Synthesis of 2-Quinolones

Related chemistry utilizing o-haloaryl ketones has been employed to generate the regioisomeric 4-quinolones [95], 

6 Multi-component Reactions (lmidazo[l,2-a]annulated N-heterocycles -Ugi reaction) 

A similar strategy has been used for the Biginelli condensation reaction to synthesize a set of pyrimidinones (65-95%) in a household MW oven [152]. This MW approach has been successfully applied to combinatorial synthesis [153]. Yet another example is the convenient synthesis of pyrroles (60-72 %) on silica gel using readily available enones, amines and nitro compounds [154]. 

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Figure 9.1-2. Reactions of organic compounds in high temperature H2O (a), saponification of esters [28] (b), selective reduction of nitro-aromatics [29] (c), the synthesis of quinolones [30].

Tetrabenzo[a,c,g,i]fluorene has been used to selectively link synthetic intermediates to charcoal, for the purpose of their purification. In polar solvents, the tetrabenzo-fluorene is strongly adsorbed by charcoal this enables efficient separation of the intermediate from reagents. After centrifugation and washing, the intermediate is displaced from the charcoal and released into solution by addition of a non-polar solvent, and a new synthetic operation in solution can be conducted (Figure 3.43). Tetrabenzo-fluorene has also been used for the purification of peptides [849] and oligonucleotides [850], and for the synthesis of quinolones [851]. 

Reil E, Scoll M, Masson K et al (1994) Synthesis of quinolones and acridones and their inhibitory activity in NADH-dehydrogenases and cytochrome b/ci-complexes. Biochem Soc Trans 22 62S... 

Cycloaddition of but-l-yne to the quinolone (58a) gave the head-to-tail [2 + 2] adduct (59). This approach was coupled with a ring-opening reaction to provide a synthesis of quinolones bearing a substituent at C-3. For example, the cycloadduct (60), obtained from the quinolone (58b) and 2-methylbut-3-yn-2-ol, was transformed into edulinine (61). The photocycloaddition of allene to the quinolone (58b) affords the two [2 + 2] adducts (62, 59.6%) and (63, 9.7%). Diketene has also been used in cycloadditions to quinolones (58c) and (58d). The addition process is selective in that cycloaddition to (58c) yields the adduct (64) whereas (58d) affords (65). In the latter case, the cycloadduct is accompanied by the rearranged product (66). These adducts were used in further chemical transformations. 

A solvent-free catalysed microwave synthesis of quinolones was proposed by Yadav et al. [84]. The reaction was carried out with reactants aldehydes, amines and alkynes over montmorillonite clay impregnated with Cu(I)bromide. The yield of the product was 75-93 % (Scheme 11.31). 

In 2011, Nakai et al. found that acyclic compounds also participated in cycloaddition through carbon-carbon bond activation (Scheme 12.22). Reaction of o-arylcarboxybenzonitrile 56 and 4-octyne in the presence of a nickel catalyst, prepared in situ from Ni(cod)2 and PMes, and MAD in toluene at 120 °C for 12 h resulted in the formation of coumarin 58 in 80% yield. Sequential inter- and intramolecular carbon-carbon cleavage in the presence of a nickel catalyst has been used to construct flve-membered oxanickelacycle 57, which reacts with alkynes to furnish cycloadducts [27]. Detailed observations revealed that the catalytic reaction proceeded with the elimination of aryl cyanide. A similar sequence has been utilized for the synthesis of quinolone derivative 59 (Scheme 12.23). These reaction outcomes suggest an unusual mechanistic aspect cleavage of two independent C—CN and C—CO bonds via the formation of a heteronickelacycle intermediate. 

Palladium- and copper-catalyzed C—N bond formations can also be utilized effectively in the synthesis of quinolones. As in the synthesis of indazoles, intramolecular cyclizations have proved an efficient route. Battistuzzi et al. described such a route via cyclization of o-bromocinnamamide 43 [93]. The same palladium diacetate catalytic conditions were also found to be effective for an initial intermolecular Heck process, and thus 4-substituted 2-quinolones could be produced (Scheme 24.20). A brief mechanistic investigation confirmed that the Heck reaction occurred before the intramolecular C—N bond formation. 

Zhang and co-workers investigated Ru(II)-catalyzed asymmetric hydrogenation of protected ethyl l-(2-aminoa-ceto)cyclopropane carboxylates 55 in order to set a stereo-genic center in (5)-7-amino-5-azaspiro[2.4]heptane, a key intermediate in the synthesis of quinolone antibacterial agents such as sitalloxacin and olamulloxacin. ... 

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