Acyl fluorides synthesis

SCHEME 7.106 Acyl fluoride synthesis from aryl bromides [171]. 

Pubhcations have described the use of HFPO to prepare acyl fluorides (53), fluoroketones (54), fluorinated heterocycles (55), as well as serving as a source of difluorocarbene for the synthesis of numerous cycHc and acycHc compounds (56). The isomerization of HFPO to hexafluoroacetone by hydrogen fluoride has been used as part of a one-pot synthesis of bisphenol AF (57). HFPO has been used as the starting material for the preparation of optically active perfluorinated acids (58). The nmr spectmm of HFPO is given in Reference 59. The molecular stmcture of HFPO has been deterrnined by gas-phase electron diffraction (13). 

Recently a very mild method was discovered for the synthesis of dinucleoside fluorophosphates in the conversion of a dinucleoside phosphite with iV V -oxalyldiimi-dazole into the corresponding phosphoric imidazolide, which is then treated with acyl fluoride [204] <202]... 

Olah Nojima Kerekes Synthesis 1973, 487. For other methods of preparing acyl fluorides, see Mukaiyama Tanaka Chem. Lett. 1976, 303 Ishikawa Sasaki Chem. Lett. 1976, 1407,... 

There is considerable promise for the synthesis of useful functionalized fluorocarbon materials using other direct fluorination techniques (46), such as the fluorination of pendant polyesters and polymers containing pendant acyl fluoride units. 

Tetrafluoroethene has been used as a 2-carbon difluoroacetic acid equivalent, methodology developed by Normanl and co-workers, in the synthesis of inhibitors of Cobra venom phospholipase A2.13 Conversion of the allyl alcohols into the 2,2-difluoropent-4-enoic acids 32 is performed in one pot. The crude acids 32 are then converted into the methyl esters 33. Although esters 33 can be obtained directly from the acyl fluorides 29, as originally described by Normant and co-workers,10 a two-step procedure facilitates the workup after the Claisen rearrangement. 

A very reactive halogen atom, such as that of mi acyl or sulfonyl halide, is replaced by fluorine by the action of almost any inorganic fluoride. The most convenient method consists in heating gently a mixture of an acyl or sulfonyl chloride with zinc or antimony fluoride in an apparatus which permits the acyl fluoride to distil as it is formed. The acyl fluoride usually boils about 40° lower than the chloride, and its removal from the reaction mixture results in quantitative yields. Com- plete interchange also can be effected with hydrogen fluoride, but more elaborate equipment is required. Good results have been reported for the synthesis of formyl and acetyl fluorides from mixtures of fonnic or... 

Alternatively, acid fluorides are used to activate the acid. Acyl fluorides are less sensitive to moisture and are more reactive toward primary and secondary amines than the corresponding acyl chloride. Furthermore, they are compatible with basic- (Fmoc and Cbz) or even acid- (Boc) labile amine protecting groups and less prone to promote racemization than their chlorinated homologs (26). Thus, the acid fluoride method is often used in peptide synthesis (27). Cyanuric fluoride 9 (28), TFFH (29), DAST (30), and deoxofluor (31) are used commonly as fluori-nating reagents (see Fig. 4). 

For reactions carried out in homogeneous solution or under solid-phase conditions the use of Fmoc amino acid chlorides is limited by the competition between their aminolysis and the formation of the less reactive oxazol-5(4//)-ones in the presence of tertiary amines, which are essential components of such reaction systems. To improve the results under these conditions a hindered base, e.g. 2,6-di-/er/-butylpyridine, can be used as a hydrogen chloride acceptor since conversion to oxazol-5(4//)-one is slow with such bases. Although shown to be advantageous in certain cases, Fmoc amino acid chlorides are used in homogeneous solution synthesis only in particular cases. They react efficiently in the presence of pyridine with weak nucleophiles such as imine 2P l (Scheme 2) where other activated species such as an active ester, anhydride, acyl fluoride, and acyl imidazolide fail. 

Synthesis of trifluoromethylated compounds 152 has been achieved via ester-enolate [2,3]-Wittig and [3,3]-lreland-Claisen rearrangements. Perfluorocyclo-butane phosphonium ylides, e.g. 153, have been used as a masked fluoride anion source in their reactions with alcohols and carboxylic acids which lead to alkyl-and acyl-fluorides. Ylides 153 are also reported to cleave Si-C and Si-O bonds, cause dimerisation of fluoro-olefins, and also react with acid chlorides or other activated aromatic compounds under halogen exchange. ... 

Generation of acyl fluorides of the protected amino acids and the in situ coupling for the peptide synthesis have been achieved by the use of fluoroformamidium salts, a new class of coupling reagents. Both 5 and 6 are easily prepared, and are nonhygroscopic, stable to handling under ordinary conditions, but reactive enough to transform carboxylic acids 8 to acyl fluorides 9 under very mild conditions, which can be coupled with amine 10 [4, 5],... 

The use of an acyl chloride in the presence of aluminum chloride constitutes the most frequently used type of Friedel-Crafts ketone synthesis. Many examples from the earlier literature are reported in the reviews mentioned at the beginning of this chapter.The reactivity of acyl halides in reactions of acyl halides with aluminum halides decreases in the order I > Br > Cl > F, but a different order was report for reactions catalyzed by boron halides. In the latter case the order was acyl fluoride > acyl bromide > acyl chloride. We shall concentrate our attention on recently reported examples. 

Method a is a direct synthesis and does not lead to by-products. The disadvantage is the necessity of using acyl fluorides instead or the more easily available chlorides. This, however, may be avoided, at least for some applications, by using the corresponding chloride and preparing the salt having mixed counterions. 

TFFH reagent, tetramethyl fluoroformami-dinium hexafluorophosphate, [(Me2N)2 CF]+ PF(i , a non-hygroscopic, stable salt suitable for generating acyl fluoride in situ (- Fmoc amino acid fluorides), but also applicable as coupling reagent for solution-or solid-phase peptide synthesis [L. A. Carpino, A. El-Faham, J. Am. Chem. Soc. 1995, 117, 5401]. 

Other enzymes can turn a pro-drug into an electrophile by inserting an oxygen atom. Thus the mixed function oxidases of the e.r, described in Section 3.5, can oxidize difluoromethyl derivatives of the normal substrate to give an acyl fluoride which acylates the active site of the enzyme. Thus, aromatase is the enzyme normally concerned with the synthesis of estrone from androst-4-ene-3,17-dione. The 19,19-difluoro-derivative of this substrate acts as an IMBI which, in the manner described, becomes permanently attached to the enzyme in the 19-position (Marcotte and Robinson, 1982). These authors hope that this drug will prove useful in treating breast cancer. 

Originally the monomer in Fig. 9 was prepared by DuPont by the synthetic scheme shown in Fig. 12 [33]. Thermolysis of the acyl fluoride in Fig. 12 did not give a desired monomer but gave a cyclo compound. In order to prevent the cyclization, a new synthetic route was developed as shown in Fig. 13, which was applied to the synthesis of Dow membranes [34]. A chlorine atom was introduced to the acyl fluoride to improve the selectivity of vinyl ether formation. The Dow membrane was also developed for brine electrolysis, but was not commercialized probably because of its high cost. Difficulty in the preparation of the acyl fluoride in Fig. 13 is one of the causes. Recently, new synthetic processes for the short side chain monomer were developed, as represented in Fig. 14. 

Scheme 17, Synthesis of the A -ring dichloroisoeverninic acyl fluoride building block 59.

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