Synthesis and stereodynamics of highly constrained 1,8-bis(2,2'-dialkyl-4,4'-diquinolyl)naphthalenes.

Abstract

The syn and anti isomers of axially chiral 1,8-diquinolylnaphthalenes have been synthesized via Pd-catalyzed Stille coupling of 1,8-dibromonaphthalene and 2-alkyl-4-trimethylstannylquinolines. Optimization of the cross-coupling reaction allowed the preparation of highly constrained 1,8-bis(2,2'-dimethyl-4,4'-diquinolyl)naphthalene, 2, and 1,8-bis(2,2'-diisopropyl-4,4'-diquinolyl)naphthalene, 3, in 42% and 41% yield, respectively. Employing Pd(PPh(3))(4) and CuO as the cocatalysts in the coupling reaction of 1,8-dibromonaphthalene and 2-alkyl-4-trimethylstannylquinolines proved to be superior over other catalysts such as PdCl(2)(dppf), Pd(2)(dba)(3)/P(t-Bu)(3), and POPd. The C(2)-symmetric anti isomers of 2 and 3 were found to be more stable than the corresponding meso syn isomer. The ratio of the two enantiomeric anti conformers to the syn conformer was determined as 7.9:1 for 2 and 8.6:1 for 3 by NMR and HPLC analysis. The atropisomers of 2 and 3 were found to be stable to rotation about the chiral axis at room temperature and all three stereoisomers of 2 were isolated by semipreparative HPLC on a Chiralpak AD column. The diastereoisomers of 3 were separated via preferential crystallization of the anti isomers from diethyl ether. Slow syn/anti interconversion was observed for both atropisomers at enhanced temperature, and the diastereomerization and enantiomerization processes were monitored by NMR and HPLC. The Gibbs activation energy, DeltaG++, for the isomerization of 2 was determined as 116.0 (112.1) kJ/mol for the conversion of the anti (syn) to the syn (anti) isomer at 71.0 degrees C. The rotational energy barrier of 3 was determined as 115.2 (111.1) kJ/mol for the conversion of the anti (syn) to the syn (anti) isomer at 66.2 degrees C.