Quinoline scaffold

Baylis-Hillman adducts such as 55 and 56 derived from 2-nitrobenzaldehydes were shown to function as useful precursors to functionalized (1H)-quinol-2-ones and quinolines. Treatment of 55 and 56 with iron and acetic acid at 110 °C afforded 57 and 58, respectively <02T3693>. A variety of other cyclization reactions utilized in the preparation of the quinoline scaffold were also reported. An iridium-catalyzed oxidative cyclization of 3-(2-aminophenyl)propanols afforded 1,2,3,4-tetrahydroquinolines <02OL2691>. The intramolecular cyclization of aryl radicals to prepare pyrrolo[3,2-c]quinolines was studied <02T1453>. Additionally, photocyclization reactions of /rans-o-aminocinnamoyl derivatives were reported to provide 2-quinolones and quinolines <02JHC61>. Enolizable quinone and mono- and diimide intermediates were shown to provide quinolines via a thermal 6jt-electrocyclization <02OL4265>. Quinoline derivatives were also prepared from nitrogen-tethered 2-methoxyphenols. The corresponding 2-methoxyphenols were subjected to a iodine(III)-mediated acetoxylation which was followed by an intramolecular Michael addition to afford the quinoline OAc O... 

The quinoline scaffold is found in the antihacterials naUdlxic acid and rapoxacin. 

Fewer NK-3 selective receptor antagonists have been described, but a quinoline scaffold previously reported to be a selective NK-3 receptor antagonist, has been converted to a dual NK-2/NK-3 inhibitor (128) = 0.8 nM... 

The quinoline scaffold and derivatives occur in a large number of natural products and drug-like compounds. A method for microwave-assisted synthesis of 2-aminoquinolines has been described by Wilson et al. [62]. The process involves rapid microwave irradiation of secondary amines and aldehydes to form enamines, then addition of 2-azidobenzophenones with subsequent irradiation to produce the 2-aminoquinoline derivatives (Scheme 10.27). Purification of the products was accomplished in a streamlined manner by using solid-phase extraction techniques to produce the desired compounds in high yields and purity. Direct comparison of the reaction under thermal and microwave conditions, using identical stoichiometry and sealed reaction vessels, showed the latter resulted in improved yield. 

Cycloaddition reactions also provide a very straightforward means for the preparation of the quinoline scaffold. Hexahydropyrrolo[3,2-c]quinolines, the core structure of the Martinella alkaloids, were prepared through an intramolecular 3 + 2] azomethine ylide-alkene cycloaddition. Condensation of an aldehyde such as 51 and W-alkyl amino acids followed by decarboxylation and cycloaddition afforded quinoline derivatives such as 52 <01T4095>. The... 

The catalytic activity of Shvo s catalyst is mainly because it dissociates into two monomeric ruthenium species in solution under thermal conditions and it can be combined well with various lipases in DKRs. Minidis and colleagues recently employed a combination of this catalyst with Novozym 435 to achieve the DKR of a series of 1-heteroaryl substituted ethanols, such as oxadiazoles, isoxazoles, l//-pyrazole, or 1//-imidazole. In the presence of / -chlorophenyl acetate as the acyl donor, the corresponding acetates were produced in moderate to high yields and excellent enantioselectivities, as shown in Scheme 4.37. In order to prepare novel chiral pincer ligands based on the 6-phenyl-2-amino-methylpyridine and 2-aminomethylbenzo[/j]quinoline scaffolds, Felluga et al. 

Several derivatives of quinoline scaffold with a flexible, semi-flexible or rigid side chains at position 8 of the quinoline ring were synthesized by Arafa et al. [25], Studied in-vitro activity versus the human colon cancer cell line HT29 and the human breast cancer cell line MDA-MB231. The derivatives with Schiff s base linkers showed excellent activity. 

Another strategy for monitoring Cd " in cells using BAPTA-based fluorescence indicators involves the use of two types of dyes that exhibit different fluorescent responses to Ca " and Cd ", respectively. As opposed to Fura-2, no change in the fluorescence of Quin-2, which is a tum-on type Ca " indicator based on a quinoline scaffold, is induced by adding Cd " [43]. By taking advantage of the different photophysical properties of Cd " complexes of Fura-2 and Quin-2, Cd " uptake by... 

The Skraup cyclization is another reaction principle that provides rapid access to the quinoline moiety. Theoclitou and Robinson have published the preparation of a 44-member library based on the 2,2,4-trisubstituted 1,2-dihydroquinoline scaffold by the Lewis acid-catalyzed cyclization of substituted anilines or aminoheterocyc-les with appropriate ketones (Scheme 6.237) [420], The best results were obtained using 10 mol% of scandium(III) triflate as a catalyst in acetonitrile as solvent at... 

Numerous replacements for the indole core have been investigated, including imidazoles, thienoimidazoles, pyrroloimidazoles, quinolines, indolizines and several aza-indoles. Attachment of an N,N-dimethylacetamide side-chain to the thienopyrrole scaffold gives compound 34 with nanomolar enzyme activity (IC50 = 58 nM) and enhanced cell activity (EC50 = 2.9 pM) compared to the unalkylated scaffold [79]. 

A cursory examination of the Cinchona catalysts used in O Donnell-type alkylation [90] of methyl (diphenylimino)glycinate (Appendix 7.A) reveals that only minor modifications to the Cinchona scaffold are required for the synthesis of a catalyst the 8-substituent on the quinuclidine core may either be a vinyl group (as in the parent alkaloids, quinine and quinidine) or can be an ethyl substituent, introduced by hydrogenation. The quinoline system at the 2-position ofthe quinuclidine ring can be unsubstituted if the catalyst is derived from quinine or quinidine, but can contain a 6-methoxy group ifit is derived from cinchonine or cinchonidine. The 3-position ofthe quinuclidine ring may contain either a hydroxy group or else a vinyloxy or benzyloxy... 

Figure 2.15 Scaffold-hopping from anilino-quinazolines (left) to cyano-quinolines...

Among the multistep solution libraries prepared, Cheng et al. [17,18] reported a dipeptide mimetic template-based 78-member library prepared via four synthetic steps and purified with an excellent protocol based on acid-base extractions. Thomas et al. [19] presented a > 1000-member benzimidazole library prepared via three steps including a 2-ethoxy-1-ethoxycarbonyl- 1,2-dihydro-quinoline (EEDQ)-assisted cyclization. Boger et al. reported two 600-member C -symmetrical [20,21] and unsymmetrical [21] libraries prepared via four-five synthetic steps, based on iminodiacetic acid as a scaffold and using the olefin metathesis reaction. 

The deoxygenative methodology allows incorporating azole residues into azaaromatic scaffolds. Pyridine, quinoline, isoquinoline, azaindole, and pyrimidine N-oxides were converted to their a-triazole and a-diazole derivatives by treatment with the corresponding p-toluenesulfonylazoles and Hunig s base at elevated temperatures [119] or by treatment with sulfuryldiimidazole in nonpolar solvents at elevated temperatures [120]. 

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