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. 2024 Feb 5;26(6):1128–1133. doi: 10.1021/acs.orglett.3c03727

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

Gustavo G Flores-Bernal 1, Luis D Miranda 1,*
PMCID: PMC10877592  PMID: 38315447

Abstract

graphic file with name ol3c03727_0008.jpg

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.

α-Aryl or heteroaryl dialkyl nitriles/esters are particularly important motifs, as these appear in bioactive molecules (Figure 1a) such as dactolisib (anticancer drug), verapamil (calcium-channel blocker), and alkaloids such as coronaridine.1,2 The nitrile group is considered a vital pharmacophore3 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.4 The retrosynthetic analysis to obtain α-aryl dialkyl nitriles is based on the classic α-deprotonation and subsequent reaction with aryl and/or alkyl halides; however, strong bases are needed, decreasing the functional group tolerance of the process.5 Transition metal-catalyzed cross-coupling reactions of arene derivatives and nucleophilic nitriles have extended the synthetic repertoire.6 However, 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 all-carbon 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 unnecessary prefunctionalization steps, improving the atom and step economy of the synthetic scheme.

Figure 1.

Figure 1

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Approaches for the synthesis of α-heteroaryl nitriles.

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 systems7 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.11 Efforts have also been made toward the group-directed C(sp2)–H alkylation using azo initiators.12−14 Notably, to the best of our knowledge, the direct C(sp2)–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.

Table 1. Optimization of the Reaction Conditionsa.

graphic file with name ol3c03727_0007.jpg

entry oxidant (equiv) solvent yield of 3a (%)b
1 Cu(OAc)2 (1.0) TCE 73 (61)c
2 – TCE 0
3 FeCl3 (1.0) TCE 0
4 MnO2 (1.0) TCE 0
5 (NH4)2S2O8 (1.0) TCE 10
6 Cu(EH)2 (1.0) TCE 69
7 CuCl2 (1.0) TCE 44
8 Cu(acac)2 (1.0) TCE 44
9 Cu(OTf)2 (1.0) TCE 0
10 Cu(OAc)2 (1.0) 1,4-dioxane 2
11 Cu(OAc)2 (1.0) DMF 20
12 Cu(OAc)2 (1.0) 2-methyl-2-butanol 20
13 Cu(OAc)2 (1.0) n-PrOH 22
14 Cu(OAc)2 (1.0) n-BuOH 29
15 Cu(OAc)2 (0.1)/(NH4)2S2O8 (1.0) TCE 27
16 Cu(OAc)2 (0.1)/air TCE 47
17 Cu(OAc)2 (0.1)/O2 (1 atm) TCE 26
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a

Conditions: 1a (0.8 mmol, 2.0 equiv), 2a (0.4 mmol, 1.0 equiv), oxidant (0.4 mmol, 1.0 equiv, unless otherwise noted), 110 °C, 2 h.

b

Isolated yield.

c

With 1 mmol of 2a. Abbreviations: TCE, 2,2,2-trichloroethanol; Cu(EH)2, copper(II) 2-ethylhexanoate; DMF, N,N-dimethylformamide.

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 successfully 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 CuCl2, 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 first-order kinetics,15 the reaction temperature determines the half-life (t1/2) 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,N-dimethylformamide (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.17 Because 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.

Under the optimal reaction conditions, we examined various heteroarenes 2 and azobis(alkylcarbonitriles) 1, affording 31 new α,α-dialkyl-α-aryl nitriles in 15–85% yields (Scheme 1). Both benzofurans (3a–e) and furans (3f–l) were suitable partners for the α-heteroarylation protocol with the cyanocyclohexyl radical derived from 1a. The reaction was selective, and no regioisomers were obtained. The presence of halogen substituents in aromatic rings was well tolerated, as demonstrated in the bromine (3b and 3k) and chlorine (3j) derivatives. In general, radical alkylation products on benzofurans and furans substituted with electron-withdrawing groups such as nitrile, ketone, ester, and nitro were obtained in lower yields (3b–d, 3h–j, and 3l) than benzofurans and furans substituted with alkyl groups (3e–g). To demonstrate the applicability of this protocol, the cyanocyclohexyl alkylation of bergapten (5-methoxypsoralen), a potent photochemotherapeutic agent, was achieved in 55% yield (3m). The yields of the synthesis of α,α-dialkyl-α-heteroaryl nitriles 3n–t with 1a and pyrrole, indole, and thiophene were the lowest (16–34%).

Scheme 1. Scope of the α-Heteroarylation of Nitriles with Azobis(alkylcarbonitriles) 1.

Scheme 1

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As in entry 1 of Table 1.

Modified conditions: 1b–e (0.8 mmol, 1.0 equiv), 2 (2.4 mmol, 3.0 equiv), Cu(OAc)2 (0.8 mmol, 1.0 equiv), TCE (0.8 M), 90 °C, 2 h.

Reaction with 2,2′-azobis(2-methylpropionitrile) (1b) and 2,2′-azobis(2-ethylbutanenitrile) (1c) produced α,α-dimethyl- and α,α-diethyl-α-(benzo)furanyl nitriles 4a–i, at yields ranging from 15% to 60%. It is worth noting that the reaction can occur in the presence of a free carboxylic acid group. This was observed when 4,4′-azobis(4-cyanovaleric acid) (1d) was used, leading to the assembly of 4-[(benzo)furanyl]-4-cyano pentanoic acids 4j–m, with yields ranging from 18% to 54%. Trapping these radicals has been a challenge in previous reports.12,18 Using 4,4′-azobis(4-cyanovaleric acid)dimethyl ester (1e) resulted in the formation of esters 4n and 4o with high yields (72–77%).

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.19

Scheme 2. Intramolecular Approach.

Scheme 2

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The protocol yields versatile synthetic intermediates, α,α-dialkyl-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 Boc2O 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.

Scheme 3. Derivatization of α-Heteroaryl Nitrile 3a.

Scheme 3

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During radical trapping experiments, either 2,6-di-tert-butylphenol 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).

Scheme 4. Radical Trapping Experiments.

Scheme 4

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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).20 Then, copper-mediated 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.

Scheme 5. Proposed Reaction Mechanism.

Scheme 5

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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 N2 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.

Acknowledgments

Financial support from DGAPA-UNAM (Project IN215322) is gratefully acknowledged. G.G.F.-B. is grateful for the scholarships awarded by CONAHCYT (581400). The authors appreciate the technical assistance from Francisco Javier Pérez Flores, Adriana Romo, Isabel Chávez, Beatriz Quiroz, Rubén Gabiño, Ma. C. García-González, María de los Ángeles Peña, Elizabeth Huerta Salazar, Everardo Tapia Mendoza, Mayra León Santiago, Simón Hernández Ortega, and Alfredo Toscano (MS, NMR, and X-ray, Instituto de Química UNAM).

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.3c03727.

  • Experimental procedures, 1H and 13C NMR spectra of products, and X-ray crystallographic information (PDF)

The authors declare no competing financial interest.

Special Issue

Published as part of Organic Lettersvirtual special issue “Radical Reactions for the Construction and Transformation of Complex Molecules”.

Supplementary Material

ol3c03727_si_001.pdf (3.8MB, pdf)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ol3c03727_si_001.pdf (3.8MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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