A [3+3] Aldol-SNAr-Dehydration Approach to 2-Naphthol and 7-Hydroxyquinoline Derivatives
Kwabena Fobi, Ebenezer Ametsetor, Richard A. Bunce
TL;DR
A new chemical method efficiently creates complex compounds like 2-naphthol and 7-hydroxyquinoline derivatives through a one-pot reaction sequence.
Contribution
A novel [3+3] aldol-SNAr-dehydration approach is introduced for synthesizing substituted naphthols and quinolines.
Findings
The reaction forms polysubstituted 2-naphthols and 7-hydroxyquinolines from acetone derivatives and 2-fluorobenzaldehyde.
The process is regioselective, favoring the most stable anionic center for aldehyde addition.
In specific cases, a Grob-type fragmentation leads to cinnamate ester products.
Abstract
A one-pot [3+3] aldol-SNAr-dehydration annulation sequence was utilized to fuse hindered phenols onto aromatic substrates. The transformation joins doubly activated 1,3-disubstituted acetone derivatives (dinucleophiles) with C5-activated 2-fluorobenzaldehyde SNAr acceptors (dielectrophiles) in the presence of K2CO3 in DMF at 65–70 °C to form polysubstituted 2-naphthols and 7-hydroxyquinolines. The reaction is regioselective in adding the most stable anionic center to the aldehyde followed by SNAr closure of the less stabilized anion to the electron-deficient aromatic ring. Twenty-seven examples are reported, and a probable mechanism is presented. In two cases where SNAr activation on the acceptor ring was lower (a C5 trifluoromethyl group on the aromatic ring or a 2-fluoropyridine), diethyl 1,3-acetonedicarboxylate initiated an interesting Grob-type fragmentation to give cinnamate…
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Taxonomy
TopicsAxial and Atropisomeric Chirality Synthesis · Chemical synthesis and alkaloids · Asymmetric Synthesis and Catalysis