Bence B. Botlik’s research while affiliated with University of Oxford and other places

The synthesis of nitrogen-containing molecules through carbon–nitrogen (C–N) bond formation is critical for the discovery and preparation of medicines, agrochemicals, and materials. Here, we report the direct insertion of a nitrogen atom into unactivated carbon-carbon double bonds to access aza-allenium intermediates, which can be converted either into nitriles or amidine products, depending on the initial alkene substitution pattern. This operationally simple and highly functionally compatible reaction works on a wide range of unactivated alkenes. PIFA, a commercially available and inexpensive hypervalent iodine reagent, is key to this reactivity. Our mechanistic proposal is supported by chemical trapping experiments, which concomitantly demonstrate the utility of our method to access valuable N -heterocycles. Additionally, our method can be used as a general strategy for synthesizing amides and amines, as well as ¹⁵ N-labeled molecules.

Catalytic enantioconvergent nucleophilic substitution reactions of alkyl halides are highly valuable transformations, but they are notoriously difficult to implement. Specifically, nucleophilic fluorination is a renowned challenge, especially when inexpensive alkali metal fluorides are used as fluorinating reagents due to their low solubility, high hygroscopicity and Brønsted basicity. Here we report a solution by developing the concept of synergistic hydrogen bonding phase-transfer catalysis. Key to our strategy is the combination of a chiral bis-urea hydrogen bond donor (HBD) and an onium salt—two phase-transfer catalysts essential for the solubilization of potassium fluoride—as a well-characterized ternary HBD–onium fluoride complex. Mechanistic investigations indicate that this chiral ternary complex is capable of enantiodiscrimination of racemic benzylic bromides and α-bromoketones, and upon fluoride delivery affords fluorinated products in high yields and enantioselectivities. This work provides a foundation for enantioconvergent fluorination chemistry enabled through the combination of a HBD catalyst with a co-catalyst specifically curated to meet the requirement of the electrophile.

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.

Herein we report the development of an oxidative amination process for the streamlined synthesis of pyridones from cyclopentenones. Cyclopentenone building blocks can undergo in situ silyl enol ether formation, followed by the introduction of a nitrogen atom into the carbon skeleton with successive aromatisation to yield pyridones. The reaction sequence is operationally simple, rapid, and carried out in one pot. The reaction proceeds under mild conditions, exhibits broad functional group tolerance, complete regioselectivity, and is well scalable. The developed method provides facile access to the synthesis of ¹⁵N‐labelled targets, industrially relevant pyridone products and their derivatives in a fast and efficient way.

We report the utilisation of an iodine(III) reagent to access α,β-unsaturated carbonyls from the corresponding silyl enol ethers of ketones and aldehydes, and from enol phosphates of lactones and lactams....

Herein we report the development of an oxidative amination process for the streamlined synthesis of pyridones from cyclopentenones. Cyclopentenone building blocks can undergo in situ silyl enol ether formation, followed by the introduction of a nitrogen atom into the carbon skeleton with successive aromatisation to yield pyridones. The reaction sequence is operationally simple, rapid, and carried out in one pot. The reaction proceeds under mild conditions, exhibits broad functional group tolerance, complete regioselectivity, and is well scalable. The developed method provides facile access to the synthesis of 15N‐labelled targets, industrially relevant pyridone products and their derivatives in a fast and efficient way.

The synthesis of nitrogen-containing molecules through C–N bond formation is critical for the discovery and preparation of medicines, agrochemicals and materials. Traditional synthetic methods using alkenes as ubiquitous substrates leverage the reactivity of the C(sp2)–C(sp2) π bond for C–N bond formation. In contrast, methods that can form C–N bonds through complete cleavage of the double bond are scarce, despite the considerable synthetic potential of such a strategy. Here, we report the direct insertion of a nitrogen atom into unactivated carbon-carbon double bonds to access aza-allenium intermediates which can be converted either into nitriles or amidine products, depending on the initial alkene substitution pattern. This operationally simple and highly functional group tolerant reaction works on a wide range of unactivated alkenes. Our mechanistic proposal is supported by chemical trapping experiments, which concomitantly demonstrate the utility of our method to access valuable N-heterocycles. Overall, this study demonstrates the possibility to access reactive nitrogen-containing intermediates (i.e. aza-alleniums), which have ample potential for downstream diversification, from unactivated alkenes, opening new avenues for the discovery and preparation of important products.

We report a convenient protocol for a nitrogen atom insertion into indenes to afford isoquinolines. The reaction uses a combination of commercially available phenyliodine(iii) diacetate (PIDA) and ammonium carbamate as the nitrogen source to furnish a wide range of isoquinolines. Various substitution patterns and commonly used functional groups are well tolerated. The operational simplicity renders this protocol broadly applicable and has been successfully extended towards the direct interconversion of cyclopentadienes into the corresponding pyridines. Furthermore, this strategy enables the facile synthesis of 15N labelled isoquinolines, using 15NH4Cl as a commercial 15N source.

We report a convenient protocol for a nitrogen atom insertion into indenes to afford isoquinolines. The reaction uses a combination of commercially available (diacetoxy¬iodo)benzene (PIDA) and ammonium carbamate to furnish a wide range of isoquinolines. Various substitution patterns and commonly used functional groups are well tolerated and the operational simplicity renders this protocol broadly applicable. Furthermore, this strategy enables the facile synthesis of 15N labeled isoquinolines, using 15NH4Cl as a commercial 15N source.