Unique Structural Properties of 2,4,6‐Tri‐tert‐butylanilide: Isomerization and Switching between Separable Amide Rotamers through the Reaction of Anilide Enolates

Abstract

Herein, we report a unique structural property of 2,4,6-tri-tert-butylanilide, which can be separated into its amide rotamers at room temperature. Interconversion between the rotamers of anilide enolates occurs readily at room temperature and their reaction with electrophiles gives mixtures of the rotamers in a ratio that depends on the reactivity of the corresponding electrophile. That is, the reaction of the 2,4,6-tri-tert-butylacetanilide enolate with reactive electrophiles, such as allyl bromide or protic acids, gives mixtures of the anilide rotamers in which the E rotamer is the major component, whereas less-reactive electrophiles, such as 1-bromopropane and 2-iodopropane, yield mixtures of the rotamers in which the Z rotamer is the major component. The rotameric ratio of the product is also strongly dependent on the reactivity of the anilide enolate. Switching between the anilide rotamers can be achieved through protonation of a less-reactive enolate by a less-reactive protic acid and thermal isomerization of the anilide.

Why Do N-Alkylated Anilides Bend Over? The Factors Dictating the Divergent Conformational Preferences of 2° and 3° N-Aryl Amides

“…In contrast to 2° amides, for which the trans conformation is nearly universally favored over the cis conformation (as shown in Figures and ), N -alkyl- N -aryl 3° amides demonstrate the opposite conformational preference. Both experimental and computational results from dozens of independent researchers, together studying hundreds examples of N -alkyl- N -aryl 3° amides have clearly identified that the cis conformation is generally favored over the trans conformation by between 0.5 and 5 kcal/mol. − Multiple studies have even taken advantage of this conformational preference, using 3° amides as cis backbones for chelating ligands and macromolecular architecture, , for preorganization to facilitate synthesis of lactams, , or for restricting rotation. − Okamoto et al synthesized 3° N -pyridyl amides and demonstrated that the conformational preference can switch upon the addition of acid , or in solvents capable of hydrogen bonding …”

Computational and DNMR Analysis of the Conformational Isomers and Stereodynamics of Secondary 2,2′-Bisanilides

“…The E / Z -isomerism and atropisomerism of tertiary benzamides, naphthamides and other structural analogues showing restricted rotation about the aryl-carbonyl bond have been studied by Clayden, Walsh, and others and are well-known to play important roles in asymmetric synthesis, medicinal chemistry, and chiral amplification processes . For similar reasons, Curran and others have investigated the relative stability and interconversion of rotational conformers and E / Z -isomers of tertiary anilides in great detail . Despite the remarkable utility of secondary anilides as auxiliary groups in asymmetric synthesis, the dynamic stereochemistry of this structural motif remains largely unexplored …”