Sigmatropic Rearrangement of Vinyl Aziridines: Expedient Synthesis of Cyclic Sulfoximines from Chiral Sulfinimines

A novel rearrangement of 2‐vinyl aziridine 2‐carboxylates to unusual chiral cyclic sulfoximines is described herein. The method allows the synthesis of substituted cyclic sulfoximines in high yields with complete stereocontrol, and tolerates a wide substrate scope. A one‐pot process starting directly from sulfinimines provides access to complex chiral sulfoximines in only two steps from commercially available aldehydes. A mechanistic hypothesis and synthetic application in the formal synthesis of trachelanthamidine, by transformation of a cyclic sulfoximine into a pyrroline, is also disclosed.     

Iron(II)‐Catalyzed Direct Synthesis of NH Sulfoximines from Sulfoxides

Free NH‐sulfoximines were directly prepared from sulfoxides through iron catalysis by applying a readily available, shelf‐stable hydroxylamine triflic acid salt. No additional oxidant is needed, and the substrate scope is broad, including a range of heterocyclic compounds.     

Direct electrophilic N-trifluoromethylation of azoles by a hypervalent iodine reagent

Effective CF(3) transfer: Various electron-rich nitrogen heterocycles (pyrazoles, triazoles, and tetrazoles) can be directly N-trifluoromethylated by a hypervalent iodine reagent in an efficient manner. The optimized procedure, which includes an in situ silylation of the substrate followed by an acid-catalyzed CF(3) transfer, provides ready access to a series of new and previously challenging or inaccessible NCF(3) compounds.     

Electrophilic Vinylation of Thiols under Mild and Transition Metal-Free Conditions

The iodine(III) reagents vinylbenziodoxolones (VBX) were employed to vinylate a series of aliphatic and aromatic thiols, providing E-alkenyl sulfides with complete chemo- and regioselectivity, as well as excellent stereoselectivity. The methodology displays high functional group tolerance and proceeds under mild and transition metal-free conditions without the need for excess substrate or reagents. Mercaptothiazoles could be vinylated under modified conditions, resulting in opposite stereoselectivity compared to previous reactions with vinyliodonium salts. Novel VBX reagents with substituted benziodoxolone cores were prepared, and improved reactivity was discovered with a dimethyl-substituted core.     

Cyclic Hypervalent Iodine Reagents for Atom‐Transfer Reactions: Beyond Trifluoromethylation

Hypervalent iodine compounds are privileged reagents in organic synthesis because of their exceptional reactivity. Among these compounds, cyclic derivatives stand apart because of their enhanced stability. They have been widely used as oxidants, but their potential for functional‐group transfer has only begun to be investigated recently. The use of benziodoxol(on)es for trifluoromethylation (Togni's reagents) is already widely recognized, but other transformations have also attracted strong interest recently. In this Review, the development in the area since 2011 will be presented. After a short summary of synthetic methods to prepare benziodoxol(on)e reagents, their use to construct carbon–heteroatom and carbon–carbon bonds will be presented. In particular, the introduction of alkynes by using ethynylbenziodoxol(on)e (EBX) reagents has been highly successful. Breakthroughs in the introduction of alkoxy, azido, difluoromethyl, and cyano groups will also be described.     

Electrophilic Chlorine from Chlorosulfonium Salts: A Highly Chemoselective Reduction of Sulfoxides

Herein, we describe a selective late-stage deoxygenation of sulfoxides based on a novel application of chlorosulfonium salts and demonstrate a new process using these species generated in situ from sulfoxides as the source of electrophilic chlorine. The use of highly nucleophilic 1,3,5-trimethoxybenzene (TMB) as the reducing agent is described for the first time and applied in the deoxygenation of simple and functionalized sulfoxides. The method is easy to handle, economic, suitable for gram-scale operations, and readily applied for poly-functionalized molecules, as demonstrated with more than 45 examples, including commercial medicines and analogues. We also report the results of competition experiments that define the more reactive sulfoxide and we present a mechanistic proposal based on substrate and product observations.     

Electrophilic Vinylation of Thiols under Mild and Transition Metal‐Free Conditions

The iodine(III) reagents vinylbenziodoxolones (VBX) were employed to vinylate a series of aliphatic and aromatic thiols, providing E‐alkenyl sulfides with complete chemo‐ and regioselectivity, as well as excellent stereoselectivity. The methodology displays high functional group tolerance and proceeds under mild and transition metal‐free conditions without the need for excess substrate or reagents. Mercaptothiazoles could be vinylated under modified conditions, resulting in opposite stereoselectivity compared to previous reactions with vinyliodonium salts. Novel VBX reagents with substituted benziodoxolone cores were prepared, and improved reactivity was discovered with a dimethyl‐substituted core.     

Diphenyliodonium‐Catalyzed Fluorination of Arynes: Synthesis of ortho‐Fluoroiodoarenes

Described is a one‐pot vicinal fluorination‐iodination of arynes at room temperature. The diphenyliodonium salt proved to be a privileged catalyst for this nucleophilic fluorination process using CsF as a fluorine source, and a subsequent facile electrophilic iodination with C₄F₉I was also found to be crucial to ensure the efficient fluorination. This new synthetic protocol has a broad substrate scope under mild reaction conditions.     

Sulfones as Chemical Chameleons: Versatile Synthetic Equivalents of Small-Molecule Synthons

Sulfones are flexible functional groups that can act as nucleophiles, electrophiles, or even radicals. Changing the reaction conditions can completely alter the reactivity of a sulfonyl group, and as a result, molecules bearing multiple sulfones are versatile building blocks. This Review highlights the unique ability of 1,1- and 1,2-bis(sulfones) to masquerade as a vast array of reactive synthons including methane polyanions, vinyl cations, and all-carbon dipoles that would be difficult or impossible to access directly.     

Electrophilic Amination: The Case of Nitrenoids

Among the numerous approaches and reagents employed for electrophilic amination, nitrenoids have long stayed out of the limelight. Here, we systematically review the discovery, structural features and chemical reactivity of these promising reagents. We highlight advances in applying the chemistry of nitrenoids as well as outline current limitations and future directions.     

Generation of Sulfonyl Radicals from Aryldiazonium Tetrafluoroborates and Sulfur Dioxide: The Synthesis of 3‐Sulfonated Coumarins

A catalyst‐free approach for the generation of sulfonyl radicals from aryldiazonium tetrafluoroborates in the presence of DABCO?(SO₂)₂ is realized. The combination of aryldiazonium tetrafluoroborates, DABCO?(SO₂)₂, and aryl propiolates affords 3‐sulfonated coumarins in good to excellent yields. This tandem reaction process involves radical addition, spirocyclization, and 1,2‐migration of esters. Additionally, the in situ diazotization of a number of anilines allows the directional synthesis of desired 3‐sulfonated coumarins in a one‐pot, two‐step process.     

A Selective C−H Deprotonation Strategy to Access Functionalized Arynes by Using Hypervalent Iodine

Described here is an efficient method to access highly functionalized arynes from unsymmetrical aryl(mesityl)iodonium tosylate salts. The iodonium salts are prepared in a single pot from either commercially available aryl iodides or arylboronic acids. The aryne intermediates are generated by ortho‐C?H deprotonation of aryl(mesityl)iodonium salt with a commercially available amide base and trapped in a cycloaddition reaction with furan in moderate to good yields. Coupling partners for the aryne intermediates beyond furan are also described, including benzyl azide and alicyclic amine nucleophiles. The regio‐ and chemoselectivity of this reaction is discussed and evidence for the spectator aryl ligand of the iodonium salt as a critical control element in selectivity is presented.     

An Electrophilic Reagent for the Direct Introduction of the SCF2PO(OEt)2 Group to Molecules

An unprecedented electrophilic difluoromethylthiolating reagent (MesNHSCF₂PO(OEt)₂) was designed. Under mild and metal‐free conditions, this new reagent reacted with various nucleophiles, thus offering an efficient and operationally simple tool for the construction of C?SCF₂PO(OR)₂, N?SCF₂PO(OR)₂, and S?SCF₂PO(OR)₂ bonds. Finally, thanks to this new methodology, the synthesis of the non‐stereoidal anti‐inflammatory diflumidone was achieved.     

Diaryl Sulfoxides from Aryl Benzyl Sulfoxides: A Single Palladium‐Catalyzed Triple Relay Process

A novel approach to produce diaryl sulfoxides from aryl benzyl sulfoxides is reported. Optimization of the reaction conditions was performed using high‐throughput experimentation techniques. The [Pd(dba)₂]/NiXantPhos catalyst system successfully promotes a triple relay process involving sulfoxide α‐arylation, C? S bond cleavage, and C? S bond formation. The byproduct benzophenone is formed by an additional palladium‐catalyzed process. It is noteworthy that palladium‐catalyzed benzylative C? S bond cleavage of sulfoxides is unprecedented. A wide range of aryl benzyl sulfoxides, as well as alkyl benzyl sulfoxides with various (hetero)aryl bromides were employed in the triple relay process in good to excellent yields (85–99 %). Moreover, aryl methyl sulfoxides, dibenzyl sulfoxides, and dimethylsulfoxide could be utilized to generate diaryl sulfoxides involving multiple catalytic cycles by a single catalyst.     

Zinc‐Mediated Formation of Trifluoromethyl Ethers from Alcohols and Hypervalent Iodine Trifluoromethylation Reagents

A (fluor)ry of activity : The transfer of an intact trifluoromethyl group from a hypervalent iodine reagent to an aliphatic alcohol occurs smoothly upon activation by zinc bis(triflimide). This constitutes a straightforward method for the preparation of trifluoromethoxy alkyl derivatives, compounds otherwise difficult to access.

     

Indole Synthesis through Sequential Electrophilic N−H and C−H Bond Activation Using Iodine(III) Reactivity

An intramolecular approach towards the regioselective construction of 2,3‐diarylated indoles is reported. The reaction follows an intramolecular electrophilic N?H and C?H bond functionalization between the aniline and acetylene. This methodology employs the concept of a traceless tether to provide access to the free 2,3‐diarylated indole products comprising a total of 18 examples. Hypervalent iodine reagents were identified as suitable promoters and four different protocols are provided, including stoichiometric and catalytic transformations.