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

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 protocols by unconventional C(acyl)–N and C(acyl)–O bond cleavage reactions.


Introduction
The amide bond represents one of the most fundamental and important functional groups in organic synthesis [1][2][3]. It is estimated that amide bonds are the common structural motif in more than 75% of new pharmaceuticals, while new methods for the formation of amide bonds have been intensively investigated [4,5]. In this context, transamidation reactions represent a highly attractive, unconventional method for the synthesis of amide bonds by transforming a more reactive amide bond into a new, more thermodynamically stable amide counterpart [6][7][8][9][10]. In recent years, the selective activation of C(acyl)-N amide bonds has been achieved by the controlled metal insertion into the resonance activated bonds in twisted amides (i.e., non-planar amides) [11][12][13]. This general approach circumvents the low reactivity of amides resulting from n N →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 airsensitive Ni(cod) 2 in combination with NHC ligands [16][17][18][19][20][21]. These reactions provide a variety of novel methods for the synthesis of ubiquitous amide bonds and have been extended to catalytic amidation reactions of activated phenolic and unactivated methyl esters by O-C(O) cleavage [22][23][24][25]. In continuation of our studies on activation of amide bonds and organometallic catalysis, in this Special Issue of Editorial Board members of the Organometallic Section of Molecules, we report transamidation of N-activated amides by selective N-C(O) cleavage mediated by air-and moisture-stable half-sandwich Ni(II)-NHC (NHC = N-heterocyclic carbenes) complexes [26][27][28][29][30][31][32][33]. Most importantly, we demonstrate that readily available cyclopentadienyl complex extensively developed by Chetcuti, namely [CpNi(IPr)Cl] (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) [34][35][36][37][38][39][40][41][42][43], promotes highly selective transamidation of the N-C(O) bond in twisted N-Boc amides with nonnucleophilic anilines (Figure 1). 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 protocols by unconventional C(acyl)-N and C(acyl)-O bond cleavage reactions.

Results
Although we have identified well-defined Pd(II)-NHC complexes for transamidation reactions of activated amides and esters [18][19][20][21], we have been investigating airand moisture-stable Ni(II)-NHCs based on naturally more abundant Ni as 3d transition metal [26][27][28]. We were attracted to the well-defined, air-and moisture-stable, halfsandwich, cyclopentadienyl [CpNi(IPr)Cl] complex ( Figure 2) owing to its ready availability, ease of handling and the potential to prepare more reactive cyclopentadienyl Ni(II)-NHC analogues [29][30][31][32][33]. Notably, [CpNi(IPr)Cl] has emerged as a highly attractive catalyst for several classes of cross-coupling reactions [29][30][31][32][33]; however, transamidations and amidation reactions using this well-defined catalyst have been elusive.  We initiated our studies by evaluating the reaction conditions for the [CpN catalyzed transamidation of N-Boc activated amide 1a with 4-methoxyaniline 2 1). Of note, twisted N-Boc amides are readily prepared from the corresponding se amides by N-chemoselective tert-butoxycarbonylation. The N-carbamate activa mits for decreasing amidic resonance (RE, resonance energy, 7.2 kcal/mol), while ing a thermodynamic pathway for transamidation by rendering the leaving gro nucleophilic [14,15]. After optimization, we have identified conditions for the t dation in quantitative yield using [CpNi(IPr)Cl] (10 mol%) as a catalyst in the pr K2CO3 as a base in toluene at 140 °C (  [5][6]. Several other optimization conditions are wort (not shown): (1) lowering the reaction temperature resulted in significantly lowe sion (110 °C, 26%); (2) reactions at low catalyst loading resulted in low conv mol%, 13%). We initiated our studies by evaluating the reaction conditions for the [CpNi(IPr)Cl]catalyzed transamidation of N-Boc activated amide 1a with 4-methoxyaniline 2a (Table  1). Of note, twisted N-Boc amides are readily prepared from the corresponding secondary amides by N-chemoselective tert-butoxycarbonylation. The N-carbamate activation permits for decreasing amidic resonance (RE, resonance energy, 7.2 kcal/mol), while providing a thermodynamic pathway for transamidation by rendering the leaving group non-nucleophilic [14,15]. After optimization, we have identified conditions for the transamidation in quantitative yield using [CpNi(IPr)Cl] (10 mol%) as a catalyst in the presence of K 2 CO 3 as a base in toluene at 140 • C ( Table 1, entry 1). We found that K 3 PO 4 is also an effective base under these conditions (Table 1, entry 2). Furthermore, decreasing the catalyst loading to [CpNi(IPr)Cl] (5 mol%) resulted in lower conversions (Table 1, entries 3-4). Importantly, control reactions in the absence of the [CpNi(IPr)Cl] catalyst resulted in the recovery of the starting material, thus demonstrating that the catalyst is required for the reaction (Table 1, entries 5-6). Several other optimization conditions are worth noting (not shown): (1) lowering the reaction temperature resulted in significantly lower conversion (110 • C, 26%); (2) reactions at low catalyst loading resulted in low conversion (1 mol%, 13%). We initiated our studies by evaluating the reaction conditions for the [CpNi(IPr)Cl]catalyzed transamidation of N-Boc activated amide 1a with 4-methoxyaniline 2a (Table  1). Of note, twisted N-Boc amides are readily prepared from the corresponding secondary amides by N-chemoselective tert-butoxycarbonylation. The N-carbamate activation permits for decreasing amidic resonance (RE, resonance energy, 7.2 kcal/mol), while providing a thermodynamic pathway for transamidation by rendering the leaving group nonnucleophilic [14,15]. After optimization, we have identified conditions for the transamidation in quantitative yield using [CpNi(IPr)Cl] (10 mol%) as a catalyst in the presence of K2CO3 as a base in toluene at 140 °C (Table 1, entry 1). We found that K3PO4 is also an effective base under these conditions (Table 1, entry 2). Furthermore, decreasing the catalyst loading to [CpNi(IPr)Cl] (5 mol%) resulted in lower conversions (Table 1, entries 3-4). Importantly, control reactions in the absence of the [CpNi(IPr)Cl] catalyst resulted in the recovery of the starting material, thus demonstrating that the catalyst is required for the reaction (Table 1, entries 5-6). Several other optimization conditions are worth noting (not shown): (1) lowering the reaction temperature resulted in significantly lower conversion (110 °C, 26%); (2) reactions at low catalyst loading resulted in low conversion (1 mol%, 13%). 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- 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 electronwithdrawing (3e-f) anilines. It is worthwhile to note that the reaction efficiency decreased using electron-deficient nucleophiles. Furthermore, di-ortho-substituted anilines were unproductive substrates in the reaction, indicating excessive steric hindrance. tron-withdrawing (3e-f) anilines. It is worthwhile to note that the reaction efficiency decreased using electron-deficient nucleophiles. Furthermore, di-ortho-substituted anilines were unproductive substrates in the reaction, indicating excessive steric hindrance.
Next, the scope of the reaction with respect to the amide group was evaluated ( Table  3). As shown, primary and secondary alkyl amides (3g-h), electron-rich (3i-j) as well as electron-deficient (3k) aromatic amides underwent efficient transamidation 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.  In consideration of the promising reactivity of twisted N-Boc amides using well-defined cyclopentadienyl half-sandwich [CpNi(IPr)Cl], we further explored amidation reactions of activated phenolic esters and unactivated methyl esters (Schemes 1 and 2). We were pleased to find that the amidation of phenyl benzoate proceeded in quantitative yield using K3PO4 as a base under otherwise the same reaction conditions as those used for the transamidation of amides (Scheme 1). Importantly, control reactions in the absence of the catalyst unambiguously verified that [CpNi(IPr)Cl] is required for the reaction. Interestingly, we also found that amidation of unactivated methyl benzoate proceeded in Next, the scope of the reaction with respect to the amide group was evaluated ( Table 3). As shown, primary and secondary alkyl amides (3g-h), electron-rich (3i-j) as well as electron-deficient (3k) aromatic amides underwent efficient transamidation 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. tron-withdrawing (3e-f) anilines. It is worthwhile to note that the reaction efficiency decreased using electron-deficient nucleophiles. Furthermore, di-ortho-substituted anilines were unproductive substrates in the reaction, indicating excessive steric hindrance. Next, the scope of the reaction with respect to the amide group was evaluated ( Table  3). As shown, primary and secondary alkyl amides (3g-h), electron-rich (3i-j) as well as electron-deficient (3k) aromatic amides underwent efficient transamidation 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.  In consideration of the promising reactivity of twisted N-Boc amides using well-defined cyclopentadienyl half-sandwich [CpNi(IPr)Cl], we further explored amidation reactions of activated phenolic esters and unactivated methyl esters (Schemes 1 and 2). We were pleased to find that the amidation of phenyl benzoate proceeded in quantitative yield using K3PO4 as a base under otherwise the same reaction conditions as those used for the transamidation of amides (Scheme 1). Importantly, control reactions in the absence of the catalyst unambiguously verified that [CpNi(IPr)Cl] is required for the reaction. Interestingly, we also found that amidation of unactivated methyl benzoate proceeded in In consideration of the promising reactivity of twisted N-Boc amides using welldefined cyclopentadienyl half-sandwich [CpNi(IPr)Cl], we further explored amidation reactions of activated phenolic esters and unactivated methyl esters (Schemes 1 and 2). We were pleased to find that the amidation of phenyl benzoate proceeded in quantitative yield using K 3 PO 4 as a base under otherwise the same reaction conditions as those used for the transamidation of amides (Scheme 1). Importantly, control reactions in the absence of the catalyst unambiguously verified that [CpNi(IPr)Cl] is required for the reaction. Interestingly, we also found that amidation of unactivated methyl benzoate proceeded in 67% yield, while a substantial enhancement of reactivity (94% yield) was observed by increasing the reaction temperature to 160 • C (Scheme 2). As expected, no reaction was observed in the absence of [CpNi(IPr)Cl] (<2%, not detected).
To gain preliminary insight into the reaction profile, kinetic studies were performed ( Figure 3). 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 in lower yields. Studies on the mechanism and the expansion of the substrate scope are ongoing and will be reported in due course.

Materials and Methods
General Information. General methods have been published [18]. General Procedure for [CpNi(IPr)Cl] Catalyzed Transamidation. In a typical procedure, an oven-dried vial was charged with a N-Boc amide or ester substrate (neat, 1. served in the absence of [CpNi(IPr)Cl] (<2%, not detected).
To gain preliminary insight into the reaction profile, kinetic studies were performed ( Figure 3). 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 in lower yields. Studies on the mechanism and the expansion of the substrate scope are ongoing and will be reported in due course.

Materials and Methods
General Information. General methods have been published [18]. General Procedure for [CpNi(IPr)Cl] Catalyzed Transamidation. In a typical procedure, an oven-dried vial was charged with a N-Boc amide or ester substrate (neat, 1. To gain preliminary insight into the reaction profile, kinetic studies were performed ( Figure 3). 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 NiCp 2 or NiCl 2 , 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.
To gain preliminary insight into the reaction profile, kinetic studies were perfor ( Figure 3). As shown, the reaction reached 60% conversion after 3 h, while 77% conver was observed after 6 h. The induction period was not observed in the kinetic prof studies. We tentatively propose that the mechanism involves oxidative addition of th C bond to nickel. Other nickel sources, such as NiCp2 or NiCl2, catalyze the reaction a in lower yields. Studies on the mechanism and the expansion of the substrate scope ongoing and will be reported in due course.

Materials and Methods
General Information. General methods have been published [18]. General Procedure for [CpNi(IPr)Cl] Catalyzed Transamidation. In 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), K 2 CO 3 (3.0 equiv), [CpNi(IPr)Cl] (10 mol%), 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 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 CH 2 Cl 2 (10 mL), filtered, and concentrated. The sample was analyzed by 1 H-NMR (CDCl 3 , 500 MHz) and GC-MS to obtain conversion, selectivity and yield using internal standard and comparison with authentic samples. All yields have been determined by 1 H-NMR spectroscopy (CDCl 3 , 500 MHz).

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 halfsandwich [CpNi(IPr)Cl] complex. This class of Ni(II)-NHC cyclopentadienyl complexes has gained significant attention in organometallic catalysis owing to the beneficial properties 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 derivatization of pharmaceuticals and natural products.