Iodine Catalysis for C(sp3 )-H Fluorination with a Nucleophilic Fluorine Source.

Iodine catalysis was developed for aliphatic fluorination through light-promoted homolytic C-H bond cleavage. The intermediary formation of amidyl radicals enables selective C-H functionalization via carbon-centered radicals. For the subsequent C-F bond formation, previous methods have typically been limited by a requirement for electrophilic fluorine reagents. We here demonstrate that the intermediary instalment of a carbon-iodine bond sets the stage for an umpolung, thereby establishing an unprecedented nucleophilic fluorination pathway.

Promoting Intermolecular C-N Bond Formation under the Auspices of Iodine(III).

The quest for the development of new protocols that provide general conditions for oxidative carbon-nitrogen bond formation has grown over recent years. Within this context, due to feasibility and benignity considerations in biochemical sciences, reactions that rely on main group oxidants as the only promoters have received particular interest. We have recently found that simple protonolysis events enable the incorporation of nitrogenated groups of the bissulfonimide family into the coordination sphere of common iodine(III) complexes such as diacetoxy iodobenzene. The products of the type ArI(OAc)(NTs2) represent rare examples of iodine(III) compounds displaying reactive iodine-nitrogen single bonds. Further protonolysis furnishes the corresponding iodine(III) compounds ArI(NTs2)2 containing two defined iodine-nitrogen single bonds for unprecedented dual transfer of both nitrogenated groups. It is of great synthetic importance that these new compounds contain iodine-nitrogen entities, which upon dissociation in solution lead to electrophilic iodine centers and nucleophilic nitrogen groups. This has enabled the development of a body of conceptually new amination reactions, which do not rely on conventional electrophilic nitrogen reagents but rather employ iodine(III) as an electrophilic activator and bissulfonimides as the source of subsequent nucleophilic amination. Additional diversification arises from the ambident nature of bissulfonimines enabling oxygenation pathways. The exciting chemistry covered in this Account comprises structural features of the reagents (including X-ray analysis), scope and limitation in synthetic amination of different hydrocarbons (including sp-, sp2-, and sp3-hybridized centers as in acetylenes, alkenes, enols, butadienes, allenes, arenes, and alkylketones), and physical-organic and theoretical analysis of the underlying reaction mechanisms. The oxidative transformations with all their rich diversifications originate from the versatile redox chemistry of the iodine(III) and iodine(I) pair, which shares several aspects of transition metal high oxidation state chemistry. For the present aryliodine(III) reagents, steric and electronic fine-tuning is possible through accurate engineering of the arene substituent. In addition to the general reactivity of the I-N bond, chiral aryliodine(III) reagents with defined stereochemical information in the aryl backbone are conceptually compatible with this approach. Thus, the development of enantioselective amination reactions with up to 99% ee was also successful. Several of the active enantioselective reagents have been isolated and structurally characterized. Following this approach for the important class of chiral vicinal diamines, an unprecedented direct diamination of alkenes could be conducted in an enantioselective catalytic manner under full intermolecular reaction control. This latter reaction is based on the precise engineering of a chiral aryliodine(III) catalyst in combination with bismesylimide as nitrogen source. It is the consequence of the precise understanding of the reaction behavior of structurally defined bisimidoiodine(III) reagents.

Alkyliodines in High Oxidation State: Enhanced Synthetic Possibilities and Accelerated Catalyst Turn-Over.

In contrast to aryliodine(III) compounds, which have matured into a particularly attractive class of oxidants in modern synthesis, the synthetic potential of related alkyliodine(III) derivatives has remained widely underestimated. This is surprising since several unique synthetic possibilities arise directly from the low stability of their central carbon-iodine bond. In this respect, these high-oxidation-state iodine compounds resemble environmentally benign variants of the prominent metal counterparts such as those derived from palladium, nickel and copper. This Concept article summarizes the general reactivity trends in alkyliodine(III) chemistry and discusses selected examples of their strategic use as highly reactive, transient species in organic synthesis and homogeneous catalysis.

Intermolecular Radical C(sp3 )-H Amination under Iodine Catalysis.

The direct amination of aliphatic C-H bonds has remained one of the most tantalizing transformations in organic chemistry. Herein, we report on a unique catalyst system, which enables the elusive intermolecular C(sp3 )-H amination. This practical synthetic strategy provides access to aminated building blocks and fosters innovative multiple C-H amination within a new approach to aminated heterocycles. The synthetic utility is demonstrated by the synthesis of four relevant pharmaceuticals.

Copper-Catalyzed N-F Bond Activation for Uniform Intramolecular C-H Amination Yielding Pyrrolidines and Piperidines.

The dual function of the N-F bond as an effective oxidant and subsequent nitrogen source in intramolecular aliphatic C-H functionalization reactions is explored. Copper catalysis is demonstrated to exercise full regio- and chemoselectivity control, which opens new synthetic avenues to nitrogenated heterocycles with predictable ring sizes. For the first time, a uniform catalysis manifold has been identified for the construction of both pyrrolidine and piperidine cores. The individual steps of this new copper oxidation catalysis were elucidated by control experiments and computational studies, clarifying the singularity of the N-F function and characterizing the catalytic cycle to be based on a copper(I/II) manifold.

Multiple Halogenation of Aliphatic C-H Bonds within the Hofmann-Löffler Manifold.

An innovative approach to position-selective polyhalogenation of aliphatic hydrocarbon bonds is presented. The reaction proceeded within the Hofmann-Löffler manifold with amidyl radicals as the sole mediators to induce selective 1,5- and 1,6-hydrogen-atom transfer followed by halogenation. Multiple halogenation events of up to four innate C-H bond functionalizations were accomplished. The broad applicability of this new entry into polyhalogenation and the resulting synthetic possibilities were demonstrated for a total of 27 different examples including mixed halogenations.

An Electrophilic Bromine Redox Catalysis for the Synthesis of Indole Alkaloid Building Blocks by Selective Aliphatic C-H Amination.

A new homogeneous bromine(-I/I) redox catalysis is described, which is based on monomeric bromine(I) compounds containing transferable phthalimidato groups. These catalysts enable intermolecular C-H amination reactions at previously unaccessible aliphatic positions and thus enlarge the synthetic potential of direct C-N bond formation, including its application in the synthesis of alkaloid building blocks. This aspect is demonstrated by a new synthetic approach to aspidospermidine. In addition to the development of the catalyst system, the structures of the involved bromine(I) key catalysts were fully elucidated, including by X-ray analyses.

Designing Homogeneous Bromine Redox Catalysis for Selective Aliphatic C-H Bond Functionalization.

The potential of homogeneous oxidation catalysis employing bromine has remained largely unexplored. We herein show that the combination of a tetraalkylammonium bromide and meta-chloroperbenzoic acid offers a unique catalyst system for the convenient and selective oxidation of saturated C(sp3 )-H bonds upon photochemical initiation with day light. This approach enables remote, intramolecular, position-selective C-H amination as demonstrated for 20 different examples. For the first time, an N-halogenated intermediate was isolated as the active catalyst state in a catalytic Hofmann-Löffler reaction. In addition, an expeditious one-pot synthesis of N-sulfonyl oxaziridines from N-sulfonamides was developed and exemplified for 15 transformations. These pioneering examples provide a change in paradigm for molecular catalysis with bromine.

Catalytic Asymmetric Diamination of Styrenes.

An enantioselective catalytic vicinal diamination of styrenes is reported, which proceeds under entirely intermolecular reaction control. It relies on a chirally modified aryliodine(I) catalyst and proceeds within an iodine(I/III) manifold with conventional 3-chloroperbenzoic acid as a terminal oxidant. An environmentally benign solvent combination not only adds to the attractiveness of the process but also slows down the rate of the undesired background reaction. A total of 30 examples are presented, which consistently provide high enantiomeric excesses in the range 91-98%.

Dioxoiodane Compounds as Versatile Sources for Iodine(I) Chemistry.

The general synthesis, isolation and characterization of electrophilic iodine reagents of the general formula R4 N[I(O2 CAr)2 ] is reported. These compounds are air- and moisture-stable iodine(I) reagents, which were characterized including X-ray analysis. They represent conceptually new iodine(I) reagents with anions as stabilizers. These compounds display the expected performance as electrophilic reagents upon interaction with electron-rich substrates. The performance of these compounds in a total of 47 different reactions of vicinal iodooxygenation of alkenes is studied and some key features on the reagents are revealed.

Cooperative Light-Activated Iodine and Photoredox Catalysis for the Amination of Csp3 -H Bonds.

An unprecedented method that makes use of the cooperative interplay between molecular iodine and photoredox catalysis has been developed for dual light-activated intramolecular benzylic C-H amination. Iodine serves as the catalyst for the formation of a new C-N bond by activating a remote Csp3 -H bond (1,5-HAT process) under visible-light irradiation while the organic photoredox catalyst TPT effects the reoxidation of the molecular iodine catalyst. To explain the compatibility of the two involved photochemical steps, the key N-I bond activation was elucidated by computational methods. The new cooperative catalysis has important implications for the combination of non-metallic main-group catalysis with photocatalysis.

Aminations with Hypervalent Iodine.

Recent progress in the area of hypervalent iodine-mediated and catalyzed amination reaction of hydrocarbons is reviewed. These reactions comprise processes under both intra and intermolecular control and include the functionalization of aromatic C-H bonds as well as conversion of sp-, sp(2)-, and sp(3)-hybridized carbon atoms. These developments demonstrate that hypervalent iodine(III) methodology has reached a high level in amination chemistry. The individual reactions are discussed with a focus on mechanistic details and emphasis is made to the underlying hypervalent iodine reagents, for which structural information is available.

Defined Palladium-Phthalimidato Catalysts for Improved Oxidative Amination.

New palladium(II)-phthalimidato complexes have been synthesized, isolated, and structurally characterized. As demonstrated from over 30 examples, they constitute superior catalysts for oxidative amination reactions of alkenes with phthalimide as the nitrogen source. This work streamlines vicinal difunctionalization of alkenes and provides access to significantly improved and experimentally simplified synthetic protocols.

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.

Towards Uniform Iodine Catalysis: Intramolecular C-H Amination of Arenes under Visible Light.

A photochemical catalytic amination of arenes is presented. The reaction proceeds under benign iodine catalysis in the presence of visible light as the initiator and provides access to a range of differently substituted arylamines. A total of 29 examples demonstrate the broad applicability of this mild oxidation method. The scope of the reaction could further be expanded to silyl-tethered derivatives, which undergo intramolecular amination upon formation of seven-membered heterocycles. Cleavage of the silicon tether provides access to the corresponding 3-substituted anilines.

DFT Rationalization of the Diverse Outcomes of the Iodine(III)-Mediated Oxidative Amination of Alkenes.

A computational study of the mechanism for the iodine(III)-mediated oxidative amination of alkenes explains the experimentally observed substrate dependence on product distribution. Calculations with the M06 functional have been carried out on the reaction between PhI(N(SO2 Me)2 )2 and three different representative substrates: styrene, α-methylstyrene, and (E)-methylstilbene. All reactions start with electrophilic attack by a cationic PhI(N(SO2 Me)2 )(+) unit on the double bond, and formation of an intermediate with a single C-I bond and a planar sp(2) carbocationic center. The major path, leading to 1,2-diamination, proceeds through a mechanism in which the bissulfonimide initially adds to the alkene through an oxygen atom of one sulfonyl group. This behavior is now corroborated by experimental evidence. An alternative path, leading to an allylic amination product, takes place through deprotonation at an allylic C-H position in the common intermediate. The regioselectivity of this amination depends on the availability of the resonant structures of an alternate carbocationic intermediate. Only in cases where a high electronic delocalization is possible, as in (E)-methylstilbene, does the allylic amination occur without migration of the double bond.

The Quest for Palladium-Catalysed Alkyl-Nitrogen Bond Formation.

Our interest in the development of transition-metal catalysis for the realisation of vicinal diamination reactions of alkenes started about a decade ago. A number of successful transformations in this area have been developed using palladium catalysis. As a challenging aspect of major importance, the palladium-catalysed coupling of alkyl-nitrogen bonds constitutes the second step in diaminations of alkenes. We here discuss the details that led us to consider high-oxidation-state palladium catalysis as a key feature in such C-N bond-forming reactions. This work discusses both our own contributions and the ones from colleagues and combines the discussion of catalytic reactions and stoichiometric control experiments. It demonstrates that reductive alkyl-nitrogen bond formation from palladium(IV) proceeds with a low activation barrier and through a linear transition state of nucleophilic displacement.

Substitution Effects of Hypervalent Iodine(III) Reagents in the Diamination of Styrene.

The influence of electronic parameters on the reaction performance of hypervalent iodine(III) reagents in the vicinal diamination of styrene has been investigated. It demonstrates the influence of the relative electron density on the aryl substituent of the hypervalent iodine reagent. In these cases, compounds with donor substituents outperform the corresponding acceptor-substituted systems. In line with this observation, a rapid enantioselective diamination was observed for a preformed chiral bisimidoiodine(III) reagent. For the first time, X-ray structural data could be obtained for an isolated chiral bisimidoiodine(III).

Iodine(III)-Mediated Selective Intermolecular C-H Amination for the Chemical Diversification of Tryptamines.

Defined hypervalent iodine reagents of the general structure PhI[N(SO2R)(SO2R')]2 promote the selective direct C-H-amination of the indole core of various tryptamines. Starting from a general C2-amination strategy, subsequent transformations enable a variety of site-selective functionalizations, which proceed with noteworthy high chemoselectivity and provide an overall access to structurally diversified products.

Sterically Congested 2,6-Disubstituted Anilines from Direct C-N Bond Formation at an Iodine(III) Center.

2,6-Disubstituted anilines are readily prepared from the direct reaction between amides and diaryliodonium salts. As demonstrated for 24 different examples, the reaction is of unusually broad scope with respect to the sterically congested arene and the nitrogen source, occurs without the requirement for any additional promoter, and proceeds through a direct reductive elimination at the iodine(III) center. The efficiency of the coupling procedure is further demonstrated within the short synthesis of a chemerin binding inhibitor.