Trifluoromethyl Vinamidinium Salt as a Promising Precursor for Fused β-Trifluoromethyl Pyridines

Abstract

An efficient chlorotrimethylsilane-promoted synthetic protocol for the preparation of functionalized fused β-trifluoromethyl pyridines by cyclization of electron-rich aminoheterocycles or substituted anilines with a trifluoromethyl vinamidinium salt was developed. The efficient and scalable approach for producing represented trifluoromethyl vinamidinium salt demonstrated huge prospects for further use. The structure specificities of the trifluoromethyl vinamidinium salt and their impact on the reaction progress were determined. The procedure’s scope and alternative ways of the reaction were investigated. The possibility of increasing the reaction scale up to 50 g and further modification of obtained products was shown. A minilibrary of potential fragments for 19F NMR-based fragment-based drug discovery (FBDD) was synthesized.

Water-promoted defluorinative synthesis of fluoroalkylated 1,5-diazapentadienes by using (NH4)2CO3 as an NH2 and NH source

“…Unfortunately, the reaction of (3,3,4,4,5,5,6,6,6-nonafluoro-1iodohex-1-en-1-yl)benzene (1a) with aniline (13, Scheme 2E) or o-phenylenediamine (15a, Scheme 2F) became complex, and failed to produce any monoaminated or diaminated products, reflecting the unique property of (NH 4 ) 2 CO 3 in the defluorination system. We believe that the failure is mainly attributed to the reduced nucleophilicity of aniline (13) and diamine 15a when compared to (NH 4 ) 2 CO 3 . 22 In contrast, the reactions using stronger dinucleophilic benzamidine (15b) or hydrazine (15c) smoothly proceeded to deliver the cyclized products 16b and 16c in 77% and 54% yields, respectively, which once again demonstrates that nucleophilicity of the N-source is a key factor for the success of the defluorinative transformation.…”

“…6 Indeed, the development of efficient and reliable strategies for the facile assembly of azadiene systems from easily synthesized, inexpensive, and low-toxic starting materials would be of great interest to chemists. 7–13…”

“…12 1,5-Diazapentadienes are thus readily accessible, but their synthesis is hindered by several apparent drawbacks, including distillation for purification, multistep manipulation, harsh reaction conditions, moisture exclusion, and the use of toxic/sensitive reagents, which make them less efficient in building up a congener library. Moreover, these strategies have limited flexibility in installing functional groups, especially fluorinated moieties, 13 which are known to confer unique chemical and physical features to the parent molecules.…”

“…6 Indeed, the development of efficient and reliable strategies for the facile assembly of azadiene systems from easily synthesized, inexpensive, and lowtoxic starting materials would be of great interest to chemists. [7][8][9][10][11][12][13] Classical processes to access 1,5-diazapentadienes typically relied on the condensation of 1,3-dicarbonyl compounds with amines (Fig. 1B(a)).…”

Sulfamide instead of urea in Biginelli reaction: from black box to reality

“…In such cases, DMF was successfully switched to pyridine as a solvent to avoid acidic media during isolation. 21,22 However, in the currently investigated reaction, such changes in reaction conditions did not lead to success. Therefore, we decided to keep the synthesis protocol intact and optimize the isolation procedure.…”