Structural Characterization of N‐Alkylated Twisted Amides: Consequences for Amide Bond Resonance and N−C Cleavage

Abstract

Herein, we describe the first structural characterization of N-alkylated twisted amides prepared directly by Nalkylation of the corresponding non-planar lactams.This study provides the first experimental evidence that N-alkylation results in ad ramatic increase of non-planarity around the amide N À C(O) bond. Moreover,w er eport ar are example of amolecular wire supported by the same amide C = O-Ag bonds. Reactivity studies demonstrate rapid nucleophilic addition to the NÀC(O) moiety of N-alkylated amides,indicating the lack of n N to p * C=O conjugation. Most crucially,wedemonstrate that N-alkylation activates the otherwise unreactive amide bond towards s NÀCcleavage by switchable coordination.Over the last three decades,t wisted amides have emerged as valuable transition state mimics of numerous biologically relevant enzymatic reactions. [1][2][3][4] Studies have implicated Ncoordination as am ethod to disrupt the amide bond resonance,w here as uitable ligand activates the amide bond towards isomerization [5] or s N À Cb ond cleavage.[6] The characterization of N-protonated amides represents asignificant challenge because the O-protonated structure is more thermodynamically stable than the N-protonated one (e.g. formamide,1 3.9 kcal mol À1 ); [7] to date only few structural examples of N-protonated amides have been reported (Figure 1A). [8] There is an intrinsic bias favoring N-alkylation vs. O-alkylation by ca. 2.5 kcal mol À1 compared with N-/Oprotonation affinities.[9] O-methylation of dimethylacetamide is favored over N-alkylation by ca. 3kcal mol À1 .[9] N-alkylation of amides plays ac rucial role in av ast range of biologically relevant mechanisms, [10a-g] including enzymatic N-methylation of carboxamido groups, [10a] enzymatic Nalkylation of toxins, [10b] and N-alkylation of polypeptides; [10c] however, the study of N-alkylation of non-planar amides has been severely limited.[11] Alkyl groups exert amore stabilizing effect on the NÀC(O) bond than Hd ue to s C-H to s* N-C hyperconjugation; [12] however, alkyl functions are also more sterically-demanding,w hich contributed to the formidable challenge in straightforward isolation of N-alkylated species. [11] Recently,t here has been as ignificant interest in the activation of NÀC(O) amide bonds by selective metal insertion into the NÀC(O) bond.[13] To date,the vast majority of these transformations involve ag round-state amide distortion [14] such as twisted cyclic imides reported by our group [14a,b,g,h] and acyclic twisted imides reported independently by Zou [14c] and Garg, [14d,e] where N-coordination [7f,g] is believed to activate the amide bond towards metal insertion ( Figure 1B). Moreover,w hile deuterium labeling has been used to investigate mechanisms of amide bond activation, [6a] the NH proton undergoes exchange.T hus,astraightforward access to N-alkylated amides would shed light on the mechanistic details of the NÀCb ond activation reactions.Herein, we demonstrate the first structural characterization of N-alkylated twi...

Synthesis of Symmetric and Unsymmetric Secondary Amines from the Ligand-Promoted Ruthenium-Catalyzed Deaminative Coupling Reaction of Primary Amines

“…10 Catalytic C–N cleavage methods have also been successfully utilized for constructing nitrogen heterocycles. 11 …”

ChemInform Abstract: Nucleophilic and Electrophilic Activation of Non‐Heteroaromatic Amides in Atom‐Economical Asymmetric Catalysis

“…Recently,a ni ntriguing exploration of the CÀNb ond cleavage of amides by using twisted amides and transition metal catalysis has gained growinga ttentiona sapromising tool in organic synthesis. [35] Productive interplay of the new activation mode and enantioselectivec arbon-carbon bond-forming reactions in the near future is highly anticipated.…”

Structures of the Most Twisted Thioamide and Selenoamide: Effect of Higher Chalcogens of Twisted Amides on N−C(X) Resonance

“…The structure of 4 b was unambiguously confirmed by X‐ray crystallography (Figure 3E). This reactivity stands in sharp contrast to the isologous twisted amide 3 , which has been shown to undergo N‐protonation, [34] N‐methylation [34] and σ N−C scission [35] under identical reaction conditions (Figure 3B). Furthermore, we established that the twisted thioamide 4 undergoes reactions with the preservation of the bridged structure to give an unusual bridged amidine ( 4 d ) and saturated twisted thioamide 7 (Figure 3C).…”

“…This system features significantly distorted amide bond ( τ =30.8°; χ N =49.7°; Σ( τ +χ N )=80.5° in the parent amide, Winkler–Dunitz parameters) [16] . Electronically, N‐/O‐ protonation is at the cross‐over point, where N‐ and O‐protonated forms are almost equal in energy, [14] while the x‐ray structure of the parent amide [34] and reactivity of the amide linkage in 1‐azabicyclo[3.3.1]nonan‐2‐one system are well‐established, including N−C(O) reactivity, [34] σ N−C scission, [34, 35] remote C=C cleavage [36] and polymerization, [37] permitting facile comparison of structure and reactivity.…”

“…The Winkler‐Dunitz parameters in 4 indicate χ N of 48.3° and τ of 23.8°, with the additive parameter Σ( τ +χ N ) of 72.1°. The availability of the X‐ray structure of the parent twisted amide 3 [34] (Figure 2C) permits to elucidate the structural changes of isologous N→C=O to N→C=S exchange. The thioamide bond distortion in 4 can be compared with the amide bond parameters of χ N =49.7°, τ =30.8°, N−C(O)=1.386 Å; C=O of 1.226 Å.…”