Trisubstituted Alkenes Research Articles

Highly Regioselective Cobalt‐Catalyzed Hydroboration of Internal Alkynes

Highly Regioselective Cobalt‐Catalyzed Hydroboration of Internal Alkynes

Highly Regioselective Cobalt-Catalyzed Hydroboration of Internal Alkynes.

Herein, we report the development of new Co complexes that have cyclopropane-based diphosphine ligands and can catalyze highly chemo-, regio-, and stereoselective hydroboration reactions of unsymmetrical internal alkynes. These reactions exhibited unusual regioselectivity: specifically, reactions of aryl alkyl internal alkynes showed excellent cis-β-addition selectivity, and reactions of dialkyl internal alkynes gave excellent cis-α-addition selectivity. Highly regioselective hydroboration of unsymmetrical dialkyl internal alkynes cannot be achieved by other known methods. The reactions described herein are highly synthetically useful, particularly for the stereoselective synthesis of trisubstituted alkenylborates and alkenes. Mechanistic studies indicate that a CoI -H species is a plausible active catalyst and the rigid structure of the cyclopropane skeleton of the ligands and the crowded reaction pocket were responsible for the unprecedented regioselectivity.

Ligand-Controlled Cobalt-Catalyzed Regiodivergent Alkyne Hydroalkylation.

Regiodivergent alkyne hydroalkylation to generate different isomers of an alkene from the same alkyne starting material would be beneficial; however, it remains a challenge. Herein, we report a ligand-controlled cobalt-catalyzed regiodivergent alkyne hydroalkylation. The sensible selection of bisoxazoline (L1) and pyridine-oxazoline (L8) ligands led to reliable and predictable protocols that provided (E)-1,2-disubstituted and 1,1-disubstituted alkenes with high E/Z stereoselectivity and regioisomeric ratio starting from identical terminal alkyne and alkyl halide substrates and produced trisubstituted alkenes in the case of internal alkynes. This method exhibits a broad scope for terminal and internal alkynes with a wide range of activated and unactivated alkyl halides and shows excellent functional group compatibility.

Rhodium-Catalyzed Three-Component Reaction of Alkynes, Arylzinc Chlorides, and Iodomethanes Producing Trisubstituted/Tetrasubstituted Alkenes with/without 1,4-Migration.

A three-component reaction of alkynes, arylzinc chlorides, and iodomethanes was found to proceed in the presence of a rhodium catalyst to give high yields of trisubstituted/tetrasubstituted alkenes. The usual arylzinc chlorides only gave trisubstituted alkenes, generated through a migratory carbozincation-cross-coupling sequence, where 1,4-Rh migration from an alkenyl carbon to an aryl carbon occurred. In contrast, 5-membered heteroarylzinc chlorides only gave the tetrasubstituted alkenes via a carborhodation-cross-coupling pathway without 1,4-migration.

Isolation of a Cu-H Monomer Enabled by Remote Steric Substitution of a N-Heterocyclic Carbene Ligand: Stoichiometric Insertion and Catalytic Hydroboration of Internal Alkenes.

Transient Cu-H monomers have long been invoked in the mechanisms of substrate insertion in Cu-H catalysis. Their role from Cu-H aggregates has been mostly inferred since ligands to stabilize these monomeric intermediates for systematic studies remain limited. Within the last decade, new sterically demanding N-heterocyclic carbene (NHC) ligands have led to isolable Cu-H dimers and, in some cases, spectroscopic characterization of Cu-H monomers in solution. We report an NHC ligand, IPr*R, containing para R groups of CHPh2 and CPh3 on the ligand periphery for the isolation of a Cu-H monomer for insertion of internal alkenes. This reactivity has not been reported for (NHC)CuH complexes despite their common application in Cu-H-catalyzed hydrofunctionalization. Changing from CHPh2 to CPh3 impacts the relative concentration of Cu-H monomers, rate of alkene insertion, and reaction of a trisubstituted internal alkene. Specifically, for R = CPh3, monomeric (IPr*CPh3)CuH was isolated and provided >95% monomer (10 mM in C6D6). In contrast, for R = CHPh2, solutions of [(IPr*CHPh2)CuH]2 are 80% dimer and 20% (IPr*CHPh2)CuH monomer at 25 °C based on 1H, 13C, and 1H-13C HMBC NMR spectroscopy. Quantitative 1H NMR kinetic studies on cyclopentene insertion into Cu-H complexes to form the corresponding Cu-cyclopentyl complexes demonstrate a strong dependence on the rate of insertion and concentration of the Cu-H monomer. Only (IPr*CPh3)CuH, which has a high monomer concentration, underwent regioselective insertion of a trisubstituted internal alkene, 1-methylcyclopentene, to give (IPr*CPh3)Cu(2-methylcyclopentyl), which has been crystallographically characterized. We also demonstrated that (IPr*CPh3)CuH catalyzes the hydroboration of cyclopentene and methylcyclopentene with pinacolborane.

Nickel-Catalyzed Dimerization of Di- and Trisubstituted Olefins

The dimerization of a series of di- and trisubstituted C5-olefins catalyzed by hexafluoroacetylacetonate (acacCF3) nickel complexes is described. The dimerization of the trisubstituted olefin 2-methyl-2-butene by both a single-component nickel precatalyst and in situ activation of a bis(acacCF3) nickel precatalyst produced predominantly C10-dimers with nearly identical product distributions. The dimers produced by the nickel catalysts are less-branched than acid-catalyzed (e.g., BF3) dimers, due to the ability of the nickel intermediate to function as both an olefin isomerization and a dimerization catalyst, whereby C–C bond formation occurs preferentially between a primary carbon of one olefin and the less substituted carbon of the inserting olefin. The dimerization of the regioisomers of 2-methyl-2-butene, 2-methyl-1-butene, and 3-methyl-1-butene, utilizing the aforementioned nickel precatalysts, resulted in the same structural isomers of the dimers but different product distributions, indicating that dimerization occurred at similar rate or faster than isomerization. Stoichiometric experiments, product analysis, and observations from in situ nuclear magnetic resonance spectroscopy support a mechanism whereby a short-lived nickel-hydride intermediate promotes chain insertion, chain walking, and isomerization to give less-branched dimers from highly substituted olefins than would be achieved with acid-catalyzed dimerization.

Rhodium‐Catalyzed Chemo‐, Regio‐ and Enantioselective Hydroformylation of Cyclopropyl‐Functionalized Trisubstituted Alkenes

The first rhodium-catalyzed highly chemo-, regio- and enantioselective hydroformylation of cyclopropyl-functionalized trisubstituted alkenes affording useful chiral cyclopropyl entities was reported. Compared to generally used diphosphine ligands for asymmetric catalysis, the modified hybrid phosphorus ligand, named (R,S)-DTBM-Yanphos, can convert a series of readily available cyclopropyl-functionalized trisubstituted alkenes to high-value chiral cyclopropyl-functionalized aldehydes with high selectivities (81-98% ee). Gram-scale reaction (TON up to 1,500) and follow-up transformations to the corresponding alcohol, acid, esters and nitrile were also presented. Finally, a possible hydroformylation mechanism involving ring-open-hydroformylation pathways was proposed as evidenced by control and deuteroformylation reactions.

Rhodium-Catalyzed Chemo-, Regio- and Enantioselective Hydroformylation of Cyclopropyl-Functionalized Trisubstituted Alkenes.

The first rhodium-catalyzed highly chemo-, regio- and enantioselective hydroformylation of cyclopropyl-functionalized trisubstituted alkenes affording useful chiral cyclopropyl entities is reported. Compared to generally used diphosphine ligands for asymmetric catalysis, the modified hybrid phosphorus ligand, named (R,S)-DTBM-Yanphos, can convert a series of readily available cyclopropyl-functionalized trisubstituted alkenes into high-value chiral cyclopropyl-functionalized aldehydes with high selectivities (81-98 % ee). Gram-scale reactions (TON up to 1500) and follow-up transformations to the corresponding alcohol, acid, esters and nitrile are also presented. Finally, a possible hydroformylation mechanism involving ring-open-hydroformylation pathways is proposed based on control and deuteroformylation reactions.

Base‐Promoted Reaction of Phenols with Spirocylic λ3‐Iodanes: Access to Both 2‐Iodovinyl Aryl Ethers and Diaryl Ethers

AbstractHerein, an efficient method for vinyl or aryl C(sp2)−O bond forming to construct both the (Z)‐2‐iodovinyl aryl ethers and diaryl ethers under metal‐, photocatalyst‐ and light‐free condition in one‐step, has been developed. To generate the two desired products, we proposed a SNAr2 reaction of phenol with vinyl aryl iodonium salts intermediates that subsequently lead to the phenyl‐I bond cleavage and phenyl‐O bond formation. We firstly found that the vinyl aryl iodonium salts was formed in situ from the spiro‐cis‐β‐phenol‐VBXs, which was generated between electrophilic spiro‐EBXs and nucleophilic arylols. Trisubstituted alkenes and functionalized diaryl ethers can be afforded from the two desired products.

Nickel catalyzed multicomponent stereodivergent synthesis of olefins enabled by electrochemistry, photocatalysis and photo-electrochemistry

Trisubstituted alkenes are important organic synthons and have broad applications in the synthesis of many pharmaceuticals and materials. The stereoselective synthesis of such compounds has long been a research focus for organic researchers. Herein, we report a three-component, reductive cascade, cross-coupling reaction for the arylalkylation of alkynes. A wide range of trisubstituted alkenes are obtained in good to high yields with excellent chemo- and stereoselectivity by switching between electrochemistry and photocatalysis. The E isomer of the product is obtained exclusively when the reaction is conducted with electricity and nickel, while the Z isomer is generated with high stereoselectivity when photo- and nickel dual catalysts are used. Moreover, photo-assisted electrochemically enabled nickel catalyzed protocol is demonstrated to selectively deliver Z-trisubstituted alkenes without the addition of photocatalysts.

Cobalt‐Catalyzed Asymmetric Sequential Hydroboration/Isomerization/Hydroboration of 2‐Aryl Vinylcyclopropanes

AbstractA cobalt‐catalyzed asymmetric sequential hydroboration/isomerization/hydroboration of 2‐aryl vinylcyclopropanes was for the first time reported for the preparation of valuable chiral 1,5‐bis(boronates) in good yields with excellent enantioselectivity via asymmetric sequential isomerization/hydroboration of a trisubstituted alkene intermediate. The reaction was carried out smoothly and this protocol was used for asymmetric syntheses of (−)‐preclamol in gram‐scale. The two primary C(sp3)−B bonds in chiral 1,5‐bis(boronates) could be distinguished in iterative Suzuki–Miyaura cross‐coupling reaction, delivering chiral 1,2,5‐triaryl alkanes with excellent enantioselectivity. Based on experimental and computational studies, a cobalt‐hydride species was proposed as the active intermediate in hydroboration, isomerization, and second hydroboration reactions.

Cobalt‐Catalyzed Asymmetric Sequential Hydroboration/Isomerization/Hydroboration of 2‐Aryl Vinylcyclopropanes

A cobalt-catalyzed asymmetric sequential hydroboration/isomerization/hydroboration of 2-aryl vinylcyclopropanes was for the first time reported for the preparation of valuable chiral 1,5-bis(boronates) in good yields with excellent enantioselectivity via asymmetric sequential isomerization/hydroboration of a trisubstituted alkene intermediate. The reaction was carried out smoothly and this protocol was used for asymmetric syntheses of (-)-preclamol in gram-scale. The two primary C(sp3) -B bonds in chiral 1,5-bis(boronates) could be distinguished in iterative Suzuki-Miyaura cross-coupling reaction, delivering chiral 1,2,5-triaryl alkanes with excellent enantioselectivity. Based on experimental and computational studies, a cobalt-hydride species was proposed as the active intermediate in hydroboration, isomerization, and second hydroboration reactions.

Highly Diastereoselective Synthesis of Oxindoles Containing Vicinal Quaternary and Tertiary Stereocenters by a Domino Heck/Decarboxylative Alkynylation Sequence.

A palladium-catalyzed domino Heck/decarboxylative alkynylation reaction of trisubstituted alkenes or enamines is reported. For two different types of substrates, the current domino reaction employing different solvents and bases led to 3,3-disubstituted oxindoles and hydropyrimidinyl spirooxindoles containing vicinal quaternary and tertiary stereocenters in moderate to good yields, respectively. The general applicability of this method was shown by gram-scale syntheses and diverse transformations of the reaction products. The enantioselective version for this domino process was also studied.

Imidazolidine Hydride Donors in Palladium-Catalyzed Alkyne Hydroarylation

Aldehyde-derived imidazolidines participate as hydride donors in intramolecular reductive Heck-type reactions. N,N′-Diphenylimidazolidines prepared from ortho-alkynyl benzaldehydes underwent regio- and stereoselective palladium-catalyzed hydroarylation followed by formal 1,5-hydride transfer and reductive elimination to afford substituted alkenes and imidazolium moieties, the latter conveniently converted in situ to ring-opened benzanilides to simplify product isolation. Internal alkynes were converted to trisubstituted alkenes via a syn hydroarylation process, while a terminal alkyne was converted to a cis alkene via a formal trans hydroarylation reaction. Benzanilide products could be converted to carboxylic acid derivatives under basic conditions, resulting in the net conversion of alkynyl aldehydes to alkenyl carboxylic acids. A styrene derivative with an attached N,N′-dimethylbenzimidazoline hydride donor was also found to undergo an analogous hydroarylation/benzimidazoline oxidation to give a diarylethane product.

Highly (E)-Selective Trisubstituted Alkene Synthesis by Low-Valent Titanium-Mediated Homolytic Cleavage of Alcohol C-O Bond.

Ti-mediated homolytic C-O bond cleavage was useful for cascade radical-ionic reactions. Benzyl alcohols treated with TiCl4(col) (col = 2,4,6-collidine) and Mn powder generated the corresponding benzyl radicals; in addition, their reaction with 2-carboxyallyl acetates and the subsequent elimination of the acetoxy group yielded α,β-unsaturated carbonyl compounds with exclusive (E)-stereoselectivity. The simplicity of the procedure and its wide substrate scope represent a solution to the drawbacks associated with the reactions.

Picolinamides and Iodoalkynes Enable Palladium‐Catalyzed syn‐Aminoalkynylation of Di‐ and Trisubstituted Alkenes to Give Pyrrolidines

AbstractPalladium‐catalyzed aminoalkynylation of electronically unbiased olefins with iodoalkynes is reported. The picolinamide auxiliary enables for the first time the syn‐selective aminoalkynylation of mono‐, di‐ and trisubstituted alkenes to afford the corresponding pyrrolidines in up to 97 % yield and as single diastereomers. Furthermore, through a C−H activation approach, the picolinamide allows the rapid synthesis of functionalized olefins, which are suitable cyclization precursors. Facile and orthogonal deprotection of the amides and SiiPr3‐acetylenes in the products, and a subsequent Pictet–Spengler reaction is demonstrated.

E- and Z-trisubstituted macrocyclic alkenes for natural product synthesis and skeletal editing.

Many therapeutic agents are macrocyclic trisubstituted alkenes but preparation of these structures is typically inefficient and non-selective. A possible solution would entail catalytic macrocyclic ring-closing metathesis, but these transformations require high catalyst loading, conformationally rigid precursors and are often low yielding and/or non-stereoselective. Here we introduce a ring-closing metathesis strategy for synthesis of trisubstituted macrocyclic olefins in either stereoisomeric form, regardless of the level of entropic assistance. The goal was achieved by addressing several unexpected difficulties, including complications arising from pre-ring-closing metathesis alkene isomerization. The power of the method is highlighted by two examples. The first is the near-complete reversal of substrate-controlled selectivity in the formation of a macrolactam related to an antifungal natural product. The other is a late-stage stereoselective generation of an E-trisubstituted alkene in a 24-membered ring, en route to the cytotoxic natural product dolabelide C.

Picolinamides and Iodoalkynes Enable Palladium‐Catalyzed syn‐Aminoalkynylation of Di‐ and Trisubstituted Alkenes to Give Pyrrolidines

Palladium‐catalyzed aminoalkynylation of electronically unbiased olefins with iodoalkynes is reported. The picolinamide auxiliary enables for the first time the syn‐selective aminoalkynylation of mono‐, di‐ and trisubstituted alkenes to afford the corresponding pyrrolidines in up to 97 % yield and as single diastereomers. Furthermore, through a C−H activation approach, the picolinamide allows the rapid synthesis of functionalized olefins, which are suitable cyclization precursors. Facile and orthogonal deprotection of the amides and Si i Pr3‐acetylenes in the products, and a subsequent Pictet–Spengler reaction is demonstrated.

Air Stable Chalcogen-Doped Rubicenes with Diradical Character

Air Stable Chalcogen-Doped Rubicenes with Diradical Character

Radical-Mediated Functionalization of Internal Alkenes: Synthesis of Multisubstituted Allylic and Homoallylic Azides.

Radical-mediated functionalization of alkenes provides a powerful tool for transformation of simple alkenes into numerous value-added products. The precedent radical functionalization of alkenes is mainly restricted to terminal alkenes, while the conversion of internal alkenes generally remains challenging, as the increased steric congestion on alkenes significantly conflicts with the intermolecular addition of radicals. Herein, we describe an efficient photoredox catalytic functionalization of internal trisubstituted alkenes, leading to a plethora of valuable multifunctionalized allylic and homoallylic azides, which are otherwise difficult to obtain. The azide products serve as versatile feedstock for construction of useful heterocycles. Allylic or homoallylic azides are selectively generated in the transformation, regulated by the regioselective deprotonation process. This method also features mild reaction conditions and high product diversity.