2-Aryl-4-quinolones

Non-hemiterpenoid Quinolines.—A re-examination of the alkaloids of Haplophyllum dubium resulted in the isolation of two members of the 2-aryl-4-quinolone group, i.e. graveoline (2 R = Me) and the new alkaloid norgraveoline (2 R = H).5 A new bacterial pseudan (3) has been obtained from Pseudomonas aeruginosa.8... 

Because the 2 -aminochalcones are known to form 2-aryl-4-quinolones, the authors undertook an investigation of possible reductive coupling reactions of 2 -hydroxy-2-nitrochalcones <03TL5893>. With a limited number of examples, the reactions were carried out via a one-pot synthesis. Quinoline-iV-oxides formed as side products are likely intermediates and can be carried on to the final material. 

Aryl-4-quinolones and 3-hydroxyflavones. The quinolones are obtained from 2,3-dihydro compounds and flavones are hydroxylated at C-3. KOH is added to the reaction medium. 

Quinoline, Isoquinoline, and their Benzo- and Hydro- derivatives 6- and 7- Substituted quinolines have been prepared by reaction of the appropriately substituted anilinobutenoate with the Vilsmeier reagent (Scheme 16).92 Reaction of a N-methylisatoic anhydride (70) with the lithium enolate of an acetophenone gives good yields of 2-aryl-4-quinolones (71). 93... 

Data for 2-alkyl- and 2-aryl-4-quinolone alkaloids are given in Table VIII (3, 69, 134, 208-217). 

An easy access to 2-aryl-4-quinolone (85) has been achieved from 2-aryl-l,2,3,4-tetrahydro-4-quinolone (86) using hypervalent iodine as the oxidizing agent (Scheme 47) (94SC(24)2167). 

Alternatively, 2-aryl-4-quinolones (124, R =Ar) are obtained from (2-amino)aceto-phenones 125 by base-induced aldol condensation with aromatic aldehydes (—>-126), Lewis acid-promoted cyclization to the 2,3-dihydro-4-quinolones 127, and their dehydrogenation with PhI(OAc)2 (127 -> 124, R=Ar) [186],... 

Microwaves also provide an easy access to 2-alkyl and 2-aryl-4-quinolones by the addition-elimination reaction of 5-methylthioalkylidene isopropylidene malonates with arylamine, followed by cyclization (Huang et al., 2000). A condensation, addition, cyclization and elimination reactions of aromatic aldehydes, 5,5-dimethyl-l,3-cyclohexandione and isopropylidene malonate afforded a series of 4-aryl-7,7-dimethyl-2, 5-dioxo-l,2,3,4,5,6,7,8-octahydroquinoline and 4-aiyl-7,7-dimethyl-5-oxo-3,4,5,6,7,8-hexahydroconmarin under microwaves only in 3-5 min (Tu et al., 2002). Basic silica gel (NaOH/SiO ) in solvent-free conditions and microwave exposure acts as a very efficient medium for the p-elimination (dehydrosulfe-nylation) of sulfoxides (Moghaddam and Jamshidi, 2001). 

In the general preparation of quinolones by forming the nitrogen aryl bond a in the ring closure, typical precursors are prepared as shown in Figure 2. The ring closure involves nucleophilic displacement of a halogen, usually a chlorine or fluorine (76) eg, (29) and (30) lead to (31) [86483-54-7] and (32) [123942-15-4] respectively. 

When reacted with dimethyl acetylenedicarboxylate, the amines produced ben-zotriazolylaminobutendioates 188 accompanied by A-benzotriazolyl substituted 2-pyridones only in the case of 5-amino-2-methyl-2//-benzotriazole, the triazolo-9,10-dihydrobenzo[d]azepine and an unusual cyclization product, triazolo-2-oxindole (convertible into 2-methyltriazolo[4,5-/]carbostyril-9-carboxylate) were formed. The quinolones 189 were aromatized to chloroesters 190 these in turn were hydrolyzed to chloroacids 191 and decarboxylated to 9-chlorotriazolo[4, 5-/]quinolines 192 (Scheme 58) (93H259). The chlorine atom could be replaced with 17 various secondary amines to give the corresponding 9-aminoalkyl(aryl) derivatives 193, some of which exhibit both cell selectivity and tumor growth inhibition activity at concentrations between 10 and 10 " M (95FA47). 

The last method for the preparation of 2-quinolones described in this chapter relies on a intramolecular Heck cyclization starting from heteroaryl-amides (Table 2) [57]. These are synthesized either from commercially available pyrrole- and thiophene-2-carboxylic acids (a, Table 2) or thiophene-and furan-3-carboxylic acids (b, Table 2) in three steps. The Heck cyclization is conventionally performed with W,Ar-dimethylacetamide (DMA) as solvent, KOAc as base and Pd(PPh3)4 as catalyst for 24 h at 120 °C resulting in the coupled products in 56-89% yields. As discussed in Sect. 3.4, transition metal-catalyzed reactions often benefit from microwave irradiation [58-61], and so is the case also for this intramolecular reaction. In fact, derivatives with an aryl iodide were successfully coupled by conventional methods, whereas the heteroarylbromides 18 and 19, shown in Table 2, could only be coupled in satisfying yields by using MAOS (Table 2). 

A typical second step after the insertion of CO into aryl or alkenyl-Pd(II) compounds is the addition to alkenes [148]. However, allenes can also be used (as shown in the following examples) where a it-allyl-r 3-Pd-complex is formed as an intermediate which undergoes a nucleophilic substitution. Thus, Alper and coworkers [148], as well as Grigg and coworkers [149], described a Pd-catalyzed transformation of o-iodophenols and o-iodoanilines with allenes in the presence of CO. Reaction of 6/1-310 or 6/1-311 with 6/1-312 in the presence of Pd° under a CO atmosphere (1 atm) led to the chromanones 6/1-314 and quinolones 6/1-315, respectively, via the Jt-allyl-r 3-Pd-complex 6/1-313 (Scheme 6/1.82). The enones obtained can be transformed by a Michael addition with amines, followed by reduction to give y-amino alcohols. Quinolones and chromanones are of interest due to their pronounced biological activity as antibacterials [150], antifungals [151] and neurotrophic factors [152]. 

The readily available 2 -aminochalcones provide easy access to 2-aryl-l,2,3,4-tetrahy-dro-4-quinolones in yet another solvent-free cydization reaction using montmorillo-nite K 10 clay under microwave irradiation conditions [150] the products are valuable precursors for the medicinally important quinolones (Scheme 6.47). 

Scheme 6.47 Synthesis of 2-aryl-l, 2,3,4-tetrahydro-4-quinolones via cyclization reaction on clay.

Aryl-l,2,3,4-tetrahydro-4-quinolones 348 can be dehydrogenated to the corresponding 4-quinolones 349 by using IBD-KOH/MeOH (94SC2167) (Scheme 89). Surprisingly, the expected product a-hydroxydimethylacetal 350 is not obtained. 

The influence of a C-2 substituent upon the reaction course has been investigated. If only a 2-aryl group is present, as in 145 (R = H), then 4-quinolones 146 are formed (85H2375). But ferricyanide oxidation of 2,4-diphenyl derivatives resulted in the release of the 2-phenyl group and formation of the quinolones 147 instead of the exptected indole derivatives (83CCC2965). 

Keywords 2 -aminochalcone, microwave irradiation, 2-aryl-1,2,3,4-tetrahydro-4-quinolone... 

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... 

Among the more recently developed quinolone products, garenoxacin, a 6-des-fluoroquinolone, is the first highly active compound without a fluorine atom in the 6-position and with an aryl side-chain replacing the diamine in the 7-position. 

Alkoxy-2-arylquinolines 2-Aryl-l,2,3,4-tetrahydro-4-quinolones undergo dehydrogenation and O-methylation when treated with PhI(OTs)OH, HCIO, and HCjOMejj. 

Hydroxamic acids react with diaryliodonium salts to afford the O-phenyl derivatives. number of heterocyclic compounds containing A -hydroxyamino groups were selectively arylated on the oxygen atom. 0 (Table 5.4) In the case of oximate anions, ambident behaviour was observed, with predominant 0-arylation. With heterocyclic oximes, the 0-aryl ethers were mainly formed and served as precursors to prepare unstable aryl fulminates, 19 (Table 5.5) In the reaction of quinolone derivatives with diaryliodonium salts, the products of O- or C-arylation were obtained.(Table 5.6)... 

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