Aryl thiols can be selectively converted to sulfonimidates or sulfonamides with three new S-X connections being made selectively in one pot. Using hypervalent iodine reagents in the presence of ammonium carbamate, NH- and O-groups are transferred under mild and practical conditions. Reducing the loading of ammonium carbamate changed the product distribution, converting the sulfonimidate to the sulfonamide. Studies into the possible intermediate species are presented, suggesting that multiple pathways may be possible via sulfinate esters, or related intermediates, with each species forming the same products.

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.

Sulfonimidamides are intriguing new motifs for medicinal and agrochemistry, and provide attractive bioisosteres for sulfonamides. However, there remain few operationally simple methods for their preparation. Here, the synthesis of NH‐sulfonimidamides is achieved directly from sulfenamides, themselves readily formed in one step from amines and disulfides. A highly chemoselective and one‐pot NH and O transfer is developed, mediated by PhIO in iPrOH, using ammonium carbamate as the NH source, and in the presence of 1 equivalent of acetic acid. A wide range of functional groups are tolerated under the developed reaction conditions, which also enables the functionalization of the antidepressants desipramine and fluoxetine and the preparation of an aza analogue of the drug probenecid. The reaction is shown to proceed via different and concurrent mechanistic pathways, including the formation of novel S≡N sulfanenitrile species as intermediates. Several alkoxy‐amino‐λ6‐sulfanenitriles are prepared with different alcohols, and shown to be alkylating agents to a range of nucleophiles.

Vinyl sulfones and sulfonamides are valued for their use as electrophilic warheads in covalent protein inhibitors. Conversely, the S(VI) aza-isosteres thereof, vinyl sulfoximines and sulfonimidamides, are far less studied and have yet to be applied to the field of protein bioconjugation. Herein, we report a range of different synthetic methodologies for constructing vinyl sulfoximine and vinyl sulfonimidamide architectures that allows access to new areas of electrophilic chemical space. We demonstrate how late stage functionalization can be applied to these motifs to incorporate alkyne tags, generating fully functionalized probes for future chemical biology applications. Finally, we establish a workflow for determining the absolute configuration of enantioenriched vinyl sulfoximines and sulfonimidamides by comparing experimentally and computationally determined electronic circular dichroism spectra, enabling access to configurationally assigned enantiomeric pairs by separation. File list (2) download file view on ChemRxiv S&C Vinyl S(VI) ChemRxiv.pdf (2.21 MiB) download file view on ChemRxiv Supplementary S&C Vinyl S(VI) .pdf (15.81 MiB)

Bioisosteres provide valuable design elements for medicinal chemists to adjust the structural and pharmacokinetic characteristics of bioactive compounds towards viable drug candidates. Aryl oxetane amines offer exciting potential as bioisosteres for benzamides, an extremely common pharmacophore, but are rarely examined due to the lack of available synthetic methods. Here, we describe a new class of reactions for sulfonyl fluorides to form aminooxetanes by an alternative pathway to the established SuFEx (sulfonyl-fluoride exchange) click reactivity. An unprecedented defluorosulfonylation forms planar oxetane carbocations simply on warming. This disconnection, comparable to a typical amidation, will allow the application of vast existing amine libraries. The reaction is tolerant to a wide range of polar functionalities and is suitable for array formats. Ten oxetane analogues of bioactive benzamides and marketed drugs are prepared.Kinetic and computational studies support the formation of an oxetane carbocation as the rate determining step, followed by a chemoselective nucleophile coupling step.New reaction classes have enormous potential to access underexplored chemical space and influence molecular design. 1,2 A limited set of reliable and predictable reactions continue to have a disproportionate influence on the ability to construct medicinal and agrochemical compounds. 3 Such reactions can enable rapid access to derivatives, while also influencing, and limiting, molecular design. Most notably, click reactions have had an enormous impact in the chemical and biological sciences, which proceed on complex substrates without stringent conditions. 4,5,6,7 In drug discovery, amide bond formation continues to be the most common reaction, 3 exploiting vast amine and carboxylic acid libraries available to pharmaceutical companies. Amides are therefore prevalent in marketed pharmaceutical and agrochemical compounds, and display valuable features being more stable than other carbonyl derivatives, powerful H-bond donors and acceptors, and ubiquitous as critical bonding units in natural peptides and proteins. 8 Nonetheless, the amide sub-structure will frequently not provide the subtle balance of properties that is required for a successful active ingredient. Consequently, bioisosteres of amides are also common, providing a mimic of the features of the amide and adjusting the global properties of a compound. 9,10,11 While amidation is extensively investigated, with powerful, mostly stoichiometric coupling reagents, 12 the same cannot be said for amide-isosteres, which often require bespoke synthetic efforts (Fig. 1a).3,3-Disubstituted oxetanes have garnered considerable interest as carbonyl replacements, due to the similar dipole moments, hydrogen-bonding capacity, and oxygen lone pair orientation. 13,14 Their use as a bioisostere or replacement group also introduces a more 3-dimensional element to a drug compound that can have beneficial binding and solubility effects. 15 The motif is exemplified by antiviral Ziresovir, bear...

Protein–carbohydrate interactions are implicated in many biochemical/biological processes that are fundamental to life and to human health. Fluorinated carbohydrate analogues play an important role in the study of these interactions and find application as probes in chemical biology and as drugs/diagnostics in medicine. The availability and/or efficient synthesis of a wide variety of fluorinated carbohydrates is thus of great interest. Here, we report a detailed study on the synthesis of monosaccharides in which the hydroxy groups at their 4- and 6-positions are replaced by all possible mono- and difluorinated motifs. Minimization of protecting group use was a key aim. It was found that introducing electronegative substituents, either as protecting groups or as deoxygenation intermediates, was generally beneficial for increasing deoxyfluorination yields. A detailed structural study of this set of analogues demonstrated that dideoxygenation/fluorination at the 4,6-positions caused very little distortion both in the solid state and in aqueous solution. Unexpected trends in α/β anomeric ratios were identified. Increasing fluorine content always increased the α/β ratio, with very little difference between regio- or stereoisomers, except when 4,6-difluorinated.

Sulfonimidamides are intriguing new motifs for medicinal and agrochemistry,a nd provide attractive bioisosteres for sulfonamides.However,there remain few operationally simple methods for their preparation. Here,t he synthesis of NH-sulfonimidamides is achieved directly from sulfenamides,themselves readily formed in one step from amines and disulfides.Ahighly chemoselective and one-pot NH and O transfer is developed, mediated by PhIO in iPrOH, using ammonium carbamate as the NH source,and in the presence of 1equivalent of acetic acid. Awide range of functional groups are tolerated under the developed reaction conditions,w hich also enables the functionalization of the antidepressants desipramine and fluoxetine and the preparation of an aza analogue of the drug probenecid. The reaction is shown to proceed via different and concurrent mechanistic pathways, including the formation of novel SNsulfanenitrile species as intermediates.Several alkoxy-amino-l 6 -sulfanenitriles are prepared with different alcohols,a nd shown to be alkylating agents to arange of nucleophiles. Scheme 1. Potential bioisosteres for sulfones and sulfonamides, examples of bioactive sulfonimidamides, and current strategies for the synthesis of sulfonimidamides.

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