Tetramethylfluoroformamidinium hexafluorophosphate (TFFH)/benzyltriphenylphosphonium dihydrogen trifluoride (PTF): a unique reagent for the conversion of carboxylic acids to the corresponding alcohols as well as hydroxamic acids

Abstract

The present work describes the utility of TFFH (1) for the conversion of carboxylic acids to the corresponding alcohols 4 as well as the hydroxamic acids 5 in the presence or absence of the fluoride additive PTF (3). The addition of the fluoride additive 3 during the activation step improves the yield and purity of the products, due to the fast activation to the acid fluoride derivatives as observed from IR examination.

Amino acid fluorides: viable tools for synthesis of peptides, peptidomimetics and enantiopure heterocycles

“…Beginning with cyanuric uoride (C 3 F 3 N 3 ) 45, 46 (1) and followed quickly by Carpino's TFFH 47,48 (2), an array of uorinating reagents are now available (Fig. 1).…”

Utilization of N,N,N′,N′-Tetramethylfluoroformamidinium Hexafluoro­phosphate (TFFH) in Peptide and Organic Synthesis

“…More interestingly, conversion of the acid into the acid fluoride was also observed upon treatment with N,N¢-dicyclohexylcarbodiimide (DCC, 18), diisopropylcarbodiimide (DIC, 19) (Figure 6), N-HATU (14), or N-HBTU (15) in the presence of the additive PTF (16). 27,28 Figure 6 Because the fluoride additive binds excess hydrogen fluoride as part of the complex dihydrogen trifluoride anion, an accompanying acidic buffering effect might prove to be of value in the case of coupling reactions where loss of configuration at the activated carboxylic acid residue might be important. Such a protective effect was in fact observed in the case of the sensitive histidine derivative Fmoc-His(Trt)-OH upon reaction with proline amide, which with TFFH/DIPEA under ordinary conditions gave the desired dipeptide in good yield with 7.4% stereomutation; in the presence of additive 16, stereomutation dropped to 1.8%.…”

“…27 Presumably, this technique can also be used to improve conversion into the isolable acid fluorides. 28…”

“…Addition of the fluoride additive (PTF) avoids symmetric anhydride formation and allows maximum formation of the acid fluoride. 27,28 12.5 Preparation of 2-Aminobenzimidazole, 2-Aminobenzoxazole, and 2-Aminobenzothiazole Derivatives 68 Formamidinium salts have been mainly used as coupling reagents in peptide synthesis by activation of the carboxyl group of the amino acid; however, during the much slower activation of hindered amino acids, protected peptide segments, or carboxylic acids involved in cyclization, the formamidinium salts may undergo reaction with the amino component to give the corresponding guanylated derivatives. 69 Recently, advantage was taken of this side reaction which was used for the synthesis of 1,1,3,3tetrasubstituted 4-aminoguanidines 65, as well as the [1,2,4]triazolo derivatives 67 and 69 70 (Scheme 17).…”

The synthesis of Nα-protected amino hydroxamic acids from Nα-protected amino acids employing versatile chlorinating agent CPI-Cl

“…For this purpose, activation of carboxylic acids via converting them to acid halides were achieved using thionyl chloride (SOCl2), 10 and tetramethylfluoroformamidinium hexafluorophosphate (TFFH) and benzyl triphenylphosphonium dihydrogen trifluoride (PTF). 11 Hydroxamic acids have been prepared by coupling mixed anhydride, obtained by the addition of carboxylic acid and ethyl chloroformate, with hydroxylamine. 7,12 Other coupling reagents like cyanuric chloride, 13 N, N'-carbonyldiimidazole (CDI), 14 1-[(1-(cyano-2ethoxy-2-oxoethylidenaminooxy)-dimethylamino-morpholinomethylene)] methaneaminium hexafluorophosphate (COMU), 15 propanephosphonic acid anhydride (T3P), 16,17 and ethyl-2-cyano-2-(4nitrophenylsulfonyloxyimino)acetate (NBsOXY), 18 were also employed to obtain hydroxamic acids from their corresponding carboxylic acids.…”