Amide N–C(O) bond activation and designing of NHC ligands for organic transformations
Creators: name: Rahman, Md. Mahbubur
Publisher: name: No Publisher Supplied
Year: 2021

description: The amide bond is one of the most important functional group in chemistry, biology and materials science. At the same time, NHCs (NHC = N-heterocyclic carbene) are among the most important ligands that are extensively utilized in organometallic chemistry, catalysis and organic synthesis, where their unique electronic and steric properties mimic the characteristics of tertiary phosphines. One of the main challenges in activating amide bonds is the high stability of amides resulting from nN→π*C=O (15–20 kcal/mol) resonance, which renders the amide N−C(O) bond very difficult to cleave. With respect to NHC ligands, ItBu (ItBu = 1,3-di-tert-butylimidazol-2-ylidene) represents the most important and versatile N-alkyl N-heterocyclic carbene available in organic synthesis and catalysis. This dissertation will (1) address the challenges in activating amide bonds enabled by the development of efficient ground-state-destabilization methods to facilitate N–C(O) bond activation for acyl addition and cross-coupling reactions via acyl-metal or tetrahedral intermediates; (2) demonstrate the synthesis, characterization and catalytic studies of more sterically-hindered analogues of ItBu, which represent the most bulky N-alkylN-heterocyclic carbenes prepared to date. The first part of this thesis will detail our studies on the effect of activating group on the structures, electronic properties and reactivity of activated amides. We developed a family of N-acyl-glutarimide amides that achieve full twist of the amide bond (τ = 89.1°) and show high reactivity in cross-coupling reactions. Furthermore, we developed N-acyl-δ-valerolactams as a highly effective class of mono-N-acyl-activated amide precursors in cross-coupling that are characterized by a substantial distortion of the amide bond (Σ(τ+χN) = 54.0°). This dissertation will also discuss the development of highly chemoselective transition-metal-free methods for transamidation, thioesterification, selenoesterification and synthesis of sulfoxonium ylides from amides by N–C(O) cleavage via tetrahedral intermediates. These exceedingly mild procedures show broad substrate scope and tolerate a large number of useful functional groups. Moreover, application to the novel synthesis of Tigan, an antiemetic drug, and late-stage derivatization of pharmaceuticals will be described. The second part of this thesis will detail the synthesis, structural characterization and catalytic studies of three classes of NHC ligands, namely ItOct, SItOct, ItOct-bimy, ItHept and SItHept. These N-alkyl NHC ligands are higher homologues of ItBu, while their unique steric and electronic properties make them potentially very attractive in various applications in chemical science, including organometallic chemistry, organic synthesis and catalysis. In this part, we will demonstrate that replacement of the t-Bu side chain with t-Oct or t-Hept side chains results in a significantly increased steric volume, while retaining the electronic properties inherent to N-alkyl NHC ligands, such as strong σ-donation and π-acceptance. Simple and efficient large-scale syntheses of the imidazolium (SItOct, SItHept), imidazolinium (SItOct, SItHept) and benzimidazolium (ItOct-bimy) precursors will be described. Beneficial effects in using the sterically-demanding N-alkyl NHC ligands in catalysis using their complexes with Au, Cu, Ag and Pd will be presented. Considering the tremendous importance of ItBu, we anticipate that this new class of ItOct, ItHept and ItOct-bimy ligands will find wide application in organic synthesis.