Palladium-catalyzed oxidative alkynylation of alkenes via C-C bond bleavage under oxygen atmosphere

Palladium-catalyzed oxidative alkynylation of alkenes using tert-propargylic alcohols as alkynylation reagents via C-C bond cleavage under an oxygen atmosphere affords the corresponding ene-yne compounds.     

Enantiospecific Alkynylation of Alkylboronic Esters

Enantioenriched secondary and tertiary alkyl pinacolboronic esters undergo enantiospecific deborylative alkynylation through a Zweifel‐type alkenylation followed by a 1,2‐elimination reaction. The process involves use of α‐lithio vinyl bromide or vinyl carbamate species, for which application to Zweifel‐type reactions has not previously been explored. The resulting functionalized 1,1‐disubstituted alkenes undergo facile base‐mediated elimination to generate terminal alkyne products in high yield and excellent levels of enantiospecificity over a wide range of pinacolboronic ester substrates. Furthermore, along with terminal alkynes, internal and silyl‐protected alkynes can be formed by simply introducing a suitable carbon‐ or silicon‐based electrophile after the base‐mediated 1,2‐elimination reaction.     

Density functional computations of alkynylation of ethanimine catalyzed by chiral zinc(II)‐complexes

The alkynylation of ethanimine catalyzed by chiral zinc(II)‐complexes was studied by means of the density functional theory (DFT). All the intermediates and transition states were optimized completely at the B3LYP/6‐31G(d,p) level. Calculation results confirm that the alkynylation of ethanimine is exothermic and the total released energy is about ?13 kJ/mol. The formation of the catalyst–alkynyl complexes M4 is the rate‐determining step for this alkynylation, and the formation of the catalyst–amine complexes M5 is the chirality‐limiting step for this alkynylation. The transition states for the chirality‐limiting step have a H? O? Zn? C? C? N six‐membered ring. The dominant products predicted theoretically for this alkynylation are, respectively, S‐amine for ethanimine anti and R‐amine for ethanimine syn . © 2007 Wiley Periodicals, Inc. Int J Quantum Chem, 2008     

Synthesis of the N-acetylcysteamine thioester of seco-proansamitocin

[structure: see text] The enantioselective total synthesis of the N-acetylcysteamine thioester of seco-proansamitocin, a key biosynthetic intermediate of the highly potent antitumor agent ansamitocin, is described, which twice utilizes the Nagao acetate aldol reaction, as well as an indium-mediated alkynylation of a benzyl bromide followed by carboalumination. The key step is a Heck reaction between two terminal alkenes for merging the two major fragments.     

Radical‐Induced Metal‐Free Alkynylation of Aldehydes by Direct CH Activation

A direct C(sp²)?H alkynylation of aldehyde C(O)?H bonds with hypervalent iodine alkynylation reagents provides ynones under metal‐free conditions. In this method, 1‐[(triisopropylsilyl)ethynyl]‐1,2‐benziodoxol‐3(1H)‐one (TIPS‐EBX) constitutes an efficient alkynylation reagent for the introduction of the triple bond. The substrate scope is extended to a variety of (hetero)aromatic, aliphatic, and α,β‐unsaturated aldehydes.     

Cross-coupling reactions by cooperative Pd/Cu or Ni/Cu catalysis based on the catalytic generation of organocopper nucleophiles

In this review, cross-coupling reactions by cooperative Pd/Cu or Ni/Cu catalysis based on catalytically generated organocopper nucleophiles are summarized. Compared to conventional methods based on the use of stoichiometric amounts of pre-synthesized organometallic reagents, these methods are powerful tools for the alkynylation, arylation, alkenylation, and alkylation of organic electrophiles, especially as they can be carried out in a highly step-economical manner with readily available starting materials based on simple arenes, carboxylic acids, alkenes, and alkynes as pre-nucleophiles.     

Merging Distal Alkynyl Migration and Photoredox Catalysis for Radical Trifluoromethylative Alkynylation of Unactivated Olefins

Disclosed herein is a novel, redox‐neutral protocol for the visible‐light‐induced radical alkynylation of unactivated olefins. The intramolecular migration of an alkynyl group, by cleaving an inert C−C σ bond, is realized for the first time. A wide range of synthetically useful trifluoroethylated linear alkynes are readily obtained under mild reaction conditions.     

OH‐Directed Alkynylation of 2‐Vinylphenols with Ethynyl Benziodoxolones: A Fast Access to Terminal 1,3‐Enynes

The first direct alkynylation of 2‐vinylphenols was developed. The rationally optimized hypervalent iodine reagent TIPS‐EBX* in combination with [(Cp*RhCl₂)₂] as a C? H‐activating transition metal catalyst enables the construction of a variety of highly substituted 1,3‐enynes in high yields of up to 98 %. This novel C? H activation method shows excellent chemoselectivity and exclusive (Z)‐stereoselectivity, and it is also remarkably mild and tolerates a variety of functional groups. Furthermore, synthetic modifications of the resulting 1,3‐enynes were demonstrated. To our knowledge, this is the first example for an OH‐directed C? H alkynylation with hypervalent iodine reagents.     

Cyclopropanation of Terminal Alkenes through Sequential Atom‐Transfer Radical Addition/1,3‐Elimination

An operationally simple method to affect an atom‐transfer radical addition of commercially available ICH₂Bpin to terminal alkenes has been developed. The intermediate iodide can be transformed in a one‐pot process into the corresponding cyclopropane upon treatment with a fluoride source. This method is highly selective for the cyclopropanation of unactivated terminal alkenes over non‐terminal alkenes and electron‐deficient alkenes. Due to the mildness of the procedure, a wide range of functional groups such as esters, amides, alcohols, ketones, and vinylic cyclopropanes are well tolerated.     

Pd‐NHC‐Catalyzed Alkynylation of General Aryl Sulfides with Alkynyl Grignard Reagents

Cross‐coupling reactions of unactivated aryl sulfides with alkynylmagnesium chloride have been invented to afford 1‐aryl‐1‐alkynes with the aid of a palladium/N‐heterocyclic carbene complex. This reaction has by far the widest scope of all transformations utilizing aryl sulfides and alkynes, while known cross‐coupling alkynylations of aryl‐sulfur electrophiles require activated azaaryl sulfides, thiolactams, or arenesulfonyl chlorides. The alkynylation of aryl sulfides is compatible with typical protecting functional groups. The alkynylation is applied to the synthesis of benzofuran‐based fluorescent molecules by taking advantage of characteristic organosulfur chemistry.     

Palladium‐Catalyzed Vicinal Amino Alcohols Synthesis from Allyl Amines by In Situ Tether Formation and Carboetherification

Vicinal amino alcohols are important structural motifs of bioactive compounds. Reported herein is an efficient method for their synthesis based on the palladium‐catalyzed oxy‐alkynylation, oxy‐arylation, or oxy‐vinylation of allylic amines. High regio‐ and stereoselectivity were ensured through the in situ formation of a hemiaminal tether using the cheap commercially available trifluoroacetaldehyde in its hemiacetal form. The obtained compounds are important building blocks, which can be orthogonally deprotected to give either free alcohols, amines, or terminal alkynes.     

Iridium‐Catalyzed β‐Alkynylation of Aliphatic Oximes as Masked Carbonyl Compounds and Alcohols

An Ir‐catalyzed C(sp³)?H alkynylation of aliphatic ketones, aldehydes, and alcohols was achieved by using the corresponding oxime derivatives and a Ir^III catalyst. This general reaction is selective towards primary C(sp³)?H bonds and can be used for the late‐stage C?H alkynylation of complex molecules.     

Intermolecular Radical Carbofluorination of Non‐activated Alkenes

The Meerwein arylation has recently become an even more powerful tool for the functionalization of alkenes. Besides the attachment of an aryl group, radical reactions of this type allow the introduction of several different heteroatoms and a broad variety of alkenes are meanwhile tolerated as substrates. Closing a long‐standing gap of the methodology, this communication describes the first intermolecular Meerwein‐type carbofluorination. In metal‐free reactions, arylalkyl fluorides were obtained from arylhydrazines and alkenes with Selectfluor acting as oxidant and as radical fluorine source.     

Palladium‐Catalyzed Cascade Cyclization/Alkynylation Reactions

Palladium‐catalyzed cascade cyclization reactions have witnessed significant improvements in recent years. Among them, palladium‐catalyzed cascade cyclization/alkynylation are especially attractive, which can assemble structurally diverse monocyclic, bicyclic, fused polycyclic, and spirocyclic skeletons with excellent chemoselectivities. In this Minireview, palladium‐catalyzed cascade cyclization/alkynylation have been summarized and discussed in detail with focus on oxypalladation and aminopalladation‐initiated cascade cyclization, intramolecular Heck‐type cascade cyclization, carbocyclizations, cascade cyclizations, and other types of cascade cyclization reactions. Some significant and representative synthetic methodologies and their synthetic applications and reaction mechanisms have also been described.     

NHC–Copper(I) Halide‐Catalyzed Direct Alkynylation of Trifluoromethyl Ketones on Water

An efficient and easily scalable NHC–copper(I) halide‐catalyzed addition of terminal alkynes to 1,1,1‐trifluoromethyl ketones, carried out on water for the first time, is reported. A series of addition reactions were performed with as little as 0.1–2.0 mol % of [(NHC)CuX] (X=Cl, Br, I, OAc, OTf) complexes, providing tertiary propargylic trifluoromethyl alcohols in high yields and with excellent chemoselectivity from a broad range of aryl‐ and more challenging alkyl‐substituted trifluoromethyl ketones (TFMKs). DFT calculations were performed to rationalize the correlation between the yield of catalytic alkynylation and the sterics of N‐heterocyclic carbenes (NHCs), expressed as buried volume (%VBur), indicating that steric effects dominate the yield of the reaction. Additional DFT calculations shed some light on the differential reactivity of [(NHC)CuX] complexes in the alkynylation of TFMKs. The first enantioselective version of a direct alkynylation in the presence of C₁‐symmetric NHC–copper(I) complexes is also presented.     

A Highly Efficient Gold‐Catalyzed Photoredox α‐C(sp3)H Alkynylation of Tertiary Aliphatic Amines with Sunlight

A new α‐C(sp³)? H alkynylation of unactivated tertiary aliphatic amines with 1‐iodoalkynes as radical alkynylating reagents in the presence of [Au₂(μ‐dppm)₂]²⁺ in sunlight provides propargylic amines. Based on mechanistic studies, a C? C coupling of an α‐aminoalkyl radical and an alkynyl radical is proposed for the C(sp³)? C(sp) bond formation. The mild, convenient, efficient, and highly selective C(sp³)? H alkynylation reaction shows excellent regioselectivity and good functional‐group compatibility. A scale‐up to gram quantities is possible with sunlight used as a clean and sustainable energy source.     

Assembly of Functionalized 4‐Alkynylisoxazoles by Palladium‐Catalyzed Three‐Component Cascade Cyclization/Alkynylation

A novel N‐heterocyclic carbene (NHC)‐palladium‐catalyzed three‐component cascade cyclization/alkynylation for the synthesis of structurally diverse 4‐alkynylisoxazoles was efficiently developed in ionic liquids. The operational simplicity, without additives, no additional ligands, and 0.5 mol % catalyst loading under air are some of the attractive features of this present protocol.     

Ligand‐Enabled Alkynylation of C(sp3)−H Bonds with Palladium(II) Catalysts

The palladium(II)‐catalyzed β‐ and γ‐alkynylation of amide C(sp³)−H bonds is enabled by pyridine‐based ligands. This alkynylation reaction is compatible with substrates containing α‐tertiary or α‐quaternary carbon centers. The β‐methylene C(sp³)−H bonds of various carbocyclic rings were also successfully alkynylated.     

Hydrosulfonylation of Alkenes with Sulfonyl Chlorides under Visible Light Activation

Sulfonyl chlorides are inexpensive reactants extensively explored for functionalization, but never considered for radical hydrosulfonylation of alkenes. Herein, we report that tris(trimethylsilyl)silane is an ideal hydrogen atom donor enabling highly effective photoredox‐catalyzed hydrosulfonylation of electron‐deficient alkenes with sulfonyl chlorides. To increase the generality of this transformation, polarity‐reversal catalysis (PRC) was successfully implemented for alkenes bearing alkyl substituents. This late‐stage functionalization method tolerates a remarkably wide range of functional groups, is operationally simple, scalable, and allows access to building blocks which are important for medicinal chemistry and drug discovery.     

Expanding the Scope of Arylsulfonylacetylenes as Alkynylating Reagents and Mechanistic Insights in the Formation of Csp2?Csp and Csp3?Csp Bonds from Organolithiums

We describe the unexpected behavior of the arylsulfonylacetylenes, which suffer an “anti‐Michael” addition of organolithiums producing their alkynylation under very mild conditions. The broad scope, excellent yields, and simplicity of the experimental procedure are the main features of this methodology. A rational explanation of all these results can be achieved by theoretical calculations, which suggest that the association of the organolithiums to the electrophile is a previous step of their intramolecular attack and is responsible for the unexpected “anti‐Michael” reactions observed for substituted sulfonylacetylenes.