Fluoro-ketones. V reaction of alkyl and aryllithium compunds with perfluoroalkylether esters

n-Butyllithium and a variety of aryllithium compounds have been shown to react with a perfluoroalkylether ester (R_fOR_fCO₂R) at ?78°C to produce perfluoroalkylether ketones. In the absence of competing reactions, which may be due to additional reactive groups on the ester, high yields of ketones can be prepared. Steric hindrance adjacent to the carbonyl group has an important effect on rates of reactions. Low reaction temperature ?78°C is an important factor when secondary esters are used. At higher reaction temperatures >;?30°C, the secondary esters produce decreased yields of ketone due to the instability of the intermediate lithium salt of the hemiketal which decomposes to an aryl ester and a perfluorinated olefin.     

Thermal decomposition of some perfluoroalkyl grignard reagents. Synthesis of trans-1-halo and trans-1-alkylperfluorovinyl compounds

The thermal decomposition of perfluoroalkyl Grignard reagents (R_fMgX), formed from halogen-metal exchange with alkyl Grignard reagents, provides a good synthetic route to trans-1-haloperfluorovinyl compounds.

The decomposition of R_fMgX (where X = Cl, Br, I) in the presence of RMgX generally leads to a mixture of trans-1-alkylperfluorovinyl and trans-1-haloperfluorovinyl compounds. However, the choice of RMgX with respect to both the alkyl group and halogen is critical as regards the formation of the trans-1-alkylperfluorovinyl compounds.Several possible mechanisms are suggested to account for the experimental observations.     

Fluoro-ketones IV. Synthesis of phenylperfluoroalkyl ketones - mechanism of reaction between phenyllithium and fluoroesters

Although fluorine containing ketones (R_fC(O)R_f and R_fC(O)R, R_f = perfluoroalkyl) have been prepared from the reaction between organolithium reagents and perfluoroalkyl esters, the reaction has not found general applicability. Variable yields of ketones and co-production of secondary and tertiary alcohol by-products have in most instances been experienced. We have examined in more detail the factors e.g., temperature, mode of addition and perfluoroalkyl ester structure which influence ketone product and by-products formation. By controlling experimental conditions excellent yields of C₆H₅C(O)R_f compounds can be attained. A lithium salt of a hemiketal (II) has been isolated and shown to be the active intermediate in the production of the ketone. The stability of the salt and its potential reaction with the solvent dictates the type of reaction products. Low temperature favors stability of the lithium salt of the hemiketal whereby high yields of ketones are produced on hydrolysis.     

Asymmetric addition of Grignard reagents to ketones: culmination of the ligand-mediated methodology allows modular construction of chiral tertiary alcohols

A new class of biaryl chiral ligands derived from 1,2-diaminocyclohexane (1,2-DACH) has been designed to enable the asymmetric addition of aliphatic and, for the first time, aromatic Grignard reagents to ketones for the preparation of highly enantioenriched tertiary alcohols (up to 95% ee). The newly developed ligands L12 and L12′ together with the previously reported L0 and L0′ define a set of complementary chiral promoters, which provides access to the modular construction of a broad range of structurally diverse non-racemic tertiary alcohols, bearing challenging quaternary stereocenters. The present advancements bring to completion our asymmetric Grignard methodology by expanding the scope to aromatic organomagnesium reagents, while facilitating its implementation in organic synthesis thanks to improved synthetic routes for the straightforward access to the chiral ligands. The synthetic utility of the method has been demonstrated by the development of a novel and highly enantioselective formal synthesis of the antihistamine API clemastine via intermediate (R)-3a. Exploiting the power of the 3-disconnection approach offered by the Grignard synthesis, (R)-3a is obtained in 94% ee with ligand (R,R)-L12. The work described herein marks the finalization of our ongoing effort towards the establishment of an effective and broadly applicable methodology for the asymmetric Grignard synthesis of chiral tertiary alcohols.

Easily applied enantioselective addition of aliphatic and aromatic Grignard reagents to ketones provides modular and universal access to challenging chiral tertiary alcohols, enabling the straightforward preparation of natural products and APIs.     

Total Synthesis of (R,R,R)‐γ‐Tocopherol through Cu‐Catalyzed Asymmetric 1,2‐Addition

Based on the asymmetric copper‐catalyzed 1,2‐addition of Grignard reagents to ketones, (R,R,R)‐γ‐tocopherol has been synthesized in 36 % yield over 12 steps (longest linear sequence). The chiral center in the chroman ring was constructed with 73 % ee by the 1,2‐addition of a phytol‐derived Grignard reagent to an α‐bromo enone prepared from 2,3‐dimethylquinone.     

The reaction of hexafluoropropene oxide with grignard reagents

The reactions of hexafluoropropene oxide and equimolar amounts of Grignard reagents lead to the formation of 2-halotetrafluoropropanoyl fluorides which were converted to the methyl or ethyl ester for isolation purposes. Treatment of hexafluoropropene oxide with excess Grignard reagent formed an unsaturated ketone of the type R₂CCFCOR (RCH₃ or CH₂CH₃; a route by which this product is formed is postulated.     

Condensation des bromures de perfluoro-alkylmagnesium sur les aldehydes et cetone α-halogenes

Perfluoroalkyl magnesium halides react with α halogenocarbonyl compounds producing diastereoisomeric halohydrines which lead to perfluoroalkyl epoxydes by cyclisation.NMR study shows that the epoxyde configuration may be deduced from the coupling constant value ⁴J(H-F) between the epoxyde proton and the R_F radical.The condensation on the carbonyl group is less stereo-selective with R_FMgX than with usual Grignard reagents.     

Some perfluoroalkyl grignard reagents and their derivatives

Some perfluoroalkyl Grignard reagents have been prepared in high yields through halogen-metal exchange reactions between perfluoroalkyl iodides (R_fI) and EtMgBr. Derivatization with Me₃SiCl gave satisfactory yields of the corresponding silylated products in THF. However, ether was a very poor solvent for reaction of R_fMgBr with these chlorosilanes. The exchange reaction between R_fI and EtMgBr was nearly quantitative in ether as evidenced by high yields of the 1-hydroperfluoroalkanes upon hydrolysis, but the major production from the attempted silylation in ether was a trans- vinyl bromide [1], i. e.

Spectral data are presented for several new compounds.     

Continuous Flow Synthesis of Ketones from Carbon Dioxide and Organolithium or Grignard Reagents

We describe an efficient continuous flow synthesis of ketones from CO₂ and organolithium or Grignard reagents that exhibits significant advantages over conventional batch conditions in suppressing undesired symmetric ketone and tertiary alcohol byproducts. We observed an unprecedented solvent‐dependence of the organolithium reactivity, the key factor in governing selectivity during the flow process. A facile, telescoped three‐step–one‐flow process for the preparation of ketones in a modular fashion through the in‐line generation of organometallic reagents is also established.     

CF bond activation in the reaction of BiCl3 with sodium 2,4,6-tris(trifluoromethyl)phenoxide

BiCl₃ reacts with sodium 2,4,6-tris(trifluoromethyl)phenoxide (NaOR_4f) in ether solution to produce an unusual condensation product in which three OR_f functions have been coupled with the elimination of three fluorine atoms. The product is R_fOC₆H₂(CF₃)₂C(O)OR_f, which has been characterized spectroscopically and by X-ray crystallography (triclinic space group P 1; a = 8.958(1), b = 12.652(2), c = 13.722(2)Å, α = 89.596(8)°, β = 75.92(1)°, γ = 71.412(7)°, V = 1425.6(3)ų, Z = 2). Bi(OR_f)₃ is believed to be an intermediate in this process. The carbonfluorine bond activation is not observed in the absence of BiCl₃.     

Direct Addition of Grignard Reagents to Aliphatic Carboxylic Acids Enabled by Bulky turbo-Organomagnesium Anilides

The synthesis of ketones through addition of organometallic reagents to aliphatic carboxylic acids is a straightforward strategy that is limited to organolithium reagents. More desirable Grignard reagents can be activated and controlled with a bulky aniline-derived turbo-Hauser base. This operationally simple procedure allows the straightforward preparation of a variety of aliphatic and perfluoroalkyl ketones alike from functionalized alkyl, aryl and heteroaryl Grignard reagents.     

Ligand exchange reactions of aryl pyridyl sulfoxides with grignard reagents: Convenient preparation of 3- and 4-pyridyl grignard reagents and examination of the leaving abilities of pyridyl anions

Aryl 3- and 4-pyridyl sulfoxides undergo ligand exchange in reactions with aryl Grignard reagents to generate 3- and 4-pyridyl Grignard reagents, which, upon treatment with aldehydes or ketones, give the corresponding addition products in moderate-to-good yields. The mechanism for the exchange reaction was investigated by treating optically active 3- and 4-pyridyl p-tolyl sulfoxides with a phenyl Grignard reagent. Inversion of the configuration of the sulfur atom was the stereochemical result of the reactions. In the reactions of phenyl 2-pyridyl sulfoxide with Grignard reagents, the leaving ability of the 2-pyridyl group competes with that of the phenyl group. Both the experimental and MO calculated enthalpy values for deprotonation of α-, β-, and γ-protons of pyridine in the gas phase [1] are in accordance with the following order of the leaving abilities of aryl and pyridyl Grignard reagents: 4-PyMgBr > 3-PyMgBr » PhMgBr > p-TolMgBr > 2-PyMgBr.     

Cp2 TiCl 2-Catalyzed Reaction of Grignard Reagents with Diaryl Ketones,Formation of Pinacolic Coupling from Diaryl Ketones

Diaryl ketones react with Grignard reagents in the presence of a catalytic amount of Cp₂ TiC1 ₂ to give the corresponding pinacolic coupling products.     

Highly stereoselective synthesis of 6-perfluoroalkyl-6-fluoroalka-2,3,5-(Z)-trienols through carbometallation-elimination of 5-perfluoroalkyl-substituted 4(E)-alken-2-ynols with Grignard reagents

A highly regio- and stereoselective sequential carbometallation and Z-selective β-elimination reaction of 5-perfluoroalkyl-4(E)-en-2-ynols with Grignard reagents in Et₂O has been developed to afford various 6-perfluoroalkyl-6-fluoroalka-2,3,5(Z)-trienols in good to excellent yields. Primary or secondary alkyl or aryl Grignard reagents may be used to introduce the R² group to the 2-position of the starting materials referring to the hydroxyl group. A mechanism for this transformation has been proposed.     

Organometallic Compounds of Titanium and Zirconium as Selective Nucleophilic Reagents in Organic Synthesis

The addition of carbanionic organometallic compounds (usually RLi or RMgX) to a carbonyl group—a key step in numerous syntheses—is not always straightforward. Depending on the substrate, various complications and problems may arise, but in many cases these can be remedied by addition of (RO)₃TiCl, (RO)₃ZrCl or (R₂N)₃TiX to the classic lithium and Grignard reagents. This usually leads to formation of stable organo-titanium and -zirconium compounds which react highly selectively with carbonyl groups. For example, CH₃Ti(OiPr)₃ reacts five orders of magnitude faster with benzaldehyde than with acetophenone at room temperature; reagents of the type RTi(OiPr)₃ add smoothly to nitro-, ido-, or cyano-subsituted benzaldehyde, and the reactions may be performed in chlorinated solvents or acetonitrile; the zirconium analogues have particularly low basicity and add in high yield to α- and β-tetralones or to substrates containing a nitroaldol group; the inclusion of chiral OR^* groups gives enantioselective reagents (up to 90% ee); allylic (RO₃)Ti- derivatives react only at the more highly substituted carbon atom and, in addition, react diastereoselectively (up to 98% ds) with unsymmetrical ketones. Finally, titanium reagents have also been found to effect novel transformations such as direct geminal dialkylation (C?O→CMe₂) and alkylative amination [C?O→CR(NR)]. The modification and finetuning (“taming”) of carbonyl reactivity obtainable by use of the new reagents is not dearly bought; starting materials are the cheap and harmless “titanates”, “zirconates” and the corresponding tetrachlorides.     

Stéréochimie des réactions de substitution des alcoxygermanes par les organolithiens et par les réactifs de Grignard

The reactions of organolithium reagents and Grignard reagents with optically active alkoxygermanes R₃GeOR′ have been studied [R₃GeOR′ = ()-i-PrPhNpGeOCH₃, ()-i-PrPhNPGeOMen and ()-MePhNpGeOMen]. Saturated reagents (e.g. butyllithium) give retention of configuration at germanium whilst unsaturated reagents (e.g. allyl- or benzyllithium) lead to inversion.     

Reactifs de Grignard vinyliques γ fonctionnels : III. Addition a quelques derives carbonyles

Δt^α,β-Butenolides can be obtained by carbonation of γ-functionally substituted vinylic Grignard reagents, prepared by addition of organomagnesium compounds to α-acetylenic or α-allenic alcohols. By addition to aldehydes and ketones, these vinylic Grignard reagents yield diols, which give unsaturated ethers by cyclization reactions.     

The formation of grignard compounds—III : The influence of the solvent

The reaction of 6-bromo-1-hexene with Mg was studied in order to obtain information on the role of the solvent during the formation of Grignard reagents. The 5-hexenyl radical (R_nc^.) is known to cyclize rapidly and irreversibly to the cyclopentylmethyl radical (R_c^.). Changes in yields of the cyclized and non-cyclized Grignard compounds have been found on varying the solvent. Information on the radical pairs involved is obtained from the yields of the three possible coupling products (R_ncR_nc, R_ncR_c and R_cR_c). Results are correlated to the intensity of the CIDNP spectra of the Grignard compounds. It is found that basicity and viscosity of the solvents influence the reactions at the site of single electron transfer. Formation of Grignard compounds via radical pairs increases: (a) with decreasing basicity of the solvent, (b) with decreasing viscosity of the solvent, and (c) on dilution of THF with benzene. It is proposed that interaction between the radical and the π-electron rich solvent benzene plays a role in reactions run in Bz/THF mixtures.     

Influence of catalytic system composition on formation of adamantane containing ketones

The preparation of non-symmetrical ketones by the reaction of acyl chlorides and the corresponding Grignard reagents in the presence of catalytic amounts of metal halides is described. The composition of catalyst has a great influence on the yield of the required ketone as well as on side product formation. For each catalytic system, the yield of ketone and the number of side products changes with the time of addition of the Grignard reagent. We examined the influence of both factors in our model reaction of adamantane-1-carbonyl chloride with ethylmagnesium bromide and discussed the possible mechanisms from this point of view. We have found ZnCl₂, MnCl₂, AlCl₃ and CuCl to be active catalytic components and developed very efficient, cheap and fast methods for the preparation of alkyl adamantyl ketones. The procedure was also tested for the synthesis of other alkyl aryl ketones.     

Cp2TiCl2-catalyzed grignard reactions. 2. Reactions with ketones and aldehydes

The reaction of Grignard reagents with ketones or aldehydes in the presence of a catalytic amount of Cp₂TiCl₂ leads to the corresponding reduction products in high yields. Cp₂TiH intermediate was proposed to account for this observation.