Preparation of fluoroolefins

Horner-Emmons. Fluorophosphono dithioacetate (34) in the preparation of fluoroolefin peptide isostere precursors... 

Methyl fluoro(diethoxyphosphono)dithioacetate (34) has been prepared from difluorinated precursors [56], Fluorophosphonothioacetamides (35) derived from this dithioester, have been successfully transformed into highly functionalized fluoroalkenes (36). Judicious selection of the aldehyde coupling partner can lead expeditiously to the preparation of fluoroolefin dipeptide isosteres following elaboration of the carboethoxy group and desulfurization (Scheme 11). 

Nickel fluoride is used in marking ink compositions (see Inks), for fluorescent lamps (4) as a catalyst in transhalogenation of fluoroolefins (5), in the manufacture of varistors (6), as a catalyst for hydrofluorination (7), in the synthesis of XeF (8), and in the preparation of high purity elemental fluorine for research (9) and for chemical lasers (qv) (10). 

The direct chlorination of hydrofluorocarbons and fluoroolefins has also been used commercially, eg, in the preparations of CH2CCIF2 from CH2CHF2 and CCIF2CCIF2 from tetrafluoroethylene. 

The importance of solvent effects in the preparation of perfluoroalkyzinc reagents is further illustrated in the reaction of perfluoroalkyl iodides with zinc-copper couple. In DMSO, DMF, and HMPA, the main products are the fluo-roolefins The formation of the fluoroolefin is facilitated when the reaction is carried out in the presence of potassium thiocyanate [30] (equation 21)... 

Fluorinated cyclobutanes and cyclobutenes are relatively easy to prepare because of the propensity of many gem-difluoroolefins to thermally cyclodimerize and cycloadd to alkenes and alkynes. Even with dienes, fluoroolefins commonly prefer to form cyclobutane rather than six-membered-ring Diels-Alder adducts. Tetrafluoroethylene, chlorotrifluoroethylene, and l,l-dichloro-2,2-difluoroethyl-ene are especially reactive in this context. Most evidence favors a stepwise diradical or, less often, a dipolar mechanism for [2+2] cycloadditions of fluoroalkenes [S5, (5], although arguments for a symmetry-allowed, concerted [2j-t-2J process persist [87], The scope, characteristic features, and mechanistic studies of fluoroolefin... 

Today microemulsions are used in catalysis, preparation of submicron particles, solar energy conversion, extraction of minerals and protein, detergency and lubrication [58]. Most studies in the field of basic research have dealt with the physical chemistry of the systems themselves and only recently have microemulsions been used as a reaction medium in organic synthesis. The reactions investigated to date include nucleophilic substitution and additions [59], oxidations [59-61], alkylation [62], synthesis of trialkylamines [63], coupling of aryl halides [64], nitration of phenols [65], photoamidation of fluoroolefins [66] and some Diels-Alder reactions. 

The preparation of the fluoroolefin amide isosteres is reviewed. The incorporation of the amide isosteres in peptidomimetics and the influence of that isosteric substitution on biological activity on inhibition of peptidyl prolyl isomerases cyclophilin (CyP) and Pini, dipeptidyl peptidase IV/CD26 (DPP IV) and thermolysin is described. In addition, select fiuoroolefination procedures which may have utility in the construction of fluoroolefin amide isosteres are illustrated. 

The synthesis and utility of fluoroolefin peptide isosteres has previously been reviewed [45], The fluoroolefin isostere preparations summarized below are organized by the synthetic method employed to introduce the fluoroolefin rather than by the dipeptide isostere formed. 

The preparations of Glyi/r[CF=CH]Gly (4) and Phei/r[CF=CH]Gly (5) were described by Allmendinger and his coworkers [46,47]. The Gly-Gly fluoroolefin dipeptide isostere (4) was synthesized from cyclic acetal (6), obtained by the procedure of Dehmiow [48] involving a carbene insertion and reexpansion reaction. Further elaboration as detailed in Scheme 1 ultimately afforded the A/-protected amino acids (4). 

The potential utility of peptides as therapeutics with clinical applications is limited by its metabolic instability or poor transmembrane mobility. Consequently, the preparation of metabolically stable peptide analogs that can either mimic or block the function of natural peptides or enzymes is an important area of medicinal chemistry research. Synthesis of fluoroolefin amide isosteres, its incorporation in peptidomimetics, and the influence of that isosteric substitution on the inhibition of several enzymes such as peptidyl prolyl isomerases, dipeptidyl peptidase IV, and thermolysin is described. Moreover, protein folding and activity... 

Progress in the preparation and isolation of different hypohaiites [92] results in a substantial number of publications exploring the addition of these materials to fluoroolefins. In contrast to addition of hypofluorites, which at this time is viewed as a radical process, a polar mechanism was proposed for addition of poly-fluorinated hypochlorites and hypobromites to olefins. Reactions of fluoroolefins... 

Indeed, free radical polymerization of fluoroolefins continues to be the only method which will produce high-molecular weight fluoropolymers. High molecular weight homopolymers of TFE, CFC1 = CF2, CH2CF2, and CH2=CHF are prepared by current commercial processes, but homopolymers of hexafluoro-propylene or longer-chain fluoroolefins require extreme conditions and such polymerizations are not practiced commercially. Copolymerization of fluoroolefins has also led to a wide variety of useful fluoropolymers. Further discussion of the subject of fluoroolefin polymerization may be found elsewhere and is beyond the scope of this review [213-215]. 

Treatment of methyl phenyl sulfoxide with diethylaminosulfur trifluoride (DAST), in the presence of antimony trichloride provides 159 in quantitative yield (66). The reaction proceeds in good yield with dialkyl sulfoxides and alkyl aryl sulfoxides (163). Reoxidation of the a-fluorosulfide (165) to the corresponding sulfoxide (161), followed by pyrolysis, provides a direct synthesis of fluoroolefins (65). The reaction is believed to proceed by a Pummerer-type mechanism (l.e., a fluoro-Pummerer reaction, Scheme 48). Similarly, Umemoto (67) reported that N-fluorocollidine (167) converted sulfides to ot-fluorosulfides (170) presumably via an S-fluorosulfonium cation species 168 (Scheme 49). The synthetically challenging fluorovinyl ether nucleosides (175) and (176) were prepared using the fluoro-Pummerer reaction (Scheme 50) (60) the (E)-isomer (175) could be isomerized to 176 under photolytic conditions. Finch and co-workers (69) converted 160 to the sulfoximine 178 and demonstrated the utility of this compound as a mild fluoromethylene synthon (Scheme 51). Base-catalyzed condensation 178 with a carbonyl compound gave 179 which afforded... 

Two general routes to a new class of dipeptide mimics, the fluoroolefin dipeptide isosteres, will be presented. They allow the preparation of compounds of formula 2 with a wide variety of residues R, and r3 in racemic or enantiomerically pure form. Some of the mimics have been introduced into small peptides of biological interest. Some preliminary results will also be discussed. 

By comparison of the calculated electrostatic potentials (77) of trans-2-butene and 2-fluoro-2(Z)-butene with N-methyl acetamide as simple models of the peptidic bond and its isosteres (see figure 1) the fluoroolefin clearly is the better replacement of the amide bond, since it not only mimics its steric but also, at least in part, its electronic feature. Calculating dipole moments Abraham (73) came to similar results, but attempts to synthesize the corresponding dipeptide isostere 2 have been until now unsuccesful (14). As part of our ongoing program in fluoroorganic chemistry we developed two general methods for the preparation of these compounds. 

This synthesis can be easily adopted for the preparation of chiral material. Corresponding intermediates have already been obtained, as outlined in scheme 4. Yeast reduction of ethyl 2-oxocyclopentanecarboxylate (25) afforded the optically pure hydroxyester (+)-13, which was further transformed to the (S)-2-silyloxymethyl cyclopentanone (-)-8 according to scheme 4. Fluoroolefination and reduction gave optically active (-)-14, which can be used for the preparation of the optically pure (S,S)- and (R,S)-diasteieomers of the Phe-Pro mimic. 

We have established two routes to a new class of peptide mimics, the fluoroolefin dipeptide isosteres. By appropriate selection of the precursors they allow the preparation of anaolgues of dipeptidic combinations of aminoacids bearing no other functionalities in their side chains, e.g. Gly, Ala, Val, Phe, Pro. 

However, they are too slow to react with 9-BBN. Catecholborane and pinacolborane react with fluoroolefins in the presence of a transition metal catalyst. However, reactive boranes, such as dichloroborane-methyl sulpfide readily react with mono, and disubstituted terminal perfluoroaUcenes in the presence of BCI3. The latter coordinates to Me2S and releases the free dichloro-borane, which instantaneously hydroborates theperfluoroalkenes. Oxidation under alkaline conditions furnishes the primary alcohol in >98% regioselectivity (eq 8). Alternatively, the free dichloroborane prepared via Matteson s protocol can also be used for the hydroboration of fluoroolefins. 

Fluorinated tertiary selenoetheis are prepared by reaction of branched per-fluoroolefins with an alkali metal fluoride and phenylselenenyl chloride 1S2] (equation 31)... 

Fluonnated ylides have also been prepared in such a way that fluonne is incorporated at the carhon P to the carbamonic carbon Vanous fluoroalkyl iodides were heated with tnphenylphosphine in the absence of solvent to form the necessary phosphonium salts Direct deprotonation with butyUithium or hthium dusopropy-lamide did not lead to yhde formation, rather, deprotonation was accomparued by loss of fluonde ion Flowever deprotonation with hydrated potassium carbonate in thoxane was successful and resulted in fluoroolefin yields of45-S0% [59] (equation 54) P-Fluorinated ylides may also be prepared by the reaction of an isopropyli-denetnphenylphosphine yhde with a perfluoroalkanoyl anhydnde The intermediate acyl phosphonium salt can undergo further reaction with methylene tnphenylphosphorane and phenyUithium to form a new yhde, which can then be used in a Wittig olefination procedure [60] (equation 55) or can react with a nucleophile [6/j such as an acetyhde to form a fluonnated enyne [62] (equation 56)... 

Fluoroolefins may he prepared by the reaction of Wittig reagents and other pho sphorus-containtng y tides with fluorinated carbonyl compounds. (A discussion of the fluorinated Wittig reagents or other fluonnated phosphorus reagents with nonfluorinated carbonyl compounds is on page 581.) Tnphenylphosphoranes, derived from alkyltriphenyl phosphonium salts, react with 1,1,1-trifluoroacetone [3/] or other trifluoromethyl ketones [32, iJ] (equation 26) (Table 10). 

Horner-Emmons. The use of 2-fluoro-2-diethylphosphonoacetic acid (41) or acylfluorodiethylphosphonoacetate to prepare fluoroolefin dipeptide isostere precursors (42)... 

Alai/r[(Z)-CF=C]-Pro containing N, 0-diacylhydroxamic acid type protease inhibitors have been prepared as shown in Scheme 18 [63,64], The synthesis is based upon the use of fert-butyl-a-fluoro-trimethylsilylacetate in a variation of the Peterson olefination procedure to construct the necessary functionalized fluoroolefin. Treatment of 51 with 4 equiv. of lithium diisopropylamide (LDA) and 6equiv. of chlorotri-methylsilane at 78°C formed 52 in 71% yield. The key step is the Peterson olefination reaction of the TBDMS-protected 2-(hydroxymethyl)cyclopentanone (53) with tert-butyl-a-fluoro-a-trimethylsilylacetate (52). The fluoroolefin product was obtained as a mixture of (Z) (E) isomers (54). Separation of the double-bond isomers by column chromatography provided (Z) isomer (54) in 43% yield. Further... 

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