur. J. , 2009, 15 , 1300 22. S. Singh, G. Kaur, V. Mangla and M. K. Gupta, J. Enzyme Inhib. 1308. Med. Chem. , 2014, PMID: 25032745. 58. D. M. D’Souza and T. J. J. Muller, Chem. Soc. Rev. , 2007, 36 , 60 23. O. Afzal, S. Kumar, M. R. Haider, M. R. Ali, R. Kumar, M. Jaggi 1095–1108. and S. Bawa, Eur. J. Med. Chem. , 2014, PMID: 25073919. 59. V. Estevez, M. Villacampa and J. C. Menendez, Chem. Soc. Rev. , 24. S. Vlahopoulos, E. Critselis, I. F. Voutsas, S. A. Perez, M. 135 2010, 39 , 44024421. Moschovi, C. N. Baxevanis and G. P. Chrousos, Curr. Drug 60. M. Shiri, Chem. Rev. , 2012, 112 , 35083549. Targets , 2014, 15 , 843851. 61. C. Allais, J.M. Grassot, J. Rodriguez and T. Constantieux, Chem. 65 25. P. Zajdel, A. Partyka, K. Marciniec, A. J. Bojarski, M. Pawlowski Rev. , 2014, 114 , 1082910868. and A. Wesolowska, Future Med. Chem. , 2014, 6, 5775. 62. H. Bienayme, C. Hulme, G. Oddon and P. Schmitt, Chem. Eur. J. , 26. S. Mukherjee and M. Pal, Drug Discov. Today , 2013, 18 , 389398. 140 2000, 6, 33213329. 27. S. Mukherjee and M. Pal, Curr. Med. Chem. , 2013, 20 , 43864410. 28. R. Musiol, Curr. Pharm. Des. , 2013, 19 , 18351849.

This journal is © The Royal Society of Chemistry [year] Journal Name , [year], [vol] , 00–00 | 33 RSC Advances Page 34 of 35

63. J. B. Bharate, A. Wani, S. Sharma, S. I. Reja, M. Kumar, R. A. 101. K. Wang, E. Herdtweck and A. Domling, ACS Comb. Sc. , 2012, 14 , Vishwakarma, A. Kumar and S. B. Bharate, Org. Biomol. Chem. , 75 316322. 2014, 12 , 62676277. 102. M. Cameron, R. S. Hoerrner, J. M. McNamara, M. Figus and S. 64. X. Zhang, X. Xu, L. Yu and Q. Zhao, Asian J. Org. Chem. , 2014, 3, Thomas, Org. Process Res. Dev. , 2006, 10 , 149152. 5 281284. 103. Z. Hu, Y. Li, L. Pan and X. Xu, Adv. Synth. Catal. , 2014, 356 , 65. K. C. Majumdar, S. Ponra, D. Ghosh and A. Taher, Synlett , 2011, 1, 29742978. 104110. 80 104. M. Rehan, G. Hazra and P. Ghorai, Org. Lett. , 2015, DOI: 66. L. Pan, X. Bi and Q. Liu, Chem. Soc. Rev. , 2013, 42 , 12511286. 10.1021/acs.orglett.1025b00419. 67. Y.L. Zhao, W. Zhang, S. Wang and Q. Liu, J. Org. Chem. , 2007, 105. P. Selig and W. Raven, Org. Lett. , 2014, 16 , 5192−5195. 10 72 , 49854988. 106. Q.L. Liu, Q.L. Li, X.D. Fei and Y.M. Zhu, ACS Comb. Sci. , 68. S. Khadem, K. A. Udachin, G. D. Enright, M. Prakesch and P. Arya, 2011, 13 , 1923. Tetrahedron Lett. , 2009, 50 , 66616664. 85 107. L. Fu, X. Feng, J.J. Wang, Z. Xun, J.D. Hu, J.J. Zhang, Y.W. 69. C. R. Borel, L. C. A. Barbosa, C. R. A. Maltha and S. A. Fernandes, Zhao, Z.B. Huang and D.Q. Shi, ACS Comb. Sci. , 2014, Tetrahedron Lett. , 2014, doi: dx.doi.org/10.1021/co500120b. 15 http://dx.doi.org/10.1016/j.tetlet.2014.1012.1016 . 108. H. Zhu, R. F. Yang, L. H. Yun and J. Li, Chin. Chem. Lett. , 2010, 70. N. Shindoh, H. Tokuyama, Y. Takemoto and K. Takasu, J. Org. 21 , 35–38. Chem. , 2008, 73 , 74517456. 90 109. A. Rineh, M. A. Khalilzadeh, M. M. Hashemi, M. Rajabi and F. 71. N. A. Magomedov, Org. Lett. , 2003, 5, 25092512. Karimi, J. Heterocycl. Chem. , 2012, 49 , 789791. 72. G. Shan, X. Sun, Q. Xia and Y. Rao, Org. Lett. , 2011, 13 , 5770 110. A. Alizadeh, L. Moafi, R. Ghanbaripour, M. H. Abadi, Z. Zhu and 20 5773. M. Kubicki, Tetrahedron , 2015, doi: 10.1016/j.tet.2015.1003.1062. 73. B. Mirza and S. S. Samiei, J. Chem. Chem. Eng. , 2011, 5, 644647. 111. J.y. Kato, H. Aoyama and T. Yokomatsu, Org. Biomol. Chem. , 74. S. Tu, S. Wu, S. Yan, W. Hao, X. Zhang, X. Cao, Z. Han, B. Jiang, 95 2013, 11 , 11711178. F. Shi, M. Xia and J. Zhou, J. Comb. Chem. , 2009, 11 , 239242. 112. J.y. Kato, R. Ijuin, H. Aoyama and T. Yokomatsu, Tetrahedron , 75. A. T. Khan and D. K. Das, Tetrahedron Lett. , 2012, 53 , 2345–2351. 2014, 70 , 27662775. 25 76. S.J. Tu, B. Jiang, R.H. Jia, J.Y. Zhang, Y. Zhang, C.S. Yao and 113. J.y. Kato, Y. Ito, R. Ijuin, H. Aoyama and T. Yokomatsu, Org. F. Shi, Org. Biomol. Chem. , 2006, 4, 36643668. Lett. , 2013, 15 , 3794–3797. 77. J. Azizian, A. S. Delbari and K. Yadollahzadeh, Synth. Commun. , 100 114. S. Kumar, P. Sharma, K. K. Kapoor and M. S. Hundal, Tetrahedron , 2014, 44 , 32773286. 2008, 64 , 536542.

78. H. HosseinjaniPirdehi, K. RadMoghadam and L. Youseftabar 115. Z. Xia, J. Huang, Y. He, J. Zhao, J. Lei and Q. Zhu, Org. Lett. , Manuscript 30 Miri, Tetrahedron , 2014, 70 , 17801785. 2014, 16 , 25462549. 79. C. Yu, H. Zhang, C. Yao, T. Li, B. Qin, J. Lu and D. Wang, J. 116. M. Arnould, M.A. Hiebel, S. Massip, J. M. Leger, C. Jarry, S. Heterocyclic Chem. , 2014, 51, 702705. 105 BerteinaRaboin and G. Guillaumet, Chem. Eur. J. , 2013, 19 , 80. M. Narasimhulu, T. S. Reddy, K. C. Mahesh, P. Prabhakar, C. B. 1224912253. Rao and Y. Venkateswarlu, J. Mol. Catal. A Chem. , 2007, 266 , 114 117. H. Zhou, L. Liu and S. Xu, J. Org. Chem. , 2012, 77 , 9418−9421. 35 117. 118. Y.M. Ren, C. Cai and R.C. Yang, RSC Adv. , 2013, 3, 71827204. 81. S.y. Tanaka, M. Yasuda and A. Baba, J. Org. Chem. , 2006, 71 , 119. Q. Gao, S. Liu, X. Wu and A. Wu, Org. Lett. , 2014, 16 , 45824585. 800803. 110 120. R. Deshidi, S. Devari and B. A. Shah, Org. Chem. Front. , 2015, 82. V. B. Bojinov and I. K. Grabchev, Org. Lett. , 2003, 5, 21852187. DOI: 10.1039/C1035QO00010F. 83. F. Yu, S. Yan, L. Hu, Y. Wang and J. Lin, Org. Lett. , 2011, 13 , 121. X. Li, Z. Mao, Y. Wang, W. Chen and X. Lin, Tetrahedron , 2011, 40 47824785. 67 , 38583862. 84. F.C. Yu, B. Zhou, H. Xu, Y.M. Li, J. Lin, S.J. Yan and Y. Shen, 122. X.S. Wang, Q. Li, J.R. Wu and S.J. Tu, J. Comb. Chem. , 2009, Accepted Tetrahedron , 2015, 71 , 10361044. 115 11 , 433437. 85. J. Quiroga, J. Trilleras, B. Insuasty, R. Abonía, M. Nogueras, A. 123. X.S. Wang, Q. Li, J. Zhou and S.J. Tu, J. Heterocycl. Chem. , Marchal and J. Cobo, Tetrahedron Lett. , 2010, 51 , 1107–1109. 2009, 46 , 12221228. 45 86. L. Liu, H. Lu, H. Wang, C. Yang, X. Zhang, D. ZhangNegrerie, Y. 124. X.S. Wang, J. Zhou, M.Y. Yin, K. Yang and S.J. Tu, J. Comb. Du and K. Zhao, Org. Lett. , 2013, 15 , 29062909. Chem. , 2010, 12 , 266269. 87. Z. Song, Y.M. Zhao and H. Zhai, Org. Lett. , 2011, 13 , 63316333. 120 125. D.S. Chen, Y.L. Li, Y. Liu and X.S. Wang, Tetrahedron , 2013, 88. J. Tummatorn, C. Thongsornkleeb, S. Ruchirawat and T. 69 , 70457050. Gettongsong, Org. Biomol. Chem. , 2013, 11 , 14631467. 126. W. Wang, M. M. Zhang and X. S. Wang, J. Heterocycl. Chem. , 50 89. P. Zhao, X. Yan, H. Yin and C. Xi, Org. Lett. , 2014, 16 , 11201123. 2014, 51 , 175178. 90. L. Peng, H. Wang, C. Peng, K. Ding and Q. Zhu, Synthesis , 2011, 127. W. Wang, H. Jiang, M.M. Zhang and X.S. Wang, J. Heterocyclic. 11 , 17231732. 125 Chem. , 2014, 51 , 830834. 91. B. V. Subba Reddy, D. Medaboina, B. Sridhar and K. K. Singarapu, 128. P. Ghosh and A. Mandal, Catal. Commun. , 2011, 12 , 744–747. J. Org. Chem. , 2013, 78 , 81618168. 129. N. C. Ganguly and S. Chandra, Tetrahedron Lett. , 2014, 55 , 1564 Advances 55 92. Q. Zhang, Z. Zhang, Z. Yan, Q. Liu and T. Wang, Org. Lett. , 2007, 1568. 9, 36513653. 130. J. Wu, H.G. Xia and K. Gao, Org. Biomol. Chem. , 2006, 4, 126– 93. A. V. Aksenov, A. N. Smirnov, N. A. Aksenov, I. V. Aksenova, L. 130 129. V. Frolova, A. Kornienko, I. V. Magedov and M. Rubin, Chem. 131. R. Venkatesham, A. Manjula and B. V. Rao, J. Heterocyclic Chem. , Commun. , 2013, 49 , 93059307. 2012, 49 , 833838. 60 94. Y. Yamaoka, T. Yoshida, M. Shinozaki, K.i. Yamada and K. 132. B. P. Bandgar, P. E. More and V. T. Kamble, J. Chin. Chem. Soc. , Takasu, J. Org. Chem. , 2015, 80 , 957964. 2008, 55 , 947951. RSC 95. F.W. Wu, R.S. Hou, H.M. Wang, I.J. Kang and L.C. Chen, J. 135 133. L.Y. Zeng and C. Cai, Org. Biomol. Chem. , 2010, 8, 4803–4805. Chin. Chem. Soc. , 2012, 59 , 535539. 134. J. Fotie, H. V. Kemami Wangun, F. R. Fronczek, N. Massawe, B. T. 96. Y. Zhu and C. Cai, RSC Adv. , 2014, DOI: Bhattarai, J. L. Rhodus, T. A. Singleton and D. S. Bohle, J. Org. 65 10.1039/C1034RA07858F. Chem. , 2012, 77 , 27842790. 97. H. V. Mierde, P. V. D. Voort and F. Verpoort, Tetrahedron Lett. , 135. R. Halim, P. J. Scammells and B. L. Flynn, Org. Lett. , 2008, 10 , 2008, 49 , 68936895. 140 19671970. 98. R. Martínez, D. J. Ramón and M. Yus, J. Org. Chem. , 2008, 73 , 136. H. Batchu, S. Bhattacharyya and S. Batra, Org. Lett. , 2012, 14 , 97789780. 63306333. 70 99. M.C. Yan, Z. Tu, C. Lin, S. Ko, J. Hsu and C.F. Yao, J. Org. 137. S. Ali, H.T. Zhu, X.F. Xia, K.G. Ji, Y.F. Yang, X.R. Song and Chem. , 2004, 69 , 15651570. Y.M. Liang, Org. Lett. , 2011, 13 , 2598–2601. 100. A. Arcadi, F. Marinelli and E. Rossi, Tetrahedron , 1999, 55 , 13233 145 138. S. Ali, Y.X. Li, S. Anwar, F. Yang, Z.S. Chen and Y.M. Liang, J. 13250. Org. Chem. , 2012, 77 , 424431.

34 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 35 of 35 RSC Advances

139. S. Sadjadi and M. M. Heravi, Tetrahedron , 2011, 67 , 2707–2752. 140. A. Kruithof, E. Ruijter and R. V. Orru, Chem. Asian J. , 2015, 10 , 508520. 141. A. Domling, Chem. Rev. , 2006, 106 , 1789. 5 142. B. Jiang, C. Li, S.J. Tu and F. Shi, J. Comb. Chem. , 2010, 12 , 482 487. 143. T. Mitamura and A. Ogawa, J. Org. Chem. , 2011, 76 , 11631166. 144. J. B. Bharate, S. B. Bharate and R. A. Vishwakarma, ACS combinatorial science , 2014, 16 , 624630. 10 145. Y. Wan, R. Yuan, F.R. Zhang, L.L. Pang, R. Ma, CaiHui, Y. Lin, W. Yin, R.C. Bo and a. H. Wu, Synth. Commun. , 2011, 41 , 2997 3015. 146. L. Xia, A. Idhayadhulla, Y. R. Lee, S. H. Kim and Y.J. Wee, ACS Comb. Sci. , 2014, 16 , 333341. 15 147. M. R. P. Heravi, Ultrason. Sonochem. , 2009, 16 , 361366. 148. E. Kowsari and M. Mallakmohammadi, Ultrason. Sonochem. , 2011, 18 , 447454. 149. Y. Sun, P.J. Cai and X.S. Wang, Res. Chem. Intermed. , 2014, doi: 10.1007/s111641101411819y. 20 150. H. Y. Guo and Y. Yu, Chin. Chem. Lett. , 2010, 21 , 1435–1438. 151. J. Alemán and S. Cabrera, Chem. Soc. Rev. , 2013, 42 , 774793. 152. R. Mahrwald, Drug Discov. Today Technol. , 2013, 10 , e2936. 153. U. Scheffler and R. Mahrwald, Chemistry , 2013, 19 , 1434614396. 154. F. Shi, G.J. Xing, Z.L. Tao, S.W. Luo, S.J. Tu and L.Z. Gong, J. 25 Org. Chem. , 2012, 71 , 6970−6979. 155. C. Shi, J. Wang, H. Chen and D. Shi, J. Comb. Chem. , 2010, 12 , 430–434 156. A. KhalafiNezhad, S. Sarikhani, E. S. Shahidzadeh and F. Panahi,

Green Chem. , 2012, 14 , 28762884. Manuscript 30 157. S. Karamthulla, S. Pal, T. Parvin and L. H. Choudhury, RSC Adv. , 2014, 4, 1531915324. 158. Z.H. Yu, H.F. Zheng, W. Yuan, Z.L. Tang, A.D. Zhang and D. Q. Shi, Tetrahedron , 2013, 69 , 81378141. 159. K. Wu, Z. Huang, C. Liu, H. Zhang and A. Lei, Chem. Commun. , 35 2015, DOI: 10.1039/c1034cc08074b. 160. C. Qi, Q. Zheng and R. Hua, Tetrahedron , 2009, 65 , 13161320. 161. Y.J. Zhou, D.S. Chen, Y.L. Li, Y. Liu and X.S. Wang, ACS Comb. Sci. , 2013, 15 , 498502. 162. A. Fayol and J. Zhu, Angew. Chem. Int. Ed. , 2002, 41 , 3633–3635. 40 163. B. K. Mehta, K. Yanagisawa, M. Shiro and H. Kotsuki, Org. Lett. , 2003, 5, 16051608. Accepted 164. P. Yuvaraj, K. Manivannan and B. S. R. Reddy, Tetrahedron Lett. , 2015, 56 , 78–81. 165. B. D. Bala, K. Balamurugan and S. Perumal, Tetrahedron Lett. , 45 2011, 52 , 45624566. 166. A. Alizadeh and A. Rezvanian, C. R. Chim. , 2014, 17 , 103107. 167. P. Chidurala, V. Jetti, R. Pagadala, J. S. Meshram and S. B. Jonnalagadda, J. Heterocyclic Chem. , 2014, DOI: 10.1002/jhet.2230. 50 168. E. Fındık, M. Ceylan and M. Elmastas, J. Heterocyclic Chem. , 2012, 49 , 253260. 169. R. GhorbaniVaghei and S. M. Malaekehpoor, Tetrahedron Lett. , 2012, 53 , 4751–4753. 170. A. S. Plaskon, S. V. Ryabukhin, D. M. Volochnyuk, K. S. Advances 55 Gavrilenko, A. N. Shivanyuk and A. A. Tolmachev, J. Org. Chem. , 2008, 73 , 6010–6013. 171. S. Khong and O. Kwon, J. Org. Chem. , 2012, 77 , 82578267. 172. L. Xia and Y. R. Lee, Org. Biomol. Chem. , 2013, 11 , 5254–5263. 173. Z. Mao, H. Qu, Y. Zhao and X. Lin, Chem. Commun. , 2012, 48, 60 9927–9929. 174. A. Mondal, M. Brown and C. Mukhopadhyay, RSC Adv. , 2014, 4, RSC 3689036895. 175. H. Fang, J. Zhao, S. Ni, H. Mei, J. Han and Y. Pan, J. Org. Chem. , 2015, DOI: 10.1021/acs.joc.1025b00058.

65

This journal is © The Royal Society of Chemistry [year] Journal Name , [year], [vol] , 00–00 | 35