Some approaches to the synthesis of fluorinated alcohols and esters. II. Use of F-alkyl iodides for the synthesis of F-alkyl alkanols

Free radical addition of an F-alkyl iodide (R_FI) to an alkenol or ester, followed by appropriate reduction is an efficient method for preparing the corresponding F-alkyl-alkanols of the homologous series, R_F(CH₂)_n?OH. When n = 2,4 or higher, the two steps take place smoothly. The 1,2,3-substituted systems R_FCH₂CHYCH₂Z, however, are susceptible to surprising difficulties. Reduction of R_FCH₂CHICH₂ON to R_F(CH₂)₃OH by hydrogen and catalyst (strong base acid acceptor), can be done either in one step or $\text{via}$ R_FCHCHCH₂OH; however, dehydrohalogenation may also give the epoxide, and reduction in this case leads to the secondary alcohol, R_FCH₂CH(CH₃)OH. By contrast, reduction of R_FCH₂CHICH₂OAc by tributyltin hydride or with hydrogen over palladium (diethylamine acid acceptor) goes smoothly. Zinc and acid reduction of R_FCH₂CHICH₂OAc gives elimination to R_FCH₂CHCH₂; even R_FCHCICH₂OH gives R_FCHCCH₂ besides R_FCHCHCH₂OH. R_FCHCICH₂CH₂OH, however, with zinc and acid is reduced cleanly to R_FCHCHCH₂CH₂OH.     

Some approaches to the synthesis of fluorinated alcohols and esters. I. Completely fluorinated esters from the hunsdiecker reaction of silver F-alkanoates with iodine

A completely fluorinated ester of the type R_FCO₂CF₂R_F′ was obtained from reaction of silver 3,6,9-trioxa-F-undecanoate and iodine with a diluent at 130°. This new substance resembled closely the previously prepared 1,1-dichloro-F-alkyl esters and was hydrolytically and thermally labile. Substitution products, R_FCOY (Y = nucleophile) and pyrolysis products, R_FCOF and R_F′COF were isolated and characterized. It appears probable that the acyl hypoiodite and the iodo-F-alkane reacted by an S_Ei-type process to give the completely fluorinated ester.     

Some new approaches to modifying aromatic and heteroaromatic compounds by means of fluorine-containing substituents

Modification of physiologically active substances by means of fluorine atoms or fluoroalkyl groups is known in numerous cases to lead to compounds with a markedly higher activity. The optimum change in the properties is considered to be achieved by inserting 1-3 fluorine atoms into the molecule. Therefore modifications of compounds by such groups as CHF₂, CF₃, CH₂F are most frequently used in synthesis of fluorine-containing pharmaceutical and agricultural chemicals.

At the same time, the data obtained in recent years indicate the existence of some others regularities. Thus, in a number of cases highly active drugs have been revealed among highly fluorinated substances containing polar groups of atoms in the molecule. The physiological activity of fluorine-containing compounds seems to be determined not so much by the degree of fluorination as by the relationship between the hydrophobic and the hydrophilic properties. This conclusion is quite justified, since it is the compound's lipophilic-hydrophilic balance that determines its transport in biosystems and the possibility of the interaction with the lipoprotein sites of biomembranes. Moreover, compounds with a heightened fluorine con-     

New approaches to the synthesis of diphosphine dioxides and hypophosphoric acid esters

An anion >P–O⁻ has been applied as an efficient synthetic precursor of four coordination compounds of the R₂P(O)–(O)PR₂ type, namely diphosphine dioxides (R = alkyl, aryl) as well as hypophosphoric acid esters (R = alkoxy, aryloxy), in a one‐pot reaction. Furthermore, there were elaborated some mechanistic aspects of the origin of the >P(O)–O–(O)P< anhydride, as a side‐product of the reaction between the anion >P–O⁻ and >P(O)X (X = Cl, Br) electrophiles. Attention is focused on the synthesis of the >P(O)–(O)P< compounds. © 2006 Wiley Periodicals, Inc. Heteroatom Chem 17:310–316, 2006; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20208     

Synthesis of fluorine-containing betulin esters

28-O-Fluoroacylbetulins were synthesized via acylation of betulin by fluorocarboxylic (perfluorobutyric, perfluorooctanoic, 3-fluorobenzoic, perfluorobenzoic) acid chlorides in CHCl₃ in the presence of Py. 3,28-Di-O-fluoroacylbetulins were prepared by treatment of betulin with fluorocarboxylic (trifluoroacetic, pentafluoropropionic) acid anhydrides in Py in the presence of 4-dimethylaminopyridine. 3,28-Di-O- (3-fluorobenzoyl)betulin was obtained from acylation of betulin by 3-fluorobenzoic acid in CH₂Cl₂ in the presence of N,N′-dicyclohexylcarbodiimide and 4-dimethylaminopyridine whereas acylation by perfluorobutyric acid under the same conditions gave 28-O-perfluorobutanoylbetulin.     

A novel one-pot synthesis of secondary alcohols from esters

Alkylation or vinylation by using organometallic reagents after partial reduction of carboxylic esters with LDBBA gave secondary alcohols, also involving allyl alcohols, without any isolation of intermediates in good yield (54-78%).     

A simple and efficient method for synthesis of fluorine-containing saccharide esters and antiviral activity

Sixteen new fluorine-containing saccharide esters from fluorine-containing benzoic acids and α-O-acetylglycosyl bromide were synthesized in the presence of 4-dimethylaminopyridine (DMAP) and triethylamine (Et₃N) under mild conditions in good yields and their structures were clearly verified by IR, ¹H NMR, MS and elemental analysis. This method has high stereospecificity, the configuration is unitary, the new synthesized compounds are all of β-configuration. The results of bioassay showed that these title compounds possess potential antiviral activities against tobacco mosaic virus (TMV).     

Some approaches to the synthesis of fluorinated alcohols and esters. III. Synthesis of 2-(F-alkyl)ethanols from 2-(F-alkyl)-1-iodoethanes and amides.

1-Iodo-2-(F-alkyl)ethanes, R_FCH₂CH₂I, when heated with a large excess of N-methylformamide (NMF) give in high yield, mixtures of predominately R_FCH₂CH₂OH, some formate ester and a little R_FCHCH₂. In a study of this process, significant variables were examined, including solvent, reactant ratio, effect of water, and alternative amide reactants. The coproduct from NMF is the amidine salt, [MeNHCH(NHMe)]⁺I⁻. By contrast, R_FCH₂CH₂I with N,N-dimethylformamide (DMF) and water (one or two mols) gives chiefly the formate ester; the coproduct is Me₂NH₂⁺I⁻. A mechanistic scheme is proposed: in the first step, an alkyl imidate salt, e.g., [HC(NH Me)OCH₂CH₂R_F]⁺I⁻ is formed by O-alkylation of NMF; reaction of the imidate with more NMF gives a tetrahedral intermediate that breaks down rapidly to R_FCH₂CH₂OH, and HC(NHMe)NMeCHO⁺I⁻. The formate ester is derived from the alcohol and this N-formyl acylating agent, in a subsequent step. Analogously, the alkyl imidate salt from DMF and R_FCH₂CH₂I reacts with water as nucleophile (but not with DMF) to give a tetrahedral intermediate that cleaves under stereoelectronic control to formate ester and amine salt, but not to alcohol. Quantitative isolation of amine salt and amidine salt, and observed rates of reaction give solid support to this proposed mechanism.     

A new and general one-pot synthesis of propargyl alcohols from esters

Intermediates easily prepared by partial reduction of various esters with LDBBA as a reducing agent smoothly react with lithium acetylides to give propargyl alcohols, without isolation of partial reduction intermediates, in good yields (73-83%).     

Spiroborate esters in the borane-mediated asymmetric synthesis of pyridyl and related heterocyclic alcohols

The effectiveness of several spiroborate ester catalysts was investigated in the asymmetric borane reduction of 2-, 3-, 4-acetylpyridines under different reaction conditions. Highly enantiomerically enriched 1-(2-, 3- and 4-pyridyl)ethanols and 1-(heterocyclic)ethanols were obtained using 1 to 10% catalytic loads of the spiroborate 5 derived from diphenylprolinol and ethylene glycol.     

One-step, synthesis of Hantzsch esters and polyhydroquinoline derivatives in fluoro alcohols

Hantzsch 1,4-dihydropyridine, polyhydroquinoline and 1,8-dioxodecahydroacridines derivatives were synthesized in excellent yields in trifluoroethanol (TFE). The solvent (TFE) can be readily separated from reaction products and recovered in excellent purity for direct reuse.     

Cp2TiCl2-catalyzed grignard reactions. 3. Reactions with esters: Efficient methodology for the synthesis of secondary alcohols and for the reduction of esters to primary alcohols

Cp₂TiCl₂-catalyzed Grignard reactions with esters provide general methodology for preparation of secondary alcohols or for reduction of esters to the corresponding primary alcohols.     

Ruthenium catalyzed transformation of alcohols to esters and lactones

Homogeneous catalytic oxidative condensation of alcohols and diols to their corresponding esters and lactones has been accomplished using RuH₂(PPh₃)₄.     

Synthesis of fluorine-containing esters of 2,5-furandicarboxylic acid

Fluorinated esters of 2,5-furandicarboxylic acid have been synthesized starting from 2,5-furan dicarboxylic acid dichloride and fluorine-containing diols. The reaction control was performed by means of ¹H, ¹⁹F NMR, and IR-spectroscopy. Thermal stability, as well as glass transition temperature, and intrinsic viscosity parameters of the obtained oligomers have been determined.