Metal-Free Difunctionalization of Pyridines: Selective Construction of N-CF₂H and N-CHO Dihydropyridines

Abstract

The reactivity of N-difluoromethylpyridinium salts is seldom explored because of their instability and low availability. Here we present a novel nucleophilic addition of N-difluoromethylpyridinium salts with nitroalkanes to synthesize N-CF2H-dihydropyridines and N-CHO-dihydropyridines in a highly efficient and regioselective pathway. This protocol exhibits good functional group tolerance and good to excellent yields.

Site‐Selective 1,4‐Difunctionalization of Nitrogen Heteroaromatics for Constructing Vinylidene Heterocycles

“…A plausible mechanistic pathway, which is based on recent literature reports [7,18] and control experiment (SI, Scheme S1), is shown in Scheme 2. First, quinoline reacts with benzyl bromide to form a N‐alkylazaarene zwitterionic species 4 A‐1 .…”

“…The reaction was performed with a 1:10 ratio of product 4 a (0.2 mmol): Et 3 SiH and 10 mol% B(C 6 F 5 ) 3 in the open air at 100 °C for 16 h. Effective reduction of the nitro group and C=C double bond were achieved (Table 6b). A plausible mechanistic pathway, which is based on recent literature reports [7,18] and control experiment (SI, Scheme S1), is shown in Scheme 2. First, quinoline reacts with benzyl bromide to form a N-alkylazaarene zwitterionic species 4 A-1.…”

“…[5] The synthesis of C4substituted N-heterocycles is limited because functionalization occurs preferentially at the electrophilic C2 position of the azaarene when adding organometallic reagents to pyridinium and quinolinium species. Although several research groups have recently made notable advances in the synthesis of C4-substituted Nheterocycles, most of the reported methods have one of the following disadvantages: a pre-activated substrate, [6] limited substrate scope, [7] multi-step operation, [8] use of metal catalysts, [9] and use of organic solvents [10] (Scheme 1).…”

In silico reaction screening with difluorocarbene for N-difluoroalkylative dearomatization of pyridines

“…Pyridines 2a and 2b, which bear a more nucleophilic nitrogen atom on their structures than those of the imines, exhibited low barriers (1.0 and 1.3 kcal mol −1 , respectively) that are comparable to that of difluorocarbene dimerization. Encouraged by these calculations and by previous reports using pyridines and difluorocarbene 40,41 , we conducted the reaction with 2a, which resulted in an N-difluoroalkylative cycloaddition that involves the dearomatization of the pyridine skeleton to provide the desired fluorinated heterocyclic compound in 70% yield in the crude mixture 42 . However, despite intensive attempts, the product could not be isolated, presumably due to the elimination of the fluoride assisted by the nitrogen atom, which would trigger its further decomposition.…”

Direct Synthesis of N-Difluoromethyl-2-pyridones from Pyridines

“…Due to the difficulty in preparation, the subsequent conversion of N -difluoromethylpyridinium salts is greatly limited. Until now, only a few examples about the synthesis of N -difluoromethylpyridinium salts were reported . In 2020, Marchán et al.…”