Conformational analysis of chiral hindered amides

Abstract

The static and dynamic structures of the amide derivatives of racemic and (R)-(+)-2-methoxy-2-phenyl-3,3,3-trifluoropropanoic acid (MPTA) with diisopropyl amine (1), meso-2,6-dimethylpiperidine (2), (R)-(−)- and (S)-(+)-2-methylpiperidine (3 and 4, respectively) were investigated by proton nmr spectroscopy. The piperidine rings adopt a single dominant conformation in which the substituent methyl groups occupy axial positions. One of the isopropyl groups of 1 is oriented in the same way as the corresponding side of the piperidine ring of 2–4 but the other (syn to carbonyl oxygen) is turned so that the methyl groups are toward the carbonyl oxygen and the oxygen lies in the plane bisecting the C—C—C angle. Rotation about the amide C(O)—N bond of 1 is accompanied by concurrent rotation about each of the N—iPr single bonds. The free energies of activation of the hindered rotation about the C(O)—N bond in 1–4, 81 kJ/mol, 77 kJ/mol, 77 kJ/mol, and 79 kJ/mol, respectively, are higher than found in most other hindered amides, suggesting that buttressing due to the steric crowding around the amide functionality is felt throughout the rotational pathway.

Synthesis and Repellent Efficacy of a New Chiral Piperidine Analog: Comparison with Deet and Bayrepel Activity in Human-Volunteer Laboratory Assays Against <I>Aedes aegypti</I> and <I>Anopheles stephensi</I>

“…The diastereoisomeric resolution of 2-methylpiperidine was accomplished by using commercially available (R)-(-)-mandelic acid as described by Craig and Pinder (1971) and Rauk et al (1983). This procedure was supposedly improved by Adamo et al (1999), but in our hands it failed to reproduce the reported yield.…”

Synthesis, NMR and Crystallographic Studies of 2-Substituted Dihydroquinazolinones Derived from (S)-Phenylethylamine

“…To highlight the usefulness of the NMR method, only δ values of specific hydrogen atoms attached to sp 3 carbons are commented briefly (however, complete data is given in the Experimental section). In the 1 H-NMR spectrum of 8, the diastereotopic hydrogens attached to C2 (H2) constitute the AB part of an ABC system.…”

“…The detection of the low energy conformation 1 of the resulting amides is fundamental to establish the correlation between the chemical shifts (δ) of the hydrogen nuclei of the amine moiety and the configuration of the chiral derivatizing agent [2]. Although this strategy can be used to study the configuration of cyclic secondary amines, inherent ring conformations and slow rotation about amide bonds (see 2) make it difficult to interpret the NMR spectra [3]. In this context, incorporation of a 1-arylethyl group as the amidic nitrogen substituent, might be the recommended strategy to avoid free rotation about amide bond.…”

Assignment of absolute configuration of cyclic secondary amines by NMR techniques using Mosher's method: a general procedure exemplified with (−)‐isoanabasine

“…1 -3 After initial studies on the applications of Mosher's method to secondary amines by Tavares and coworkers, 4,5 Hoye and Renner summarized the common characteristics of 1 H NMR spectra of Mosher's amides derived from cyclic secondary amines with a chiral center in the ring. 6,7 It has been proved that Hoye's protocol can be an efficient guideline for assigning the absolute configuration or enantiomeric excess of substituted cyclic secondary amines.…”