Controllable access to trifluoromethyl-containing indoles and indolines: palladium-catalyzed regioselective functionalization of unactivated alkenes with trifluoroacetimidoyl chlorides

The synthesis of diverse products from the same starting materials is always attractive in organic chemistry. Here, a palladium-catalyzed substrate-controlled regioselective functionalization of unactivated alkenes with trifluoroacetimidoyl chlorides has been developed, which provides a direct but controllable access to a variety of structurally diverse trifluoromethyl-containing indoles and indolines. In more detail, with respect to γ,δ-alkenes, 1,1-geminal difunctionalization of unactivated alkenes with trifluoroacetimidoyl chloride enables the [4 + 1] annulation to produce indoles; as for β,γ-alkenes, a [3 + 2] heteroannulation with the hydrolysis product of trifluoroacetimidoyl chloride through 1,2-vicinal difunctionalization of alkenes occurs to deliver indoline products. The structure of alkene substrates differentiates the regioselectivity of the reaction.

A palladium-catalyzed dual functionalization of unactivated alkenes with trifluoroacetimidoyl chlorides toward the synthesis of structurally diverse trifluoromethyl-containing indoles and indolines has been developed.     

Phosphine-catalyzed divergent domino processes between γ-substituted allenoates and carbonyl-activated alkenes

Highly enantioselective and chemodivergent domino reactions between γ-substituted allenoates and activated alkenes have been developed. In the presence of NUSIOC-Phos, triketone enone substrates smoothly reacted with γ-substituted allenoates to form bicyclic furofurans in good yields with high stereoselectivities. Alternatively, the reaction between diester-activated enone substrates and γ-substituted allenoates formed chiral conjugated 1,3-dienes in good yields with excellent enantioselectivities. Notably, by employing substrates with subtle structural difference, under virtually identical reaction conditions, we were able to access two types of chiral products, which are of biological relevance and synthetic importance.

Highly enantioselective and chemodivergent domino reactions between γ-substituted allenoates and activated alkenes have been developed.     

Vinylazaarenes as dienophiles in Lewis acid-promoted Diels–Alder reactions

Described are the first examples of Lewis acid-promoted Diels–Alder reactions of vinylpyridines and other vinylazaarenes with unactivated dienes. Cyclohexyl-appended azaarenes constitute a class of substructures of rising prominence in drug discovery. Despite this, thermal variants of the vinylazaarene Diels–Alder reaction are rare and have not been adopted for synthesis, and Lewis acid-promoted variants are virtually unexplored. The presented work addresses this gap and in the process furnishes increased scope, dramatically higher yields, improved regioselectivity, and high levels of diastereoselectivity compared to prior thermal examples. These reactions provide scalable access to druglike scaffolds not readily available through other methods. More broadly, these studies establish a useful new class of dienophiles that, based on preliminary mechanistic studies, should be amenable to conventional strategies for enantioselective catalysis.

Vinyl-substituted azaarenes are rare and challenging substrates as dienophiles in Diels–Alder reactions; by employing Lewis acid activation, high yielding and highly selective cycloadditions with unactivated dienes are enabled.     

Nickel-catalyzed asymmetric reductive aryl-allylation of unactivated alkenes

Herein we report a nickel-catalyzed asymmetric reductive aryl-allylation of aryl iodide-tethered unactivated alkenes, wherein both acyclic allyl carbonates and cyclic vinyl ethylene carbonates can serve as the coupling partners. Furthermore, the direct use of allylic alcohols as the electrophilic allyl source in this reaction is also viable in the presence of BOC anhydride. Remarkably, this reaction proceeds with high linear/branched-, E/Z- and enantio-selectivity, allowing the synthesis of various chiral indanes and dihydrobenzofurans (50 examples) containing a homoallyl-substituted quaternary stereocenter with high optical purity (90–98% ee). In this reductive reaction, the use of pregenerated organometallics can be circumvented, giving this process good functionality tolerance and high step-economy.

A nickel-catalyzed reductive asymmetric aryl-allylation of tethered unactivated alkenes has been developed, providing diverse benzene-annulated cyclic compounds bearing a quaternary stereocenter with high regio-, E/Z- and enantio-selectivity.     

Copper-catalyzed enantioselective carbonylation toward α-chiral secondary amides

Secondary amides are omnipresent structural motifs in peptides, natural products, pharmaceuticals, and agrochemicals. The copper-catalyzed enantioselective hydroaminocarbonylation of alkenes described in this study provides a direct and practical approach for the construction of α-chiral secondary amides. An electrophilic amine transfer reagent possessing a 4-(dimethylamino)benzoate group was the key to the success. This method also features broad functional group tolerance and proceeds under very mild conditions, affording a set of α-chiral secondary amides in high yields (up to 96% yield) with unprecedented levels of enantioselectivity (up to >99% ee). α,β-Unsaturated secondary amides can also be produced though the method by using alkynes as the substrate.

A copper-catalyzed regioselective and enantioselective intermolecular hydroaminocarbonylation of alkenes with electrophilic hydroxylamines has been developed.     

Copper-catalyzed hydroformylation and hydroxymethylation of styrenes

Hydroformylation catalyzed by transition metals is one of the most important homogeneously catalyzed reactions in industrial organic chemistry. Millions of tons of aldehydes and related chemicals are produced by this transformation annually. However, most of the applied procedures use rhodium catalysts. In the procedure described here, a copper-catalyzed hydroformylation of alkenes has been realized. Remarkably, by using a different copper precursor, the aldehydes obtained can be further hydrogenated to give the corresponding alcohols under the same conditions, formally named as hydroxymethylation of alkenes. Under pressure of syngas, various aldehydes and alcohols can be produced from alkenes with copper as the only catalyst, in excellent regioselectivity. Additionally, an all-carbon quaternary center containing ethers and formates can be synthesized as well with the addition of unactivated alkyl halides. A possible reaction pathway is proposed based on our results.

A copper-catalyzed hydroformylation and hydroxymethylation of alkenes has been realized.     

Nickel-catalyzed enantioselective 1,2-vinylboration of styrenes

A novel nickel-catalyzed asymmetric 1,2-vinylboration reaction has been developed to afford benzylic alkenylboration products with high yields and excellent enantioselectivities by using a chiral bisoxazoline ligand. Under optimized conditions, a wide variety of chiral 2-boryl-1,1-arylvinylalkanes are efficiently prepared from readily available olefins and vinyl halides in the presence of bis(pinacolato)diboron as the boron source in a mild and easy-to-operate manner. This three-component cascade protocol furnishes exceptional chemo- and stereoselectivity, and its usefulness is illustrated by its application in asymmetric modifications of several structurally complex natural products and pharmaceuticals.

A novel nickel-catalyzed asymmetric 1,2-vinylboration reaction has been developed to afford benzylic alkenylboration products with high yields and excellent enantioselectivities by using a chiral bisoxazoline ligand.     

Azine-N-oxides as effective controlling groups for Rh-catalysed intermolecular alkyne hydroacylation

Heterocycle-derived aldehydes are challenging substrates in metal-catalysed hydroacylation chemistry. We show that by using azine N-oxide substituted aldehydes, good reactivity can be achieved, and that they are highly effective substrates for the intermolecular hydroacylation of alkynes. Employing a Rh(i)-catalyst, we achieve a mild and scalable aldehyde C–H activation, that permits the coupling with unactivated terminal alkynes, in good yields and with high regioselectivities (up to >20 : 1 l:b). Both substrates can tolerate a broad variety of functional groups. The reaction can also be applied to diazine aldehydes that contain a free N-lone pair. We demonstrate conversion of the hydroacylation products to the corresponding azine, through a one-pot hydroacylation/deoxygenation sequence. A one-pot hydroacylation/cyclisation, using N-Boc propargylamine, additionally leads to the synthesis of a bidentate pyrrolyl ligand.

Heterocycle-derived aldehydes are challenging substrates in metal-catalysed hydroacylation chemistry; using the N-oxide derivatives allows efficient reactions to be achieved.     

Catalytic alkene skeletal modification for the construction of fluorinated tertiary stereocenters

Herein we describe the first construction of fluorinated tertiary stereocenters based on an alkene C(sp²)–C(sp²) bond cleavage. The new process, that takes advantage of a Rh-catalyzed carbyne transfer, relies on a branched-selective fluorination of tertiary allyl cations and is distinguished by a wide scope including natural products and drug molecule derivatives as well as adaptability to radiofluorination.

We report a previously unknown disconnection approach to valuable fluorinated tertiary stereocenters based on the skeletal modification of 1,1-disubstituted alkenes by a Rh-catalyzed carbyne transfer.     

Photoredox-catalyzed aminofluorosulfonylation of unactivated olefins

The development of efficient approaches to access sulfonyl fluorides is of great significance because of the widespread applications of these structural motifs in many areas, among which the emerging sulfur(vi) fluoride exchange (SuFEx) click chemistry is the most prominent. Here, we report the first three-component aminofluorosulfonylation of unactivated olefins by merging photoredox-catalyzed proton-coupled electron transfer (PCET) activation with radical relay processes. Various aliphatic sulfonyl fluorides featuring a privileged 5-membered heterocyclic core have been efficiently afforded under mild conditions with good functional group tolerance. The synthetic potential of the sulfonyl fluoride products has been examined by diverse transformations including SuFEx reactions and transition metal-catalyzed cross-coupling reactions. Mechanistic studies demonstrate that amidyl radicals, alkyl radicals and sulfonyl radicals are involved in this difunctionalization transformation.

A three-component aminofluorosulfonylation of unactivated alkenes has been developed by merging photocatalytic PCET with radical relay processes, affording various aliphatic sulfonyl fluorides featuring medicinally privileged heterocyclic scaffolds.     

Radical-mediated vicinal addition of alkoxysulfonyl/fluorosulfonyl and trifluoromethyl groups to aryl alkyl alkynes

The addition of sulfonyl radicals to alkenes and alkynes is a valuable method for constructing useful highly functionalized sulfonyl compounds. The underexplored alkoxy- and fluorosulfonyl radicals are easily accessed by CF₃ radical addition to readily available allylsulfonic acid derivatives and then β-fragmentation. These substituted sulfonyl radicals add to aryl alkyl alkynes to give vinyl radicals that are trapped by trifluoromethyl transfer to provide tetra-substituted alkenes bearing the privileged alkoxy- or fluorosulfonyl group on one carbon and a trifluoromethyl group on the other. This process exhibits broad functional group compatibility and allows for the late-stage functionalization of drug molecules, demonstrating its potential in drug discovery and chemical biology.

An unprecedented method for vicinal addition of alkoxysulfonyl/fluorosulfonyl and trifluoromethyl groups to aryl alkyl alkynes has been developed to afford useful alkenylsulfonate esters and alkenylsulfonyl fluorides.     

OvoAMtht from Methyloversatilis thermotolerans ovothiol biosynthesis is a bifunction enzyme: thiol oxygenase and sulfoxide synthase activities

Mononuclear non-heme iron enzymes are a large class of enzymes catalyzing a wide-range of reactions. In this work, we report that a non-heme iron enzyme in Methyloversatilis thermotolerans, OvoA_Mtht, has two different activities, as a thiol oxygenase and a sulfoxide synthase. When cysteine is presented as the only substrate, OvoA_Mtht is a thiol oxygenase. In the presence of both histidine and cysteine as substrates, OvoA_Mtht catalyzes the oxidative coupling between histidine and cysteine (a sulfoxide synthase). Additionally, we demonstrate that both substrates and the active site iron''s secondary coordination shell residues exert exquisite control over the dual activities of OvoA_Mtht (sulfoxide synthase vs. thiol oxygenase activities). OvoA_Mtht is an excellent system for future detailed mechanistic investigation on how metal ligands and secondary coordination shell residues fine-tune the iron-center electronic properties to achieve different reactivities.

Modulation of OvoA_Mtht''s dual activities: sulfoxide synthase and thiol oxygenase.     

Enantioselective palladaelectro-catalyzed C–H olefinations and allylations for N–C axial chirality

Enantioselective palladaelectro-catalyzed C–H alkenylations and allylations were achieved with easily-accessible amino acids as transient directing groups. This strategy provided access to highly enantiomerically-enriched N–C axially chiral scaffolds under exceedingly mild conditions. The synthetic utility of our strategy was demonstrated by a variety of alkenes, while the versatility of our approach was reflected by atroposelective C–H allylations. Computational studies provided insights into a facile C–H activation by a seven-membered palladacycle.

Enantioselective palladaelectro-catalyzed C–H alkenylations and allylations were achieved by the means of an easily-accessible amino acid for the synthesis of N–C axially chiral indole biaryls.     

Palladium-catalyzed 1,1-alkynylbromination of alkenes with alkynyl bromides

The palladium-catalyzed 1,1-alkynylbromination of terminal alkenes with a silyl-protected alkynyl bromide is reported. The method tolerates a diverse range of alkenes including vinylarenes, acrylates, and even electronically unbiased alkene derivatives to afford propargylic bromides regioselectively. Mechanistic studies and DFT calculations indicate that the 1,1-alkynylbromination reaction proceeds via the migration of the Pd center followed by the formation of a π-allenyl Pd intermediate, leading to the stereoselective reductive elimination of the C(sp³)–Br bond at the propargylic positon.

The first Pd-catalyzed 1,1-alkynylbromination of terminal alkenes using alkynyl bromides, which provides direct access to a variety of functionalized propargylic bromides without the need for an external brominating reagent, is reported.     

Nickel-catalyzed three-component olefin reductive dicarbofunctionalization to access alkylborates

We report a three-component olefin reductive dicarbofunctionalization for constructing alkylborates, specifically, nickel-catalyzed reductive dialkylation and alkylarylation of vinyl boronates with a variety of alkyl bromides and aryl iodides. This reaction exhibits good coupling efficiency and excellent functional group compatibility, providing convenient access to the late-stage modification of complex natural products and drug molecules. Combined with alkylborate transformations, this reaction could also find applications in the modular and convergent synthesis of complex compounds.

Nickel-catalyzed three-component olefin reductive dicarbofunctionalization for constructing alkylborates was achieved.     

Front Cover: Enhancement of Chiroptical Responses of trans‐Bis[(β‐iminomethyl)naphthoxy]platinum(II) Complexes with Distorted Square Planar Coordination Geometry (ChemistryOpen 4/2022)

The Front Cover shows the comparison of circularly polarized luminescence (CPL) properties of square planar platinum(II) complexes with different coordination geometries. Computational studies have revealed that the distortion of the coordination geometry is key to enhancement of the chiroptical responses of these compounds. More information can be found in the Research Article by Masahiro Ikeshita et al.     

Tailoring Lewis/Brønsted acid properties of MOF nodes via hydrothermal and solvothermal synthesis: simple approach with exceptional catalytic implications

The Lewis/Brønsted catalytic properties of the Metal–Organic Framework (MOF) nodes can be tuned by simply controlling the solvent employed in the synthetic procedure. In this work, we demonstrate that Hf-MOF-808 can be prepared from a material with a higher amount of Brønsted acid sites, via modulated hydrothermal synthesis, to a material with a higher proportion of unsaturated Hf Lewis acid sites, via modulated solvothermal synthesis. The Lewis/Brønsted acid properties of the resultant metallic clusters have been studied by different characterization techniques, including XAS, FTIR and NMR spectroscopies, combined with a DFT study. The different nature of the Hf-MOF-808 materials allows their application as selective catalysts in different target reactions requiring Lewis, Brønsted or Lewis–Brønsted acid pairs.

The Brønsted/Lewis acid properties of Hf-MOF-808 can be tuned by simply controlling the solvent employed in its synthesis, with direct catalytic implications on the activity and selectivity of organic reactions sensitive to the active site nature.     

Combining palladium and ammonium halide catalysts for Morita–Baylis–Hillman carbonates of methyl vinyl ketone: from 1,4-carbodipoles to ion pairs

Here we report that Morita–Baylis–Hillman carbonates from diverse aldehydes and methyl vinyl ketones can be directly utilised as palladium-trimethylenemethane 1,4-carbodipole-type precursors, and both reactivity and enantioselectivity are finely regulated by adding a chiral ammonium halide as the ion-pair catalyst. The newly assembled intermediates, proposed to contain an electronically neutral π-allylpalladium halide complex and a reactive compact ion pair, efficiently undergo asymmetric [4 + 2] annulations with diverse activated alkenes or isatins, generally with high regio-, diastereo- and enantio-selectivity, and even switchable regiodivergent or diastereodivergent annulations can be well realised by tuning the substrate or catalyst assemblies. An array of control experiments, including UV/Vis absorption study and density functional theory calculations, are conducted to rationalise this new double activation mode combining a palladium complex and an ammonium halide as an ion-pair catalyst.

A double activation catalytic system combining a palladium complex and an ammonium halide was developed to promote the asymmetric [4 + 2] annulations of Morita–Baylis–Hillman carbonates of methyl vinyl ketone.     

Palladium-catalyzed hydroalkylation of methylenecyclopropanes with simple hydrazones

A palladium-catalyzed hydroalkylation reaction of methylenecyclopropanes via highly selective C–C σ-bond scission was achieved under mild conditions, in which simple hydrazones served as carbanion equivalents. This method featured good functional group compatibility, affording high yields of C-alkylated terminal alkenes.

A palladium-catalyzed hydroalkylation of methylenecyclopropanes via selective C–C σ-bond scission was achieved, in which simple hydrazones served as carbanion equivalents. This method affords high yields of C-alkylated terminal alkenes with good functional group compatibility.     

Phenanthroline-imine ligands for iron-catalyzed alkene hydrosilylation

Iron-catalyzed organic reactions have been attracting increasing research interest but still have serious limitations on activity, selectivity, functional group tolerance, and stability relative to those of precious metal catalysts. Progress in this area will require two key developments: new ligands that can impart new reactivity to iron catalysts and elucidation of the mechanisms of iron catalysis. Herein, we report the development of novel 2-imino-9-aryl-1,10-phenanthrolinyl iron complexes that catalyze both anti-Markovnikov hydrosilylation of terminal alkenes and 1,2-anti-Markovnikov hydrosilylation of various conjugated dienes. Specifically, we achieved the first examples of highly 1,2-anti-Markovnikov hydrosilylation reactions of aryl-substituted 1,3-dienes and 1,1-dialkyl 1,3-dienes with these newly developed iron catalysts. Mechanistic studies suggest that the reactions may involve an Fe(0)–Fe(ii) catalytic cycle and that the extremely crowded environment around the iron center hinders chelating coordination between the diene and the iron atom, thus driving migration of the hydride from the silane to the less-hindered, terminal end of the conjugated diene and ultimately leading to the observed 1,2-anti-Markovnikov selectivity. Our findings, which have expanded the types of iron catalysts available for hydrosilylation reactions and deepened our understanding of the mechanism of iron catalysis, may inspire the development of new iron catalysts and iron-catalyzed reactions.

Newly developed iron complexes bearing 2-imino-9-aryl-1,10-phenanthroline ligands were successfully used to catalyze hydrosilylation of terminal alkenes and conjugated dienes in high yields with excellent anti-Markovnikov selectivity.