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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 HSV-1 and HSV-2 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 (1-aza-napthalene 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 N-donor ligands. The 55 30 quinoline scaffold has been reported to possess diverse range of 3-14 15-20 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, anti-HIV, 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, NPC-1161B, AQ-13, 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 (anti-TB), etc. The 2-(2- bAcademy of Scientific & Innovative Research (AcSIR), CSIR-Indian fluorophenyl)-6,7-methylenedioxy quinolin-4-one monosodium Institute of Integrative Medicine, Canal Road, Jammu-180001, India. phosphate (CHM-1-P-Na) is a preclinical anticancer agent, *E-mail: [email protected] ; [email protected] † showing excellent antitumor activity in a SKOV-3 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 β-diketones); (b) Skraup Chloroquine Piperaquine F Pyronaridine 45 synthesis (from ferrous sulfate, glycerol, aniline, nitrobenzene, Cl Cl O O H N and sulfuric acid); (c) Conrad-Limpach synthesis (from anilines N NH F N OH OH OH O O H2N and β-ketoesters); (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) Doebner-Miller Ciprofloxacin Pitavastatin Lenvatinib Tipifarnib 50 reaction (from anilines and α,β-unsaturated carbonyl O compounds); (g) Gould-Jacobs 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 β-ketoanilide 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) Meth-Cohn 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) quinoline-based kinase inhibitors development of new metal-free 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. 41-47 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 anti-cancer activity of 2-substituted 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 1,2,3,4-tetrahydroquinolines, 2,3-dihydro-4(1H)-quinolinones domino one-pot protocols or multicomponent reactions (MCRs) and 4(1H)-quinolinones using domino reactions.