Use of trifluoroacetaldehyde N-tfsylhydrazone as a trifluorodiazoethane surrogate and its synthetic applications

Abstract

Trifluorodiazoethane (CF₃CHN₂), a highly reactive fluoroalkylating reagent, offers a useful means to introduce trifluoromethyl groups into organic molecules. At present, CF₃CHN₂ can only be generated by oxidation of trifluoroethylamine hydrochloride under acidic conditions; due to its toxic and explosive nature, its safe generation and use remains a prominent concern, hampering wider synthetic exploitation. Here we report the development of trifluoroacetaldehyde N-tfsylhydrazone (TFHZ-Tfs) as a CF₃CHN₂ surrogate, which is capable of generating CF₃CHN₂ in situ under basic conditions. The reaction conditions employed in this chemistry enabled a difluoroalkenylation of X-H bonds (X = N, O, S, Se), affording a wide range of heteroatom-substituted gem-difluoroalkenes, along with Doyle-Kirmse rearrangements and trifluoromethylcyclopropanation reactions, with superior outcomes to approaches using pre-formed CF₃CHN₂. Given the importance of generally applicable fluorination methodologies, the use of TFHZ-Tfs thus creates opportunities across organic and medicinal chemistry, by enabling the wider exploration of the reactivity of trifluorodiazoethane.

Fig. 1

Generation and transformations of trifluorodiazoethane, and synthesis of TFHZ-Tfs. a Synthesis and applications of trifluoromethyldiazomethane (CF₃CHN₂) in organic synthesis. CF₃CHN₂ is a highly reactive trifluoroalkylation reagent, but its simplex synthesis method, inherent toxicity and explosiveness limit its widespread application. Because of its hazardous nature, manifold methods have been developed for the safer use of CF₃CHN₂ such as slow addition of oxidants, small-scale preparation of CF₃CHN₂ solution, recycling of gaseous CF₃CHN₂ and continuous-flow chemistry. b Method for the generation of CF₃CHN₂ from trifluoroacetaldehyde N-tfsylhydrazone under basic condition and gem-difluoroalkenylation of X–H

Fig. 2

Optimization of the iron-catalyzed gem-difluoroalkenylation of p-methylthiophenol with trifluoromethyl sulfonylhydrazones. Reaction conditions: thiophenol (0.3 mmol), sulfonylhydrazone (0.6 mmol), Fe porphyrin catalyst, SDBS (sodium dodecylbenzenesulfonate) (0.09 mmol), DCM (1.0 mL), and KOH solution (5.0 mL, 20% wt %), 40 °C, 18 h, under air. ^aYields determined by ¹H NMR spectroscopic analysis with CH₂Br₂ as an internal standard. ^bReaction carried out under Ar atmosphere. ^cYield in parentheses is the isolated yield

Fig. 3

Scope of gem-difluoroalkenylation of X–H (X = N, O, S, Se). Reaction conditions: Method A: thiophenol (0.3 mmol), TFHZ-Tfs (0.6 mmol), Fe[P2] (1 mol%), SDBS (30 mol%), KOH (aq.)/DCM (5:1), air, 40 °C, 18 h. Method B: amine (0.3 mmol), TFHZ-Tfs (0.6 mmol), Cu(OTf)₂ (20 mol%), LiO^tBu (4 equiv), DCE: toluene (3:1), Ar, 40 °C, 24 h. Method C: TFHZ-Tfs (1.0 mmol), NaH (4 equiv) and DCE (8.0 mL) were stirred at rt for 1 h under Ar, then CuBr (30 mol%), alcohol (0.5 mmol), and LiO^tBu (1 equiv) were added and the mixture was stirred at 40 °C under Ar for 24 h. *Reaction performed for 30 h. ^†Number in parentheses is the yield based on recovered starting material (brsm). ^‡The yield was determined by ¹H NMR spectroscopic analysis with CH₂Br₂ as an internal standard

Fig. 4

Gram-scale synthesis and further transformations. Gram-scale synthesis of product 9 (1). Mono-defluorination of product 9 (2). Double defluorination of product 9 (3)

Fig. 5

Mechanistic investigations. Base promotes fluoride elimination (4) Intermediate experience verification (5) and (6)

Fig. 6

Proposed mechanism. Mechanistic insights regarding to formation of oxonium ylide and fluoride elimination

Fig. 7

Scope of Doyle–Kirmse reaction. Reaction conditions: thioether (0.3 mmol), TFHZ-Tfs (0.6 mmol), FeTPPCl (3 mol%), NaOH (aq.)/DCM (5:1), 40 °C, 18 h

Fig. 8

Scope of trifluoromethylcyclopropanation. Reaction conditions: olefin (0.3 mmol), TFHZ-Tfs (0.6 mmol), FeTPPCl (3 mol%), NaOH (aq.)/DCM (5:1.5), 40 °C, 22 h