Practical synthesis of gem-difluorides from cyclohexanone: Synthesis of gem-bistrifluoroacetates and their reactions with fluoride nucleophiles

Formation of ketone acylals bearing trihaloacetoxy groups and their nucleophilic geminal disubstitution by fluoride ions were investigated. Cyclohexanone reacted with trifluoroacetic anhydride without catalyst to give gem-bistrifluoroacetates via a concerted bimolecular reaction. Treatment with hydrogen fluoride under mild conditions efficiently yielded the corresponding gem-difluorides. In this reaction process, trifluoroacetic acid was recovered and converted to trifluoroacetic anhydride using P₂O₅. Since gem-difluorides were derived from ketones, HF and P₂O₅, this constitutes a practical synthesis of gem-difluorides.     

Sulfinatodehalogenation reactions of gem-aryl disubstituted methylenecyclopropanes with perfluoroiodoalkanes

Sulfinatodehalogenation reaction of gem-aryl disubstituted methylenecyclopropanes (MCPs) 1 with perfluoroiodoalkanes produces the corresponding ring-opened products 4-iodo-1,1-diaryl-2-perfluorobutyl-but-1-enes 2, rearranged products 1,2-dihydronaphthalenes 3, and addition products 1-perfluoroalkyl-1-(diarylmethyl)cyclopropanes 4 in the presence of sodium dithionite in moderate yields through a radical process under mild conditions. The major product 2 is derived from radical ring-opening reaction of MCPs 1.     

Palladium(II) allylic complexes by carbene transmetalation and migratory insertion reactions: Synthesis and side reactions

New 1,1-alkoxy, aryl substituted palladium η³-allyls [Pd(μ-Br){η³-C(C₆F₅)(OMe)CHR¹CHR²}]₂ can be synthesized from [W(CO)₅{C(OMe)CHR¹CHR²}] and a palladium perfluoroaryl complex. The allyls are formed by transmetalation of the carbene fragment followed by migratory insertion of C₆F₅ to the putative and highly reactive Pd carbene complex. This reaction pathway predominates in all cases, but insertion of the double bond of the tungsten alkoxyvinylcarbenes into the Pd-C₆F₅ bond leads to secondary products, namely C₆F₅(OMe)CCR¹CH(C₆F₅)R².     

An efficient of Grignard-type procedure for the preparation of gem-diallylated compound

An efficient and a new procedure for the conversion of various carboxylic acid derivatives into the corresponding gem-diallylated compound under mild reaction condition has been developed. The triallylaluminum mediated Grignard-type addition of carboxylic acid derivative was utilized as a key operation to affect the transformation. The procedure is operationally simple, giving good to excellent product yields for a broad range of substrates. The chemoselectivity and regioselectivity of triallylaluminum were also demonstrated.     

Synthesis of gem-dihaloenynes and butatrienes from gem-dihalovinyl derivatives

gem-Dihaloenynes were synthesized in high yields from 1,1,4,4-tetrahalo-1,3-butadienes through the Fritsch-Buttenberg-Wiechell (FBW) rearrangement mediated by an organolithium compound. Butatriene derivatives could be obtained efficiently via an organolithium-mediated reaction of o-halo-(2,2-dihalovinyl)benzenes.     

Preparation of new gem-difluoro heterocyclic-fused 1,2,3-triazole derivatives

Starting from easily accessible gem-difluoropropargylic derivatives a cascade nucleophilic substitution by N₃^–, followed by an intramolecular 1,3 dipolar cycloaddition, afforded in fair to good yields new 1,2,3-triazoles fused to pyrrolidines or piperidines. These molecules, with a gem-difluoro group vicinal to the triazoles, are fluorinated analogues of bioactive heterocycles. In parallel, a few open chain analogues have been prepared in order to evaluate the possible role of the bicyclic core on the biological properties of such molecules.     

Preparation and some reactions of halomagnesium diorganocuprates

Bromomagnesium diphenylcuprate and iodomagnesium dimethylcuprate have been prepared, and their thermal stability and some of their reactions investigated. In diethyl ether, 50% of the BrMgPh₂Cu decomposes in 12h at room temperature and 50% of the IMgMe₂Cu decomposes at 0°C in 14 but the cuprates are more stable in THF at or below 0°C. They react with acid chlorides to give 16–76% yields of the corresponding ketones. With bromine and iodine, BrMgPh₂Cu gives bromobenzene and iodobenzene in 56 and 48% yield, respectively. Oxidation of BrMgPh₂Cu with nitrobenzene or copper(II) chloride gives, respectively, 61 and 34% of biphenyl. Reaction of BrMgPh₂Cu with acetic or benzoic anhydride yields 46–55% of the corresponding ketone and 34–37% of the corresponding carboxylic acids.     

Preparation and some reactions of 3-oxazoline N-oxides

Substituted 3-oxazolines react with m-chloroperoxybenzoic acid to give the corresponding 3-oxazoline N-oxides. These heterocyclic nitrones underwent molecular rearrangements, but would not react with 1,3-cyclo-addition type reagents.     

Preparation and some reactions of 2,3,5,6-tetrafluorobenzenesulfenyl chloride

2,3,5,6-Tetrafluorobenzenesulfenyl chloride was prepared from the thiol and chlorine. Its reactions with olefins, ammonia, aromatic and heterocyclic compounds show that it acts as a typical sulfenyl chloride and several new compounds have been isolated. These were characterized by elemental analysis, as well as by NMR (H-1 and F-19), mass and infrared spectroscopy.     

Three-component reactions of polynitromethanes with alkynes. The first synthesis of gem-dinitroaziridines

Three-component one-pot reactions of tetranitro- and bromotrinitromethanes with alkoxyacetylenes, mediated by diazomethane or bicyclobutylidene, yielding gem-dinitroaziridines via sequential electrophile transfer followed by [3+2]-cycloaddition, have been studied. A series of novel N-alkoxy-2,2-dinitroaziridines have been prepared by these reactions.     

gem-Difluoromethylation of α- and γ-ketoesters: preparation of gem-difluorinated α-hydroxyesters and γ-butyrolactones

PhSCF₂SiMe₃ has been demonstrated as difluoromethyl carbanion synthon (⁻CF₂H). It reacts chemoselectively with α- and γ-ketoesters at the keto group in the presence of a catalytic amount of TBAF in THF to give the corresponding α-hydroxy ester adducts as well as γ-gem-difluorophenylsulfanylmethylated-γ-butyrolactones in good yields. Reductive cleavage of the phenylsulfanyl group of these products employing Bu₃SnH/AIBN gives the corresponding gem-difluoromethylated α-hydroxyesters and γ-butyrolactones in good yields.     

Synthesis of gem-difluoromethylenated massoialactone by ring-closing metathesis

4,4-Difluoromassoialactone has been synthesized for the first time via a very short sequence, where the ring-closing metathesis (RCM) was employed as a key step. The efficient procedure can easily be extended to the synthesis of other gem-difluoromethylenated α,β-unsaturated-δ-lactone moiety. In addition, the viability of RCM of high electron-deficient olefins has been demonstrated.     

The gem-dimethyl effect: amphiphilic bilirubins

New bilirubin congeners (1a-1d) with the central C(10) CH₂ replaced by C(CH₃)₂ were smoothly synthesized by coupling two identical dipyrrinones with 2,2-dimethoxypropane under acid catalysis. The new yellow pigments, with acid chains varying from acetic (n=1) to propionic (n=2) to butyric (n=3) to hexanoic (n=5), exhibit unusual amphiphilicity relative to the parent mesobilirubins without the gem-dimethyls and have highly favorable solubility in organic solvents ranging from nonpolar (benzene) to polar (CH₃OH). Like the parent rubins, 1a-1d can easily bend about the middle but unlike the parents they cannot form mesobiliverdin analogs. NMR spectroscopic analysis and molecular dynamics calculations indicate that, like the parents, 1a-1d adopt ridge-tile shapes that are stabilized by intramolecular hydrogen bonding. Confirmation of the conformation in 1b comes from its X-ray crystallographic structure.     

Isopropenyldihydrofuran derivatives. Preparation and reactions of some isopropenyldihydrofurandicarboxylates

Diethyl 5-isopropenyl-4,5-dihydrofuran-2,3-dicarboxylate 1a and methyl 5-isopropenyl-3-methoxy-carbonyl-4,5-dihydrofuran-2-acetate 2a were prepared by cylization of diethyl 2-oxosuccinate or dimethyl 3-oxoglutarate with (E)-1,4-dibromo-2-methyl-2-butene. Their chemical properties were studied.     

Preparation and reactions of some 2,2-difunctional 1,1-dibromocyclopropanes

The synthesis of 2,2-dibromocyclopropane-1,1-dicarboxylic acids is described. Reaction of substituted 1,1-dibromo-2-acyloxymethylcyclopropanes with methyl lithium at low temperature leads to a bromine-lithium exchange and then either formal protonation to give the corresponding monobromocyclopropanes or intramolecular cyclisation to give a substituted 3-oxabicyclo[3.1.0]hexane. Oxidative ring opening of these compounds leads stereoselectively to 1,1,2,2-tetrasubstituted cyclopropanes with four functionalities on the ring.     

Highly regio- and stereocontrolled SN2′ reactions of gem-difluorinated vinyloxiranes with monoalkylcopper reagents

Reaction of gem-difluorinated vinyloxiranes with RCu(X)Li allowed us to introduce the R group regioselectively at the fluorine-attached terminal carbon atom in an S_N2′ manner to afford (E)-allylic alcohols exclusively, while homoallylic alcohols with anti stereochemical relationship were found to be obtained selectively from higher-ordered cuprates derived from CuCl and RMgBr in a ratio of 1:3.     

Preparation and some reactions of organogermylmercuryplatinum complexes and related compounds

A single-crystal X-ray diffraction study of tetracarbonyl-ferra-3-cyclopentene-2,5-dione has been made. Formally the compound can be derived from maleic anhydride by substitution of the bridging oxygen by Fe(CO)₄. Accordingly the bonding character is similar to that of maleic anhydride. The ironcarbon distances in the ring indicate partial double bonds. The octahedrally coordinated iron atom is linked to four terminal carbon monoxide ligands, with a longer bond distance to the equatorial than to the axial ones (FeC_ax 1.809 Å, FeC_eq 1.854 Å). The axial CO groups are strongly inclined towards the ring (C_axFeC_ax 164°). The latter effect is explained by electronic repulsion of the CO groups.IR, ¹H NMR, and ¹³C NMR data are reported. Crystal data: space groupPnama:α  12.708(10),b  10.058(7),c  7.527(5) Å;Z  4. With 625 reflections [F_o > 3o(F_o)] the structure has been refined anisotropically (hydrogen isotropically) to R0.022.     

Synthetic applications of ethyl 3-bromodifluoromethyl-3-benzyloxy-acrylate as a gem-difluorination building-block: Its reactions with aldehyde and epoxide

Synthetic applications of ethyl 3-bromodifluoromethyl-3-benzyloxy-acrylate as a versatile and multifunctionalized gem-difluorination building block to introduce difluoromethene subunit into some new hydroxy esters have been investigated. It was found that its zinc mediated reaction with a variety of aldehyde in DMF gave the Reformatsky reaction mode product, β-hydroxy ester, in good yield, while its tetrakis(dimethylamino)ethylene (TDAE) promoted reaction with a limited scope of aldehyde produced Barbier reaction mode product, δ-hydroxy ester, in moderate yield. The reaction of its zinc reagent with styrene oxide resulted in rearrangement of the epoxide to 2-phenyl-acetaldehyde, and then the zinc reagent condensed with this aldehyde to provide the Reformastsy reaction type product, β-hydroxy ester, in low yield.