Elsevier

Molecular Catalysis

Volume 502, February 2021, 111394
Molecular Catalysis

Mechanistic insights into the C(sp3)-H heteroarylation of amides and Fukui function analysis of regioselectivity

https://doi.org/10.1016/j.mcat.2021.111394Get rights and content

Highlights

  • The underlying mechanism of visible-light-enabled C(sp3)-H heteroarylation of amides.

  • Protonated heteroarenes promoting coupling reaction.

  • Fukui functions predicting the reactive sites of the protonated heteroarenes in heteroarylation of amides.

Abstract

A computational study is carried out to understand the mechanism and excellent regioselectivity in metal-free heteroarylation of amides reported by Zhu’s group. The heteroarylation reaction started with the initial generation of key nitrogen-centered radicals via ligand exchange between reactant 1a and initiator PIFA under visible-light irradiation. Following, this reaction undergoes four-stages: 1,5-hydrogen atom transfer, Csingle bondC coupling, single electron transfer and proton transfer. The Csingle bondC coupling step is identified as the selectivity-determining step in which the carbon-centered radical (C) selectively only attacks the carbon atom adjacent to nitrogen of lepidine (2a). And the radical C more easily attacks the protonated 2a, compared with unprotonated 2a, due to significantly lowered SOMO/LUMO energy difference between them to promote this nucleophilic radical addition. From the calculated result, we can see that the positive effect of the acidity of the reaction substrates on the nucleophilic addition to heteroarenes. Fukui functions of different types of heteroarene substrates are calculated to predict the favorable nucleophilic sites. The calculated most favorable reactive sites of heteroarene substrates are well consistent with the experimental observed ones. This theoretical research provides deeper understandings for the underlying mechanism and the origin of exclusive regioselectivity of the heteroarylation of amides.

Introduction

Nitrogen-containing heteroaryl rings are important structural backbone in a large number of natural products, medically valuable small molecules, and pharmaceuticals [[1], [2], [3], [4]]. Research demonstrates that successful drug candidates include an average of 0.38 to 0.69 heteroaryl rings per molecules by 2010 corresponding to an 80 % rise [5]. Rapid construction and direct structural modification to synthetized N-heteroaryl rings are of important value. Minisci reaction is an attractive method for the synthesis of multiply substituted heteroaryl rings via C–H functionalization. The classic Minisci reaction (Scheme 1a) is broadly referred as the addition of a carbon-centered radical to a basic heteroaryl ring resulting in C–H functionalization. The pioneering work indicated that the alkyl radical generated from the decarboxylation of pivalic acid in the presence of ammonium persulfate could couple with the protonated pyridine to achieve the mixture of C-2 and C-4 alkylation isomers [6]. The primal reaction has poor regioselectivity and needs transition metal catalyst, oxidant, stoichiometric acid additive and elevated temperature. With the increasing interest in new transformations based on free radical reactivity, more and more developments of Minisci-type reaction are now available to synthetic chemists. Tremendous efforts in recent years have been done to vary the classic Minisci reaction conditions [1]. They include seeking functional heterocycles in a rapid and direct manner avoiding the need for de novo heterocycle synthesis, exploiting a wider variety of radical precursors under milder and more benign conditions, developing different radical generation approaches which utilize thermal cleavage or in situ generation, applying different types of catalysts besides cheap transition metal or metal-free catalysts, photoredox catalysts and chiral Brønsted acid catalysts to initiate the generation of alkyl radical species. And these results have induced the exclusive regioselectivity and excellent enantioselectivity. The sustainability, functional group compatibility and the control of selectivity are exciting new developments in Minisci reaction.

In 2019, Zhu’s group reported a metal-free remote heterorarylation of amides via unactivated C(sp3)-H bond functionalization to give exclusive regioselective (C-2) products (Scheme 1b) [7]. Inspired by the well-established Hofmann–Löffler–Freytag reaction (HLF), they used a wide scope of aliphatic amides to produce the nitrogen-centered radicals which were applied to initiate alkyl radical species via 1,5-HAT. This radical generation method by radical translocation triggered by nitrogen-centered radicals through HLF reaction via HAT has caused intense interest [[8], [9], [10], [11], [12], [13], [14], [15]]. In general, the overall mechanism of Minisci-type reactions involves the key step where a typically nucleophilic carbon-centered radical adds to a basic heteroarene. Opatz and coworkers studied the theoretical background about Minisci-type reactions in terms of frontier orbital theory [16]. Nevertheless, the overall mechanism for this individual transformation is typically rather more complicated owing to the need for integrating the mechanism of radical generation with the underlying Minisci-type addition mechanism.

In this work, we are interested in the underlying detailed mechanism and origin of exclusive regioselectivity of Zhu group’s work. Therefore, reaction of tosylamide (1a) and lepidine (2a) is used as model reaction (Scheme 1b) in the following computational study. The proposed mechanism for this reaction is shown in Scheme 2. This reaction undergoes the initial generation of nitrogen-centered radicals intermediate (B) and the subsequent 1,5-HAT, Csingle bondC coupling, single electron transfer (SET) and proton transfer (PT). Fukui function correctly predicts the reactive site of various heteroaromatic substrates. We hope these insights on mechanism could provide further understanding for such kind of Minisci-type reactions and provide valuable information for designing and predicting reactive site of new Minisci-type reactions.

Section snippets

Computational details

All DFT calculations are employed by using the Gaussian 09 [17] in solution phase with SMD solvation model [18] (solvent = dichloroethane (DCE), ε = 10.125). M06−2X functional is used to optimize molecular structures and calculate the single energy with an ultrafine integration grid [[19], [20], [21]]. The SDD basis set [[22], [23], [24]] is used for iodine atom and the 6−31 G(d) basis set [25] for the other atoms. The resulting structure is the real minima or saddle points on the potential

Generation of nitrogen-centered radicals (NCRs) B

Initially, amide 1a reacts with phenyiodine bis(trifluoroacetate) (PIFA) to form the N-I(III) complex A and trifluoroacetic acid (TFA) via ligand exchange, which is slightly exergonic by -1.0 kcal/mol (Scheme 2). Actually, this approach to form N-I(III) complex through the ligand exchange of Nsingle bondH complex benzamide and PhI(OAc)2 has been reported by shi et al. [28] Subsequently, Nsingle bondI bond in complex A is initiated by visible light to cleave homolytically to yield an iodany radical and the reactive

Conclusions

In summary, the metal-free heteroarylation of amides via unactivated C(sp3)-H bond functionalization expands a novel strategy for synthesis of heteroarenes via Minisci reaction. We performed a DFT study to get deeper insights into its mechanism and excellent regioselectivity. A reasonable mechanism for the heteroarylation of amides with 2a, which is protonated by TFA generated in situ, has been studied. This heteroarylation mechanism mainly consists of the initial generation of key

CRediT authorship contribution statement

Liying Mu: Formal analysis, Writing - original draft. Wenjing Fan: Investigation, Software. Xiang-Ai Yuan: Funding acquisition, Writing - review & editing. Congcong Huang: Validation. Dan Li: Validation. Siwei Bi: Funding acquisition, Writing - review & editing.

Declaration of Competing Interest

The authors declare no competing interest.

Acknowledgements

This work is supported by the National Natural Science Foundation of China (Grant Nos. 21703118 and 21873055) and High Performance Computing Center of Qufu Normal University.

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