Conformational analysis of 1,2,3,4‐tetrahydroisoquinolines

Abstract

Ring and nitrogen inversion account for the conformational equilibria of 3‐phenyl‐1, 2,3, 4‐tetrahydroiso‐quinolines. In order to quantitate the relative contribution of each conformer to the equilibrium, we undertook a molecular mechanics study on several substituted 3‐phenyl‐1, 2, 3, 4‐tetrahydroisoquinolines. Predictions from calculations were checked against cmr chemical shift data. No boat conformation contributed significantly to the equilibrium. A general result of our calculations is that in all cases the 3‐phenyl group in the equatorial position is strongly favored (by at least 2.50 kcal/mole). For 3‐phenyl‐1, 2, 3, 4‐tetrahydroisoquinolines without substitution at nitrogen, N‐H in equatorial position is preferred over the axial conformer, although the energy difference between both is always small (0.30–1.10 kcal/mole). For the cis‐1,3‐disubstituted compounds the le'3e conformers are the only species present (at least 99.8%). The calculated energy differences between the la′3a conformer and the le′3e conformer are always large (3.80–6.10 kcal/mole for the NHe conformers and 3.60–3.80 kcal/mole for the NHa conformers). The lack of a γ1a upfield shift at C3 also points to the preference for the pseudoequatorial‐equatorial conformer. For N‐methyl‐3‐phenyl‐1,2,3,4‐tetrahydroisoquinoline a preference for the NMe group in the equatorial position is predicted (0.60–2.00 kcal/mole). The small downfield shift at C4 (γNa = 0.5 ppm) is consistent with the equatorial NMe preference. For the cis‐1,2,3‐trisubstituted compounds no significant γ1a effect at C3 (γ1a = ‐0.2 and 1.0 ppm) or γNa effect at C4 (γNa = 0.1 and 0.4 ppm) is observed. For these compounds, deformations due to steric congestion are evidenced by the deviation from the values of the C4a‐C8a‐Cl‐N and C4a‐C4‐C3‐N torsional angles, as compared to less crowded 3‐phenyl‐1,2,3,4‐tetrahydroisoquinolines. Here the heterocyclic ring adopts a distorted half‐chair conformation.

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

“…Despite its wide occurrence, no systematic study has been made of the conformational equilibrium (axial f equatorial) of substituents on the heterocyclic ring of THIQ. In an early X-ray crystallographic study of quaternary salts 4 it was found that this ring has the shape of a half-chair (3), a conclusion which was confirmed in later studies of 1-5 and 3-substituted 6 THIQs.…”

“…The value for 3-methyl is smaller, 1.6 kcal mol -1 , presumably because one of the syn-axial Me/H interactions is replaced by Me/lone pair, the lone pair being less "space consuming" than a hydrogen atom. 18 In contrast, the value for 2-methyl, 2.5 kcal mol -1 , is substantially larger, presumably because the axial methyl group is considerably closer to the synaxial hydrogen atom [at C (6)] than in cyclohexane and thus sterically more destabilized. (This results from the shorter C-N distance, 147 pm, as compared to C-C, 153 pm.)…”

Synthesis of Chiral Tetrahydroisoquinoline and C 2-Symmetric Bistetrahydroisoquinoline Ligands and Their Application in the Enantioselective Henry Reaction

“…With a low energy barrier for N-inversion, 26 Bowen et al 27 demonstrated the significant presence of two conformers of THIQs in which the N-H was at the pseudoaxial or pseudoequatorial positions. 28 We believe that restricting the N-inversion would give more conformationally restricted THIQ ligands and this would lead to improvement in the enantioselectivity. Therefore, we prepared N-methylated ligands 7a-h. To examine the axial/equatorial disposition at the nitrogen, the chemical shifts of the C1-protons of the THIQs were compared before and after N-methylation.…”

Racemic and Diastereoselective Synthesis of Aryl and Heteroaryl Tetrahydroisoquinolines via the Pictet—Spengler Reaction.

“…Conversely, the signals of the C(1) and C(3) for carbon atoms in cisisomers appeared at a lower field in the nmr spectra than those of the corresponding trans-isomers, as already described by Cook and co-workers [19,52] for the tetrahydro-β-carboline analogues. Conformational analysis [56] and examination of molecular models showed two possible half chair conformations (A or B, Figure 1) for the cisisomer 13a. Conformer A should represent the structure of the more stable species due to the unfavoured interactions between both the axial methyl ester and p-cyano-phenyl groups in the conformer B.…”