A Copper-Mediated Radical α-Heteroarylation of Nitriles with Azobis(alkylcarbonitriles)

A new practical method has been developed for the α-heteroarylation of aliphatic nitriles with heteroarenes and azobis(alkylcarbonitriles) using Cu(OAc)2 as an oxidizing agent. This method allows the easy construction of nitrile-, aryl-, and dialkyl-bearing quaternary carbon centers from readily available building blocks, without requiring prefunctionalization steps. This reaction is based on adding cyanodialkyl radicals onto heteroarenes, including benzofurans, furans, pyrroles, and indoles. The resulting α-heteroaryl nitriles are useful synthetic intermediates and pharmacophores in biologically active molecules.

dine. 1,2The nitrile group is considered a vital pharmacophore 3 and a valuable synthetic intermediate.Its reactivity allows its transformation into various functional groups, such as esters, amides, ketones, aldehydes, carboxylic acids, amines, and nitrogen-containing heterocycles. 4The retrosynthetic analysis to obtain α-aryl dialkyl nitriles is based on the classic αdeprotonation and subsequent reaction with aryl and/or alkyl halides; however, strong bases are needed, decreasing the functional group tolerance of the process. 5Transition metalcatalyzed cross-coupling reactions of arene derivatives and nucleophilic nitriles have extended the synthetic repertoire. 6owever, the required catalysts and ligands are often not readily available (Figure 1b).In general, previous approaches have mainly focused on obtaining secondary alkyl nitriles, very few methods have addressed the construction of sterically hindered α,α-dialkyl-α-aryl nitriles, and even fewer attempts have tackled the challenge of constructing the quaternary allcarbon center through direct C−H alkylation of heteroarenes. 1 In this context, protocols that rely on the innate reactivity of the aromatic system, such as electrophilic and homolytic aromatic substitution, offer a practical method for functionalizing a C−H bond directly.This approach helps avoid  The addition of a radical to an aromatic system poses two main challenges (Figure 1c).First, it is a relatively high-energy process because the aromatic system is disrupted.Second, this step can be highly reversible, especially when a stabilized radical A is involved.Therefore, an efficient oxidation system must be found for radical B to evolve into the rearomatized product.
Our interest in the addition of a radical to aromatic systems 7 has recently led us to explore using azobis(alkylcarbonitriles) 1 as radical precursors for this process.This functional group has unique properties because it cleanly fragments into a pair of alkyl radicals and a nitrogen molecule.The process requires only heating a solution of 1, and the temperature can be adjusted to control the half-life.For instance, several reports have demonstrated that azobis(alkylcarbonitirles) 1 are suitable radical precursors for functionalizing π-systems such as alkenes, 8 alkynes, 9 isocyanides, 10 and aldehydes. 11Efforts have also been made toward the group-directed C(sp 2 )−H alkylation using azo initiators. 12−14 Notably, to the best of our knowledge, the direct C(sp 2 )−H functionalization of heteroarenes using azobis(alkylcarbonitriles) 1 (Figure 1c) has not been explored.In this study, we present a copper-mediated radical α-heteroarylation method using azobis-(alkylcarbonitriles) to synthesize α,α-dialkyl-α-aryl nitriles.
After a thorough evaluation of various potential coupling partners, the reaction between the cyanocyclohexyl radical derived from 1,1′-azobis(cyclohexanecarbonitrile) (1a) and 2,3-benzofuran (2a) was selected as a useful model system.The results are listed in Table 1.
Our experiment revealed that when we subjected 1a to thermal cleavage using 1.0 equiv of Cu(OAc) 2 as an oxidizing agent in a 2,2,2-trichloroethanol (TCE) solvent, we success-fully obtained α-heteroarylation product 3a in 73% yield.The reaction showed complete regioselectivity for position C-2 of the heteroarene and did not require any additives, bases, activating agents, or extended reaction times.The presence of Cu(OAc) 2 was found to be crucial for the reaction as no product was obtained in its absence (Table 1, entry 2).Other oxidizing agents, which are usually used in similar radical alkylation processes, had a negative impact on reactivity (Table 1, entries 3−5).Evaluation of different Cu(II) sources showed that Cu(OAc) 2 was better than CuCl 2 , Cu(acac) 2 , and Cu(OTf) 2 (Table 1, entries 7−9, respectively), whereas copper(II) 2-ethylhexanoate [Cu(EH) 2 ] (Table 1, entry 6) showed activity similar to that of Cu(OAc) 2 .As the thermal decomposition of azobis(alkylcarbonitriles) 1 follows a firstorder kinetics, 15 the reaction temperature determines the halflife (t 1/2 ) and consequently the reaction time.In this case, after 2 h, solvents with boiling points of ≥100 °C completely decomposed 1a.The evaluation of selected polar solvents showed that TCE was essential for coupling success.Table 1 shows that when other polar solvents like 1,4-dioxane, N,Ndimethylformamide (DMF), or alcohols were used, the yields were poorer (entries 10−14).Even though solvents did not significantly affect the decomposition rates of azo initiators, 16 they still play a crucial role in cage effects, diffusion rates, and radical stabilization and trapping.Indeed, perhalogenated solvents have demonstrated significant usefulness in difficult C−H functionalizations. 17Because TCE is cheaper and has a boiling point higher than that of either hexafluoroisopropanol (HFIP) or trifluoroethanol (TFE), the conditions of entry 1 were determined to be optimal.Some assays carried out with a co-oxidant using catalytic amounts of Cu(OAc) 2 considerably decreased the yield of 3a.
To further extend the methodology, we next examined the intramolecular cyclization reaction for the construction of a pyrido[1,2-a]indole skeleton bearing a quaternary all-carbon center from indole-containing azobis(alkylcarbonitriles) 5a−c (Scheme 2).Compounds 5a−c were synthesized through the N-acylation of indole with 4,4′-azobis(4-cyanovaleric acid) (1d).To our delight, in a less concentrated reaction medium (0.1 M) than the intermolecular radical addition, the thermolysis of azo compounds 5a−c in the presence of Cu(OAc) 2 (2.0 equiv) gave cyclized products 6a−c, respectively, in 48−85% yields.Our laboratory is currently investigating the potential of this promising intramolecular cyclization reaction to synthesize valuable scaffolds for Aspidosperma alkaloids. 19he protocol yields versatile synthetic intermediates, α,αdialkyl-α-heteroaryl nitriles, which can be converted into important derivatives (Scheme 3).For instance, hydrogenation of the nitrile to the primary amine and in situ protection with

Organic Letters
Boc 2 O gave 7 in 73% yield.Similarly, the reduction of benzofuran-containing nitrile 3a with DIBAL-H furnished the corresponding aldehyde 8 in 77% yield.It was possible to convert nitrile into ketone 9 with a 34% yield by using MeMgBr in toluene.The same substrate was also transformed into tetrazole derivative 10 in excellent yield using microwave irradiation.
During radical trapping experiments, either 2,6-di-tertbutylphenol or BHT was used as the radical scavenger in the presence of stoichiometric Cu(OAc) 2 without heteroarene (Scheme 4).As a result, cyanoalkyl radicals were added directly to the aromatic ring, leading to the formation of phenols 11a and 11b (64% and 81% yields, respectively) and dearomatized products 12a and 12b (73% and 92% yields, respectively).
In the proposed reaction mechanism (Scheme 5) after the thermal decomposition of 1, a pair of cyanoalkyl radicals A are formed along with a nitrogen molecule.Then, direct addition of radical 2 affords the intermediate radical (σ-complex B) in a reversible process whose progress is favored mainly by the strength of the new bond formed, the aromaticity of the system (enthalpy effect), and the electronic match of the heteroarene−alkyl radical pair (polar effect). 20Then, coppermediated oxidative radical−polar crossover provides the corresponding carbocation C, and the subsequent loss of a proton regenerates the aromaticity to afford α-heteroaryl nitrile 3.
In summary, we have developed a practical protocol for the α-heteroarylation of aliphatic nitriles with non-prefunctionalized heteroarenes using readily available Cu(OAc) 2 and commercially available azobis(alkylcarbonitriles).The success of this method relies on generating cyanoalkyl radicals by thermolysis of the azobis(alkylcarbonitriles), releasing N 2 as the only waste product.The direct copper-mediated radical cyanoalkylation of heteroarenes offers a new method for synthesizing valuable sterically hindered α,α-dialkyl-α-aryl nitriles under mild conditions and short reaction times.The process is highly regioselective and compatible with diverse functional groups.Our work contributes to the growing demand for the direct introduction of quaternary all-carbon centers into heteroarenes, which could be of great interest to the scientific community working in the field of organic synthesis.
Letter pubs.acs.org/OrgLettunnecessary prefunctionalization steps, improving the atom and step economy of the synthetic scheme.