Lithium Perchlorate-, Acetic Anhydride-, and Triphenylphosphine-assisted Multicomponent Syntheses of 4-Unsubstituted 2,5-Dioxooctahydroquinoline-3-carboxylates and 3-carbonitriles

Abstract

Lithium perchlorate and acetic anhydride were the key additives for the multi-component reaction between 3-aminocyclohex-2-enones, formaldehyde, and malonates yielding adducts that were annulated under acidic conditions to afford bicyclic 2,5-dioxooctahydroquinoline-3-carboxylates. When methyl cyanoacetate was subjected to the same reaction conditions in the presence of a catalytic amount of triphenylphosphine, the bicyclic 2,5-dioxooctahydroquinoline-3-carbonitriles were obtained in a one-flask reaction.

Keywords: 2,5-dioxooctahydroquinolines; Multicomponent reaction; acetic anhydride; catalysis; lithium perchlorate; triphenylphosphine.

Figure 1.

Representative structures of cardiovascular drugs, 1,4-dihydropyridine nifedipine (1), a calcium channel blocker, TGFb inhibitor 2, milrinone (3), annulated 2-pyridone phosphodiesterase-3 inhibitor 4, human type I steroid 5-α-reductase inhibitor LY191704, and target scaffold 5.

Scheme 1.

Multicomponent literature methods for the synthesis of 5-oxohexahydroquinoline-3-carboxylates (eq 1), 2,5-Dioxooctahydroquinoline-3-carboxylates (eq 2 and 3) and a stepwise reaction to form 2,5-dioxooctahydroquinoline-3-carboxylates (eq 4).

Scheme 2.

Multi-component reactions of 3-(benzylamino)cyclohex-2-enone (6a) with and without LiClO₄ as additive.

Scheme 3.

Reaction of enaminone 6a with Knoevenagel intermediate 9a.

Scheme 4.

Proposed mechanism for the LiClO₄-catalyzed Knoevenagel reaction in the presence of acetic anhydride.

Scheme 5.

Proposed mechanism for the triphenylphosphine catalyzed synthesis of 10a.