Events & News

Events & News

Latest Innovations

One-Step C-to-N Swap: Direct Magic Conversion of Indoles to Benzimidazoles

21 October 2025

Latest Innovations

Recommended Products View More

Recently, the group of Bill Morandi at ETH Zürich has unveiled a novel “C-to-N swap” strategy for N-alkyl indoles: at room temperature in methanol, using commercially available PIDA (phenyliodine(III) diacetate) as oxidant and H₂NCO₂NH₄ as nitrogen source, the protocol converts indoles into the corresponding benzimidazoles in a one-pot process within only 30 minutes. The reaction leverages the innate reactivity of the indole scaffold to engage in an initial oxidative cleavage step, followed by oxidative amidation, Hofmann-type rearrangement and cyclization. The reaction tolerates a wide range of functional groups, which is demonstrated by the interconversion of 15 drug-like molecules. The work is reported in Nat. Chem.

Key Innovations

1. C-to-N swap: drug-relevant indole cores are directly transformed into benzimidazoles through a pinpoint carbon-to-nitrogen swap, eliminating the conventional pre-functionalization of the substrate and streamlining the route by exploiting the innate reactivity of the indole nucleus.
2. One-pot protocol: the entire process is compressed into a single operation that employs inexpensive, bench-stable reagents (PIDA and H₂NCO₂NH₄), requires only mild conditions and is operationally straightforward.
3. Broad functional-group tolerance: the transformation accommodates a wide scope of functionalities, enabling late-stage remodeling of complex drug-like molecules.

Introduction

Molecular skeleton editing has emerged as a frontier in contemporary organic chemistry, and single-atom swap reactions are attracting particular attention because they allow the core of a molecule to be altered with surgical precision. 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. As of 2024, indole is still the sixth most prevalent nitrogen heterocycle in FDA-approved drugs, yet it is regarded as a problematic scaffold in modern drug discovery: its metabolic hot-spots (that is, 2- and 3-position) are readily oxidized to highly reactive metabolites, leading to undesirable absorption-distribution-metabolism-excretion and/or toxicity profiles. Changing from a more electron-rich heterocycle, such as an indole, to a less electron-rich one, such as a benzimidazole, often has a positive effect on pharmacokinetics (Fig. 1c, top) by removing metabolic hot spots and decreasing phase I (cytochrome P450 enzyme) oxidations, ultimately improving the success rate in lead optimization campaigns.

Figure 1. Background and this work. [from Nature Chemistry]

Reaction discovery and optimizations

First, the authors chose the Witkop oxidation product Ia—readily accessible from the oxidative cleavage of the corresponding methyl indole 1a—as a model substrate to probe possible rearrangements (Fig. 2a). An initial screen revealed that the PIDA / H₂NCO₂NH₄ pair delivered the desired benzimidazole in 7 % ¹H-NMR yield. Further optimization showed that performing the reaction at lower concentration with 17 equiv of H₂NCO₂NH₄ and 6 equiv of PIDA furnishes 2a in 42 % ¹H-NMR yield in a one-pot reaction (Fig. 2b).

Figure 2. Reaction development. [from Nature Chemistry]

Key Reagent

CAS: 3240-34-4

Substrate scope

Under the optimized reaction conditions, the authors systematically explored the substrate scope (Fig. 3). Indoles bearing diverse N-alkyl substituents—ethyl (2c), isopropyl (2d), allyl (2e), and benzyl (2f, 2g)—were all tolerated, delivering the corresponding benzimidazoles in good yields. Notably, the N-benzyl derivative underwent an atom swap-dealkylation sequence to access the free NH benzimidazole 2h in 47 % isolated yield over two steps. Substrates with electron-donating groups (e.g., methoxy (2b), amide (2v)), electron-withdrawing groups (halogens (2i-2k, 2q, 2r), esters (2l, 2s), sulfones (2p)), free alcohol (2u), pyridine (2n), or indoles with substituents in proximity to the reactive centre (4- or 7-substituted, 2y-2ac) were efficiently transformed. The C-to-N atom swap could also be successfully applied to various aza-indoles (2ad-2af). For 5-substituted indoles (2q-2t), the formation of a dinitrile side-product derived from the Witkop intermediate was observed; however, complete consumption of starting material could still be achieved by a second portion of reagents. Despite its broad generality, the protocol does not tolerate nitro, nitrile, or boronic ester functionalities. Finally, a slightly modified protocol enabled the synthesis of 15N-labelled methyl-benzimidazole 2x.

Figure 3. Substrate scope for the carbon-to-nitrogen atom swap. [from Nature Chemistry]

Finally, the protocol was deployed for late-stage diversification of drug-like scaffolds (Fig. 4). Fifteen medicinally relevant cores were successfully converted, including precursors of a 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) kinase and protein tyrosine kinase 6 (PTK6) inhibitor, a survival-motor-neuron-targeting derivative, a 5-HT1C antagonist analogue, a glucokinase activator, an NAB-14-based negative allosteric modulator of NMDA receptors, an HDAC inhibitor, a PI3 kinase inhibitor, an ENT1 inhibitor, and PPAR modulators. The structures of 2ag, 2ah, 2ai, 2ak and 2aq were unambiguously confirmed by single-crystal X-ray analysis.

Figure 4. Carbon-to-nitrogen atom swap methodology applied to drug-like molecules. [from Nature Chemistry]

Conclusion

This study overcomes a central challenge in skeletal editing and develops a reaction that can directly convert structurally complex N-alkyl indoles into the corresponding benzimidazoles in a single step. Compared with existing methods, it offers three decisive advantages: (1) no substrate pre-activation is required; (2) only inexpensive, bench-stable reagents are used; and (3) an exceptional functional-group tolerance is displayed. The work delivers a powerful molecular diversification platform for drug discovery and sets a new paradigm for designing analogous atom-exchange reactions in other heterocyclic scaffolds. Its operational simplicity and efficiency make it immediately applicable within the pharmaceutical industry.

AmBeed's Products Support Related Research:

AmBeed supplies a complete range of high-purity building blocks and reagents for the synthetic route described above—including the oxidant (PIDA) and indole derivatives—fully meeting your experimental needs and powering your research forward.

Related Products:

Click the image to find out more

Product Information

A276445|A115315|A332488|A210542|A878270|A105019|A139857|A109501|A922262|A181137|A479405|A621767

References

[1]Paschke, AS.K., Brägger, Y., Botlik, B.B. et al. Carbon-to-nitrogen atom swap enables direct access to benzimidazoles from drug-like indoles. Nat. Chem. 2025.

Prev: Stereo- reversed E2 unlocks Z- selective C–H functionalization

Next: Photocatalytic Oxygen-Atom Transmutation in Oxetanes