Elsevier

Chinese Journal of Catalysis

Volume 42, Issue 11, November 2021, Pages 1865-1875
Chinese Journal of Catalysis

Review
Radical denitrogenative transformations of polynitrogen heterocycles: Building C–N bonds and beyond

https://doi.org/10.1016/S1872-2067(21)63814-7Get rights and content

Abstract

Polynitrogen heterocycles are readily available and have recently arisen as versatile synthons for the formation of various C–C and C–X bonds, and medicinally active nitrogen-containing heterocycles. Several cascade reactions, including annulation, radical cascade, and borylation reactions, have been reported in which polynitrogen heterocycles are applied as arylation reagents. The success of these exceptional reactions illustrates the great synthetic potential of polynitrogen heterocycles, which provides a direct and useful approach to arylation reactions and the synthesis of nitrogen-containing heterocycles. The use of photocatalysts to effectively transfer energy from visible light to non-absorbing compounds has gained increasing attention as this method allows for the mild and efficient generation of radicals in a controlled manner. This approach has thus led to new methods that involve unique bond formation reactions. In addition, the use of free radical intermediates stabilized by transition metal catalysts is a powerful way to construct new chemical bonds. The aim of this review is to highlight the rapidly expanding area of radical-initiated denitrogenative cascade reactions of polynitrogen heterocycles and elaborate on their mechanisms from a new perspective by using photocatalysis and metal-based catalysis.

Graphical abstract

This review provides a thorough overview of radical-initiated denitrogenative cascade reactions of polynitrogen heterocycles in the formation of various C–X bonds and medicinally active nitrogen-containing heterocycles.

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Introduction

To date, thousands of natural products and biologically active compounds that contain one or more nitrogen heterocycles have been identified. In addition, polynitrogen heterocycles are valuable intermediates in organic synthesis and can be used as functional materials [1, 2, 3, 4]. Therefore, significant efforts have been made toward the transformation and application of nitrogen-containing heterocycles. Denitrogenative cascade reactions of polynitrogen heterocycles are one of the most attractive approaches for the formation of several chemical structures that have variable activities. This field has attracted considerable interest from synthetic chemists as polynitrogen heterocyclic compounds can easily interact with corresponding metal carbenoid or radical species [5, 6, 7, 8]. For example, several studies on the denitrogenation of N-sulfonyl-1,2,3-triazoles, pyridotriazoles, and their related compounds have been reported recently, and have been assembled in several reviews. In these cases, the transannulation or cascade reaction involves metal-carbenes derived from polynitrogen heterocycles after denitrogenation, which undergo ring closure through an ionic mechanism (Scheme 1, left panel). However, radical-initiated denitrogenative cascade reactions of polynitrogen heterocycles are underrepresented. Representative strategies for denitrogenative transformation of polynitrogen heterocycles, such as triazoles, tetrazoles and benzotriazoles, mainly involve transition metal catalysts or the use of strong oxidants. From a synthetic point of view, these denitrogenative reactions accomplish powerful transformations from simple polynitrogen heterocycles to more complex molecules in modern synthetic chemistry, medicinal chemistry, and drug discovery. Thus, a summary of the recent progress in this field from a new perspective is required.

Free radicals have high chemical reactivities and unique stabilities, thus, synthesis of organic compounds through free radical reactions usually involves mild conditions, broad scopes, high efficiencies, and high yields [9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21]. At present, exploring and expanding the pool of radical-based reactions has become an important task for the research community. The past two decades have witnessed exponential growth in this field, especially in combination with visible-light irradiation synthesis, since MacMillan, Yoon, and Stephenson proposed a revival of this remarkable field of research in 2008 [22, 23, 24, 25, 26, 27, 28, 29, 30, 31]. Several original photochemical radical transformations have been reported and can be regarded as real breakthroughs in organic chemistry. For example, visible light photoredox catalysis has emerged as a great option for the generation of various N-radical species and methodology development towards the construction of diverse N-containing compounds. In addition, the construction and functionalization of heterocycles through photoredox catalysis has also proved to be powerful and efficient [32]. In the last few decades, it has been demonstrated that free radical intermediates stabilized by transition metal catalysts can interact with catalysts through redox bond formation, coordination, atom transfer, etc. [33, 34]. In this review, we wish to provide an overview covering recent examples of transition metal-catalyzed or visible-light-induced radical denitrogenative cascade reactions of polynitrogen heterocycles, as they mirror the traditional trend in the field of polynitrogen heterocycle transformations. Scheme 2 shows an outline of recent advances in radical-enabled denitrogenation of polynitrogen heterocycles. We classified these denitrogenative cascade reactions into four sections (Scheme 2) based on the different denitrogenation reagents and reaction types.

Section snippets

Radical denitrogenation of benzotriazin and benzothiatriazine

Cleavage of polynitrogen heterocycles (N–N bond homolysis) to generate aryl radicals through oxidative denitrogenation has been achieved in a similar manner to oxidative decarboxylation of R-CO2H (C–C bond homolysis), which has been widely used in the Minisci reaction. Aryl radical species are important reaction intermediates for the introduction of stable aromatic rings in organic molecules [35, 36]. Generally, there are several types of aryl radical precursors, such as aromatic amines or

Radical denitrogenation of 1,2,3-triazoles via an aryl radical

As a unique and important chemical structure in organic synthesis, pesticides, and pharmaceuticals, triazoles are present in many bioactive compounds and synthetic drugs [42, 43, 44, 45]. Late-stage modification and transformation of triazoles, especially 1,2,3-triazoles, are common research topics along with azide cycloaddition, also known as the “click reaction” [46, 47]. Among the various studies on 1,2,3-triazoles, “ring opening” through extrusion of nitrogen gas is an interesting method in

Radical denitrogenation of pyridotriazoles and tetrazoles

Pyridotriazoles are also an incredibly important class of polynitrogen heterocyclic compounds, which are not only valuable structural units used in many pharmaceutical and material science fields, but also key building motifs for the synthesis of multifunctional nitrogen heterocycles via transition metal-catalyzed oxidative cross-coupling reactions, direct heterocycle synthesis, cycloadditions, and ring expansions [62, 63, 64, 65, 66]. Generally, this transformation occurs through a non-radical

Denitrogenation of 3-aminoindazoles

3-Aminoindazoles are readily available and have recently arisen as versatile synthons for the formation of various C–C and C–X bonds, and medicinally active nitrogen-containing heterocycles [83, 84, 85, 86]. Several cascade reactions, including annulation, radical cascade, and borylation reactions, have been reported in which 3-aminoindazoles are used as the arylation reagents. The success of these exceptional reactions illustrates the great synthetic potential of 3-aminoindazoles, which

Conclusions and outlook

Denitrogenative radical cascade or cyclization reactions of polynitrogen heterocycles have become valid alternatives to the existing classical transition metal-mediated cross-coupling reactions. The field of denitrogenative chemistry has continued to expand in the past decade as a growing number of light-triggered cascade reactions have been reported that are based on the photochemical generation of reactive species, thus avoiding the use of toxic metal catalysts or reagents. The use of light

Acknowledgments

We also thank Hong-Di Yang, Yan-Li Wang, and Cai-Zhen Ding for their useful help.

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    This work was supported by the National Natural Science Foundation of China (21772107) and Shandong Province Key Research and Development Plan (2019GSF108017).

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