Ex Situ Generation of Difluorodiazoethane (CF₂HCHN₂): Application in the Regioselective Synthesis of CF₂H-Containing Pyrazoles

Abstract

A new method for the ex situ generation of difluorodiazoethane (CF2HCHN2) and a procedure for its efficient use in [3 + 2] cycloaddition with nitroolefins by the AcOH/O2 catalyst system were developed by using a simple two-chamber system. The method provides a facile and straightforward access to a series of 4-substituted 5-difluoromethyl-3-nitro-1H-pyrazoles that are of interest in medicinal chemistry. Interestingly, the key factor for the success of this method is the efficient preparation of CF2HCHN2 by an ex situ process.

Fluorinated Pyrazoles: From Synthesis to Applications

“…In 2019, Han and Chen developed a one-step approach to difluoromethyl-substituted pyrazoles from gaseous CF 2 HCHN 2 and nitroalkenes (Scheme 13). 56 First, the authors generated CF 2 HCHN 2 ex situ from 69 and then transferred the gaseous reagent into another chamber containing a solution of the nitroalkene in dioxane and an external balloon with oxygen. The [3 + 2] cycloaddition was performed under heating, whereby the intermediate pyrazoline was directly oxidized with oxygen to give the final difluoromethylated pyrazole.…”

Diazotrifluoroethyl Radical: A CF3-Containing Building Block in [3 + 2] Cycloaddition

“…As shown in Figure a, CF 3 CHN 2 , with three resonance structures ( A , B , and C ), is a versatile building block widely used as a metal carbene precursor, 1,3-dipole, C -nucleophile, and N -electrophile. Compared with the extensively utilized CF 3 CHN 2 , the diazotrifluoroethyl radical [ D , CF 3 C­(·)­N 2 ], the trifluoroethylcarbyne (CF 3 CĊ:) equivalent from hypervalent iodine­(III) reagent 2 pioneered by Suero in 2018, remains rarely exploited (Figure b). − With our continuing interest in the assembly of fluorine-containing molecules and heterocycles, we wondered if [CF 3 C­(·)­N 2 ] could act as an unusual CF 3 -containing building block for the construction of CF 3 -containing heterocycles.…”

Recent Progress in the Application of Difluoromethyl Diazomethane as Fluorine-Containing Building Block

“…(1)由于 47 还原性较弱, 反应中需添加强还原剂锌粉使 Fe(III)还原为 Fe(II); (2)过量的锌粉会分解 47, 降低产 率. 该团队 [42] 4)仅通过原位 [19] 和非原 位 [29] 方式制备, 且由于反应过程中迅速生成的大量二 氟甲基重氮甲烷(4)会积聚于反应器中, 该制备方法存 在着一定的安全隐患. 2020 年, 毕锡和团队 [48]…”

“…直到 2015 年, Mykhailiuk [19] [24] ; (2)在甲苯中回流 2 h 后, 18 可进一步脱去一分子氮气转化为含有二氟甲基的螺 环丙烷氧化吲哚类化合物 19, 值得注意的是, 该类化合 物对前列腺癌(PC-3)和人非小细胞肺癌细胞(A549)的生 长有一定的抑制作用, 且该方法可用于合成一种 HIV-1 NNRTI 抑制剂类似物 [25] ; (3)以四氢呋喃(THF)为溶剂时, [26] ; (4)以乙 [27] . [29] .…”