Carboxylic acid amide fluorides

Amino groups bound to sulfur can be replaced by fluorine via diazotization. In contrast to carboxylic acid amides, fluorodediazoniation of aromatic sulfonamides IS readily accomplished to give sulfonyl fluorides in high yields [52, 7S (equation 16) Tetrazotization-fluorination of sulfanilamide can also be effected to give a 38% yield of p-fluorobenzenesulfonyl fluoride [52],... 

Many aldehydes and ketones have been converted to g m-difluoro compounds with sulfur tetrafluoride (SF4), " including quinones, which give 1,1,4,4-tetra-fluorocyclohexadiene derivatives. With ketones, yields can be raised and the reaction temperature lowered, by the addition of anhydrous HF. Carboxylic acids, acyl chlorides, and amides react with SF4 to give 1,1,1-trifluorides. In these cases the first product is the acyl fluoride, which then undergoes the ge i-difluorination reaction ... 

The acid fluoride (3 mmol), obtained from the carboxylic acid and cyanuric fluoride, and TBA-F (5 mg, 0.02 mmol) are added to the silylamine (3 mmol) in MeCN (5 ml) under N2 and the solution is stirred for 6 h at room temperature. The solvent is removed under reduced pressure and the residue is taken up in CH2Cl2. The organic solution is washed with aqueous NaHCO, (5%, 2 x 10 ml), aqueous HCI (4M, 2 x 10 ml) and H20 (20 ml), dried (Na2S04), and evaporated to yield the amide (>75%). 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

The enantiomeric synthesis of rranj-3,4-disubstituted tetrahydrothiophenes using a sulfur ylide cycloaddition has been reported <990L1667>. The sulfur ylide derived from the action of cesium fluoride on sulfide 111 underwent an asymmetric cycloaddition with chiral a,p-unsaturated camphorsultam amide 112 giving tetrahydrothiophene 113 (80% de). The configuration was confirmed by cleavage of the chiral auxiliary followed by reductive desulfurization with Raney-Ni which gave known carboxylic acid 114. 

With BF3 and PF5, SF5NH2 forms 1 1 adducts (183). Reaction occurs at room temperature between SF5NH2 and various acid chlorides and fluorides containing electron-deficient carbonyl groups to produce iV-pentafluorosulfanyl amides, F5SNHC(0)R (R = F, CF3, CH3) (149). The reaction of SF5NCO with certain carboxylic acids at room temperature provides an alternate route for the preparation of amides, SF5-... 

Cyclic anhydrides react well with trimethyl(trifluoromethyl)silane however, a stoichiometric amount of tctrabutylammonium fluoride is required. - For example, succinic anhydride undergoes efficient addition of trimethyl(trifluoromethyl)silane to initially form an adduct, which upon hydrolysis aflbrds the trifluoromethyl-substiluted 0x0 carboxylic acid 27. Simple amides, such as benzamide and acetamide, do not react with trimetliyl(trifluoromethyl)silane even when a molar quantity of tetrabutylainmonium fluoride is used. Furthermore, lactams, such as caprolactam, do not react with trimethyl(trifluoromethyl)silane under similar conditions. An activated amide carbonyl, such as that in A -methylsuccinimide. however, reacts smoothly to afford an interesting adduct, which upon acid hydrolysis affords the hcmiaminal 28. 

Review. New synthetic reactions based on the onium salts of aza-arenes have been reviewed (75 references). The reactions discussed involve activation of carboxylic acids or alcohols with 2-haIopyridinium, benzoxazolium, benzothiazolium, and pyridinium salts to afford 2-acyloxy or 2-alkoxy intermediates, which can be transformed into esters, amides, thiol esters, (macrocyclic) lactones, acid fluorides, olefins, allenes, carbodiimides, isocyanates, isothiocyanates, and nitriles under appropriate conditions. 

Carboxylic acid fluorides are more stable to water and other nucleophiles. They are readily prepared by the use of cyanuric fluoride and converted to amides by siiylated amines. In contrast to the chlorides, protected amino acid fluorides exert virtually no racemization in peptide coupling. ... 

Activation of aliphatic and aromatic carboxylic acids with sulfuric acid derivatives yields amides (Table 3). Sulfuryl chloride fluoride and primary amines or chlorosulfonyl isocyanate and secondary amines are used as reaction partners. 

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