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Carbon-to-nitrogen atom swap enables direct access to benzimidazoles from drug-like indoles
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Abstract
The ability to selectively edit organic molecules at the atomic level has the potential to streamline lead discovery and optimization in the pharmaceutical and agrochemical industry. While numerous atom insertion and deletion reactions have recently been reported, examples of single atom swaps remain scarce due to the challenge of orchestrating the selective cleavage and formation of multiple chemical bonds around the same atom. We herein report a method for the carbon-to-nitrogen atom swap in N-alkyl indoles, allowing for the direct conversion of indoles to the corresponding benzimidazoles. The reaction leverages the innate reactivity of the indole scaffold to engage in an initial oxidative cleavage step, followed by oxidative amination, Hofmann-type rearrangement and cyclization. This complex sequence of steps is mediated by the simple combination of commercially available PIDA and ammonium carbamate as nitrogen atom source. The reaction tolerates a wide range of functional groups which is demonstrated by the interconversion of 15 drug-like molecules implying its immediate applicability across a wide range of discovery programs. Furthermore, it shows how leveraging the innate reactivity of a common heterocycle can unlock otherwise challenging skeletal editing reactions.
... We recently reported a strategy to leverage the innate reactivity of indoles to perform a rare C-to-N atom swap to benzimidazoles. 16 Benzofurans are another class of attractive heterocycles for such a transformation, as they are ubiquitous in natural products and pharmaceuticals (Fig. 1B). 17 Replacing a carbon with a nitrogen atom in the benzofuran core would thus facilitate chemical space exploration around this valuable motif. ...
... Unfortunately, the method we previously developed for indole editing using hypervalent iodine-mediated cleavage and Hofmann-type rearrangement could not be extended to benzofurans, calling for a new approach. 16 Herein, we describe a facile, chemodivergent one-pot method to transform 3-substituted benzofurans to benzoxazoles or benzisoxazoles as well as benzofurans to benzisoxazoles, using commercially available reagents (Fig. 1C). § Key to the reaction's success was the combination of a photomediated oxidative benzofuran cleavage with suitable electrophilic nitrogen sources in a one-pot sequential protocol. ...
Facile derivatization of biologically active compounds without prefunctionalization expands the chemical space and accelerates the discovery of new molecules. Atom swap reactions have recently emerged as powerful molecular editing tools, yet such reactions remain rare. Herein, we describe a convenient, chemodivergent protocol to perform a net C-to-N atom swap in benzofurans, affording benzoxazoles or benzisoxazoles via a cascade of oxidative cleavage, oxime formation, and cyclization using commercially available reagents.
... These latter two important compound classes are formed through C to N atom swapping with concomitant skeletal reorganization. During the preparation of this manuscript, Morandi and coworkers reported a similar C to N swap approach of indoles to benzimidazoles through sequential oxidation with subsequent Beckmann rearrangement 26 . This strategy operates orthogonal to ours while selectively transforming 2,3-unsubstituted indoles. ...
Skeletal editing comprises the structural reorganization of compounds. Such editing can be achieved through atom swapping, atom insertion, atom deletion or reorganization of the compound’s backbone structure1,2. Conducted at a late stage in drug development campaigns, skeletal editing enables diversification of an existing pharmacophore, enhancing the efficiency of drug development. Instead of constructing a heteroarene classically from basic building blocks, structural variants are readily accessible directly starting from a lead compound or approved pharmacophore. Here we present C to N atom swapping in indoles at the C2 position to give indazoles through oxidative cleavage of the indole heteroarene core and subsequent ring closure. Reactions proceed through ring-opened oximes as intermediates. These ring deconstructed intermediates can also be diverted into benzimidazoles resulting in an overall C to N atom swapping with concomitant skeletal reorganization. The same structural diverting strategies are equally well applicable to benzofurans leading to either benzisoxazoles or benzoxazoles. The compound classes obtained through these methods—indazoles3,4, benzisoxazoles⁵, benzimidazoles6,7 and benzoxazoles⁸—are biologically relevant moieties found as substructures in natural products and pharmaceuticals. The procedures introduced substantially enlarge the methods portfolio in the emerging field of skeletal editing.
... 135 Removal, addition, or exchange of a single atom in a molecule is oen achieved by modifying the synthesis of the compound from an early point in the route or by a totally different route. However, recent advantages in direct atom deletion, insertion, and exchange [136][137][138][139][140][141][142][143][144][145][146][147][148][149][150][151][152][153] can in some cases remove the need for new retrosynthetic analysis and provide new diverse compounds more efficiently. Additionally, subtle changes to the overall molecular shape and not just single atoms can have a large impact on the function and properties of compounds. ...
Natural products play a major role in the discovery of novel bioactive compounds. In this regard, the synthesis of natural product-inspired and -derived analogues is an active field that is further developing. Several strategies and principles for the design of such compounds have been developed to streamline their access and synthesis. This perspective describes how individual strategies or their elements can be combined depending on the project goal. Illustrative examples are shown that demonstrate the blurred lines between approaches and how they can work in concert to discover new biologically active molecules. Lastly, a general set of guidelines for choosing an appropriate strategy combination for the specific purpose is presented.
Skeletal editing of aromatic heterocycles represents a straightforward approach to rapidly expand the accessible chemical space. While notable progress has been made on the direct modification of various nitrogen‐ and oxygen‐heterocycles, editing of prevalent sulfur‐containing heteroarenes, especially for single‐atom insertion, remains exceedingly rare. This disparity is primarily attributed to the sulfur atom's inherent nucleophilicity and high susceptibility to oxidation. Here we present a conceptually distinct photocatalytic strategy that enables the insertion of a boron atom into a diverse range of thiaarenes, furnishing previously inaccessible cyclic thioborane scaffolds and synthetically valuable alkyl boronates in an efficient manner. Furthermore, mechanistic studies have revealed that the boron insertion step proceeds through an unprecedented mechanism.
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