Copper‐Catalyzed Trifluoromethylation of Trisubstituted Allylic and Homoallylic Alcohols

An efficient copper‐catalyzed trifluoromethylation of trisubstituted allylic and homoallylic alcohols with Togni’s reagent has been developed. This strategy, accompanied by a double‐bond migration, leads to various branched CF₃‐substituted alcohols by using readily available trisubstituted cyclic/acyclic alcohols as substrates. Moreover, for alcohols in which β‐H elimination is prohibited, CF₃‐containing oxetanes are isolated as the sole product.     

Rapid and Slow Generation of 1‐Trifluoromethylvinyllithium: Syntheses and Applications of CF3‐Containing Allylic Alcohols,Allylic Amines,and Vinyl Ketones

1‐(Trifluoromethyl)vinylation is accomplished in two protocols by the in situ generation of thermally unstable 3,3,3‐trifluoroprop‐1‐en‐2‐yllithium ( 1 ): 1) a rapid lithium–halogen‐exchange reaction of 2‐bromo‐3,3,3‐trifluoroprop‐1‐ene ( 2 ) takes effect with sec‐BuLi at ?105 °C to generate vinyllithium 1 , which reacts with more reactive electrophiles, such as aldehydes and N‐tosylimines before its decomposition, to afford 2‐(trifluoromethyl)allyl alcohols and N‐[2‐(trifluoromethyl)allyl] sulfoamides in good yield; 2) treatment of 2 with nBuLi at ?100 °C causes a slow lithium–halogen exchange of 2 , which gives rise to a mixture of 1 and nBuLi. Vinyllithium 1 is preferentially trapped with less reactive electrophiles, such as N,N‐dimethylamides in the presence of BF₃?OEt₂, to afford 1‐(trifluoromethyl)vinyl ketones in good yield. Versatility of the products toward syntheses of CF₃‐containing ring‐fused cyclopentenones is also demonstrated by the Pauson–Khand reaction and the Nazarov cyclization.     

Copper‐Catalyzed γ‐Selective and Stereospecific Allylic Cross‐Coupling with Secondary Alkylboranes

The scope of the copper‐catalyzed coupling reactions between organoboron compounds and allylic phosphates is expanded significantly by employing triphenylphosphine as a ligand for copper, allowing the use of secondary alkylboron compounds. The reaction proceeds with complete γ‐E‐selectivity and preferential 1,3‐syn stereoselectivity. The reaction of γ‐silicon‐substituted allylic phosphates affords enantioenriched α‐stereogenic allylsilanes.     

Copper‐Catalyzed 1,2‐Addition of α‐Carbonyl Iodides to Alkynes

β,γ‐Unsaturated ketones are an important class of organic molecules. Herein, copper catalysis has been developed for the synthesis of β‐γ‐unsaturated ketones through 1,2‐addition of α‐carbonyl iodides to alkynes. The reactions exhibit wide substrate scope and high functional group tolerance. The reaction products are versatile synthetic intermediates to complex small molecules. The method was applied for the formal synthesis of (±)‐trichostatin A, a histone deacetylase inhibitor.     

Synthesis of Branched Alkylboronates by Copper‐Catalyzed Allylic Substitution Reactions of Allylic Chlorides with 1,1‐Diborylalkanes

Reported herein is a copper‐catalyzed S_N2′‐selective allylic substitution reaction using readily accessible allylic chlorides and 1,1‐diborylalkanes, a reaction which proceeds with chemoselective C?B bond activation of the 1,1‐diborylalkanes. In the presence of a catalytic amount of [Cu(IMes)Cl] [IMes=1,3‐bis(2,4,6‐trimethylphenyl)imidazole‐2‐ylidene] and LiOtBu as a base, a range of primary and secondary allylic chlorides undergo the S_N2′‐selective allylic substitution reaction to produce branched alkylboronates. The synthetic utilities of the obtained alkylboronates are also presented.     

Manganese‐Catalyzed Hydrogen‐Autotransfer C−C Bond Formation: α‐Alkylation of Ketones with Primary Alcohols

A novel catalytic hydrogen‐autotransfer protocol for the atom‐efficient α‐alkylation of ketones with readily available alcohols is presented. The use of manganese complexes bearing non‐innocent PNP pincer ligands enabled the functionalization of a broad range of valuable ketones, including 2‐oxindole, estrone 3‐methyl ether, and testosterone. Mechanistic investigations suggest the participation of an intramolecular amidate‐assisted alcohol‐dehydrogenation process.     

Metal‐Free Oxidative Radical Addition of Carbonyl Compounds to α,α‐Diaryl Allylic Alcohols: Synthesis of Highly Functionalized Ketones

A metal‐free direct alkylation of simple carbonyl compounds (ketones, esters, and amides) with α,α‐diaryl allylic alcohols is described. The protocol provides facile access to highly functionalized dicarbonyl ketones by a radical addition/1,2‐aryl migration cascade. The regioselectivity of the reaction was precisely controlled by the nature of the carbonyl compound.     

Palladium‐Catalyzed Allylic Alkylation of Simple Ketones with Allylic Alcohols and Its Mechanistic Study

Allylic alcohols were directly used in Pd‐catalyzed allylic alkylations of simple ketones under mild reaction conditions. The reaction proceeded smoothly at 20 °C by the concerted action of a Pd catalyst, a pyrrolidine co‐catalyst, and a hydrogen‐bonding solvent, and does not require any additional reagents. A computational study suggested that methanol plays a crucial role in the formation of the π‐allylpalladium complex by lowering the activation barrier.     

Copper‐Catalyzed Dehydrogenative Cross‐Coupling Reaction between Allylic CH Bonds and α‐CH Bonds of Ketones or Aldehydes

A dehydrogenative cross‐coupling reaction between allylic C?H bonds and the α‐C?H bond of ketones or aldehydes was developed using Cu(OTf)₂ as a catalyst and DDQ as an oxidant. This synthetic approach to γ,δ‐unsaturated ketones and aldehydes has the advantages of broad scope for both ketones and aldehydes as reactants, mild reaction conditions, good yields and atom economy. A plausible mechanism using Cu(OTf)₂ as a Lewis acid catalyst was also proposed (DDQ=2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone; Tf=trifluoromethanesulfonate).     

Iridium‐Catalyzed Enantioselective Allylic Substitution of Unstabilized Enolates Derived from α,β‐Unsaturated Ketones

We report Ir‐catalyzed, enantioselective allylic substitution reactions of unstabilized silyl enolates derived from α,β‐unsaturated ketones. Asymmetric allylic substitution of a variety of allylic carbonates with silyl enolates gave allylated products in 62–94 % yield with 90–98 % ee and >20:1 branched‐to‐linear selectivity. The synthetic utility of this method was illustrated by the short synthesis of an anticancer agent, TEI‐9826.     

Iridium‐Catalyzed Diastereoselective and Enantioselective Allylic Substitutions with Acyclic α‐Alkoxy Ketones

The asymmetric alkylation of acyclic ketones is a longstanding challenge in organic synthesis. Reported herein are diastereoselective and enantioselective allylic substitutions with acyclic α‐alkoxy ketones catalyzed by a metallacyclic iridium complex to form products with contiguous stereogenic centers derived from the nucleophile and electrophile. These reactions occur between allyl methyl carbonates and unstabilized copper(I) enolates generated in situ from acyclic α‐alkoxy ketones. The resulting products can be readily converted into enantioenriched tertiary alcohols and tetrahydrofuran derivatives without erosion of enantiomeric purity.