Room-Temperature Cu-Catalyzed Amination of Aryl Bromides Enabled by DFT-Guided Ligand Design

Abstract

Ullmann-type C–N coupling reactions represent an important alternative to well-established Pd-catalyzed approaches due to the differing reactivity and the lower cost of Cu. While the design of anionic Cu ligands, particularly those by Ma, has enabled the coupling of various classes of aryl halides and alkyl amines, most methods require conditions that can limit their utility on complex substrates. Herein, we disclose the development of anionic N¹,N²-diarylbenzene-1,2-diamine ligands that promote the Cu-catalyzed amination of aryl bromides under mild conditions. Guided by DFT calculations, these ligands were designed to (1) increase the electron density on Cu, thereby increasing the rate of oxidative addition of aryl bromides, and (2) stabilize the active anionic Cu¹ complex via a π-interaction. Under optimized conditions, structurally diverse aryl and heteroaryl bromides and a broad range of alkyl amine nucleophiles, including pharmaceuticals bearing multiple functional groups, were efficiently coupled at room temperature. Combined computational and experimental studies support a mechanism of C–N bond formation that follows a catalytic cycle akin to the well-explored Pd-catalyzed variants. Modification of the ligand structure to include a naphthyl residue resulted in a lower energy barrier to oxidative addition, providing a 30-fold rate increase relative to what is seen with other ligands. Collectively, these results establish a new class of anionic ligands for Cu-catalyzed C–N couplings, which we anticipate may be extended to other Cu-catalyzed C–heteroatom and C–C bond-forming reactions.

Graphical Abstract

INTRODUCTION

N-aryl amines are among the most prevalent structural features found in natural products,^1–4 pharmaceuticals,^1,5–7 agrochemicals,^8,9, and organic materials.^10–12 While a number of approaches to form C–N bonds have been developed, transition-metal-catalyzed aryl amination reactions have emerged as some of the most widely utilized methods due to their versatility and functional group tolerance.^13–15 In particular, our group has developed an array of dialkylbiaryl monophosphine ligands^16,17 to support Pd catalysts that have enabled the coupling of many classes of aryl (pseudo)halide electrophiles with a broad range of amine nucleophiles.^18–20 Despite these advances, the cost and issues of removal^21,22 of Pd have motivated the development of alternative metal catalysts. Metal-catalyzed coupling reactions are notably prevalent in the active pharmaceutical ingredient (API) forming step of many pharmaceuticals where residual metal toxicity matters immensely,^22–24 rendering innocuous metal catalysts particularly advantageous. Accordingly, Ullmann-type couplings have been reexamined as viable methods to form structurally diverse C–N bonds due to the diminished cost and immunotoxicity of Cu,^8,25,26 as well as the orthogonal reactivity to Pd.^27,28

Since the initial report of Cu-catalyzed C–N coupling by Ullmann,^29,30 the development of several ligand scaffolds has enabled these aminations to proceed under increasingly milder conditions with broader reaction scopes.^8,25,31 Early variations involved the use of neutral ligands, such as trans-N,N′-dimethylaminocyclohexane-1,2-diamine, to facilitate amidation^32–38 or N-heterocycle arylation (Figure 1A).^35,39 However, many of these systems were not readily adopted to the coupling of alkyl amines and aryl halides, likely due to the energetically unfavorable oxidative addition of aryl halides to the corresponding ligated Cu-species. Anionic ligands readily accessed through deprotonation under the basic reaction conditions have been demonstrated to lower the energetic barrier to oxidative addition, thereby enabling the coupling of alkyl amines and various aryl halides (Figure 1B).^40–43 For instance, our group has employed anionic phenol-based ligands to facilitate the couplings of primary alkyl amines and aryl bromides.⁴⁴ Similarly, Liu disclosed a system relying on N,N-dimethylglycine and an ionic organic base, which allowed the coupling to proceed at room temperature.⁴⁵ In an effort to build on their original methods utilizing proline and N-methylglycine ligands⁴² and to expand the generality of this approach, Ma has pioneered the use of oxoacetic acid and oxalamide ligands for the coupling of various aryl halides with a variety of alkyl amines,^46–48 aniline derivatives,^49,50 and ammonia surrogates.^8,48,51 With optimized ligand systems, the Ma group has achieved efficient catalysis with low loadings of Cu that rival those in comparable Pd-catalyzed reactions.^48,49,51 Despite this noteworthy progress, a majority of these methods are unable to effect the efficient coupling of acyclic secondary amines and rely on somewhat forcing conditions that, in some instances, hamper their applicability to increasingly complex substrates, including pharmaceuticals bearing multiple functional groups. With these considerations in mind, we aimed to develop a new class of anionic Cu ligands that would enable the general coupling of structurally diverse aryl halides and alkyl amines under mild conditions.

Figure 1.

Cu-catalyzed C–N bond formation. (A) Amidation and N-arylation of heterocycles enabled by neutral ligands. (B) Coupling of aryl bromides and alkyl amines employing anionic ligands. (C) This work in which N¹,N²-diarylbenzene-1,2-diamine ligands enable a general Cu-catalyzed amination of aryl bromides under mild conditions.

Here, we report the development of a new class of anionic ligands based on an N¹,N²-diarylbenzene-1,2-diamine scaffold that enables Cu-catalyzed C–N bond formation at room temperature and is widely tolerant of many functional groups. Several iterations of ligand design afforded a catalyst system that enables the efficient coupling of structurally diverse aryl and heteroaryl bromides with a range of alkyl amine nucleophiles, including pharmaceuticals bearing multiple functional groups. A combination of computational and experimental studies demonstrated that the mechanism of C–N bond formation follows a catalytic cycle akin to related Pd-mediated transformations, where the initial oxidative addition of the aryl bromide is followed by coordination and deprotonation of the amine and a final reductive elimination to form the desired product. The optimized ligand yielded a 30-fold increase in the rate of C–N bond formation by facilitating rate-determining oxidative addition.

RESULTS AND DISCUSSION

We commenced our investigations by targeting ligands based on N¹,N²-diarylbenzene-1,2-diamine scaffolds, which upon deprotonation would form the corresponding doubly anionic bidentate ligands (Figure 2A). In addition to strongly coordinating Cu, these ligands are expected to increase the electron density of Cu in the active catalyst, resulting in facile oxidative addition. However, in the absence of additional stabilizing interactions, the active catalyst supported by the simplest ligand in this class (L1) was predicted to be unstable at room temperature. Consistent with this, L1-ligated Cu was unable to affect the coupling of 4-bromoanisole (1a) and morpholine (2a) to form N-arylamine 3a (Table 1, Entry 1).

Figure 2.

Ligand design through computational and experimental optimization. (A) Conceptual design of the N¹,N²-diarylbenzene-1,2-diamine scaffold. (B) Stabilization of the active catalyst via π-interaction. (C) Oxidative addition barrier of 4-bromoanisole to L2-ligated Cu.

Table 1.

Optimization of Cu-Catalyzed C–N Coupling^a

^aStandard reaction conditions: aryl halide (1a, 0.20 mmol, 1.0 equiv), morpholine (2a, 0.24 mmol, 1.2 equiv), NaOMe (0.40 mmol, 2.0 equiv), CuI (2.5 mol%), ligand (5.0 mol%), DMSO (0.20 mL), rt, 24 h. Yields were determined by ¹H NMR spectroscopy of the crude reaction mixtures using 1,3,5-trimethoxybenzene as an internal standard.

Given many examples of noncovalent interactions shown to have positive effects on transition-metal catalysts,^16–18 we set out to design ligands capable of stabilizing the catalytically active Cu intermediate. Accordingly, pendant phenyl groups were installed onto the ligand scaffold to stabilize the corresponding Cu(I) complex via a π-interaction with the metal center (L2, Figure 2A). To examine the effect of the pendant phenyl groups, the L2-ligated copper complex was modeled using density functional theory (DFT) calculations. The calculation was conducted employing the B3LYP-D3/LACVP/6–31G** level of theory,⁵² which is widely used for transition-metal-catalyzed reaction calculations, for geometry optimization, vibration, and solvation energy calculations. The electronic energies of all optimized structures were reevaluated with B3LYP-D3/LACV3P/cc-pVTZ(-f).⁵² According to our calculations, upon establishing a π-interaction with the biphenyl arm of L2 (L2_Int, Figure 2B), the active Cu catalyst was stabilized by 13.6 kcal/mol relative to its open form (L2_Open). In addition, these calculations revealed that the energy barrier to oxidatively add 4-bromoanisole to L2_Int could be traversed at room temperature (Figure 2C) and that deactivation of the catalyst via reductive elimination of the aryl halide with the ligand would be impeded by the pendant phenyl groups. When L2 was employed in the coupling of 1a and 2a, N-arylamine 3a was formed in quantitative yield utilizing NaOMe as the base and DMSO as the solvent ([1a] = 1M, Table 1, Entry 2). The use of alternative alkoxide bases such as NaOiPr (Table 1, Entry 3) or NaOtBu (Table 1, Entry 4) resulted in a significant decrease in the observed yield. Consistent with the required deprotonation of the N–H bonds of these ligands to form the active catalyst, weaker inorganic bases, such as K₂CO₃, resulted in 0% conversion (Table 1, Entry 5). Other polar aprotic solvents, such as MeCN, DMF, and NMP, resulted in poor conversion (see the Supporting Information). Notably, when the aryl halide was changed from 1a to a coordinating N-heterocycle, 3-bromopyridine, a significant decrease in yield was observed (Table 1, Entry 6).

The installation of larger substituents onto the ligand (L2) was hypothesized to increase the yield by preventing coordination of the pyridine to Cu. However, changing the ligand structure from L2 to L3 did not affect the observed yield (Table 1, Entry 7), suggesting alternative designs would be needed to allow the efficient amination of coordinating heteroaryl bromides. The ligand structure was accordingly modified to increase the acidity of one of the amines, thereby facilitating the rapid formation of the active catalyst (Figure 2A). Upon installation of a naphthyl group (L4), 3-bromopyridine was coupled with morpholine in excellent yield (90%, Table 1, Entry 8).⁵³ The ability of the complex resulting from L4-ligated Cu to functionalize challenging substrates was also demonstrated in the coupling of morpholine with N-methyl-4-bromopyrazole (80% yield). In addition to allowing the transformation of N-heterocycles, L4 was found to offer an advantage in that larger alkoxide bases, such as NaOiPr (Table 1, Entry 10) or NaOtBu (Table 1, Entry 11), could be utilized without significant loss in yield (92 and 81%, respectively). This is important for the coupling of substrates that are sensitive to nucleophilic attack by methoxide. Importantly, the coupling reaction of 1a and 2a exhibited a significant rate increase when L4 was utilized in place of L1 (Table 1, Entry 12), with the reaction reaching completion in only one hour.

We first set out to determine the substrate scope using the catalyst derived from L4. The process was found to proceed at room temperature for a range of aryl bromides (Scheme 2). Both electron-rich and electron-poor arenes were readily combined with primary (1b, 1e, 1f, 1g, 1h, 1k, 1l, and 1o), acyclic secondary (1n), or cyclic secondary (1a, 1c, 1d, 1i, 1j, 1m, 1p, and 1q) amines in good-to-excellent yields. The reaction was found to be tolerant of a number of common functional groups as shown in Scheme 1, most notably a sulfone (1b), aryl chloride (1e), pendant heterocycles (1f and 1q), acetal (1h), ketone (1i), nitrile (1j), alcohol (1n), tetrahydropyran (1o), and amide (1p). The room-temperature conditions of this method allowed for the coupling of base-sensitive 2,2,2-trifluoroethylamine in moderate yield (1g). Notably, the presence of relatively small groups at the ortho position on the aryl halide, such as methoxy (1e and 1l) or thiomethyl (1k) groups, was well tolerated. Additionally, an ortho-fluoride containing aryl bromide (1h) was coupled in good yield. With respect to limitations, the reactions of morpholine with arenes containing primary or secondary amides, aniline motifs with acidic protons, unprotected phenols, esters, or enolizable ketones led to little or no formation of the desired product (see the Supporting Information).

Scheme 2. Substrate Scope of the Copper-Catalyzed Amination of Heteroaryl Bromides^a,b,c,d.

^aAll yields represent the average of two isolated yields. Standard reaction conditions: aryl halide (0.5 mmol), amine (0.6 mmol), NaOMe (1.0 mmol), CuI (2.5 mol %), L4 (5.0 mol%), DMSO (0.5 mL), rt, 3 h. ^bReactions employed 5 mol % CuI and 10 mol % L4 while keeping all other conditions the same as the standard reaction conditions. ^cReactions were run for 16 h while keeping all other conditions the same as the standard reaction conditions. ^dNaOtBu replaced NaOMe as the base for the coupling reaction to mitigate undesired S_NAr reactivity. Reactions also employed 5 mol% CuI and 10 mol% L4.

Scheme 1. Substrate Scope of the Copper-Catalyzed Amination of Aryl Bromides^a.

^a All yields represent the average of two isolated yields. Standard reaction conditions: aryl halide (0.5 mmol), amine (0.6 mmol), NaOMe (1.0 mmol), CuI (2.5 mol%), L4 (5.0 mol%), DMSO (0.5 mL), rt, 3 h.

A variety of heteroaryl bromides were combined with an array of amines to provide the desired arylamine products (Scheme 2). Heterocycles, which often present difficulties in metal-catalyzed coupling reactions, due to their propensity to coordinate with the catalyst,⁵⁴ were good substrates in reactions with primary and cyclic secondary amines. N-heterocyclic aryl bromides including pyridine (2a), N-methylindazoles (2b and 2h), N-methlyindole (2d), N-methypyrazole (2e), pyrimidine (2f), pyrazine (2g), and carbazole (2i) were all aminated in good-to-excellent yields. However, when 5-bromodindole featuring a free N–H heterocycle was utilized, 0% conversion was observed, presumably as a result of catalyst inhibition by the deprotonated heterocycle (for further details, see the Supporting Information). Additionally, attempting to couple aryl bromides derived from 1,3-azoles resulted in substrate decomposition (see the Supporting Information), as is typically observed in the presence of strong alkoxide bases.^55,56 In the case of coupling a pyrazine derivative with 2-piperazinylpyridine, the standard reaction conditions yielded minimal amounts of the desired product (2g, 13% ¹H NMR yield). Instead, the product arising from a competitive S_NAr by the methoxide ion was observed. To circumvent this problem, substitution of the less nucleophilic NaOtBu resulted in a good yield of the desired coupling product (2g). In addition to N-containing heterocycles, the reaction proceeded efficiently in the presence of other heteroatom-containing heterocycles, such as dibenzofuran (2c). The reaction tolerated various functional groups on both the heteroaryl halide and amine, including an aliphatic alcohol (2h), olefin (2f), and pendant heterocycles (2a and 2g).

To further highlight the synthetic utility and generality of this method, severally structurally complex pharmaceuticals bearing secondary amines were coupled with aryl (3b, 3c, 3e, and 3f) or heteroaryl (3a and 3d) bromides (Scheme 3). C–N cross-coupling reactions involving pharmaceutical derivatives bearing multiple functional groups have been shown to exhibit a high failure rate, even under Pd catalysis.^57–59 Utilizing an L4-ligated Cu catalyst, various pharmaceuticals including Norchlorcyclizine (3a), Duloxetine (3b), and Desloratadine (3d) were all diversified to form the corresponding aminated products in excellent yields at room temperature. The newly developed catalyst system was found to be amenable to preparative-scale synthesis. Using standard Schlenk techniques, the coupling of Norchlorcyclizine and 3-bromoquinoline was scaled up by a factor of 10 (5.0 mmol) to provide 3a in excellent yield (89%, 1.85 g). Paroxetine was also coupled with 4-bromoanisole to provide 3c in good yield. Additional pharmaceuticals bearing coordinating substituents were also coupled with aryl bromides in moderate-to-good yields. Cystinicline, a smoking cessation aid bearing a 2-pyridone substructure, was coupled with 3,4-(methylenedioxy)bromobenzene (3e). Additionally, a fragment of the antidiabetic Januvia bearing a functionalized triazole was coupled with 2-bromo-6-methoxynaphtalene in 64% yield (3f). Increasing the catalyst loading to 10 mol % CuI and 20 mol % L4 in addition to diluting the reaction mixture to 0.5 M with respect to the aryl halide resulted in an increase in 3f yield to 78%. Collectively, the ability of this method to perform efficient C–N couplings on complex pharmaceuticals is particularly noteworthy and further establishes its generality.

Scheme 3. Diversification of Pharmaceuticals Using This Copper-Catalyzed Aryl Halide Amination Protocol^a.

^aAll yields represent the average of two isolated yields. Standard reaction conditions: aryl bromide (0.5 mmol), amine (0.6 mmol), NaOMe (1.0 mmol), CuI (5.0 mol %), L4 (10 mol %), DMSO (0.5 mL), rt, 16 h.

Despite the ability of the L4-based Cu catalyst to efficiently aminate a wide variety of aryl and heteroaryl bromides, the installation of ortho-alkyl groups on the aryl bromide resulted in a severely diminished yield. For instance, attempting to couple morpholine with a model hindered aryl bromide, 3,5-dimethyl-4-bromoanisole (4a), resulted in poor yield and conversion (Scheme 4A, Entry 1). Additional substrates were evaluated to further probe this observation. As an example, while 4b was isolated in good yield, the introduction of a single ortho-methyl group resulted in a significant decrease in the isolated yield (4c). The introduction of a second ortho-methyl group had negligible additional impact on the yield (4d). In both cases, the remaining mass balance was made up by unreacted starting material. We hypothesized that the poor conversion of the hindered bromides was a result of catalyst deactivation, presumably via an intramolecular C–H amination of L4. To retard this undesired process while retaining the crucial design elements of L4, we installed tert-butyl groups on the pendant phenyl arms of L4 to afford L5. Utilizing L5 in the coupling of 4a and morpholine resulted in a significant yield increase (Scheme 4A, Entry 2), enabling a ligand that can be utilized for the coupling of hindered coupling partners such as ortho-substituted aryl bromides or α-tertiary amines. Consistent with the model reaction, L5-ligated Cu efficiently aminated 2-bromocumene (4g). L5 also enabled the efficient coupling of α-tertiary amines, such as adamantylamine to yield the psychostimulant Bromantane (4f), and 1,1,3,3-tetramethylbutylamine (4h), which was coupled with an aryl bromide bearing two ortho-methyl groups. Additionally, 4c and a structurally similar molecule to 4d (4e) were reevaluated with L5, and significant increases in yields were observed. Taken together, L5 overcomes limitations in the coupling of hindered aryl bromides and amines, further establishing the generality of this method.

Scheme 4. Optimization of the Ligand Structure to Enable the Coupling of Hindered Aryl Bromides and α-Tertiary Amines^a,b.

^aStandard reaction conditions: aryl halide (1a, 0.20 mmol, 1.0 equiv), morpholine (2a, 0.24 mmol, 1.2 equiv), NaOMe (0.40 mmol, 2.0 equiv), CuI (5.0 mol%), ligand (10 mol%), DMSO (0.20 mL), rt, 24 h. Yields were determined by ¹H NMR spectroscopy of the crude reaction mixtures using 1,3,5-trimethoxybenzene as an internal standard. ^bAll yields represent the average of two isolated yields. Standard reaction conditions: aryl bromide (0.5 mmol), amine (0.6 mmol when utilizing L4, 0.7 mmol when utilizing L5), NaOMe (1.0 mmol), CuI (5.0 mol%), L4 or L5 (10 mol%), DMSO (0.5 mL), rt, 3 h.

The mechanism of the Cu-catalyzed aryl halide amination was explored using a combined experimental and computational approach. The commonly accepted mechanism for reactions catalyzed by Cu ligated with anionic ligands is similar to Pd-catalyzed C–N couplings.^25,60 In these systems, oxidative addition is followed by sequential amine binding and deprotonation as well as reductive elimination to provide the aminated product (Figure 3). Conversely, Cu-based systems employing charge-neutral ligands typically engage in amine binding/deprotonation prior to oxidative addition, which may account for why these systems are generally inefficient in the coupling of alkyl amines and aryl halides.^25,60,61

Figure 3.

Commonly accepted mechanism of C–N cross-couplings catalyzed by phosphine-ligated Pd or Cu species ligated with anionic ligands.

To elucidate the mechanism of the described catalytic system, we first turned to DFT calculations.⁵⁰ The energy profile of the most probable mechanism is illustrated in Figure 4. The catalytic cycle begins with the formation of the active catalyst. In situ-generated [Cu(OMe)₂]⁻ (1) deprotonates L4 to yield the L4-ligated complex 2 at −3.6 kcal/mol, which represents the resting state in the proposed mechanism.

Figure 4.

Energy profile of the proposed mechanism for the coupling of 4-bromoanisole and morpholine by copper species supported by L4.

Subsequent deprotonation of L4 via 2-TS with an overall barrier of 15.3 kcal/mol followed by dissociation of a methoxide ion forms the catalytically active complex (4), which features a stabilizing π-interaction between the metal center and the biphenyl arm of L4. Oxidative addition of 4-bromoanisole to the active Cu catalyst proceeds with an overall barrier of 17.5 kcal/mol (via 4-TS) with respect to the resting state. Dissociation of the bromide ion from oxidative addition of complex 5 followed by binding (7) and deprotonation of morpholine yields 8, which produces the desired N-arylamine via an energetically facile, post-rate-limiting reductive elimination. Overall, the results of these calculations predict oxidative addition to be rate-limiting and are consistent with the observation that the entire reaction sequence can take place at room temperature.⁶²

To experimentally probe the mechanism proposed by DFT calculations, we determined the experimental rate law for the coupling of 4-bromoanisole and morpholine catalyzed by L4-ligated Cu using initial rate measurements.⁶³ Independently varying the concentrations of morpholine or NaOMe did not impact the initial rate of the transformation, discounting the possibility that amine binding and deprotonation or catalyst formation were rate-limiting. The reaction exhibited a positive first-order dependence on the concentrations of both 4-bromoanisole and Cu/L4, consistent with a rate-limiting oxidative addition event. In addition to probing the reaction kinetics by initial rates, a Hammett analysis (see the Supporting Information for details) of the reaction rates of various 4-substituted bromobenzene derivatives revealed a positive ρ value (+0.27), in line with observations made in related Cu-catalyzed transformations featuring rate-limiting oxidative addition.⁶⁰ Taken together, the results of the kinetic experiments support the results of the DFT calculations and are consistent with the mechanism commonly proposed for Cu-catalyzed C–N couplings employing anionic ligands.

We next set out to determine the origin of the rate enhancement displayed by reactions utilizing L4 relative to those using L2. Initial rate experiments in the presence of varying numbers of equivalents of 4-bromoanisole demonstrated that reactions catalyzed by L2-ligated Cu exhibited a first-order rate dependence, suggesting that ligand identity does not alter the operative mechanism. Comparison of the initial rates of reactions employing L2 and L4 revealed a 30-fold rate enhancement in the case of the latter, suggesting that L4 plays a significant role in lowering the energy barrier to the rate-determining oxidative addition (Figure 5A). DFT calculations were utilized to probe the impacts of the naphthyl group on the apparent lowering of the barrier to oxidative addition (Figure 5B). Within the oxidative addition transition state (4-TS), the incoming aryl halide can approach in one of two orientations: the aryl ring can position itself parallel to either the naphthyl group (4-TS) or the biphenyl arm of L4 (4-TS′). Calculations revealed that positioning the incoming aryl halide over the naphthyl ring leads to a significant lowering of the energetic barrier (4.6 kcal/mol). To clarify the factors responsible for this energy difference, 4-TS and 4-TS′ were studied using a distortion-interaction analysis by partitioning the transition-state structures into substrate and ligated metal fragments (Figure 5C).^64,65 As shown in Figure 5C, the analysis revealed that the energy difference between 4-TS and 4-TS′ originates primarily from the differences in interaction energies between the aryl bromide and the catalyst (6.6 kcal/mol). This analysis implies that L4 enables facile oxidative addition by leveraging the stabilizing π–π interaction between the incoming aryl halide and the naphthyl residue, thereby leading to the observed rate increase. The optimized structure for 4-TS demonstrates that the two aryl rings stack in a slightly tilted offset fashion with a spacing of 3.44 Å, consistent with other π–π stacking interactions. Collectively, the results of the DFT calculations and kinetic experiments highlight the importance of noncovalent interactions in this catalyst design to (1) stabilize the active catalyst and (2) accelerate oxidative addition.

Figure 5.

Interactions underlying rate enhancements of reactions employing L4 vs L2. (A) Comparison of initial rates of reactions employing L4 (red) and L2 (blue) to couple 4-bromoanisole and morpholine. (B) Energy barriers to oxidative addition when the aryl bromide approaches parallel to the naphthyl group of L4 (4-TS) vs parallel to the biphenyl group of L4 (4-TS′). (C) Distortion-interaction analysis of 4-TS and 4-TS′. Energies in (B) and (C) are referenced to [Cu(OMe)₂]⁻ and are expressed in kcal/mol.

CONCLUSIONS

In summary, we have developed a general method for Cu-catalyzed amination of aryl bromides at room temperature. Central to this advance was the design of new anionic ligands that substantially lower the energy barrier to oxidative addition and stabilize the active catalyst through noncovalent interactions. This method was successfully applied to the amination of structurally diverse aryl and heteroaryl halides using a variety of amine nucleophiles, including pharmaceuticals bearing multiple functional groups. Combined experimental and computational experiments demonstrate that amination takes place by a mechanism akin to the well-explored Pd analogues and that the naphthyl group of L4 plays a crucial role in accelerating the transformation by stabilizing the rate-limiting oxidative addition transition state through π-stacking aromatic interactions. We anticipate that the results of this study will motivate further explorations into Cu-catalyzed C–heteroatom bond-forming reactions.