Quinolinone derivatives, synthesis

The original Gould-Jacobs reaction, i.e. the reaction of an aniline or naphthylamine with diethyl (ethoxymethylene)malonate followed by cyclization of the intermediate at ca. 250 °C to give quinolinone derivatives (see Houben-Weyl, Vol. E 7a, p 345),194 has been extended to the synthesis of pyridopyrimidines. The method of first preparing the intermediate (pyrimidiny-lamino)methylene compound and its subsequent thermal cyclization has been discussed (vide supra). 

The constituents of the tumorigenic plant Melochia tomentosa include 6-methoxy-7,8-methylenedioxycoumarin, three cyclopeptide alkaloids, melo-chinone (a quinolinone derivative), and two novel phenylpentyl-isatins, melosatins A and B, for which the structures (3) and (4) have been deduced. The structure of melosatin A was confirmed by synthesis (Scheme 1),... 

This methodology with some variations has been utilized in the synthesis of numerous heterocyclic systems, such as heterocycle-fused quinolinone derivatives [391], l,4-benzodiazepin-2-ones [392], benzo-, naphtho- and heterocycle-fused pyrrolo[2,l-c][l,4]diazepines [393], quinolinone or pyrrolidinone derivatives [394], dibenzo[fl,c]phenanthridines [395], thiazolo-fused quinolinones [396], isoindolinone and isoquinolin-2-one derivatives [397], indoline derivatives [398], 5-aroyl-pyrrolidinones [399,400], indazolone derivatives [401,402], substituted indolizidinones [403], 1-arylpyrrolopyrazinones [404], stmcturally diverse... 

In 2012, T2ik2ihashi et al. [30] reported the catalytic enantioselective synthesis of atropisomeric 2-aryl-4-quinolinone derivatives using the Buchwald-Hartwig reaction with a (i )-MOP-Pd2(dba)3 catalyst. This reaction involved the 1,4-addition of aniline to an ynone, followed by an intramolecular Buchw2ild-Hartwig amination. An enantioselectivity as high as 72% ee could be achieved (Scheme 2.4). 

Shaharyar M, Ah M, Abdullah M (2007) Synthesis and antiproliferative activity of l-[(sub)]-6-fluoro-3-[(sub)]-l, 3,4-oxadiazol-2-yl-7-piperazino-l, 4-dihydro-4-quinolinone derivatives. Med Chem Res 16 292—299... 

Chiral butyrolactones of type 27 and 28 have substantial value in asymmetric synthesis because they contain readily differentiable difunctional group relationships e.g. 1,5-di-carboxylic acid, 1,4-hydroxy carboxylic acid, 1,6-hydroxy-carboxylic acid, 1,6-diol etc.) that would be difficult to assemble by existing asymmetric condensation and pericyclic processes. Applications of these chiral derivatives of glutaric acid to syntheses of indole, indoline and quinolinone alkaloids are illustrated in Schemes 16-18. 

In the above reactions of enamine derivatives with oxazolidines and oxazinanes, pyridine systems did not constitute direct targets but were formed, in a few cases, by air oxidation of initially formed dihydropyridine derivatives. Oxazolidines 30, possessing electron-withdrawing groups in C-2 substituents, exist mainly as tautomeric acyclic enamines 28 (Section II.C.2), which in the presence of an acid would also generate iminium cations such as 54 that should react with nucleophiles. Thus, it has been found that such oxazolidines in presence of an acid, react with acyclic, cyclic, and heterocyclic enamine derivatives in 1 1 stoichiometry to provide a unique synthesis of pyridine, quinolinone, and pyridopyrimidine derivatives (98T935). 

An elegant method for the solid-phase synthesis of quinolinone 9 derivatives has been developed by Pei et al. [43]. Using the teabag technology, the synthesis of a 4-amino-3,4-dihydro-2(l//)-quinolinone library was carried out through the rearrangement of /3-lactam intermediates on the solid phase. The condensation of o-nitrobenzaldehyde with a resin-bound amino acid yielded an imine that, following [2-1-2] cycloaddition with ketenes, afforded the -lactams (Fig. 3g). 

In 2015, Liu and coworkers reported the formal synthesis of tipifarnib, a farne-syltransferase inhibitor, by using a palladium-catalyzed C-H alkenylation as a key step (Scheme 16.35) [71]. Aniline derivative 160 reacted with AC2O to form an acetanilide intermediate, followed by ort/zo-palladation under the influence of a palladium catalyst to produce compound 162. Oxidative Heck reaction with 161 and cyclization/deacetylation then occurred to afford quinolinone 163 in 95% yield in one pot. This quinolinone was then converted to tipifarnib by the reported procedure [72]. 

A recent example of the application of Suzuki reactions to introduce diversity is shown by the synthesis of 4-carbon-based substituted quinoli-nones [118]. There are limited methods for the synthesis of such derivatives and the outlined solid phase approach involved the synthesis of a resin-bound 3-methoxycarbonyl 4-tosyl quinolinone and subsequent Suzuki coupling with several aryl boronic acids and cleavage (Scheme 43). One drawback was the formation of hydrolysis byproducts, lowering the yield. 

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