Activation of C–O and C–N Bonds Using Non-Precious-Metal Catalysis

INTRODUCTION

Metal-catalyzed cross-couplings represent one of the most important reaction platforms in modern synthetic chemistry (Figure 1A).¹ Although the field enjoys a rich history, there remains fervent interest in expanding the frontiers of cross-coupling chemistry. Some areas of current exploration include the development of new modes of reactivity (dual catalysis,² photoredox catalysis,³ cross-electrophile couplings,⁴ chemoenzymatic transformations,⁵ etc.), stereoselective couplings,⁶ and the utilization of new classes of electrophiles. With respect to the latter, non-precious-metal catalysis has been particularly enabling.

Figure 1.

(A) Classical building blocks and those historically considered inert under traditional cross-coupling conditions. (B) Overview of recently explored electrophiles in cross-coupling reactions.

In addition to potential cost, toxicity, and environmental benefits relative to precious-metal alternatives, non-precious-metal catalysts can effect unique and challenging transformations (Figure 1A).⁷ In particular, iron catalysis^7a,f,j and nickel catalysis^7f–j have become focal points in this arena. At the time our laboratory began in 2007, nickel-catalyzed cross-couplings were known but significantly underexplored, compared to palladium-catalyzed variants. Since 2007, more than 1200 manuscripts involving nickel-catalyzed cross-couplings have been published.⁸ Moreover, several reviews covering advances in nickel catalysis have been published over the past decade, highlighting the rapid growth of the field.⁷ This expansion has largely been driven by recognition of nickel’s ability to participate in single-electron processes⁹ and to activate strong bonds¹⁰ historically considered inert in cross-coupling reactions.^7e,11 Notably, the use of nontraditional building blocks (e.g., aniline, phenol, and carboxylic acid derivatives) in cross-couplings offers several advantages, because of their abundance, bench stability, utility as directing groups, and orthogonal reactivity to more common aryl and acyl halide electrophiles (Figure 1B). As a result, these methodologies can enable novel disconnections and improvements in synthetic strategy.

In the context of strong bond activation,¹² our laboratory has been particularly interested in the activation and cross-coupling of phenol, amide, and ester electrophiles, using nickel or iron catalysis. Herein, we highlight our laboratory’s contributions in this area, which are summarized in Figure 2. First, we consider cross-couplings of phenol-derived pivalates, carbonates, carbamates, and sulfamates to form C–N and C–C bonds (Figure 2A). In addition, we discuss our efforts to develop nickel-catalyzed activations of esters and amides (Figures 2B and 2C, respectively). Where illustrative, we also outline some of the many contributions from others in the field. Lastly, we provide insight into potential future directions in these areas.

Figure 2.

Scope of this review, which focuses on the activation of phenol, amide, and ester electrophiles.

Activation of Aryl C–O Bonds.

The use of phenol derivatives in cross-couplings is particularly attractive, because of their broad availability, stability, and utility as directing groups in aromatic ring functionalization (Figure 3).¹³ Although cross-couplings of aryl sulfonates are common,¹⁴ methodologies that employ inexpensive phenol derivatives that are unreactive under Pd catalysis and can serve as directing groups offer practical and conceptual advantages.^15–18 For example, phenolic electrophiles could be leveraged in conjunction with orthogonal cross-coupling handles to allow for the facile construction of privileged polyfunctionalized aromatics.¹⁹ Although couplings of aryl and vinyl methyl ethers had been described by Wenkert and Chatani, respectively,^20–24 when our laboratory opened in 2007, cross-couplings of simple O-acylated phenols were unknown.

Figure 3.

Overview of our laboratory’s studies on using phenol derivatives as cross-coupling electrophiles in base-metal-catalyzed C–C and C–N bond-forming reactions.

Our initial efforts in this area focused on nickel-catalyzed C–C and C–N bond-forming reactions of pivalates, carbonates, and carbamates (Figure 4).²⁵ We first developed the nickel-catalyzed Suzuki–Miyaura coupling of aryl pivalates. Of note, this reaction avoids competitive activation of the acyl C–O bond, which has been observed in related cross-couplings of aryl ethers.^26,27 An example of the pivalate cross-coupling methodology is shown in Figure 4 involving the synthesis of disubstituted naphthalene derivative 4. First, regioselective bromination of naphthyl-1-pivalate at C4 gave naphthyl bromide 1, which underwent Suzuki–Miyaura coupling with indolylboronic ester 2 to deliver indole 3. Subsequently, nickel-catalyzed cross-coupling of aryl pivalate 3 with phenylboronic acid gave 4 in 88% yield.²⁸ This concise route to 4 underscores the value of O-acylated phenols as orthogonal cross-coupling electrophiles in the synthesis of polyaromatic molecules.¹⁹ In a subsequent study, we found that aryl tert-butylcarbonates could serve as cross-coupling electrophiles, as illustrated by the nickel-catalyzed coupling of carbonate 5 to forge biaryl 6 in 65% yield.²⁹

Figure 4.

Select examples of Ni- and Fe-catalyzed cross-couplings of pivalates, carbonates, and carbamates reported by our laboratory.

Aryl carbamates also proved to be versatile electrophiles in C–C and C–N bond-forming cross-coupling reactions, as demonstrated by the examples shown in Figure 4.²⁹ Importantly, this substrate class can be used to functionalize the ortho position on aromatic rings via directed lithiation.³⁰ Using NiCl₂(PCy₃)₂, naphthyl carbamate 7 smoothly underwent nickel-catalyzed cross-coupling to furnish biaryl product 8 in 86% yield.²⁹ The corresponding amination of aryl carbamates was enabled by the use of N-heterocyclic carbene ligand, SIPr, and could be used to generate naphthylmorpholine (11) in excellent yield.³¹ Developing methodologies to construct sp²–sp³ C–C bonds represents another frontier in cross-couplings.³² Toward this end, we turned to iron catalysis to achieve the Kumada coupling of aryl carbamates,^33,34 which allowed for the formation of sterically hindered sp²–sp³ C–C bonds, such as that found in 12.³⁵ Finally, a catalytic reduction of aryl carbamates (7 → 14; see Figure 4) was achieved using inexpensive 1,1,3,3-tetramethyldisiloxane (TMDSO) as the reductant,³⁶ thereby providing a means to achieve the deoxygenation of aromatic rings. In addition, one can perform net cine substitution processes using directed ortho-metalation/functionalization, followed by reductive removal of the carbamate. Since our initial studies in this area, there have been many other contributions from other groups toward expanding the scope and mechanistic understanding of cross-couplings of O-acylated phenol derivatives.³⁷

The cross-coupling of sulfamate electrophiles presented another attractive opportunity, as they are also common directing groups in ortho-metalation reactions as established by Snieckus.³⁰ Nickel-catalyzed Kumada couplings of aryl sulfamates had been reported,¹⁸ but milder C–C and C–N bond-forming cross-couplings of these substrates were unknown. With regard to the former challenge, sulfamates proved to be viable substrates in nickel-catalyzed Suzuki–Miyaura cross-couplings. In fact, subsequent experimental and computational studies performed in collaboration with the Houk group revealed aryl sulfamates to be more reactive electrophiles, in comparison to aryl carbamates.³⁸ Importantly, this transformation avoids the use of highly basic and nucleophilic organometallic reagents, allowing for coupling of vinyl sulfamate 15 to give substituted cyclohexenone 17 in 75% yield (Figure 5).²⁹ Sulfamates were also competent electrophiles in iron-catalyzed Kumada couplings, as shown by the formation of tricyclic product 19 in 82% yield.³⁵ In addition, the use of aryl sulfamates in catalytic amination reactions highlights their versatility as cross-coupling handles and allowed for the rapid synthesis of linezolid (22) from fluorosulfamate 20. Following sulfamate-directed ortho-functionalization,²⁹ aryl sulfamate 20 underwent a nickel-catalyzed cross-coupling with morpholine (10) to deliver arylated amine 21 in 84% yield.³⁹ As previously mentioned, subsequent computational and experimental efforts from others in the field have greatly contributed to the rapid growth in understanding and scope of base-metal-catalyzed cross-couplings of nontraditional phenol-derived electrophiles.^37k,40

Figure 5.

Select examples of nickel- and iron-catalyzed cross-couplings of sulfamates reported by our laboratory.

A common limitation of nickel-catalyzed methodologies, including those developed by our own laboratory, is the air and moisture sensitivity of the precatalysts and/or ligands employed. To avoid the need for glovebox manipulations in the nickel-catalyzed amination of carbamates and sulfamates, we investigated the use of a variety of air-stable Ni(II) complexes.⁴¹ NiCl₂(DME) (23) and PhB(pin) were identified as a suitable precatalyst and mild reductant, respectively, to achieve a range of nickel-catalyzed aminations on the benchtop. For example, the methodology tolerated electron-deficient and heterocyclic substrates as well as a variety of amine nucleophiles, giving rise to 21 and 24–26 in yields of 50%–98% (see Figure 6).⁴² Recognizing that the use of industrially friendly solvents could further enhance the practicality of this methodology, through a collaboration with the ACS Green Chemistry Institute’s Pharmaceutical Roundtable, we evaluated the coupling of (hetero)aryl sulfamates with amine nucleophiles in 2-methyl-THF using nickel catalysis.⁴³ The robustness of this method was evidenced by the gram-scale coupling of trifluoromethyl aryl sulfamate 27 with morpholine (10) to give arylated amine 28 in 97% yield, using only 3 mol % NiCl₂(DME).

Figure 6.

Benchtop aminations of aryl sulfamates and carbamates and gram-scale coupling of 27 in a green solvent.

Activation of Aryl C–N Bonds.

Although not a focus of our laboratory’s research, base-metal-catalyzed cross-couplings of aniline derivatives also represent an active field of inquiry (see Figure 7). Historically, aniline-derived diazonium salts have been extensively employed in palladium-catalyzed cross-couplings.^44,45 However, the use of safer and more robust aniline derivatives in coupling reactions has recently garnered significant attention.⁴⁶ MacMillan and co-workers reported a nickel-catalyzed Suzuki–Miyaura coupling of aryltrimethylammonium triflates in 2003,⁴⁷ building upon the foundational report by Wenkert on Kumada couplings of these species.⁴⁸ More recently, Shi described a directing group-free nickel-catalyzed Suzuki–Miyaura coupling of N,N-dimethylaryl amines, overcoming a key limitation in comparable Ru-catalyzed reactions.^49,50 Moreover, a nickel-catalyzed Suzuki–Miyaura coupling of azoles was published by Robins,⁵¹ which allowed for the synthesis of important arylated purine nucleoside analogues 29 and 30 in good yields.⁵² Finally, the Nakao group and others have investigated transition-metal-catalyzed cross-couplings of nitroarenes and this strategy has been applied toward the syntheses of polycyclic aromatic hydrocarbons.⁵³ We are optimistic that base-metal-catalyzed aryl C–N bond activation will continue to see use in complex molecule synthesis.

Figure 7.

Overview of aniline derivatives employed in metal-catalyzed cross-coupling reactions.

Activation of Acyl C–O Bonds.

Interest in the metal-catalyzed cleavage of the acyl C–O bonds of esters dates back to Yamamoto’s seminal 1976 report utilizing stoichiometric nickel complexes.⁵⁴ Although cross-couplings of esters, including decarboxylative variants pioneered by Itami⁵⁵ and Gooßen,⁵⁶ have since established the feasibility of metal-catalyzed acyl C–O bond activation for subsequent functional group interconversion, these reports were limited to the coupling of structurally or electronically activated substrates. Specifically, aryl esters employed in these couplings featured metal-chelating⁵⁷ or electron-withdrawing⁵⁸ O-substituents to facilitate oxidative addition (see Figure 8).⁵⁹ These substrates are often synthesized from carboxylic acid precursors and are generally more reactive than alkyl esters. In contrast, simple methyl esters are naturally abundant, commercially available, and unreactive under Pd catalysis. As a result, chemists could consider sequential cross-coupling strategies that take advantage of this orthogonal reactivity.

Figure 8.

Historical approaches to metal-catalyzed ester acyl C–O bond activation and advantages of alkyl esters as substrates.

At the time our laboratory entered this field,⁶⁰ cross-couplings of methyl esters were unknown. Notably, these transformations feature high kinetic barriers to oxidative additions, because of resonance stabilization of the acyl C–O bond.⁶¹ However, we hypothesized that the unique reactivity of nickel(0) in the activation of strong bonds^7e,f,10,11 may allow for catalytic cross-couplings of methyl esters. Noting the importance of amide bond formations in industry,⁶² we first pursued a nickel-catalyzed amidation of methyl esters.⁶⁰ Ultimately, the combined use of a Ni/NHC catalyst and Al(Ot-Bu)₃ additive was found to effect the desired transformation. Computations performed by the Houk group⁶⁰ indicated that the Al(Ot-Bu)₃ additive facilitates the rate-limiting oxidative addition step and drives product formation through the generation of a favorable Lewis acid–base complex with the amide product. Although this methodology was limited to the activation of naphthyl-derived substrates, its utility was illustrated in the synthesis of complex anilide 33 (see Figure 9). Treatment of 31, which was prepared via sequential Buchwald–Hartwig and DCC couplings of a suitable methyl naphthoate precursor, with optimized amidation conditions, generated anilide 33 in 60% yield without observable epimerization. This sequence highlights the mildness of the methodology and illustrates the utility of late-stage methyl ester activations in complex molecule synthesis.

Figure 9.

Recent advances in the nickel-catalyzed amidation of methyl esters.

Further studies have improved the efficiency and scope of nickel-catalyzed amidations of methyl esters. Newman and co-workers have described an additive-free variant of this methodology utilizing elevated temperatures.⁶³ In doing so, they were able to achieve amidations of enantioenriched aliphatic methyl esters to access products such as furanylamide 34 in high yields (see Figure 9). A range of aromatic substrates could also be coupled utilizing these conditions, allowing for the improved synthesis of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) positive modulator 35. In a subsequent survey of NHC ligands in this transformation,⁶⁴ the same group reported the selective amidation of an alkyl methyl ester in the presence of an aryl methyl ester to form 36 in 65% yield. A reductive cross-coupling of nitroarenes and methyl esters has also been described.⁶⁵ Notably, nitroarenes are widely used in industry as inexpensive precursors to aryl amines. In an impressive application of this methodology, Hu and co-workers treated known ester 37 with their optimized Ni/Zn conditions to generate (−)-rhazinilam 38 in 59% yield.^65,66 As a result, the synthesis of the natural product was completed with improved step economy and comparable efficiency.

Additional advances have broadened the scope of bond formations possible using nickel-catalyzed activations of methyl esters (Figure 10). Similar to Heck-type reactions of amides developed in our laboratory (vida infra),⁶⁷ Newman recently reported domino Heck reactions of methyl esters that form a C–C bond intramolecularly as well as a terminating C–C or C–H bond in a single catalytic transformation.⁶⁸ The generation of indanones 40 and 41 in 51% and 79% yields, respectively, from methyl ester substrate 39 highlights the potential utility of this methodology in divergent synthesis. Furthermore, nickel-catalyzed activations of methyl esters that proceed with decarbonylation have been reported. Specifically, the Rueping laboratory has used methyl esters to generate a variety of aryl stannanes, such as substituted pyridine 44.⁶⁹ A decarbonylative methylation of aryl methyl esters was reported by Yamaguchi and co-workers, and was utilized to access 2-methylindole 45 in 48% yield.⁷⁰ We anticipate that the exploration of new bond formations and modes of reactivities will continue to be an important driver of innovation in this field.

Figure 10.

Nickel-catalyzed domino Heck and decarbonylative cross-couplings of methyl esters.

Activation of Acyl C–N Bonds.

Although amide C–N bond cleavage is common in Nature, synthetic methods for activation of the amide C–N bond remain challenging, because of well-understood resonance effects (Figure 11).⁷¹ However, the pronounced stability of amides renders them ideal functional handles to be carried through multistep synthetic sequences. Moreover, as they are also common directing groups in C–H activations,⁷² strategies to merge amide-directed C–H functionalization with subsequent late-stage C–N bond activation could allow for the rapid assembly of molecular architectures.

Figure 11.

Resonance stabilization of amides and potential synthetic utility of amide C–N bond activations.

Recognizing the potential utility of amides as useful synthetic handles, many strategies for the functional group interconversion of amides have been reported.⁷³ For example, the use of amides featuring chelating N-substituents such as N-methoxy-N-methylamides or “Weinreb amides”,^71a,74 has enabled the single addition of organometallic nucleophiles to amides to access ketone products. In addition, single-electron reduction of imides can generate reactive radical anion intermediates for subsequent functionalizations.⁷⁵ Notably, electrophilic activation of amides to generate versatile imidate intermediates has a rich history, with many elegant examples of this strategy being showcased by the Maulide group in recent years.⁷⁶ Another strategy for amide activation involves hydrosilylation using Vaska’s complex (IrCl(CO)(PPH₃)₂), which has been leveraged by the Dixon group⁷⁷ and others⁷⁸ for a variety of reductive functionalizations of tertiary amides. Finally, our group and others have been interested in amide activation through direct oxidative addition by a transition-metal catalyst into the amide C–N bond for subsequent cross-coupling reactions. Although unknown at the time our laboratory entered the field in 2015, we envisioned that this latter approach could provide an alternative synthetic tool for the activation of amides that avoids the use of either highly nucleophilic or electrophilic reagents.^7g,79

Beginning with our first disclosure in 2015,⁸⁰ our laboratory has reported several nickel-catalyzed transformations that proceed with amide C–N bond activation. Our early investigations focused on the use of amide substrates derived from aromatic carboxylic acids (which are often referred to as “aryl amides” and are distinct from N-aryl amides mentioned below), with select examples shown in Figure 12. We identified the conversion of amides to esters, a historically challenging transformation that often proceeds under harshly acidic or basic conditions,^71a as an exciting starting point for our studies.⁸⁰

Figure 12.

Recent advances in the nickel-catalyzed activation of aryl amide C–N bonds by our laboratory.

In collaboration with the Houk laboratory, we first computationally and experimentally investigated the effect of amide N-substituents in the nickel-catalyzed conversion of benzamides to methyl benzoate. These studies revealed two salient features of this transformation. First, N-substituents had a profound influence on the change in Gibbs free-energy values for the overall reactions (ΔG). Although esterifications of N,N-dialkyl benzamides were calculated to be largely thermodynamically unfavorable or thermoneutral, esterifications of N-aryl amides were found to be thermodynamically favorable, with a calculated ΔG value of −6.8 kcal/mol for the conversion of N-phenyl-N-methyl benzamide to methyl benzoate. The effect of amide N-substituents on the oxidative addition barrier using nickel catalysis with commercially available NHC ligand SIPr⁸¹ was also evaluated computationally. In comparison to the calculated barriers for N-dialkyl amides, those for N-aryl amides were estimated to be more reasonable, with the oxidative addition barrier for N-phenyl-N-methyl benzamide calculated to be 26 kcal/mol. Overall, the computational predictions were supported by experiments as we observed quantitative yield in the nickel-catalyzed conversion of N-phenyl-N-methyl benzamide to methyl benzoate. These initial collaborative studies with the Houk laboratory greatly informed our understanding of the impact of N-substituents on the performance of amides in various nickel-catalyzed transformations. Moreover, the Szostak group has bolstered the field by providing valuable insight into the physical properties and reactivities of nonplanar, or “twisted”, amides (in particular, glutaramides).^79a,82

Using N-alkyl-N-phenyl benzamides, we found that the use of the nickel precatalyst/ligand combination of Ni(cod)₂/SIPr allowed for the mild coupling with a range of alcohol nucleophiles to furnish ester products, such as menthyl ester 46, in high yields (see Figure 12).⁸⁰ We then explored additional C–heteroatom bond-forming reactions of N-alkyl-N-phenyl benzamides using nickel catalysis. Although water could not be directly employed as a nucleophile to access carboxylic acids from amides,⁸³ we designed a one-pot, two-step net-hydrolysis reaction. Specifically, in situ generation of a silyl ester, followed by subsequent deprotection provided carboxylic acids, such as 47, in good yields using mild reaction conditions.⁸⁴ We were also interested in overcoming the longstanding challenge of secondary amide transamidation utilizing our nickel catalysis platform.⁸⁵ Toward this end, a two-step, Boc-activation/nickel catalysis approach enabled the catalytic transamidation of secondary amides, notably providing ready access to amino-acid-derived amide 48 on gram-scale.⁸⁶ Reasoning that these reactions could proceed through a Ni(0)/Ni(II) catalytic cycle, a hypothesis supported by density functional theory (DFT) calculations performed by the Houk group, we became interested in leveraging well-established M(0)/M(II) cross-coupling platforms to form C–C bonds.⁸⁰ Indeed, we found that aryl amides could smoothly undergo nickel-catalyzed Suzuki–Miyaura (N-alkyl-N-Boc amides) and Negishi (N-Me-N-tosyl and N-benzyl-N-Boc amides) couplings to form biaryl and aryl–alkyl ketones, respectively.^87,88 Notably, both of these methodologies proved to be scalable, providing gram-scale access to ketone 49, an antiproliferative tubulin-binding agent,⁸⁹ and 50, a key intermediate in Pfizer’s synthesis of a glucagon receptor modulator,⁹⁰ respectively.

Nickel-catalyzed cross-couplings of amides that build stereocomplexity represent an important frontier of the field. Through the development of intramolecular Mizoroki–Heck cyclizations, we achieved the synthesis of indanones bearing α-quaternary stereocenters from N-benzyl-N-Boc amides (see Figure 13).⁶⁷ Notably, this methodology provided diastereoselective access to indanone 52, establishing vicinal stereocenters, one of which is quaternary, in a single transformation. Stanley and co-workers have extended this strategy to include domino-Heck reactions incorporating boron nucleophiles.⁹¹ We were also interested in pursuing methodologies that generate stereocenters at the originating amide carbonyl carbon through the net addition of two nucleophiles. Ultimately, a one-pot chemoenzymatic synthesis of enantioenriched alcohols was achieved through the combined use of nickel and biocatalysis in collaboration with Codexis.⁹² For example, enantioenriched diarylmethanol 54 was accessed in 72% yield and 97% enantiomeric excess (ee) utilizing the methodology, which combined a Suzuki–Miyaura cross-coupling and ketoreductase (KRED)-mediated reduction in a one-pot, sequential process. These studies validated the utility of amide C–N bond activation in stereocomplexity-generating transformations. We view the development of asymmetric methods as a fruitful area for further exploration in this field.

Figure 13.

Asymmetric reactions of aryl amides developed by our laboratory.

Notably, the aforementioned methodologies were limited to the activation of aryl amide substrates. The activation of amides derived from aliphatic carboxylic acids (often referred to as “aliphatic amides”) presents an even greater challenge as a result of increased steric requirements and a presumed lack of catalyst–substrate precomplexation.⁹³ In considering esterifications of aliphatic amides, the use of terpyridine as the ligand proved effective in a collaborative study with Boehringer–Ingelheim (see Figure 14).⁹⁴ This methodology provided efficient access to steroidal ester 55, and it could be used in a macrocyclic ring-opening to form ester 56. Subsequently, we evaluated C–C and C–N bond-forming reactions of alkyl amides through the use of the electron-rich NHC ligand precursor, Benz-ICy·HCl.^81,95–97 Specifically, we developed a Suzuki–Miyaura coupling of aliphatic amides, which provided access to ketone 57 from an enantioenriched amide with minimal racemization. Importantly, this methodology affords enolizable ketone products, which can then be further elaborated. For example, a Suzuki–Miyaura cross-coupling of a tetrahydropyranyl amide and concatenate Fischer indolization provided spiroindolenine 58 in rapid fashion. Transamidation of aliphatic secondary amides was also possible using this catalytic system, following C–N bond activation via N-functionalization. Of note, the stereoretentive transamidation of a prolinamide to provide secondary amide 59 in 60% yield and >99% ee was possible utilizing the methodology.⁹⁵ With the development of these protocols, our laboratory established the viability of aliphatic amides in C–O, C–C, and C–N bond-forming reactions using nickel catalysis.

Figure 14.

Recent advances in the nickel-catalyzed activation of aliphatic amide C–N bonds by our laboratory.

As previously noted, our laboratory has an interest in improving the practicality of nickel-catalyzed methods. Toward this end, we sought to optimize the catalytic efficiency of the esterification of amides reported by our laboratory.⁹⁸ A highlight of this collaborative effort with AbbVie, which combined experimentation and kinetic modeling,⁹⁹ was the realization of a 5-g scale coupling of aryl amide 60 and menthol (61) at a reduced temperature (45 °C vs 80 °C), using <1 mol % Ni(cod)₂ to give ester 46 in 97% yield (see Figure 15). Another key challenge in the area of nickel catalysis lies in the development of glovebox-free cross-couplings.¹⁰⁰ Encapsulating air- and moisture-sensitive reagents in paraffin wax has been an effective means to perform transition-metal-catalyzed reactions on the benchtop,^101,102 including in undergraduate instructional laboratories.¹⁰³ In this regard, we successfully employed paraffin–Ni(cod)₂/Benzy-ICy·HCl capsules in the benchtop Suzuki–Miyaura coupling of piperidinyl amide 62 to give polyheterocyclic ketone 64 in 73% yield on the gram-scale. We are hopeful that future advances in these areas will promote greater use of base-metal catalysis in academia and industry.

Figure 15.

Practical advances in nickel-catalyzed activations of amides disclosed by our laboratory.

The field of amide C–N bond activation using transition-metal catalysis, including breakthroughs with palladium catalysis led by Szostak,¹⁰⁴ has flourished in recent years, particularly when considering the introduction of alternative amide electrophiles and novel modes of reactivity. More than 85 studies involving transition-metal-catalyzed amide C–N bond activation have been reported since our initial study in 2015.¹⁰⁵ Select examples of amide derivatives that have been employed successfully by other groups in nickel-catalyzed cross-couplings are shown in Figure 16.¹⁰⁶ Amides have also seen use as acyl synthons in emerging cross-coupling manifolds, testifying to the rapid growth of this field. For instance, Hu and co-workers demonstrated a nickel-catalyzed reductive transamidation of N-benzyl-N-Boc benzamides using nitroarenes.^66,107 Notably, this methodology was tolerant of a range of functional groups, including aryl bromides, allowing for the formation of aryl amide 67 in 69% yield. In addition, Molander and co-workers reported a Ni/Ir dual-catalytic photoredox approach to access alkyl–alkyl ketones such as 1,4-dicarbonyl 70.¹⁰⁸ Finally, several nickel-catalyzed decarbonylative reactions of amides have been reported, expanding the scope of functional groups directly accessible from amides, as illustrated by the synthesis of compounds 71–73.^109–111 The continued exploration of new modes of reactivity and bond-forming reactions is critical to advancing amides as useful building blocks in complex molecule synthesis.

Figure 16.

N-substituent variation, alternative reaction modes, and decarbonylative reactions of amides utilizing nickel catalysis.

OUTLOOK AND FUTURE DIRECTIONS

Although the field of base-metal-catalyzed activation of strong bonds has grown rapidly in recent years, there remains tremendous opportunity for future discovery. For example, expanding the scope of substrates that can undergo activation to include (sp³)C–O/N electrophiles^112,113 and developing catalytic systems to activate amides, phenols, and anilines without the need for electron-withdrawing or chelating substituents¹¹⁴ could allow chemists to directly manipulate common moieties in commodity chemicals and natural products. Another frontier for this field lies in the application of cross-couplings involving the activation of strong bonds to the synthesis of complex molecules. In this regard, the development of both chemoselective and stereoselective reactions is expected to be highly enabling. In addition, collaborations between academia and industry, as well as among academic research groups, would help achieve the future directions outlined above and expedite the adoption of novel methodologies in industrial settings.¹¹⁵ Finally, computational investigations into reaction mechanisms and selectivities will undoubtedly lead to improvements in existing methodologies, inspire the development of others, and lead to the disclosure of tools to predict selectivities and outcomes in these transformations. Of note, although nickel catalysis has seen widespread use in the activation of strong bonds, there remains significant interest in exploring the utility of alternative non-precious-metal catalysts in this arena and more broadly in cases where it could lower the cost of drug manufacturing.^115,116 We also envision that the optimization of reaction conditions and catalyst loadings, the discovery of new inexpensive ligand frameworks,¹¹⁷ and the disclosure of well-defined, air-stable precatalysts¹¹⁸ will promote the use of base-metal catalysis in academia and industry. We hope and anticipate that strong bond activation using base-metal catalysts will continue to thrive as a field and be viewed as an increasingly valuable strategy in organic synthesis.