Site-Selective Electrochemical Arene C−H Amination

Abstract

Here we present the discovery and development of a highly selective aromatic C−H amination reaction. This electrochemical strategy involves a cathodic reduction process that generates highly electrophilic dicationic N-centered radicals that can efficiently engage in aromatic C−H functionalization and channel the regioselectivity of the aromatic substitution. The nitrogen-radical cation−pi interaction with arenes used throughout nature leads to a charge transfer mechanism, with subsequent aromatic C−N bond formation. This electrochemical process generates aryl DABCOnium salts in excellent yields and regioselectivities (single regioisomer in most cases). The scope of the reaction on arene is broad where various functionalities such as aryl halides (bromides, chlorides, fluorides), carbonyls (ketones, esters, imides), sulfonamides, and heteroarenes (pyridines, bipyridines, and terpyridines) are well tolerated. Moreover, we disclose the synthetic utility of the aryl DABCOnium salt adducts leading to the direct access of diverse aryl piperazines and the chemoselective cleavage of the exocyclic aryl C(sp²)−N bond over electrophilic C(sp³)−N⁺ bonds via photoredox catalysis to afford synthetically useful aryl radicals that can engage in aryl C−C and C−P bond formation.

The pursuit of aromatic C−H bond functionalization reactions has been a major research objective for several decades.¹ Of particular interest is transforming aromatic C−H bonds into aryl amines, as the formation of aryl C−N bonds is highly valued in drug development,² yet selectivity remains a challenge due to the abundance of C−H bonds in organic molecules. Traditional methods for nondirected aromatic C− H amination rely on a sequential nitration³/reduction/alkylation process, which suffers from limitations in site selectivity and substrate compatibility. Consequently, researchers have explored several alternative approaches utilizing transition metal catalysis,^4,5,6a stoichiometric reactive reagents,⁷ and, in the past decade, novel photocatalytic methods^8,9 to enhance selectivity and expand substrate scope.

The resurgence of electrochemistry for organic synthesis has shown to be a powerful tool to discover and develop selective organic transformations.¹⁰ As such, many substrate-directed aromatic C−H aminations have been reported;^11–14 however, their utility in nondirected selective aromatic C−H functionalization remains very limited.^15,16 In 2013, Yoshida reported the first electrochemical arene C−H amination via anodic oxidation of the arene to radical cation followed by C−N bond formation with pyridine as the nucleophile and cosolvent leading to the formation of arylpyridinium salts.^15a This electrochemical reactivity was further demonstrated with various amine sources to generate various aryl amines.¹⁵ Interestingly, photoredox catalysis was realized to enable the oxidation of electron-rich arenes followed by nucleophilic attack of an N-heteroarene or ammonia surrogate, as shown by the pioneering work of Nicewicz and co-workers.^8a

We aimed to develop a sustainable and selective electrochemical method for aromatic C−H amination through a mechanistically distinct approach compared to traditional electrochemical reactions^11–16 where frequently the arene gets oxidized into aryl radical cations¹⁵ or a transition-metal-catalyzed C−H amination^13,14 In this paper, we report that the direct cathodic reduction of Selectfluor generates a dicationic nitrogen-centered radical that undergoes a charge transfer and subsequent C−N bond formation with arenes to form aryl DABCOnium salts. This electrochemical C−H amination reaction demonstrates exceptional site selectivity, broad applicability to various arenes, and compatibility with late-stage functionalization, leading to the formation of various aryl DABCOnium salts in one step. Our mechanistic studies depict that the site selectivity and generality toward different arenes is achieved through a charge-transfer mechanism facilitated by a radical-cation−pi interaction, an interaction found in nature,¹⁷ but underutilized in organic synthesis. While a site-selective TEDA-arylation reaction (TEDA = N-(chloromethyl)-triethylenediamine) via dual transition metal catalysis was developed by Ritter,^6a it remains a limited demonstration of synthetic utility, being only a methylation reaction by nickel-catalyzed Negishi-coupling reported using a modified TEDA group.^6b Here, we also present that the resulting electrochemically generated aryl DABCOnium salts undergo a diverse range of reactivities with nucleophiles to form various classes of aryl piperazines under an operationally simple protocol. Furthermore, we introduce a previously unreported reactivity of aryl DABCOnium salts merging an electrochemical site-selective C−H amination with photoredox catalysis in two-step site-selective aromatic C−P and C−C bond formations.

At the onset of this work, we realized that a mechanism with reversed polarity from the electrochemical amination by Yoshida¹⁵ could lead to an arene C−H amination reaction that is more regioselective and broader in arene scope. Inspired by the reported photochemical reduction of N−X (X = leaving group) reagents,¹⁸ we hypothesized that cathodic reduction of an N−X reagent would generate a nitrogen-centered radical that can be exploited for arene C−H amination (Figure 1b). As such, we explored various N−X reagents including NFSI, N-fluoropyridinium, and Selectfluors I and II as a source of nitrogen radical cation with fluorobenzene as the model substrate for electrochemical arene C−H amination (Figure 2). These reagents undergo reduction, and we were very pleased to observe that the aminium radical cations generated from Selectfluor gave the desired amination product. Importantly, a regioselectivity of up to 23:1:1 (p:o:m) of the aryl DABCOnium salt 1 was obtained by the electrolysis of Selectfluor II and fluorobenzene, resulting in a quantitative yield. Moreover, the use of fluorobenzene as the arene substrate is highly notable, as this substrate and other electron-deficient starting materials are less susceptible to undergo oxidation since its oxidation potential is more positive than +2.2 V (vs Fc/Fc⁺). Control experiments in the absence of electrochemistry show no desired product, but recovery of starting material, despite reports of amination products of dialkoxybenzenes.¹⁹ Consequently, electron-deficient substrates do not undergo productive amination under Yoshida’s conditions in addition to several photocatalytic amination reactions involving arene oxidation.^8,15

Figure 1.

Selective electrochemical arene C−H amination reactions. (a) Electrochemical arene pyridination by Yoshida via anodic oxidation of electron-rich arenes, and (b, c) electrochemical arene amination (this work) via cathodic generation of N-radical cation and synthetic utility of aryl DABCOnium salts.

Figure 2.

Cathodic generation of N-radical cations and their utility in selective electrochemical arene C−H amination.

The scope of the electrochemical amination reaction was investigated and summarized in Figure 3. Various mono- and disubstituted arenes with varying electron-rich and electron-deficient substituents (1−9) gave their corresponding aryl DABCOnium salt adducts in excellent yields and predictable selectivities. Among the simple monosubstituted arenes, the para-position is favored. For disubstituted arenes where the para-position is unavailable, the C−H bond ortho to the more electron-donating substituent is preferentially functionalized. For multiarene systems (7−9), the arene with higher electron density is functionalized. Importantly, various heterocycles (10−15) including thiophene, pyridines, bipyridines, terpyridines, indazoles, and imidazopyridines undergo highly efficient C−H amination reactions. This is notable, as many of these Lewis basic N-heterocycles are commonly used as ligands in metal-catalyzed C−H functionalization reactions or can result in the inhibition of transition-metal catalysis. The application of this methodology for late-stage functionalization of various pharmaceuticals was also explored, and we are pleased to see the highly efficient and selective amination of multiaromatic and complex pharmaceuticals (16−19) including fenofibrate, flurbiprofen methylester, bifonazole, and a celecoxib derivative.

Figure 3.

Scope of electrochemical arene C−H amination. Reactivity and synthetic utility of aryl DABCOnium salts to access diverse set of aryl piperazines and photocatalytic conversion to aryl C−C and C−P bonds. The general reaction conditions are as follows: arene (0.30 mmol, 1.0 equiv), Selectfluor II (1.5 equiv −2.0 equiv), Et₃N (50 mol %), MeCN, 25 °C, 14 h. Electrolysis parameters: constant current of 1 mA, 5 F/mol, and stirring at 1500 rpm. ^aSelectfluor I was used. ^b3.0 equiv of arene was used. ^cReaction conditions of C were used. Structures shown are of the observed major product and asterisks denote position for other minor regioisomers. For detailed experimental procedures on the diversification scheme, see Supporting Information.

The resulting aryl DABCOnium salts (or arylTEDA; TEDA, N-(chloromethyl)triethylenediamine) have been reported to undergo subsequent reactions including the formation of aryl piperazines^6a,20 and Ni-catalyzed Negishi-type cross-coupling^6b to form methyl-arenes. Here, we report various reactivities of the resulting aryl DABCOnium salts that generate diverse aryl piperazines and aromatic C−C and C−P bonds through a new mode of activation of aryl DABCOnium salts via photoredox catalysis. As described in Figure 3, the resulting aryl DABCOnium salts can be easily converted into aryl piperazines in a one-pot procedure where after electrochemical reaction, the crude mixture is heated in an aqueous solution of Na₂S₂O₃ or under mild temperature with KCN in acetonitrile. Depending on the use of aminating reagents, N-methyl aryl piperazines can be obtained (from Selectfluor II) and free aryl piperazines can be obtained (from Selectfluor I) from their corresponding aryl DABCOnium salts. Moreover, when aryl DABCOnium salts are treated with an appropriate nucleophile, aryl piperazines bearing the nucleophile can be obtained in high yields.

The unexplored reactivity of aryl DABCOnium salts by means of photoredox catalysis entails a two-step, simple procedure for site-selective functionalization of arenes (Figure 3). The high electrophilicity of the aryl DABCOnium compounds could undermine their synthetic utility; however, a chemoselective cleavage of the exocyclic C(sp²)−N bond is observed over ring opening resulting from the reactive C(sp³)−N⁺ bonds in the presence of nucleophiles or base. The resulting aryl radical generated in situ is trapped by P(OEt)₃ or N-methyl pyrrole to afford C−P and C−C bond formation, respectively (Figure 3). While aryl quaternary ammonium salts, [ArNMe₃]⁺, are known to exhibit single electron transfer (SET) reduction to generate aryl radicals under photoredox conditions,²¹ a multistep reaction is required to synthesize quaternary ammonium salts from an unfunctionalized arene and methods for achieving phosphorylation or arylation reactions remain unexplored. Remarkably, the functionalization of aryl DABCOnium salts is catalyzed by phenothiazine to access aryl C−C bond formation in the absence of a base (see reaction details in the Supporting Information (SI)). On the other hand, aromatic C−P bond formation was most effective under Ir photocatalysis. These telescoped transformations are highly promising for a selective aromatic C−H functionalization strategy.

To shed light on the mechanism of the reaction, various computational and experimental mechanistic studies were performed using toluene as the substrate (Figure 4; see SI for details). First, DFT calculations provided strong support for the propensity of an N-radical-cation−pi interaction after the cathodic generation of N-radical dicationic species (Figure 4a). Interaction energies of the DABCO^2+• radical cation intermediates (E_interaction(A2)) at different positions above the aromatic ring support addition to the para-position of toluene. Moreover, these energy calculations matched those observed in the experimental regioselectivity (Figure 4a and 4b). It is worth noting that this reaction tolerates benzylic C−H bonds, as previous reports on N-radical dication generation from Selectfluor have shown a hydrogen-atom transfer (HAT) process with benzylic hydrogens.^20,21 In addition, DFT studies support the intermediacy of an N-radical-cation−pi interaction followed by C−N bond formation as a more favorable process in comparison to the TS-energy for a benzylic HAT process (Figure 4a). To understand and predict the regioselectivity of the reaction, the Fukui indices were calculated for selected substrates and found to be a major parameter in predicting the observed regioselectivity of this reaction (Figure 4b, see SI for details). Specifically, the carbon in an arene with the highest Fukui index undergoes C−H bond amination. Additionally, steric effect may also play a role, as observed in toluene where the regioselectivity of 5:1 (p:m) was obtained, and none of the ortho-aminated product was observed.

Figure 4.

Mechanistic studies using computational and experimental methods. (a) DFT studies to elucidate N-radical cation−pi interactions vs HAT. (b) Comparison between Fukui indices and experimental regioselectivity. (c) CV studies supporting charge-transfer mechanism. (d) KIE experiments (e) The role of triethylamine in the reaction. (f) Proposed mechanism.

Cyclic voltammetry (CV) was performed to elucidate the proposed charge-transfer mechanism prior to C−N bond formation (Figure 4c). From a solution of Selectfluor II, CV analyses were performed with an increasing amount of arene concentration. The resulting CV profile using a Pt disk working electrode showed an anodic shift upon increasing arene concentration; a distinct characteristic of a charge transfer mechanism²⁴ between the electrochemically generated dicationic N-radical with the arene. Kinetic isotope effect (KIE) was investigated by performing an electrochemical amination reaction with 1,3,5-trideuterated benzene as the substrate (Figure 4d). Analysis of the crude product showed a KIE of 1.1, suggesting that the aromatic C−H bond cleavage is not the rate-limiting step (see SI for details).

We next investigated the role and effects of triethylamine in the reaction (Figure 4e). The main purpose of triethylamine is that it acts as a base to convert intermediate C to generate the arylDABCOnium product. Moreover, we propose that triethylamine can also act as a sacrificial reductant via anodic oxidation (E_p/2 = +0.50 V vs Fc/Fc⁺) to facilitate the facile reduction of Selectfluor. For reactions at high triethylamine loading (e.g., 5 equiv), the reaction did not produce any product as anodic oxidation of Et₃N completely outcompetes the anodic oxidation of intermediate B to C.

Overall, we propose a mechanism (Figure 4f) in which Selectfluor undergoes cathodic reduction to generate a N-radical dication that participates in a charge-transfer step with an arene that is accompanied by a C−N bond formation. A radical intermediate B is generated, and this is anodically oxidized to form the intermediate C. The base (Et₃N) deprotonates C to form the arylDABCOnium product.

In summary, we have developed the first reductive electrochemical approach for aromatic C−H amination via the cathodic generation of N-radical cations. These reactions were found to have high to excellent regioselectivity toward para-C−H functionalization, and this regioselectivity is governed by the electrophilicity of the dicationic N-radical intermediate participating in a charge transfer mechanism with an arene. The scope of this reaction is broad comprising electron-rich, -neutral, and -deficient arenes, as well as notable reactivity and selectivity in various N-heterocycles and in the late-stage functionalization of pharmaceuticals. In addition, combined with an electrochemical site-selective aromatic C−H amination, we have demonstrated the synthetic utility of aryl DABCOnium salts: as precursors to generate various aryl piperazines and as aryl radical precursors in a tandem photocatalytic C−H phosphorylation and arylation of small-molecule pharmaceuticals, demonstrating their potential for future development in the area of selective arene C−H functionalization.