Quinolinone, 4-aryl

BMCL5089, 05BMCL4286). Most of these quinolinones present a suitable substitution pattern in the vicinity of the quinolinone-4-aryl bond to give rise to stable atropisomers. The chirality issues were first addressed in a patent (04WO5826). Examples that have been separated on a chiral support are given below (07JMC1050). 

The alkaloid dubamine contains a single bond between the two heteroarene units. This lond was formed in 79% yield by the generally valuable palladium-catalyzed eoupling of an ryltrimethylstannane with an aryl triflate (see section 1.6). The requisite stannane was pre-ared from l,3-benzodioxol-5-yl triflate and hexamethyldistannane with the same palladium atalyst, the triflate ester was obtained from 2(1 f/)-quinolinone and trifluoromethanesulfonic jihydride (A.M. Echavarren, 1987). An earlier attempt to perform this aryl coupling by dassical means gave a yield of only 1 %. 

Chiral quinolinones can be accessed by the palladium-catalyzed coupling between aryl bromides and /3-amino acids, followed by intramolecular acid-catalyzed cyclisation (Equation 136) <1998TA1137>. The reaction of 2-amino-1,3-diene with quinolinone yields the acridine derivative directly (Scheme 75) <1997J(P1)2807>. 

Regioselective palladium-catalyzed arylation of ethyl 3-futoate at either the 2- or the 5-position can be achieved by the judicious choice of solvent and palladium catalyst, as shown in Scheme 27. However, efficient arylation requires the use of aryl bromides substituted with electron-withdrawing groups (e.g., NO2) <20030L301>. This method was applied to the synthesis of furo[3,2- ]quinolinone from l-bromo-2-nitrobenzene. 

An efficient one-pot procedure for the synthesis of 4-aryl-8-arylidene-5,6,7,8-tetrahydro-2-quinolinones 66 has been developed by Yen and co-workers [54] based on a cyclocondensation reaction of W-ethoxycarbonylmethylpyridinium chloride with an aromatic aldehyde and cyclohexanone. The microwave-assisted (domestic microwave oven) MCR resulted in the formation of compound 66 in high yields (Scheme 50). 

Yan C-G, Cai X-M, Wang Q-F et al (2008) A novel four component one-pot access to 4, 6-diaryl-2-pyridinone and 4-aryl-5, 6, 7, 8-tetrahydro-2-quinolinones. Lett Org Chem... 

The Buchwald-Hartwig palladium-catalyzed aryl-amino coupling reaction was applied to the synthesis of functionalized A-phenyl-2-quinolinones <03TL4207>. This was especially powerful because known methods of cyclization preclude anilines with electron-withdrawing groups para, or any ortho substituents, for steric reasons. 

Pyrazolo[3,4-Z)]pyridines, the 7-chloro-6-fluoro-2,4-dimethylquinoline and its mercapto-thiadiazolyl or oxadiazolyl quinolines 21 were prepared via Diels-Alder reaction conversion of methyl 2-(3-oxo-3-phenylpropenylamino)benzoate into 3-benzoyl-l.S -quinolin-4-one 22 . A mixture of aniline derivatives and malonic ester gave a variety of 3-aryl-4-hydroxyquinolin-2(l//)-ones 23. Condensation of isatins with ketones afforded quinoline-4-carboxylic acids. 2-Aryl-l,2,3,4-tetrahydro-4-quinolinones 22 and carbazolylquinolone were also prepared. The substitution of 2-chloroquinoline gave the 2-substituted quinolines. Basic alumina has catalyzed the C-C bond formation between 2-hydroxy-1,4-naphthoquinone and 2-chloroquinoline derivative to give 21. Reaction of organic halides with 8-hydroxyquinolines gave the respective ethers. The azodye derivatives of 21 were prepared in the absence of solvent. Silica gel catalyzed the formation of 2-ketomethylquinolines from reaction of 2-methylquinolines with acyl chlorides. 

Reaction of the chloropyrazine 2 with furan afforded the 2-arylfuran. 2-Arylation of benzo[ >]furan (4) occurs with o-bromonitrobenzene (3) [3b]. Regioselective 2-arylation of ethyl 3-furancarboxylate with 3 occurred to give 5 in 80 % yield when Pd(PPh3)4 and AcOK were used in toluene. 5-Arylation was the main path when ligandless Pd/C was used in the polar solvent NMP. The furo[3,2-c]quinolinone 6 was obtained after hydrogenation of the nitro group [4]. 

Notably, Torii and colleagues reported the intramolecular carbonylative Heck coupling of 3-(2-haloarylamino)prop-2-enoates to the corresponding quinolinone derivatives [21]. In the presence of a catalytic amount of Pd(OAc)2 under 20 bar of CO at 120 °C, quinolinones were synthesized in good yields (Scheme 7.4). A related carbonylative cross-coupling of aryl iodides with alkynones was reported... 

An asymmetric version of the intramolecular hydroarylation of alkynes (286) to produce fused rings (287) has been developed. With the cationic Pd(II)/(5)-(285) catalyst, the resulting 4-aryl 2-quinolinones were obtained with <98% ee. Asymmetric addition of boronic acids R B(OH)2 to activated cumulenes R C=C=C=C(R )C02Et, catalysed by an NHC-palladium complex, has been shown to yield allenic products R C=C=C(R )CH(R )C02Et with moderate to good enantioselectivities. ... 

In 2010, Jackson and co-workers studied the Negishi cross-coupling of iodoalanine-derived zinc reagents with aryl iodides and aryl bromides/ In that work, they showed that a 3,4-dihydro-2( H)-quinolinone derivative can be produced by using 2-iodoaniline as a substrate. An interesting study on... 

Scheme 10 PIFA-mediated synthesis of 3-hydroxy and 3-aryl quinolinones...

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). 

Scheme 2.4 Application of an asymmetric Buchwald-Hartwig reaction for atropisomeric 2-aryl-4-quinolinone synthesis by Takahashi ef al. [30].

The oxidative aromatization of tetrahydro-5(l/f)-quinolinones and tetrahydropyrido [2,3-fif]pyrimidin-4(//)-one withpara-benzaldehydes as oxidants in NaOEt/EtOH results in the formation of the corresponding quinolone and aryl methanol because of the hydride transfer from tetrahydroquinoline to arylaldehydes during the oxidation process. The yield of the products basically depends on the substituents with -l-M effect attached to the para position of benzene rings connected to the 2- and 4-positions of the hydro-quinolinone moiety and substituents with -I effect attached to the aryl aldehydes. 

A review of the rearrangement reaction of anthranilic acid esters, thioesters, or amides under acidic conditions to 2-aryl-3-substituted 4(l//)-quinolinone has been reported and summarizes limits and scope of the reaction in the synthesis of flavonoids. " Theoretical studies of the addition-cyclization-isomerization reaction of propargyl cyanamides with thiol and methanol have been reported to occur via five steps ... 

Quinolinone-3-carboxylic acids (eq 26) and related heterocyclic carboxylic acids could be decarboxylatively coupled with aryl and heteroaryl halides under microwave conditions. ... 

The Cul-mediated photo-induced reaction of 2-alkenyl aryl azides such as 62 reported by Zhang et al. (Scheme 16.28) includes the migration of an aminocarbonyl group with ring expansion to give various azaheterocycles, such as indolo[3,2-c] quinolinone 63 [47], A similar acyl migration mechanism (Scheme 16.27) was proposed. 

A catalytic enantioselective intramolecular hydroarylation of alkynes was conducted with a cationic palladium(II)/(5)-xyl-H8-BINAP complex (Scheme 18.33) [31], With electron-rich aryl groups such as 2-naphthyl on the nitrogen atom, the intramolecular hydroarylation proceeded efficiently to give chiral 4-aryl-2-quinolinone derivatives. This palladium-catalyzed reaction using (S )-xyl-Segphos... 

A cationic Au(I)/(/ )-DTBM-Segphos complex catalyzes the atrop-selective intramolecular hydroarylation of sterically hindered alkynes, leading to enantioen-riched axially chiral 4-aryl-2-quinolinones in high yields (Scheme 18.34) [32], The use of (/ )-BINAP as a ligand improves the enantioselectivity in some cases. 

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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