Chloroformamidinium salts: Efficient reagents for preparation of 2‐aminobenzoimidazole, 2‐aminobenzoxazole, and 2‐aminobenzothiazole derivatives

Abstract

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.

N‐methylation in amino acids and peptides: Scope and limitations

“…The same group synthesized MeLeu‐MeLeu‐MeVal, which was presented in cyclosporine as a model peptide, and described the superiority of HATU‐HOAt over HBTU‐HOBt (85% vs. 8% of purity of the final product). Extension of the HOAt‐based coupling reagents was shown using 1‐(1‐pyrrolidinyl‐1 H ‐1,2,3‐triazole[4,5‐ b ]pyridin‐1‐ylmethylene) pyrrolidinmiumhexafluoro phosphate N ‐oxide (HAPyU) and [(7‐azabenzotriazol‐1‐yl)oxy]tris(pyrrolidino) phosphoniumhexafluorophosphate (PyAOP) . These results were further supported by Rich's group and Sapia et al In another report, Dechantsreiter et al described the successful synthesis of N ‐methylated cyclic RGD peptide analogs using the HATU‐HOAt Fmoc‐strategy …”

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

“…In these cases, the intermediate guanidine undergoes heterocyclization to give the corresponding [1,2,4]triazolo derivatives 67 and 69 71,72. Similar reactions occur in the case of o-substituted anilines, such as 2-aminophenol (70a), benzene-1,2-diamine (70b), and 2-aminothiophenol (70c), which give 2-aminobenzoxazole, 2-aminobenzimidazole, and 2-aminobenzothiazole derivatives 73a, 73b, and 73c, respectively (Scheme 18) 68. Compounds 73 could be formed by two alternative routes (A or B), depending on the nucleophilicity of substituent X.…”

“…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).…”

“…71,72 Similar reactions occur in the case of o-substituted anilines, such as 2-aminophenol (70a), benzene-1,2-diamine (70b), and 2-aminothiophenol (70c), which give 2aminobenzoxazole, 2-aminobenzimidazole, and 2-aminobenzothiazole derivatives 73a, 73b, and 73c, respectively (Scheme 18). 68 Compounds 73 could be formed by two alternative routes (A or B), depending on the nucleophilicity of substituent X. For route A, if X = S it is more nucleophilic than the aniline nitrogen atom, and X attacks the central carbon atom of the formamidinium salt to give an intermediate which then undergoes in situ heterocyclization with the loss of dimethylamine from intermediate 71 to give product 73c.…”

Molecular structure and DFT investigations on new cobalt(II) chloride complex with superbase guanidine type ligand

“…The ligand (btmgn) was prepared by reaction of TCFH and 1,8-diaminonaphthalene using DMF as a solvent and following the reported method for preparation of guanidine using TCFH 25 (scheme 1). The NMR spectra are presented in figure S1 (Supplementary Information).…”