Catalyst-Controlled Intermolecular Homobenzylic C(sp3)-H Amination for the Synthesis of ß-Arylethylamines.

The combination of a tailored sulfamate with a C4-symmetrical rhodium(II) tetracarboxylate allows to uncover a selective intermolecular amination of unactivated homobenzylic C(sp3)-H bonds. The reaction has a broad scope (>30 examples) and proceeds with a high level of regioselectivity with homobenzylic/benzylic ratio of up to 35:1, thereby providing a direct access to ß-arylethylamines that are of utmost interest in medicinal chemistry. Computational investigations evidenced a concerted mechanism, involving an asynchronous transition state. Based on a combined activation strain model and energy decomposition analysis, the regioselectivity of the reaction was found to rely mainly on the degree of orbital interaction between the [Rh2]-nitrene and the C-H bond. The latter is facilitated at the homobenzylic position due to the establishment of specific noncovalent interactions within the catalytic pocket.

Asymmetric Syntheses of Enantioenriched 2,5-Disubstituted Pyrrolidines.

C2-Symmetrical scaffolds are privileged ligands in metal catalysis and are also widely used in organocatalysis. Among these, 2,5-disubstituted pyrrolidines hold a paramount importance, especially since they also find application in medicinal chemistry. This review highlights the stereoselective syntheses of these C2-symmetrical nitrogen heterocycles. It includes synthetic strategies based on the use of the chiral pool as well as the more recent sequences designed following major achievements in asymmetric catalysis.

Rhodium(II)-Catalyzed Enantioselective Intermolecular Aziridination of Alkenes.

C4-Symmetrical dirhodium(II) tetracarboxylates are highly efficient catalysts for the asymmetric intermolecular aziridination of substituted alkenes with sulfamates. The reaction proceeds with high levels of efficiency and chemoselectivity to afford aziridines with excellent yields of up to 95% and enantiomeric excesses of up to 99%. The scope of the alkene aziridination includes mono-, di-, and trisubstituted olefins as well as the late-stage functionalization of complex substrates. The reaction can be performed on a gram-scale with a catalyst loading of 0.1 mol %. Our DFT study led us to propose a two-spin-state mechanism, involving a triplet Rh-nitrene species as key intermediate to drive the stereocontrolled approach and activation of the substrate.

Asymmetric Synthesis of Enantiopure Pyrrolidines by C(sp3 )-H Amination of Hydrocarbons.

The asymmetric synthesis of enantiopure pyrrolidines is reported via a streamlined strategy relying on two sequential C-H functionalizations of simple hydrocarbons. The first step is a regio- and stereoselective catalytic nitrene C-H insertion. Then, a subsequent diastereoselective cyclization involving a 1,5-hydrogen atom transfer (HAT) from a N-centered radical leads to the formation of pyrrolidines that can then be converted to their free NH-derivatives.

Catalytic Intermolecular C(sp3)-H Amination: Selective Functionalization of Tertiary C-H Bonds vs Activated Benzylic C-H Bonds.

A catalytic intermolecular amination of nonactivated tertiary C(sp3)-H bonds (BDE of 96 kcal·mol-1) is reported for substrates displaying an activated benzylic site (BDE of 85 kcal·mol-1). The tertiary C(sp3)-H bond is selectively functionalized to afford α,α,α-trisubstituted amides in high yields. This unusual site-selectivity results from the synergistic combination of Rh2(S-tfpttl)4, a rhodium(II) complex with a well-defined catalytic pocket, with tert-butylphenol sulfamate (TBPhsNH2), which leads to a discriminating rhodium-bound nitrene species under mild oxidative conditions. This catalytic system is very robust, and the reaction was performed on a 50 mmol scale with only 0.01 mol % of catalyst. The TBPhs group can be removed under mild conditions to afford the corresponding NH-free amines.

Asymmetric Intramolecular Buchner Reaction: From High Stereoselectivity to Coexistence of Norcaradiene, Cycloheptatriene, and an Intermediate Form in the Solid State.

Bicyclic compounds bearing a quaternary stereogenic center have been obtained using asymmetric intramolecular Buchner reaction with excellent yields and level of enantioselectivity. X-ray crystallography determination of the absolute configuration of one product has led to the serendipitous observation of an unusual behavior within the crystal structure, with equilibrating norcaradiene and cycloheptatriene valence isomers at the solid state, as well as an even more unexpected intermediate form. DFT calculations were performed to support these observations.

Catalytic Enantioselective Intermolecular Benzylic C(sp3 )-H Amination.

A practical general method for asymmetric intermolecular benzylic C(sp3 )-H amination has been developed by combining the pentafluorobenzyl sulfamate PfbsNH2 with the chiral rhodium(II) catalyst Rh2 (S-tfptad)4 . Various substrates can be used as limiting components and converted to benzylic amines with excellent yields and high levels of enantioselectivity. Additional key features for the reaction are the low catalyst loading and the ability to remove the Pfbs group under mild conditions to give NH-free benzylic amines.

Late-stage C-H amination of abietane diterpenoids.

This study aims at highlighting the synthetic versatility of the rhodium-catalyzed C-H amination reactions using iodine(iii) oxidants for the late-stage functionalization of natural products. Inter- and intramolecular nitrene insertions have been performed from various abietane diterpenoids, leading to the amination of the C-3, C-6, C-7, C-11 and C-15 positions. Ca. 20 aminated compounds have been isolated with yields of up to 86% and high levels of regio-, chemo- and stereoselectivities.

Hypervalent organoiodine compounds: from reagents to valuable building blocks in synthesis.

Most of the polyvalent organoiodine compounds derive from iodoarenes, which are released in stoichiometric amounts in any reaction mediated by λ3- or λ5-iodanes. In parallel to the development of solid-supported reagents or reactions catalytic in iodine, a third strategy has emerged to address this issue in terms of sustainability. The atom-economy of transformations involving stoichiometric amounts of λ3- or λ5-iodanes, thus, has been improved by designing tandem reactions that allows for incorporating the aryl motif into the products through a subsequent one-pot nucleophilic addition or catalytic coupling reaction. This review summarizes the main achievements reported in this area.

Reaction of Ynamides with Iminoiodinane-Derived Nitrenes: Formation of Oxazolones and Polyfunctionalized Oxazolidinones.

This article describes the reaction of ynamides with metallanitrenes generated in the presence of an iodine(III) oxidant. N-(Boc)-Ynamides are converted to oxazolones via a cyclization reaction. The reaction is mediated by a catalytic dirhodium-bound nitrene species that first behaves as a Lewis acid. The oxazolones can be converted in a one pot manner to functionalized oxazolidinones following a regio- and stereoselective oxyamination reaction with the same nitrene reagent generated in stoichiometric amounts.

Optimized Conditions for Passerini-Smiles Reactions and Applications to Benzoxazinone Syntheses.

Initial conditions disclosed for the Passerini-Smiles reaction are associated with a lack of efficiency that has prevented chemists from using it since its discovery. We wish to report herein our thorough study in the development of new experimental conditions for this coupling between electron-poor phenols, isocyanides, and carbonyl derivatives. These new conditions have been applied to several synthetic strategies towards benzoxazinones.

Rhodium-Catalyzed Alkene Difunctionalization with Nitrenes.

The Rh(II) -catalyzed oxyamination and diamination of alkenes generate 1,2-amino alcohols and 1,2-diamines, respectively, in good to excellent yields and with complete regiocontrol. In the case of diamination, the intramolecular reaction provides an efficient method for the preparation of pyrrolidines, and the intermolecular reaction produces vicinal amines with orthogonal protecting groups. These alkene difunctionalizations proceed by aziridination followed by nucleophilic ring opening induced by an Rh-bound nitrene generated in situ, details of which were uncovered by both experimental and theoretical studies. In particular, DFT calculations show that the nitrogen atom of the putative [Rh]2 =NR metallanitrene intermediate is electrophilic and support an aziridine activation pathway by N⋅⋅⋅N=[Rh]2 bond formation, in addition to the N⋅⋅⋅[Rh]2 =NR coordination mode.

The Multiple Facets of Iodine(III) Compounds in an Unprecedented Catalytic Auto-amination for Chiral Amine Synthesis.

Iodine(III) reagents are used in catalytic one-pot reactions, first as both oxidants and substrates, then as cross-coupling partners, to afford chiral polyfunctionalized amines. The strategy relies on an initial catalytic auto C(sp(3) )-H amination of the iodine(III) oxidant, which delivers an amine-derived iodine(I) product that is subsequently used in palladium-catalyzed cross-couplings to afford a variety of useful building blocks with high yields and excellent stereoselectivities. This study demonstrates the concept of self-amination of the hypervalent iodine reagents, which increases the value of the aryl moiety.

Tandem Catalytic C(sp(3) )-H Amination/Sila-Sonogashira-Hagihara Coupling Reactions with Iodine Reagents.

A new tandem C-N and C-C bond-forming reaction has been achieved through Rh(II) /Pd(0) catalysis. The sequence first involves an iodine(III) oxidant, then the in situ generated iodine(I) by-product is used as a coupling partner. The overall process demonstrates the synthetic value of iodoarenes produced in trivalent iodine reagent mediated oxidations.

Studies on the formal [3 + 2] cycloaddition of aziridines with alkenes for the synthesis of 1-azaspiroalkanes.

The Lewis acid-mediated [3 + 2] cycloaddition of N-sulfonyl- and N-sulfamoylaziridines with alkenes provides a rapid and efficient access to 1-azaspiro[4.n]alkanes. Experimental studies have been combined with DFT calculations to explore the mechanism of the reaction. They demonstrate that the nature of the electron-withdrawing nitrogen protecting group has a very limited influence on the course of the reaction and, particularly, on the initial formation of the 1,3-zwitterionic species through C-N bond cleavage, which has been found to be the rate-determining step. Compared to N-sulfonylaziridines, N-sulfamoylaziridines have proved to be more synthetically useful synthons that afford crystalline polycyclic structures in good yields. A short sequence of catalytic C(sp(3))-H amination-cyclization-[3 + 2] cycloaddition has then been successfully designed to afford the homologue 1-azaspiro[5.n]alkanes, thereby illustrating the higher versatility of sulfamates in these cycloadditions.

Catalytic intermolecular alkene oxyamination with nitrenes.

The Rh(II)-catalyzed intermolecular addition of nitrenes to aromatic and aliphatic alkenes provides vicinal amino alcohols with yields of up to 95 % and complete regioselectivity. This 1,2-oxyamination reaction involves the formation of an aziridine intermediate that undergoes in situ ring opening. The latter is induced by the Rh-bound nitrene that behaves as a Lewis acid.

Intermolecular C-H amination of complex molecules: insights into the factors governing the selectivity.

Transition-metal-catalyzed C-H amination via nitrene insertion allows the direct transformation of a C-H into a C-N bond. Given the ubiquity of C-H bonds in organic compounds, such a process raises the problem of regio- and chemoselectivity, a challenging goal even more difficult to tackle as the complexity of the substrate increases. Whereas excellent regiocontrol can be achieved by the use of an appropriate tether securing intramolecular addition of the nitrene, the intermolecular C-H amination remains much less predictable. This study aims at addressing this issue by capitalizing on an efficient stereoselective nitrene transfer involving the combination of a chiral aminating agent 1 with a chiral rhodium catalyst 2. Allylic C-H amination of terpenes and enol ethers occurs with excellent yields as well as with high regio-, chemo-, and diastereoselectivity as a result of the combination of steric and electronic factors. Conjugation of allylic C-H bonds with the π-bond would explain the chemoselectivity observed for cyclic substrates. Alkanes used in stoichiometric amounts are also efficiently functionalized with a net preference for tertiary equatorial C-H bonds. The selectivity, in this case, can be rationalized by steric and hyperconjugative effects. This study, therefore, provides useful information to better predict the site of C-H amination of complex molecules.

Nitrene chemistry in organic synthesis: still in its infancy?

The element nitrogen is essential to life. Considerable attention is thus paid to the development of synthetic methods for its introduction into molecules. Nitrenes, long regarded as highly reactive but poorly selective species, have recently emerged as useful tools for the formation of C-N bonds. Practical metal-catalyzed protocols are now available for the preparation of amines through either the aziridination of alkenes or the C-H amination of alkanes. Recent results highlighted in this Minireview suggest that synthetic nitrene chemistry is maturing with a wider scope not limited to these two reactions.