molecules Article Transamidation of Amides and Amidation of Esters by Selective N–C(O)/O–C(O) Cleavage Mediated by Air- and Moisture-Stable Half-Sandwich Nickel(II)–NHC Complexes Jonathan Buchspies †, Md. Mahbubur Rahman † and Michal Szostak * Department of Chemistry, Rutgers University, 73 Warren Street, Newark, NJ 07102, USA; [email protected] (J.B.); [email protected] (M.M.R.) * Correspondence: [email protected]; Tel.: +1-973-353-5329 † These authors contributed equally to this work. Abstract: The formation of amide bonds represents one of the most fundamental processes in organic synthesis. Transition-metal-catalyzed activation of acyclic twisted amides has emerged as an increasingly powerful platform in synthesis. Herein, we report the transamidation of N-activated twisted amides by selective N–C(O) cleavage mediated by air- and moisture-stable half-sandwich Ni(II)–NHC (NHC = N-heterocyclic carbenes) complexes. We demonstrate that the readily available cyclopentadienyl complex, [CpNi(IPr)Cl] (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene), promotes highly selective transamidation of the N–C(O) bond in twisted N-Boc amides with non- nucleophilic anilines. The reaction provides access to secondary anilides via the non-conventional amide bond-forming pathway. Furthermore, the amidation of activated phenolic and unactivated methyl esters mediated by [CpNi(IPr)Cl] is reported. This study sets the stage for the broad utilization of well-defined, air- and moisture-stable Ni(II)–NHC complexes in catalytic amide bond-forming Citation: Buchspies, J.; Rahman, protocols by unconventional C(acyl)–N and C(acyl)–O bond cleavage reactions. M.M.; Szostak, M. Transamidation of Amides and Amidation of Esters by Keywords: transamidation; twisted amides; NHCs; N-heterocyclic carbenes; nickel; Buchwald– Selective N–C(O)/O–C(O) Cleavage Hartwig; amidation; cyclopentadienyl; nickel–NHCs; amide bonds; N–C activation; [CpNi(NHC)X] Mediated by Air- and Moisture-Stable Half-Sandwich Nickel(II)–NHC Complexes. Molecules 2021, 26, 188. https://doi.org/10.3390/molecules 1. Introduction 26010188 The amide bond represents one of the most fundamental and important functional groups in organic synthesis [1–3]. It is estimated that amide bonds are the common Academic Editor: Derek J. McPhee structural motif in more than 75% of new pharmaceuticals, while new methods for the Received: 10 December 2020 formation of amide bonds have been intensively investigated [4,5]. In this context, transami- Accepted: 24 December 2020 Published: 2 January 2021 dation reactions represent a highly attractive, unconventional method for the synthesis of amide bonds by transforming a more reactive amide bond into a new, more thermo- Publisher’s Note: MDPI stays neu- dynamically stable amide counterpart [6–10]. In recent years, the selective activation of tral with regard to jurisdictional clai- C(acyl)–N amide bonds has been achieved by the controlled metal insertion into the reso- ms in published maps and institutio- nance activated bonds in twisted amides (i.e., non-planar amides) [11–13]. This general * nal affiliations. approach circumvents the low reactivity of amides resulting from nN!π C=O conjugation (resonance of 15–20 kcal/mol in planar amides), while providing a powerful platform for organic synthesis [14,15]. Transamidation reactions of twisted amide N–C(O) bonds have been achieved using well-defined Pd(II)–NHC catalysts as well as by using air- Copyright: © 2021 by the authors. Li- sensitive Ni(cod)2 in combination with NHC ligands [16–21]. These reactions provide censee MDPI, Basel, Switzerland. a variety of novel methods for the synthesis of ubiquitous amide bonds and have been This article is an open access article extended to catalytic amidation reactions of activated phenolic and unactivated methyl distributed under the terms and con- esters by O–C(O) cleavage [22–25]. In continuation of our studies on activation of amide ditions of the Creative Commons At- bonds and organometallic catalysis, in this Special Issue of Editorial Board members of the tribution (CC BY) license (https:// Organometallic Section of Molecules, we report transamidation of N-activated amides by creativecommons.org/licenses/by/ 4.0/). selective N–C(O) cleavage mediated by air- and moisture-stable half-sandwich Ni(II)–NHC Molecules 2021, 26, 188. https://doi.org/10.3390/molecules26010188 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 8 Molecules 2021, 26, 188 2 of 8 N–C(O) cleavage mediated by air- and moisture-stable half-sandwich Ni(II)–NHC (NHC = N-heterocyclic carbenes) complexes [26–33]. Most importantly, we demonstrate that (NHCreadily = N available-heterocyclic cyclopentadienyl carbenes) complexes complex [26–33]. extensively Most importantly, developed we demonstrate by Chetcuti, namely that[CpNi(IPr)Cl] readily available (IPr cyclopentadienyl = 1,3-bis(2,6-diisopropylphenyl)imidazol complex extensively developed by-2- Chetcuti,ylidene) namely [34–43], promotes [CpNi(IPr)Cl]highly selective (IPr = transamidation 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) of the N–C(O) bond in twisted [34– N43-],Boc promotes amides with non- highlynucleophilic selective anilines transamidation (Figure of 1). the The N–C(O) reaction bond provides in twisted access N-Boc to amides secondary with non- anilides via the nucleophilic anilines (Figure1 ). The reaction provides access to secondary anilides via the non-conventionalnon-conventional amide amide bond-forming bond-forming pathway. pathway. Furthermore, Furthermore, the amidation the ofamidation activated of activated phenolicphenolic and and unactivated unactivated methyl methyl esters esters mediated mediated by [CpNi(IPr)Cl] by [CpNi(IPr)Cl] is reported. is This reported. study This study setssets the the stage stage for thefor broad the broad utilization utilization of well-defined, of well air--defined, and moisture-stable air- and moisture Ni(II)–NHC-stable Ni(II)– complexesNHC complexes in catalytic in amidecatalytic bond-forming amide bond protocols-forming by unconventionalprotocols by unconventiona C(acyl)–N and l C(acyl)–N C(acyl)–Oand C(acyl) bond–O cleavage bond cleavage reactions. reactions. FigureFigure 1. 1.Transamidation Transamidation of N-activated of N-activated amides amides by selective by N–C(O)selective cleavage. N–C(O) cleavage. 2.2. Results Results Although we have identified well-defined Pd(II)–NHC complexes for transamida- tion reactionsAlthough of activatedwe have amides identified and esters well [-18defined–21], we Pd(II) have– beenNHC investigating complexes air- for transami- anddation moisture-stable reactions of Ni(II)–NHCs activated amides based on and naturally esters more[18–21], abundant we have Ni as been 3d transi-investigating air- tionand metal moisture [26–28-].stable We were Ni(II) attracted–NHCs to based the well-defined, on naturally air- andmore moisture-stable, abundant Ni half-as 3d transition sandwich,metal [26 cyclopentadienyl–28]. We were [CpNi(IPr)Cl] attracted to complex the well (Figure-defined,2) owing air- to and its ready moisture availability,-stable, half-sand- easewich, of handlingcyclopentadienyl and the potential [CpNi(IPr)C to preparel] morecomplex reactive (Figure cyclopentadienyl 2) owing to Ni(II)–NHC its ready availability, analogues [29–33]. Notably, [CpNi(IPr)Cl] has emerged as a highly attractive catalyst for ease of handling and the potential to prepare more reactive cyclopentadienyl Ni(II)–NHC several classes of cross-coupling reactions [29–33]; however, transamidations and amida- tionanalogues reactions [29 using–33]. this Notably, well-defined [CpNi(IPr)Cl] catalyst have has been emerged elusive. as a highly attractive catalyst for several classes of cross-coupling reactions [29–33]; however, transamidations and ami- dation reactions using this well-defined catalyst have been elusive. MoleculesMolecules 20212021, 26, 26, x, 188FOR PEER REVIEW 3 of 8 3 of 8 Molecules 2021, 26, x FOR PEER REVIEW 3 of 8 Figure 2. Structure of the air- and moisture-stable, well-defined, half-sandwich, cyclopentadienyl Figure[CpNi(IPr)Cl]Figure 2. Structure2. Structure complex. of the of air- the and air moisture-stable,- and moisture well-defined,-stable, well half-sandwich,-defined, half cyclopentadienyl-sandwich, cyclopentadienyl [CpNi(IPr)Cl][CpNi(IPr)Cl] complex. complex. We initiated our studies by evaluating the reaction conditions for the [CpNi(IPr)Cl]- catalyzedWe initiated transamidation our studies of byN-Boc evaluating activated the amide reaction 1a conditionswith 4-methoxyaniline for the [CpNi(IPr)Cl]- 2a (Table catalyzed1). Of note,We transamidation initiatedtwisted N-Boc our of amidesstudies N-Boc are activatedby readily evaluating prepared amide 1a the fromwith reaction the 4-methoxyaniline corresponding conditions 2asecondary for(Table the [CpNi(IPr)Cl]- 1amides).catalyzed Of note, by N transamidation twisted-chemoselective N-Boc amides tert of-butoxycarbonylation. N are-Boc readily activated prepared amideThe from N-carbamate 1a the with corresponding 4activation-methoxyaniline sec-per- 2a (Table ondarymits1). Of for amidesnote, decreasing twisted by N -chemoselectiveamidic N- Bocresonance amidestert (RE,-butoxycarbonylation. are resonance readily energy, prepared The7.2 kcalN from-carbamate/mol), the while corresponding activation provid- secondary permitsingamides a thermodynamic for by decreasing N-chemoselective pathway amidic resonancefor transamidatert-butoxycarbonylation. (RE,tion resonance by