Skeletal Editing of (Hetero)Arenes Using Carbenes

Abstract

(Hetero)arenes continue to prove their indispensability in pharmaceuticals, materials science, and synthetic chemistry. As such, the controllable modification of biologically significant (hetero)arenes towards diverse more‐potent complex molecular scaffolds through peripheral and skeletal editing has been considered a challenging goal in synthetic organic chemistry. Despite many excellent reviews on peripheral editing (i. e., C−H functionalization) of (hetero)arenes, their skeletal editings via single atom insertion, deletion, or transmutations have received less attention in the review literature. In this review, we systematically summarize the state‐of‐the‐art skeletal editing reactions of (hetero)arenes using carbenes, with a focus on general mechanistic considerations and their applications in natural product syntheses. The potential opportunities and inherent challenges encountered while developing these strategies are also highlighted.

Dearomative Insertion of Fluoroalkyl Carbenes into Azoles Leading to Fluoroalkyl Heterocycles with a Quaternary Center

“…Recently, formal single-atom insertion reactions (i.e., skeletal editing) that modify the core skeleton of heteroarenes have emerged as a powerful tool for synthesizing complex organic molecules. [34][35][36] Such methods not only maximize the structural diversity but also alter the chemical or biological properties of the original compounds. [37][38][39] The insertion of carbenes into heteroarenes is especially appealing due to its ready availability, structural diversity, rich reactivity, and high atom economy.…”

“…[37][38][39] The insertion of carbenes into heteroarenes is especially appealing due to its ready availability, structural diversity, rich reactivity, and high atom economy. [36] The fundamental synthetic challenge in these skeletal editing reactions is the ability to control the chemo-and regioselectivity of the insertion reaction, avoiding the harsh reaction conditions necessary to cleave the highly challenging aromatic CÀ C or CÀ X (X = N, O, S) bonds, and to prevent competitive CÀ H functionalization. Despite these formidable synthetic challenges, a series of skeletal ring expansion reactions of heteroarenes through carbene insertion have recently been reported.…”

“…Despite these formidable synthetic challenges, a series of skeletal ring expansion reactions of heteroarenes through carbene insertion have recently been reported. [36] By contrast, strategies for installing fluoroalkyl quaternary centers onto heteroarenes through fluoroalkyl carbene insertion have so far remained scarce. As a result, our group became interested in developing a general method for the synthesis of these fluoroalkyl substituted heterocycles.…”

“…Considering the applications of azoles in medicinal chemistry [41][42][43][44][45][46] and organic synthesis, [47][48][49][50][51][52][53] we envisioned that skeletal ring expansion of such a broad compound class [36,54,55] through fluoroalkyl carbene insertion would provide a privileged platform for the construction of a diverse set of heterocyclic scaffolds bearing a fluoroalkylquaternary center (Figure 1B, upper part). To date, only one example of such ring expansion strategy has been reported, in which the Novikov group achieved the conversion of Nsubstituted pyrazoles into dihydropyrimidines (Figure 1B, lower part).…”

Direct Access to Quinazolines and Pyrimidines from Unprotected Indoles and Pyrroles through Nitrogen Atom Insertion

“…Transforming parent molecular frameworks into structurally related compounds through the insertion of single atoms has gained increased attention over the last decades, further expanding the synthetically accessible chemical space. − Through the insertion of heteroatoms such as oxygen − or nitrogen − into abundant frameworks, rapid access to a diverse array of shape-similar targets with modulated pharmacokinetic properties is possible. Additionally, applying these strategies to diversify target structures at a late stage obviates time-consuming de novo syntheses and directly affords biologically interesting heterocycles expanding available medicinal chemistry libraries. , Recently, various methods were developed to interconvert widely encountered scaffolds such as indoles and pyrroles into the corresponding carbon-atom extended frameworks, including quinolines and pyridines. − Strategies to afford the corresponding N , N -heterocycles were also disclosed, however, these either depend on harsh reaction conditions and present a limited scope or rely on the use of protecting group strategies that require a separate prefunctionalization step (Figure a). , In addition, the strategically related development of a nitrogen atom insertion into pyrroles to access the corresponding pyrimidine motifs is underdeveloped and was showcased for only two selected examples, 2,3,4,5-tetraphenyl-1 H -pyrrole (Figure b) , and ethyl 4-(4-methoxyphenyl)-2,5-dimethyl-1 H -pyrrole-3-carboxylate …”