Quinoline formation, 1,3-dicarbonyl

More recently, a catalyst-free aqueous version of this strategy was proposed with simple acyclic 1,3-dicarbonyls, formaldehyde, and styrene or anilines derivatives (Scheme 40) [131], In the first case (Scheme 40), the very reactive 2-methylene-1,3-dicarbonyl intermediate reacts smoothly at 80°C with a variety of substituted styrenes to give the corresponding dihydropyrans in moderate to good yields. Remarkably, when styrenes were replaced by A-ethylaniline, a novel five-component reaction involving twofold excess of both formaldehyde and 1,3-dicarbonyl selectively occurred (Scheme 41). The result is the formation of complex fused pyranoquinolines following a Friedel-Craft alkylation - dehydration sequence to furnish the quinoline nucleus, which suffers the Hetero-Diels-Alder cyclization in synthetically useful yields. 

Substituents in the pyranone ring are derived from the dicarbonyl component and hence variation in the nature of 3- and 4-substituents is relatively easy. Thus, ethyl benzoylacetate gives 4-phenylcoumarins as for instance in a synthesis of dalbergin (357) (76T2407, 8iiJC(B)9l8) and use of ethyl trifluoroacetoacetate leads to 4-trifluoromethylcoumarins. A study of the reaction of the latter with 3-aminophenol identified the optimum conditions for coumarin formation, but noted the simultaneous formation of the two quinoline derivatives (358) and (359) (80JOC2283). 

Several classes of carbon nucleophiles have been successfully used in these systems, reflecting the utility of Reissert chemistry for derivatizing azines via carbon-carbon bond formation. Apart from cyanide anion, other classes of carbon nucleophiles have been explored. For instance, addition of indole (51) to A-acyla-zinium salts proceeds selectively at the a-position (Scheme 9). Pyrrole, quinolines and isoquinolines all behave similarly [73-76]. A related reaction, yielding adduct 70 (Scheme 12b) has also been described. In this case, azine activation is promoted by Vilsmeier reagents (generated by reaction of amides with POCI3) [77]. p-Dicarbonyls are reactive inputs in this chemistry, and dialkyl malonates 53... 

In the first step, p-enaminones 75 or A-arylimines 76 are formed which, after C=0 protonation (possibly by way of an 0-N diprotonated species), undergo intramolecular hydroxyalkylation and dehydration (via 77) to afford quinolines 74. Regioselectivity and product formation in unsymmetrical P-dicarbonyl compounds can be influenced by the acidity of the reaction medium and by the reaction temperature, eg. ... 

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