Quinoline-4-carboxylic acids, ring synthesis

Ring closure y to a heteroatom is also a rather uncommon [5 + 1] procedure although there are some important exceptions. The most widely investigated is the Bernthsen acridine synthesis in which a diarylamine is condensed with a carboxylic acid in the presence of a Lewis acid (equation 73). More recently, it has been shown that acylanilines react with the Vilsmeier-Haack reagent to give quinolines in good yield (e.g. equation 74) and the mechanism of the reaction has been elucidated. A final example of [5 +1] ring closure y to a heteroatom which is of occasional use is the pyrazine synthesis outlined in equation (75). 

Many ring-fused imidazole derivatives have been synthesized by various methods. Domino Michael addition retro-ene reaction of 2-alkoxyiminoimidazolidines and acetylene carboxylates provided a synthesis of 2,3-dihydroimidazo[l,2-a]pyrimidin-5-(l//)-ones <05T5303>. A single step synthesis of 3,5-dialkyl-9-nitroimidazo[l,2-c]quinazolin-2(3//)-ones from simple carbonyl compounds, primary amines or amino acid methyl esters and 2-azido-5-nitrobenzonitrile has been published <05TL5778>. Diels-Alder reaction of azadienes and benzimidazole-4,7-diones afforded imidazo[4,5-g ]quinoline-4,9-dione derivatives <05EJ01903>. Reaction between isocyanides and dialkyl acetylenedicarboxylates in the presence of 4,5-diphenyl-l,3-dihydro-2//-imidazol-2-one provided a one-pot synthesis of 5//-imidazo[2,l-ft][l,3]oxazine derivatives <05T2645>. Microwave irradiation was employed in the synthesis of 1-ary 1-3-acetyl-1,4,5,6-... 

Homologs of pyridine, quinoline, thiophen, and various other heterocycles can be oxidized to carboxylic acids generally without destruction of the hetero ring in the pyrrole series, however, this cannot be done directly but requires intervention of an intermediate (see Fischer et al.A05). More circuitous routes are also sometimes preferable in the quinoline series for instance, in their total synthesis of hydroquinine Rabe et a/.406 obtained the 4-carboxylic acid from 6-methoxy-4-methylquinoline by oxidizing the 4-styryl derivative (obtained by reaction with benzaldehyde) instead of oxidizing the methyl compound directly. Alkyl groups at positions 2 and 4 of pyridine are more easily oxidized than those at position 3. 

Indole-2-carboxylic acids, 121, 252, 254 Indole-3-carboxylic acids, 253, 254 Indolenines, 84, 167, 169 dichloromethyl-, 68 quatemization of, 39 quinolines from, 69-71 ring expansion of, 69-71 Indolizmes, formylation of, 73 Indolo[l,2-a]pyrazinone, 119 Indolo[2,3-a]quinolizinium salts, synthesis of, 178... 

While the synthesis of benzofuran derivatives from suitable furan derivatives has been comparatively little investigated, the synthesis of fused two-ring and three-ring compounds containing a pyridine nucleus from furan derivatives has been more successful furo[3,2-c]pyridines (345),752>753 2,3-dihydrofuro[2,3-a ]quinolines (from 4,5-dihydro-3-furoic acid),754 acrophyllin (346), and 7-hydroxydictamnine (347) (from ethyl 2-ethoxy-4-oxo-4,5-dihydrofuran-3-carboxylate),755 are examples of compounds in this class which have been prepared. 

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