A new family of immonium-type coupling reagents is described here. The differences in the carbocation skeletons of these reagents can be correlated with differences in stability and thus reactivity. The dihydroimidazole derivatives are highly unstable to air, whereas the salts derived from dimethylamine are the most stable and the pyrrolidino derivatives are of intermediate stability. These results should be taken into account mainly when coupling reagents are depositedThe activation of a carboxylic acid for the formation of an amide bond is usually carried out using the so-called peptide coupling reagents.[2] During the last decade there has been an evolution in the development of new activation methods and their application to both solution and solidScheme 1.[ ‡] For abbreviations see ref.[ in open vessels, such in some automatic synthesizers. As regards both coupling yield and retention of configuration, HOAt derivatives have been confirmed to be superior to those of HOBt in all cases. For peptides containing hindered residues, fluoroformamidinium salts are more convenient than the HOAt-based reagents.

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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.

Et 3 N / DMF 9 X= O; R 3 = R 4 = -CH 3 ; 13a X= O; R 3, R 4 = -(CH 2 ) 4 ; 13b X= O; R 3, R 4 = -(CH 2 ) 5 ; 13c X= NH; R 3 = R 4 = -CH 3 ; 14a X= NH; R 3, R 4 = -(CH 2 ) 4 ; 14b X= NH; R 3, R 4 = -(CH 2 ) 5 ; 14c X= S; R 3 = R 4 = -CH 3 ; 15a X= S; R 3, R 4 = -(CH 2 ) 4 ; 15b 13-15Cl PF 6 R 1 = R 2 = R 3 = R 4 = -CH 3 ; 1a R 1 ,R 2 = R 3, R 4 = -(CH 2 ) 4 ; 1bA Reaction involving chloroformamidinium salts (TCFH 1a, BTCFH 1b, DmCFH 1c, DmPCFH 1d, BPCFH 1e) and 2-aminophenol 9a, benzene-1,2-diamine 9b, and 2-aminothiophenol 9c afforded 2-aminobenzoxazole 13, 2-aminobenzoimidazole 14, and 2-aminobenzothiazole 15 derivatives, respectively as major products, due to the in situ heterocyclization with dimethylamine acting as the better leaving group. Attempts for preparation of 13-15 from the reaction of N,N-dimethyl carbomyl chloride 16 with 2-aminophenol 9a, benzene-1,2-diamine 9b, and 2-aminothiophenol 9c were unsuccessful, and gave the unexpected products benzoxazol-2-ol 18a, benzoimidazol-2-one 18b, and S-(2-amino-phenyl) N,Ndimethylthiocarbamate 19 respectively. On the other hand reaction of chloroformamidinium salts 1a-e with 3-benzyl-2-hydrazinoquinoxaline 3 and 1-hydrazinophthalazine hydrochloride 4 in the presence of triethylamine as a base, afforded the [1,2,4]triazolo derivatives 6 and 7 respectively in good yield and purity. These triazole derivatives were formed due to the strong tendency towards heterocyclization and substitution of dimethylamine group as a better leaving group.

Condensation reactions O 0120TFFH as a Useful Reagent for the Conversion of Carboxylic Acids to Anilides, Hydrazides and Azides. -TFFH is found to be an excellent reagent for the activation of carboxylic acids, which are converted into anilides (III), hydrazides (V) and azides (VII) in high yields. -(EL-FAHAM*, A.; ABDUL-GHANI, M.; Org. Prep. Proced.