Experimental and theoretical studies on radical trifluoromethylation of titanium ate and lithium enolates

The radical trifluoromethylation of Ti ate and Li enolates has been investigated by both experiments and density functional (UB3LYP/6-311+G//UB3LYP/6-31+G*) calculations. Radical CF3 addition to the enolates proceeds in a highly exothermic manner without significant reaction barriers in both Ti ate and Li enolates. There are two possible reaction paths after the addition of CF3 radical in the case of Ti ate enolate; one is the elimination of Ti(III) from the ketyl radical intermediate and the other is the direct reaction of the ketyl radical intermediate with CF3I. However, in the case of Li enolate, only the latter path is possible due to the high energy barrier of the elimination of the Li radical. This analysis provides an explanation of the experimental observation that the Li enolate could form the radical cycle efficiently but the Ti ate enolate could not. To make the radical cycle complete, I- has to be extracted from CF3I itself or the radical anion of CF3I. In the case of Li, formation of Li-I bond could be the driving force for the extraction of I- and regeneration of CF3 radical. However, Ti does not give exothermic Ti-I formation and thus regeneration of CF3 radical is less likely.     

Radical trifluoromethylation of ammonium enolates

The easy radical trifluoromethylation of a series of 1,3-dicarbonyl compounds with CF₃I is described. The reaction occurs in the presence of a nitrogen base and sodium dithionite in CH₃CN-H₂O solution. Additionally, we report a new access to ammonium triflinates.     

Radical trifluoromethylation of ketone Li enolates

It has generally been believed that highly basic Li enolates cannot be applied as substrates for radical trifluoromethylation due to defluorination of the α-CF₃ product. However, Li enolates can be in fact employed for radical trifluoromethylation. Moreover, the reaction is extremely fast and the minimum reaction time is only ∼1 s.     

A simple method for asymmetric trifluoromethylation of N-acyl oxazolidinones via Ru-catalyzed radical addition to zirconium enolates

A Ru-catalyzed direct thermal trifluoromethylation and perfluoroalkylation of N-acyloxazolidinones has been developed. The reaction is experimentally simple and requires inexpensive reagents while providing good yields of products with good levels of stereocontrol. Preliminary studies have shown notable compatibility with functional groups, aromatics, and certain heteroaromatic substituents. The described method provides a useful alternative for the synthesis of fluorinated materials in an experimentally convenient manner.     

A "renaissance" in radical trifluoromethylation

This Minireview highlights recent developments in radical trifluoromethylation reactions. The trifluoromethyl group belongs to the privileged moieties in medicinal chemistry. Many drugs and drug candidates contain a trifluoromethyl substituent. Also in agrochemicals, the CF(3) moiety often appears. The present article addresses the radical trifluoromethylation of alkenes and arenes mainly focussing on recent achievements. However, important earlier work in this field is also covered.     

Catalytic enantioselective protonation of lithium enolates with chiral imides

The catalytic enantioselective protonation of simple enolates was achieved using a catalytic amount of chiral imides and stoichiometric amount of achiral proton sources. Among the achiral proton sources examined in the protonation of the lithium enolate of 2,2,6-trimethylcyclohexanone catalyzed by (S,S)-imide 1, 2, 6-di-tert-butyl-p-cresol (BHT) and its derivatives gave the highest enantiomeric excess. For example, 90% ee of (R)-enriched ketone was obtained when (S,S)-imide 1 (0.1 equiv) and BHT (1 equiv) were used. Use of 0.01 equiv of the chiral catalyst still caused a high level of asymmetric induction. For catalytic protonation of the lithium enolate of 2-methylcyclohexanone, chiral imide 6 possessing a chiral amide portion was superior to (S,S)-imide 1 as a chiral proton source and the enolate was effectively protonated with up to 82% ee.     

Mixed aggregates of dilithiodiamines with alkyllithiums and lithium enolates

The formation of mixed aggregates of N,N′-dilithiodiamines with alkyllithiums and lithium enolates was investigated. Enolization of 3-pentanone with the dilithium salt of N,N′-dimethyl-1,3-propanediamine generated both the E and Z enolates and the E/Z ratio changed in the presence of a lithium enolate or excess butyllithium. The formation of mixed aggregates was modeled with the B3LYP DFT method and it was found that mixed aggregate formation is energetically favorable. The infrared spectra of dilithio-N,N′-dimethyl-1,3-propanediamine in the presence of excess butyllithium or lithium enolate are consistent with the formation of mixed aggregates.     

Synthesis of 1,3-diketones from lithium enolates and acyl cyanides

The title reaction proceeds regiospecifically under mild conditions in high yield; an application in the synthesis of an $\text{Elaeocarpus}$ alkaloid is described.     

Carbonylation of lithium enolates with carbon monoxide mediated by selenium

[reaction: see text] Lithium enolates of ketones and aldehydes undergo carbonylation with carbon monoxide with the aid of selenium under mild conditions to yield beta-keto and beta-formyl selenol esters after trapping with alkyl iodides. This reaction proceeds via a unique carbonylation mechanism comprised of O-carbonylation and subsequent migration of the SeCO moiety to the alpha-carbon.     

Synthetic utility of stannyl enolates as radical alkylating agents

[reaction: see text] The radical-initiated beta-ketoalkylation of haloalkanes with tributylstannyl enolates is described. Stannyl enolates derived from aromatic ketones are reactive toward the homolytic beta-ketoalkylation of simple haloalkanes as well as those activated by an electron-withdrawing group. The reactivity of stannyl enolates as radical alkylating agents can be utilized for an efficient three-component coupling reaction among stannyl enolates, haloalkanes, and electron-deficient alkenes.     

On the nature of the oxidative heterocoupling of lithium enolates

The coupling of enolates through single-electron oxidation is one of the most direct routes for generating 1,4-dicarbonyls. Recent work on the intermolecular heterocoupling of equimolar amounts of two different enolates through single-electron oxidation has shown that synthetically useful yields beyond those predicted by statistics can be obtained. To determine the underlying basis for the selective formation of heterocoupled products, kinetic, (7)Li NMR, and synthetic studies were performed. The collection of data obtained from these experiments shows that the selective formation of heterocoupled products is a consequence of heteroaggregation of lithium enolates.     

Threo-selective aldol condensations of lithium enolates in the presence of trialkylboranes

The reaction of preformed lithium enolates in the presence of trialkylboranes, such as Et₂B and n-Bu₃B, with aldehydes leads to product mixtures rich in the more stable threo aldol.     

Computational strategies for evaluating barrier heights for gas-phase reactions of lithium enolates

Gas-phase activation energies were calculated for three lithium enolate reactions by using several different ab initio and density functional theory (DFT) methods to determine which levels of theory generate acceptable results. The reactions included an aldol-type addition of an enolate to an aldehyde, a proton transfer from an alcohol to a lithium enolate, and an S(N)2 reaction of an enolate with chloromethane. For each reaction, the calculations were performed for both the monomeric and dimeric forms of the lithium enolate. It was found that transition state geometry optimization with B3LYP followed by single point MP2 calculations generally provided acceptable results compared to higher level ab initio methods.     

C-acylation of enolates from lithium dimethylcuprate addition to α,β-unsaturated ketones

The enolates from 1,4 addition of lithium dimethylcuprate to 2-cyclohexenone, 2-cyclopentenone and methyl vinyl ketone, with acetyl chloride, give only C-acylated products and not O-acylated products as previously reported in literature.     

Generation of the CF3 radical from trifluoromethylsulfonium triflate and its trifluoromethylation of styrenes

The CF(3) radical was generated from the reaction of S-(trifluoromethyl)diphenylsulfonium triflate with Na(2)S(2)O(4) or HOCH(2)SO(2)Na under suitable conditions without further reduction. Based on this, a method for the synthesis of α-trifluoromethylated ketones has been successfully developed.     

Facile retro diels-alder reaction of a vinyl lithium compound

Attempts to generate benzobarrelyne 8 by loss of lithium chloride from 4 resulted in a facile retro Diels-Alder reaction of the “dimeric” adduct formed by addition of 4 to 8.     

Effect of solvent on aggregation and reactivity of two lithium enolates(1)

Studies with two lithium enolates show that aggregation varies from comparable to lower in dimethoxyethane (DME) compared to tetrahydrofuran (THF) but that aggregation is much higher in methyl tert-butyl ether (MTBE). Alkylation reactions, which occur dominantly with the enolate monomers, are exceptionally slow in MTBE, but even acylation reactions that can occur with aggregates are orders of magnitude slower in MTBE. These reactions apparently require additional solvation of the lithium cation, and MTBE is ineffective at such solvation.     

Facile synthesis of functionalised spiroethers via radical cyclisations

Alcohols bearing suitable chains for radical initiation are smoothly condensed with cyclic β-diketones to afford systems which undergo radical cyclisation to give various spiroether products.