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

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 transamidation reactionsAlthough of activated we 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 amidation reactions using this well-defined catalyst have been elusive.

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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 rendering energy, the 7.2The leaving kcal/mol), N-carbamate group while non- activation per- providingnucleophilic a thermodynamic [14,15]. After optimization, pathway for we transamidation have identified by renderingconditions the for leaving the transami- group non-nucleophilicdationmits for in quantitative decreasing [14,15 ].yield Afteramidic using optimization, resonance [CpNi(IPr)Cl] we (RE, have (10 resonance identifiedmol%) as a conditions catalyst energy, in for 7.2the the presencekcal/mol), transami- of while provid- dationKing2CO a3 inasthermodynamic quantitativea base in toluene yield pathway usingat 140 [CpNi(IPr)Cl]°C (Tablefor transamidation 1, entry (10 mol%) 1). We as found by a catalyst rendering that K in3PO the4 the presenceis also leaving an group non- ◦ ofeffectivenu Kcleophilic2CO3 baseas a under base [14,15]. in these toluene After conditions at optimization, 140 (TableC (Table 1, entry1, entrywe 2). have 1).Furthermore, We identified found thatdecreasing conditions K 3PO 4theis alsocata- for the transami- anlystdation effective loading in basequantitative to [CpNi(IPr)Cl] under these yield conditions(5 mol%) using result (Table[CpNi(IPr)Cl]ed1 ,in entry lower 2). conversions (10 Furthermore, mol%) (Table as decreasing a catalyst1, entries the in3– the presence of catalyst4). Importantly, loading tocontrol [CpNi(IPr)Cl] reactions (5 in mol%) the absence resulted of inthe lower [CpNi(IPr)Cl] conversions catalyst (Table resulted1, entries in K2CO3 as a base in toluene at 140 °C (Table 1, entry 1). We found that K3PO4 is also an 3–4).the recovery Importantly, of the control starting reactions material, in thus the absencedemonstrating of the [CpNi(IPr)Cl] that the catalyst catalyst is required resulted for intheeffective the reaction recovery base (Table of under the 1, entries starting these 5–6). material, conditions Several thus other demonstrating(Table optimization 1, entry thatcondit 2). the Furthermore,ions catalyst are worth is required noting decreasing the cata- for(notlyst the shown): loading reaction (1) to (Tablelowering [CpNi(IPr)Cl]1, entries the reaction 5–6). (5 Severaltemper mol%)ature other resulted resulted optimization in in lower significantly conditions conversions lower are worthconver- (Table 1, entries 3– notingsion4). Importantly,(110 (not °C, shown): 26%); (1)control(2) loweringreactions reactions the at reactionlow incatalyst the temperature absence loading resultedresultedof the in[CpNi(IPr)in significantlylow conversionCl] lower catalyst (1 resulted in ◦ conversionmol%,the recovery 13%). (110 ofC, the 26%); starting (2) reactions material, at low catalystthus demonstrating loading resulted that in low the conversion catalyst is required for (1 mol%, 13%). the reaction (Table 1, entries 5–6). Several other optimization conditions are worth noting Table 1. Optimization of the transamidation of amide 1a using [CpNi(IPr)Cl].1 Table(not 1. shown):Optimization (1) oflowering the transamidation the reaction of amide temperat1a using [CpNi(IPr)Cl].ure resulted1 in significantly lower conversion (110 °C, 26%); (2) reactions at low catalyst loading resultedOMe in low conversion (1 O NH2 O mol%, 13%).Ph [CpNi(IPr)Cl] (cat.) N N + H Boc Table 1. Optimization of the transamidationbase, toluene of amide 1a using [CpNi(IPr)Cl].1 140 °C OMe 1a 2a 3a

EntryEntry Catalyst Catalyst [Ni] (mol%)(mol%) Base Base Solvent Solvent Yield Yield (%) (%)2 2 1 [CpNi(IPr)Cl] 10 K2CO3 toluene >98 1 [CpNi(IPr)Cl] 10 K2CO3 toluene >98 22 [CpNi(IPr)Cl] 1010 K K33POPO4 4 toluenetoluene >98 >98 33 [CpNi(IPr)Cl] 55 K K22COCO3 3 toluenetoluene 74 74 4 [CpNi(IPr)Cl] 5 K3PO4 toluene 52 4 [CpNi(IPr)Cl] 5 K3PO4 toluene 52 5 [CpNi(IPr)Cl] -K2CO3 toluene <10 5 [CpNi(IPr)Cl] - K2CO3 toluene <10 6 [CpNi(IPr)Cl] -K3PO4 toluene <10 1 6 [CpNi(IPr)Cl] - K3PO4 toluene <10 Conditions: amide (1.0 equiv), 4-MeO-C6H4-NH2 (2.0 equiv), base (3.0 equiv), [Ni] (0–10 mol%), 2 1 tolueneConditions:Entry (0.25 M),amide 140 ◦(1.0C, 18 equiv),Catalyst h. 2 Determined 4-MeO-C by6H[Ni]14H-NMR.-NH (mol%)2 (2.0 equiv), base Base(3.0 equiv), [Ni] (0–10Solvent mol%), Yield (%) 2 1 toluene (0.251 M), 140 [CpNi(IPr)Cl]°C, 18 h. Determined by H-NMR.10 K2CO3 toluene >98 With the optimized conditions in hand, the scope of the transamidation reaction cat- 2 [CpNi(IPr)Cl] 10 K3PO4 toluene >98 alyzedWith by the the well-deﬁned optimized conditions [CpNi(IPr)Cl] in hand, complex the scope was examined of the transamidation with respect to reaction the aniline cat- componentalyzed by3 the (Table well-defined2).[CpNi(IPr)Cl] As shown, [CpNi(IPr)Cl] the reaction complex performed5 was well examinedK using2CO electron-donating3with respecttoluene to the ( 3a ani-), 74 para-substitutedline component4 (Table (3b[CpNi(IPr)Cl]), ortho-sterically 2). As shown, the hindered reac5tion (3c performed), meta-substitutedK well3PO using4 ( 3delectron-donating), andtoluene electron- 52 withdrawing(3a), para-substituted (3e–f) anilines. (3b), ortho-sterically It is worthwhile hindered to note that (3c), the meta-substituted reaction efﬁciency (3d), decreased and elec- 5 [CpNi(IPr)Cl] - K2CO3 toluene <10 6 [CpNi(IPr)Cl] - K3PO4 toluene <10 1 Conditions: amide (1.0 equiv), 4-MeO-C6H4-NH2 (2.0 equiv), base (3.0 equiv), [Ni] (0–10 mol%), toluene (0.25 M), 140 °C, 18 h. 2 Determined by 1H-NMR.

With the optimized conditions in hand, the scope of the transamidation reaction catalyzed by the well-defined [CpNi(IPr)Cl] complex was examined with respect to the aniline component (Table 2). As shown, the reaction performed well using electron-donating (3a), para-substituted (3b), ortho-sterically hindered (3c), meta-substituted (3d), and elec-

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tron-withdrawing (3e–f) anilines. It is worthwhile to note that the reaction efficiency decreased using electron-deficient nucleophiles. Furthermore, di-ortho-substituted anilines Molecules 2021, 26, x FOR PEER REVIEWwere unproductive substrates in the reaction, indicating excessive steric hindrance. 4 of 8

Next, the scope of the reaction with respect to the amide group was evaluated (Table Molecules 2021, 26, 188 3). As shown, primary and secondary alkyl amides (3g–h), electron-rich (3i–j) as well4 of as 8 tron-withdrawingelectron-deficient (3e3k–) f)aromatic anilines. amides It is worthwhile underwent to noteefficient that transamidationthe reaction efficiency under Ni–de- creasedNHC catalysis. using electron-deficient Furthermore, cinnamyl nucleophiles. amide Furthermore,was found to bedi-ortho-substituted a suitable reaction anilines partner werefor the unproductive transamidation substrates (3l). Similar in the to reaction the scope, indicating of anilin es,excessive steric hindrance steric hindrance. on the amide usingcomponent electron-deﬁcient was not tolerated. nucleophiles. Furthermore, di-ortho-substituted anilines were unproductiveNext, the substratesscope of the in reaction the reaction, with indicating respect to excessivethe amide steric group hindrance. was evaluated (Table 3). As shown, primary and secondary alkyl amides (3g–h), electron-rich (3i–j) as well as Table 2. Scope of anilines in the transamidation of amide 1a using [CpNi(IPr)Cl].1 Tableelectron-deficient 2. Scope of anilines (3k) inaromatic the transamidation amides underwent of amide 1a efficientusing [CpNi(IPr)Cl]. transamidation1 under Ni– NHC catalysis. Furthermore, cinnamyl amide was found to be a suitable reaction partner for the transamidation (3l). Similar to the scope of anilines, steric hindrance on the amide component was not tolerated.

Table 2. Scope of anilines in the transamidation of amide 1a using [CpNi(IPr)Cl].1

2 2 EntryEntry AmideAmide Ar-NHAr-NH2 2 33 YieldYield (%) (%) 1 C6H5 4-MeO-C6H4 3a 98 1 C6H5 4-MeO-C6H4 3a 98 22 CC6H6H5 5 4-Me-C4-Me-C6H6H4 4 3b3b 9797 33 CC6H6H5 5 2-Me-C2-Me-C6H6H4 4 3c3c 7777 4 C H 3,5-Me -C H 3d 71 4 C6 6H5 5 3,5-Me2 2-C6 6H3 3 3d 71 5 C6H5 4-F-C6H4 3e 64 Entry5 AmideC6H5 4-F-CAr-NH6H2 4 3e3 Yield64 (%) 2 6 C6H5 4-CF3-C6H4 3f 43 16 CC66HH55 4-MeO-C4-CF3-C66HH44 3a3f 9843 1 Conditions: amide (1.0 equiv), Ar-NH (2.0 equiv), K CO (3.0 equiv), [CpNi(IPr)Cl] (10 mol%), 1 2 2 3 tolueneConditions: (0.252 M), amide 140 ◦ (1.0C, 18 equiv), h.C26DeterminedH5 Ar-NH 2 by(2.014-Me-CH-NMR. equiv),6 KH24CO 3 (3.0 equiv),3b [CpNi(IPr)Cl] (1097 mol%), toluene (0.25 M), 140 °C, 18 h. 2 Determined by 1H-NMR. 3 C6H5 2-Me-C6H4 3c 77 Next, the scope of the reaction with respect to the amide group was evaluated (Table3 ). 4 C6H5 3,5-Me2-C6H3 3d 71 AsTable shown, 3. Scope primary of amides and in secondarytransamidation alkyl with amides aniline ( 3g2a –usingh), electron-rich [CpNi(IPr)Cl]. (13i –j) as well as 5 C6H5 4-F-C6H4 3e 64 electron-deﬁcient (3k) aromatic amides underwent efﬁcient transamidation under Ni– 6 C6H5 4-CF3-C6H4 3f 43 NHC catalysis. Furthermore, cinnamyl amide was found to be a suitable reaction partner 1 Conditions: amide (1.0 equiv), Ar-NH2 (2.0 equiv), K2CO3 (3.0 equiv), [CpNi(IPr)Cl] (10 mol%), for the transamidation (3l). Similar to the scope of anilines, steric hindrance on the amide toluene (0.25 M), 140 °C, 18 h. 2 Determined by 1H-NMR. component was not tolerated. Table 3. Scope of amides in transamidation with aniline 2a using [CpNi(IPr)Cl].1 Table 3. Scope of amides in transamidation with aniline 2a using [CpNi(IPr)Cl].1

Entry Amide Ar-NH2 3 Yield (%) 2 1 n-C9H19 4-MeO-C6H4 3g 92 2 Cyclohexyl 4-MeO-C6H4 3h 98 3 4-Me-C6H4 4-MeO-C6H4 3i 86

4 4-MeO-C6H4 4-MeO-C6H4 3j 62 2 2 Entry5 4-CF Amide3-C6H 4 4-MeO-C Ar-NHAr-NH2 26 H4 33k3 Yield62 (%) (%) 16 Ph-CH=CHn-C9H19 4-MeO-C4-MeO-C66HH44 3g3l 9273 1 n-C9H19 4-MeO-C6H4 3g 92 1 2 2 3 Conditions:22 amide (1.0Cyclohexyl equiv), Ar-NH (2.0 4-MeO-C equiv),6 KH6H4CO4 (3.0 equiv),3h3h [CpNi(IPr)Cl] (109898 mol%), toluene (0.25 M), 140 °C, 18 h. 2 Determined by 1H-NMR. 33 4-Me-C6H6H4 4 4-MeO-C6H6H4 4 3i3i 8686 4 4-MeO-C H 4-MeO-C H 3j 62 4 4-MeO-C6 6H4 4 4-MeO-C6 6H4 4 3j 62 In consideration5 4-CF of the3-C 6promisingH4 4-MeO-C reactivi6tyH 4of twisted N-Boc3k amides using62 well-de- 5 4-CF3-C6H4 4-MeO-C6H4 3k 62 fined cyclopentadienyl6 Ph-CH=CH half-sandwich 4-MeO-C[CpNi(IPr)Cl],6H4 we further3l explored amidation73 reac- 1 6 Ph-CH=CH 4-MeO-C6H4 3l 73 tionsConditions: of activated amide (1.0phenolic equiv), Ar-NHesters2 (2.0and equiv), unactivated K2CO3 (3.0 methyl equiv), esters [CpNi(IPr)Cl] (Schemes (10 mol%), 1 and 2). We 1 Conditions: amide ◦(1.0 equiv),2 Ar-NH2 (2.01 equiv), K2CO3 (3.0 equiv), [CpNi(IPr)Cl] (10 mol%), weretoluene pleased (0.25 M), to 140 findC, 18 that h. Determinedthe amidation by H-NMR. of phenyl benzoate proceeded in quantitative toluene (0.25 M), 140 °C, 18 h. 2 Determined by 1H-NMR. yieldIn using consideration K3PO4 as a of base the promisingunder otherwise reactivity the same of twisted reaction N-Boc conditions amides as using those well- used deﬁnedfor theIn transamidationconsideration cyclopentadienyl of of the amides half-sandwich promising (Scheme reactivi [CpNi(IPr)Cl], 1). Importantly,ty of twisted we control N-Boc further reactions amides explored using in the amidation well-de- absence reactionsfinedof the cyclopentadienyl catalyst of activated unambiguously phenolic half-sandwich verified esters and[CpNi(IPr)Cl], that unactivated [CpNi(IPr)Cl] we methyl further is required esters explored (Schemesfor amidationthe reaction.1 and reac-2 ).In- Wetionsterestingly, were of activated pleased we also to phenolic ﬁnd found that thatesters the amidation and unac ofoftivated phenylunactivated methyl benzoate methylesters proceeded (Schemesbenzoate in 1proceeded quantitative and 2). We in yieldwere usingpleased K3 POto find4 as athat base the under amidation otherwise of phenyl the same benzoate reaction proceeded conditions in as quantitative those used foryield the using transamidation K3PO4 as a of base amides under (Scheme otherwise1). Importantly, the same reaction control conditions reactions in as the those absence used

offor the the catalysttransamidation unambiguously of amides veriﬁed (Scheme that 1). Importantly, [CpNi(IPr)Cl] control is required reactions for in the the reaction. absence Interestingly,of the catalyst we unambiguously also found that verified amidation that [C ofpNi(IPr)Cl] unactivated is methylrequired benzoate for the reaction. proceeded In- interestingly, 67% yield, we while also a found substantial that amidation enhancement of unactivated of reactivity methyl (94% yield) benzoate was proceeded observed by in increasing the reaction temperature to 160 ◦C (Scheme2). As expected, no reaction was observed in the absence of [CpNi(IPr)Cl] (<2%, not detected).

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67% yield, while a substantial enhancement of reactivity (94% yield) was observed by in- creasing67% yield, the while reaction a substantial temperature enhancement to 160 °C (Scheme of reactivity 2). As (94% expected, yield) wasno reaction observed was by ob- in- 67%served creasingyield, in while the the reaction absence a substantial temperatureof [CpNi(IPr)Cl] enhancement to 160 (<2%, °C (Scheme not ofdetected). reactivity 2). As expected, (94% noyield) reaction was was observed ob- by in- creasingservedTo the ingain thereaction preliminary absence temperature of [CpNi(IPr)Cl] insight into to the (<2%,160 reaction °C not (Scheme detected). profile, kinetic 2). As studies expected, were noperformed reaction was observed(Figure inTo the 3).gain Asabsence preliminary shown, ofthe [CpNi(IPr)Cl] reactioninsight into reached the reaction (<2%,60% conversion not profile, detec kineticafterted). 3 h,studies while were77% conversionperformed (Figure 3). As shown, the reaction reached 60% conversion after 3 h, while 77% conversion wasTo gainobserved preliminary after 6 h. The insight induction into periodthe reaction was not profile, observed kinetic in the kineticstudies profiling were performed studies.was observed We tentatively after 6 h. propose The induction that the mechanismperiod was involvesnot observed oxidative in the addition kinetic ofprofiling the N– (Figurestudies. 3). As We shown, tentatively the propose reaction that reached the mechanism 60% conversion involves oxidative after addition3 h, while of the77% N– conversion Molecules 2021, 26, 188 C bond to nickel. Other nickel sources, such as NiCp2 or NiCl2, catalyze the reaction albeit5 of 8 was inCobserved bondlower to yields. nickel. after Studies Other 6 h. nickonThe theel inductionsources, mechanism such period andas NiCp the wasexpansion2 or NiCl not2 ,observed catalyzeof the substrate the in reaction the scope kine albeit aretic profiling studies.ongoingin lower We and yields.tentatively will Studies be reported propose on the in mechanismdue that course. the mechanism and the expansion involves of the oxidative substrate scopeaddition are of the N– ongoing and will be reported in due course. C bond to nickel. Other nickel sources, such as NiCp2 or NiCl2, catalyze the reaction albeit in lower yields. Studies on the mechanism and the expansion of the substrate scope are ongoing and will be reported in due course.

SchemeScheme 1. 1.Amidation Amidation of of activated activated phenolic phenolic ester ester using using [CpNi(IPr)Cl]. [CpNi(IPr)Cl]. Scheme 1. Amidation of activated phenolic ester using [CpNi(IPr)Cl].

Scheme 1. Amidation of activated phenolic ester using [CpNi(IPr)Cl].

Scheme 2. Amidation of unactivated methyl ester using [CpNi(IPr)Cl]. SchemeScheme 2. 2.Amidation Amidation of of unactivated unactivated methyl methyl ester ester using using [CpNi(IPr)Cl]. [CpNi(IPr)Cl].

To gain preliminary insight into the reaction proﬁle, kinetic studies were performed (Figure3). As shown, the reaction reached 60% conversion after 3 h, while 77% conversion was observed after 6 h. The induction period was not observed in the kinetic proﬁling studies. We tentatively propose that the mechanism involves oxidative addition of the N–C bond to nickel. Other nickel sources, such as NiCp2 or NiCl2, catalyze the reaction albeit Schemein lower 2. Amidation yields. Studies of unactivated on the mechanism methyl andester the using expansion [CpNi(IPr)Cl]. of the substrate scope are ongoing and will be reported in due course.

Figure 3. Kinetic profile of 1a. Conditions: 1a, 4-MeO-C6H4-NH2 (2.0 equiv), [CpNi(IPr)Cl] (10 6 4 2 mol%),Figure 3.K 2KineticCO3 (3.0 profile equiv), of toluene 1a. Conditions: (0.25 M), 1a 140, 4-MeO-C °C, 0–18 Hh. -NH (2.0 equiv), [CpNi(IPr)Cl] (10 mol%), K2CO3 (3.0 equiv), toluene (0.25 M), 140 °C, 0–18 h. 3. Materials and Methods 3. Materials and Methods General Information. General methods have been published [18].

GeneralGeneral ProcedureInformation. for General [CpNi(IPr)Cl] methods Catalyzed have been Transamidation. published [18]. In a typical procedure,General an oven-dried Procedure vial for was [CpNi(IPr)Cl] charged with Catalyzed a N-Boc Transamidation.amide or ester substrate In a typical (neat, proce- 1.0 dure, an oven-dried vial was charged with a N-Boc amide or ester substrate (neat, 1.0 equiv), aniline (2.0 equiv), K2CO3 (3.0 equiv), [CpNi(IPr)Cl] (10 mol%), placed under a equiv), aniline (2.0 equiv), K2CO3 (3.0 equiv), [CpNi(IPr)Cl] (10 mol%), placed under a

Figure 3. Kinetic proﬁle of 1a. Conditions: 1a, 4-MeO-C6H4-NH2 (2.0 equiv), [CpNi(IPr)Cl] ◦ Figure(10 mol%),3. Kinetic K2CO profile3 (3.0 equiv), of 1a toluene. Conditio (0.25ns: M), 1a 140, 4-C,MeO 0–18-C h.6H4-NH2 (2.0 equiv), [CpNi(IPr)Cl] (10 mol%), K2CO3 (3.0 equiv), toluene (0.25 M), 140 °C, 0–18 h. 3. Materials and Methods 3. MaterialsGeneral and Information. Methods General methods have been published [18]. General Procedure for [CpNi(IPr)Cl] Catalyzed Transamidation. In a typical procedure, anGeneral oven-dried Information. vial was charged General with methods a N-Boc amide have or been ester published substrate (neat, [18] 1.0. equiv), anilineGeneral (2.0 equiv),Procedure K2CO for3 (3.0 [CpNi(IPr)Cl] equiv), [CpNi(IPr)Cl] Catalyzed (10 mol%), Transamidation. placed under a In positive a typical procedure, an oven-dried vial was charged with a N-Boc amide or ester substrate (neat, 1.0 equiv), aniline (2.0 equiv), K2CO3 (3.0 equiv), [CpNi(IPr)Cl] (10 mol%), placed under a

Molecules 2021, 26, 188 6 of 8

pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. Toluene (0.25 M) was added at room temperature, the reaction was placed in a preheated oil bath at 140 ◦C, and stirred at 140 ◦C. After the indicated time, the reaction was cooled down, diluted with CH2Cl2 (10 mL), filtered, and concentrated. The sample was analyzed 1 by H-NMR (CDCl3, 500 MHz) and GC-MS to obtain conversion, selectivity and yield using internal standard and comparison with authentic samples. All yields have been 1 determined by H-NMR spectroscopy (CDCl3, 500 MHz). Representative Isolation Procedure for [CpNi(IPr)Cl] Catalyzed Transamidation. An oven-dried vial was charged with tert-butyl benzoyl(phenyl)carbamate (neat, 29.7 mg, 1.0 equiv), 4-methoxyaniline (24.6 mg, 2.0 equiv), K2CO3 (41.6 mg, 3.0 equiv), [CpNi(IPr)Cl] (10 mol%, 5.6 mg), placed under a positive pressure of argon, and subjected to three evacuation/backfilling cycles under high vacuum. Toluene (0.25 M) was added at room temperature, the reaction mixture was placed in a preheated oil bath at 140 ◦C, and stirred for 18 h at 140 ◦C. After the indicated time, the reaction was cooled down, diluted 1 with CH2Cl2 (10 mL), filtered, and concentrated. A sample was analyzed by H-NMR (CDCl3, 500 MHz) and GC-MS to obtain conversion, yield and selectivity using internal standard and comparison with authentic samples. Purification by chromatography on silica gel (hexanes/ethyl acetate) afforded the title product. Yield 88% (20.1 mg). N-(4- 1 Methoxyphenyl)benzamide. White solid. H-NMR (500 MHz, CDCl3) δ 7.86 (d, J = 7.5 Hz, 2 H), 7.76 (s, 1 H), 7.59–7.51 (m, 3 H), 7.47 (t, J = 7.4 Hz, 2 H), 6.91 (d, J = 8.9 Hz, 2 H), 3.81 13 (s, 3 H). C NMR (125 MHz, CDCl3) δ 157.00, 135.40, 132.04, 131.35, 129.10, 127.31, 122.43, 114.61, 55.86. [CpNi(IPr)Cl] has been prepared by the previously reported procedure [1].

4. Conclusions In summary, we have reported on the transamidation reactions of N-activated amides by selective N–C(O) cleavage mediated by the well-defined, air- and moisture-stable half- sandwich [CpNi(IPr)Cl] complex. This class of Ni(II)–NHC cyclopentadienyl complexes has gained significant attention in organometallic catalysis owing to the beneficial proper- ties of this class of catalysts; however, transamidation reactions of amides and amidation reactions of esters mediated by these complexes have been elusive. The present study demonstrates that highly selective transamidation of the N–C(O) bond in twisted N-Boc amides as well as activated phenolic and unactivated methyl esters with non-nucleophilic anilines under [CpNi(IPr)Cl] catalysis is feasible, thus providing an unconventional and unified method for the synthesis of secondary anilides by C(acyl)–N and C(acyl)–O bond cleavage reactions. It should be mentioned that the twisted amide starting materials are prepared from 2◦ amides by N-chemoselective tert-butoxycarbonylation [14], which provides a two-step transamidation method that could potentially be applied in late-stage derivatiza- tion of pharmaceuticals and natural products. The unique versatility of [CpNi(IPr)Cl] sets the stage for the broad application of Ni(II)–NHC cyclopentadienyl complexes in amide bond-forming reactions by N–C(O)/O–C(O) cleavage. Future studies will focus on the development of new classes of [CpNi(NHC)X] complexes for selective transformations of amide and ester bonds by N–C(O)/O–C(O) activation.

Author Contributions: J.B. and M.M.R. conducted experimental work and analyzed the data. M.S. supervised the project and wrote the paper. All authors contributed to the experiment design and reaction development. All authors have read and agreed to the published version of the manuscript. Funding: Rutgers University and the NSF (CAREER CHE-1650766) are acknowledged for support. The 500 MHz spectrometer was supported by the NSF-MRI grant (CHE-1229030). Conﬂicts of Interest: The authors declare no conﬂict of interest. Sample Availability: Samples of the compounds are not available from the authors. Molecules 2021, 26, 188 7 of 8

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