Selective access to dihydrophenanthridines and phenanthridinones via cyclisation of aryl amines onto N-tethered arynes.

5,6-Dihydrophenanthridines are prepared from aryl amines via intramolecular addition to N-tethered arynes under mild conditions. A new o-silylaryl triflate precursor was developed to increase reactivity and enable electron-rich and electron-poor aryl amines to undergo cyclisation. A complete switch in product selectivity occurs when the reaction is conducted in air, affording the corresponding phenanthridin-6(5H)-one as the sole product under otherwise identical reaction conditions.

There is no market for new antibiotics: this allows an open approach to research and development.

There is an increasingly urgent need for new antibiotics, yet there is a significant and persistent economic problem when it comes to developing such medicines. The problem stems from the perceived need for a "market" to drive commercial antibiotic development. In this article, we explore abandoning the market as a prerequisite for successful antibiotic research and development. Once one stops trying to fix a market model that has stopped functioning, one is free to carry out research and development (R&D) in ways that are more openly collaborative, a mechanism that has been demonstrably effective for the R&D underpinning the response to the COVID pandemic. New "open source" research models have great potential for the development of medicines for areas of public health where the traditional profit-driven model struggles to deliver. New financial initiatives, including major push/pull incentives, aimed at fixing the broken antibiotics market provide one possible means for funding an openly collaborative approach to drug development. We argue that now is therefore the time to evaluate, at scale, whether such methods can deliver new medicines through to patients, in a timely manner.

Synthesis of Highly Enantioenriched Sulfonimidoyl Fluorides and Sulfonimidamides by Stereospecific Sulfur-Fluorine Exchange (SuFEx) Reaction.

Sulfonimidamides present exciting opportunities as chiral isosteres of sulfonamides, with potential for additional directional interactions. Here, we present the first modular enantioselective synthesis of sulfonimidamides, including the first stereoselective synthesis of enantioenriched sulfonimidoyl fluorides, and studies on their reactivity. A new route to sulfonimidoyl fluorides is presented from solid bench-stable, N-Boc-sulfinamide (Boc=tert-butyloxycarbonyl) salt building blocks. Enantioenriched arylsulfonimidoyl fluorides are shown to be readily racemised by fluoride ions. Conditions are developed, which trap fluoride and enable the stereospecific reaction of sulfonimidoyl fluorides with primary and secondary amines (100 % es, es=enantiospecificity) generating sulfonimidamides with up to 99 % ee. Aryl and alkyl sulfonimidoyl fluoride reagents are suitable for mild late stage functionalisation reactions, exemplified by coupling with a selection of complex amines in marketed drugs.

Intramolecular hydride transfer onto arynes: redox-neutral and transition metal-free C(sp3)-H functionalization of amines.

Transition metal-free intramolecular hydride transfer onto arynes is reported for the first time. This unique transformation is utilized in redox-neutral intermolecular α-functionalization reactions of different tertiary amines, generating C(sp3)-C(sp3/sp2/sp) bonds in a single synthetic operation. Deuterium labeling studies support initial cleavage of the α-C-H bond via intramolecular 1,5-hydride transfer onto the aryne, which leads to activation of a range of integrated pronucleophiles and ultimately affords a new approach to cross-dehydrogenative coupling reactions which utilize aryne intermediates.

Recent advances in fluoride-free aryne generation from arene precursors.

Aryne chemistry has experienced a remarkable renaissance in recent years, with a significant increase in the synthetic applications reported for these highly valuable reactive intermediates. This resurgence of interest is in part due to the introduction of ortho-silylaryl triflates as precursors which can be activated under mild conditions using fluoride. Alternative fluoride-free strategies have received interest in the last decade, with a number of precursors to arynes and their activators reported. These approaches offer alternative modes of reactivity which prove, in some cases, to be orthogonal to those of ortho-silylaryl triflates. This review highlights some of the more recent fluoride-free methodologies developed to access aryne intermediates that start from arene-based precursors.