Synthesis of 3-Benzyl-2-hydroxy-7,8-dihydro-6H-quinolin-5-ones from Baylis-Hillman Adducts

Abstract

2-Hydroxy-7,8-dihydro-6H-quinolin-5-one skeleton is a useful backbone for the synthesis of numerous biologically interesting compounds such as carbostyrils (2-hydroxyquinolines) or huperzine A analogues, which have shown biological activities including non-steroidal antiinflammatory activity, acetylcholinesterase (AChE) inhibitory activity and antimalarial activity. During the studies on the chemical transformation of the Baylis-Hillman adducts toward synthetically useful heterocyclic compounds we envisioned that we could synthesize 3-benzyl-5-methoxycarbostyril derivatives 5. Our synthetic rationale for 5a is depicted in Scheme 1. Reaction of the Baylis-Hillman acetate 1 and cyclic enaminone 2 would provide the tetrahydroquinoline-2,5-dione skeleton 3 via SN2' type reaction of cyclic enaminones to the BaylisHillman acetates followed by amide bond formation. We thought that the following iodine-assisted oxidative aromatization of cyclohexenone moiety and base-catalyzed isomerization of lactam moiety would afford the desired 3benzyl-5-methoxycarbostyril derivative 5. The reaction of Baylis-Hillman acetate 1a and 3-amino-2cyclohexenone (2a) in refluxing ethanol in the presence of catalytic amount of acetic acid gave 3-benzylidene-4,6,7,8tetrahydro-1H,3H-quinoline-2,5-dione (3a) as the major product (52%) together with small amounts of 4a (< 10%). The reaction could also be conducted in n-butanol without acetic acid catalyst in a similar pattern. But, when we used nbutanol as the solvent, 4a was observed as the major product on TLC presumably due to the effect of higher reaction temperature than in EtOH. But, 3a was not changed completely into 4a even after heating for a long time. Thus we examined the conditions for the effective transformation of 3a into 4a and we found a suitable condition fortunately. Conversion of 3a into 4a could be carried out easily with catalytic amounts of DBU in THF at room temperature (reflux for the conversion of 3g into 4g, entry 7 in Table 1). Thus, we prepared 4a-c according to the following procedures: reaction of 1a-c and 2a in refluxing n-BuOH, separation of 3 and 4 as a mixtures, and finally DBU treatment to form 4a-c as the final products (entries 1-3 in Table 1). It is interesting to note that the easiness for the conversion