Conformational Analysis. 50. C-Methyl-1,2,3,4-tetrahydroisoquinolines

Abstract

Conformational equilibria in 1-, 3-, and 4-methyl-1,2,3,4-tetrahydroisoquinolines (THIQs) and the diastereomeric pairs of their 1,3- and 1,4-dimethyl homologs have been determined by measurement of H3/H4(trans) coupling constants and have been confirmed by molecular mechanics [MMP2(85)] calculations. The experimental −ΔG° values (a → e) for the monomethyl compounds (computed values in parentheses) in kcal mol-1 are Me-1, 0.56 (0.46); Me-3, 1.63 (1.53); and Me-4, −0.32 (−0.22). Agreement of experimental and calculated values is very good as is the additivity of values for the dimethyl compounds (Table ). Values for the corresponding hydrochlorides are Me-1, 0.19 (−0.34); Me-3, l.15 (1.46); and Me-4, 0.35 (0.10) kcal mol-1. The less than satisfactory agreement of experimental with computed data here is probably due to neglect of solvation. The very small or negative ΔG° values for Me-1 and Me-4 were ascribed not only to the pseudoaxial (rather than axial) nature of Me(ax) and the absence of a syn-axial hydrogen on the side of the benzene ring but also to a peri interaction with H(8) and H(5), respectively, destabilizing equatorial methyl at positions 1 and 4. This was confirmed by comparing computed conformational energy values with values at corresponding positions in Δ3,4-tetrahydropyridines (THPs). While ΔG° in the two series is the same for Me-3 (THIQ numbering), that for Me-1 and Me-4 is considerably smaller in the THIQ than in the THP series which latter is devoid of peri hydrogens.

Comparison of column performances in direct high‐performance liquid chromatographic enantioseparation of 1‐ or 3‐methyl‐substituted tetrahydroisoquinoline analogs. Application of direct and indirect methods

“…The Tiq derivatives investigated were synthesized by a standard literature procedure: formylation of the corresponding phenylethylamine, followed by ring closure and sodium borohydride reduction (Olefirowicz and Eliel, 1997;Pitts et al, 2001). The derivatization reagents APPI and DANI were prepared by methods developed in our laboratory (available on request).…”