4-Quinolone synthesis

Quinazosin, 382 Quinbolone, 154 Quindonium bromide, 139 Quinolone synthesis, 363 Quinoxaline synthesis, 388 Quinterenol, 366... 

The synthesis of the important quinolone antibiotic 6.33 is shown. The key stages are the Gould-Jacobson quinolone synthesis to give 6.32, and the displacement reaction to afford 6.33. What are the mechanisms of these reactions ... 

The quinolone synthesis involves an addition-elimination reaction followed by an intramolecular aromatic acylation. 

Petersen U, et al. BAY Y 3118, a novel 4-quinolone Synthesis and in vitro activity. In 32nd Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract No. 642. Anaheim, 1992. 

To make rosoxacin two heterocyclic systems must be constructed. Workers at the pharmaceutical company Sterling decided to build the pyridine in an ingenious version of the Hantzsch synthesis using acetylenic esters on 3-nitrobenzaldehyde. The ammonia was added as ammonium acetate. Oxidation with nitric acid made the pyridine, hydrolysis of the esters and decarboxylation removed the acid groups, and reduction with Fe(TT) and HC1 converted the nitro group into the amino group required for the quinolone synthesis. 

Now the quinolone synthesis can be executed with the same reagents we used before and all that remains is ester hydrolysis and alkylation at nitrogen. Notice that the quinolone cyclization could in theory have occurred in two ways as the two positions ortho to the amino group are different. In practice cyclization occurs away from the pyridine ring as the alternative quinolone would be impossibly crowded. 

The Conrad-Limpach reaction, which employs )8-anilinocrotonates, is also a valued method for 4-quinolone synthesis (1887CB944 48CRV53 52HC38), and a recent example is included in Table V (entry 6). 

In a 2-quinolone synthesis a trans cinnamate must isomerise during the ring closing process. 

Benzisothiazolium salts are hydrolysed to ort/zo-aminobenzaldehydes their use as synthons for such aldehydes is illustrated by the quinolone synthesis below. 

N-allyl/N-vinyl anilines were characterized by a rearrangement of the ahphatic moiety. The aromatic system had not been touched during the course of the process (Winterfeldt quinolone synthesis [15c]). The rearrangement of a NH allyl vinyl amine failed [15dj. 

A variation of the Friedlander quinolone synthesis has been developed using Al(OTf)3. With as low as 5 mol % of the Lewis acid in solvent-free conditions, various 2-aininobenzophenones reacted with ketones to afford quinolone derivatives in good yields (eq 20). ... 

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