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.

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.

Photocatalytic Synthesis of Polycyclic Indolones.

In this work, a photocatalytic strategy for a rapid and modular access to polycyclic indolones starting from readily available indoles is reported. This strategy relies on the use of redox-active esters in combination with an iridium-based photocatalyst under visible-light irradiation. The generation of alkyl radicals through decarboxylative single electron reductions enables intramolecular homolytic aromatic substitutions with a pending indole moiety to afford pyrrolo- and pyridoindolone derivatives under mild conditions. Furthermore, it was demonstrated that these radicals could also be engaged into cascades consisting of an intermolecular Giese-type addition followed by an intramolecular homolytic aromatic substitution to rapidly assemble valuable azepinoindolones.

Efficient Access to Chiral Trisubstituted Aziridines via Catalytic Enantioselective Aza-Darzens Reactions.

Herein, we report a Zn-ProPhenol catalyzed aza-Darzens reaction using chlorinated aromatic ketones as nucleophilic partners for the efficient and enantioselective construction of complex trisubstituted aziridines. The α-chloro-ß-aminoketone intermediates featuring a chlorinated tetrasubstituted stereocenter can be isolated in high yields and selectivities for further derivatization. Alternatively, they can be directly transformed to the corresponding aziridines in a one-pot fashion. Of note, the reaction can be run on gram-scale with low catalyst loading without impacting its efficiency. Moreover, this methodology was extended to α-bromoketones which are scarcely used in enantioselective catalysis because of their sensitivity and lack of accessibility.

Direct Catalytic Asymmetric Mannich Reactions for the Construction of Quaternary Carbon Stereocenters.

Herein, we report a Zn-ProPhenol catalyzed Mannich reaction using α-branched ketones as nucleophilic partners for the direct enantio- and diastereoselective construction of quaternary carbon stereocenters. The reaction can be run on a gram-scale with a low catalyst loading without impacting its efficiency. Moreover, the Mannich adducts can be further elaborated with complete diastereocontrol to access molecules possessing complex stereotriads.

Catalytic Asymmetric Mannich Reactions with Fluorinated Aromatic Ketones: Efficient Access to Chiral ß-Fluoroamines.

Reported herein is a Zn/Prophenol-catalyzed Mannich reaction using fluorinated aromatic ketones as nucleophilic partners for the direct enantio- and diastereoselective construction of ß-fluoroamine motifs featuring a fluorinated tetrasubstituted carbon. The reaction can be run on a gram scale with a low catalyst loading without impacting its efficiency. Moreover, a related aldol reaction was also developed. Together, these reactions provide a new approach for the preparation of pharmaceutically relevant products possessing tetrasubstituted C-F centers.

Access to ß-lactams by enantioselective palladium(0)-catalyzed C(sp3)-H alkylation.

ß-Lactams are very important structural motifs because of their broad biological activities as well as their propensity to engage in ring-opening reactions. Transition-metal-catalyzed C-H functionalizations have emerged as strategy enabling yet uncommon highly efficient disconnections. In contrast to the significant progress of Pd(0)-catalyzed C-H functionalization for aryl-aryl couplings, related reactions involving the formation of saturated C(sp(3))-C(sp(3)) bonds are elusive. Reported here is an asymmetric C-H functionalization approach to ß-lactams using readily accessible chloroacetamide substrates. Important aspects of this transformation are challenging C(sp(3))-C(sp(3)) and strain-building reductive eliminations to for the four-membered ring. In general, the ß-lactams are formed in excellent yields and enantioselectivities using a bulky taddol phosphoramidite ligand in combination with adamantyl carboxylic acid as cocatalyst.

Enantioselective C-H arylation strategy for functionalized dibenzazepinones with quaternary stereocenters.

Tada! Highly functionalized chiral dibenzazepinones are obtained by a mild palladium(0)-catalyzed enantioselective C-H arylation with excellent selectivities by using simple taddol phosphoramidite ligands. The amide tether allows exclusive regioselectivity through a rare eight-membered palladacycle intermediate.

Synthesis of functionalized spiroindolines via palladium-catalyzed methine C-H arylation.

The synthesis of cyclopropyl spiroindolines is described using an intramolecular palladium(0)-catalyzed C-H functionalization of a methine C(sp(3))-H bond. This transformation can be coupled with intermolecular Suzuki couplings or direct arylations of heteroaromatics to access functionalized indoline scaffolds in a single step.

Heteroatom nucleophile induced C-C fragmentations to access functionalized allenes.

The rich structural and reactivity profile of allenes render them versatile synthetic intermediates. However, application of allenes in organic chemistry is often attenuated by inconvenient methods of preparation. Herein we present an operationally simple route to functionalized allenes from vinyl triflate precursors through a Grob-type fragmentation induced by heteroatom nucleophiles such as water, alcohols, thiols or amines. The fragmentation occurs under mild conditions and is well suited for one-pot or domino processes allowing access to a range of synthetically useful intermediates.

Formal homo-Nazarov and other cyclization reactions of activated cyclopropanes.

The Nazarov cyclization of divinyl ketones gives access to cyclopentenones. Replacing one of the vinyl groups by a cyclopropane leads to a formal homo-Nazarov process for the synthesis of cyclohexenones. In contrast to the Nazarov reaction, the cyclization of vinyl-cyclopropyl ketones is a stepwise process, often requiring harsh conditions. Herein, we describe two different approaches for further polarization of the three-membered ring of vinyl-cyclopropyl ketones to allow the formal homo-Nazarov reaction under mild catalytic conditions. In the first approach, the introduction of an ester group α to the carbonyl on the cyclopropane gave a more than tenfold increase in reaction rate, allowing us to extend the scope of the reaction to non-electron-rich aryl donor substituents in the ß position to the carbonyl on the cyclopropane. In this case, a proof of principle for asymmetric induction could be achieved using chiral Lewis acid catalysts. In the second approach, heteroatoms, especially nitrogen, were introduced ß to the carbonyl on the cyclopropane. In this case, the reaction was especially successful when the vinyl group was replaced by an indole heterocycle. With a free indole, the formal homo-Nazarov cyclization on the C3 position of indole was observed using a copper catalyst. In contrast, a new cyclization reaction on the N1 position was observed with Brønsted acid catalysts. Both reactions were applied to the synthesis of natural alkaloids. Preliminary investigations on the rationalization of the observed regioselectivity are also reported.

Cyclobutanes in catalysis.

The exploitation of ring strain as a driving force to facilitate chemical reactions is a well-appreciated principle in organic chemistry. The most prominent and most frequently used compound classes in this respect are oxiranes and cyclopropanes. For rather a long time, cyclobutanes lagged behind these three-membered-ring compounds in their development as reactive substrates, but during the past decade an increasing number of useful reactions of four-membered-ring substrates have emerged. This Minireview examines corresponding catalytic reactions ranging from Lewis or Brønsted acid catalyzed processes to enzymatic reactions. The main focus is placed on transition-metal-catalyzed C-C bond-insertion and ß-carbon-elimination processes, which enable exciting downstream reactions that deliver versatile building blocks.