Synthesis, Properties, and Enantiomerization Behavior of Axially Chiral Phenolic Derivatives of 8-(Naphth-1-yl)quinoline and Comparison to 7,7′-Dihydroxy-8,8′-biquinolyl and 1,1′-Bi-2-naphthol

Abstract

An aza-analogue of 1,1′-bi-2-naphthol (BINOL, 3), 7-hydroxy-8-(2-hydroxynaphth-1-yl)quinoline (8-azaBINOL, 2), was prepared in 3 steps and 49% yield from N,N-diethyl O-(7-hydroxy-8-iodoquinolyl)carbamate via Suzuki coupling with 1-naphthylboronic acid followed by Sanford oxidation and saponification. 8-AzaBINOL (2) was resolved into (–)-(aS) and (+)-(aR) atropisomers via enzymatic hydrolysis of its racemic divalerate derivative with bovine pancreas acetone powder. The configurational stability of diol 2 was found to be intermediate to that of 7,7′-dihydroxy-8,8′-biquinolyl (8,8′-diazaBINOL, 1, least stable) and BINOL (3, most stable). Eyring plot analysis of the enantiomerization kinetics of 1, 2, and 3, in DMSO solution revealed activation parameters of ΔH^‡ = +27.4, +19.9, +23.2 kcal mol^–1, and ΔS^‡ = +3.8, –27.9, –25.3 cal mol^–1 K^–1, respectively. The unique character of ΔH^‡ and ΔS^‡ values for biquinolyl 1 suggests that the enantiomerization mechanism for 1 is distinct to that for naphthalenes 2 and 3. Monohydroxy analogues of 2, 7-hydroxy-8-(naphth-1-yl)quinoline (7) and 8-(2-hydroxynaphth-1-yl)quinoline (8), were similarly prepared and their racemization half-lives at room temperature were determined; τ _1/2(rac) was strongly dependent on solvent for naphthol 8 [τ _1/2(rac) at 24 °C: in CHCl₃ = 2.7 h, in MeOH = 89 h] but not for the quinol 7 [τ _1/2(rac) at 24 °C: in CHCl₃ = 106 h, in MeOH = 120 h].

Key words

atropisomerism - azaBINOLs - circular dichroism - enzymatic resolution - quinolines

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