2,2,2-Trifluorodiazoethane (CF₃CHN₂): A Long Journey since 1943

Abstract

2,2,2-Trifluorodiazoethane (CF3CHN2) has been proven to be a valuable reagent for the rapid synthesis of various classes of trifluoromethyl-substituted organic molecules in both academic and industrial research. The reagent was prepared first in 1943, but only recently it received a great attention from the scientific community. Protocols for in situ generation, in flow generation, and crystalline analogues of CF3CHN2 were developed during the past decade and have led to an ever-increasing number of publications on the topic. The current review summarizes and comprehensively analyzes all manuscripts in a peer-reviewed literature on 2,2,2-trifluorodiazoethane since its discovery in 1943 until today (as of 19 June 2020). These include contributions mostly overseen by scientific community before. A particular emphasis of this review is to classify the existing reactivity modes of CF3CHN2 and to systematically analyze the corresponding reaction mechanisms in details. At the end of this review, several undeveloped areas for CF3CHN2 are outlined, based on the overseen precedents in the literature.

Spiro‐2‐oxindoles via 1,3‐dipolar cycloadditions. A decade update

“…2,2,2‐Trifluorodiazoethane has been the subject of a very recent review [100] . The intervention of such 1,3‐dipole allowed the synthesis of racemic spiro(cyclopropyl)‐2‐oxindoles by nitrogen extrusion from the primary spiro(2‐oxindolo)pyrazoline cycloadduct, the thermal ring contraction of Δ 1 ‐pyrazolines to cyclopropanes being a well‐known matter [95] .…”

Fluoroalkyl N-sulfonyl hydrazones: An efficient reagent for the synthesis of fluoroalkylated compounds

“…is an effective method for synthesizing bioactive molecules with diverse applications [76]. However, the safe and scalable use of 2,2,2-trifluorodiazoethane in X-H bond insertions is still hampered by its volatility, storage, toxicity, and explosiveness [22]. Titanyuk and co-workers [77] developed the trifluoroacetaldehyde N-tosyl hydrazone (TFHZ-Ts) as a CF 3 CHN 2 precursor for Cu-catalyzed carbene insertion X-H bonds in 2019 (Scheme 13).…”

“…α-Trifluoromethyl sulfides are an essential class of compounds in pharmaceutical and agrochemical research, for example, as stromelysin 1 inhibitors [81]. Notably, the use of TFHZ-Tfs in this reaction is proved superior for the generation of trifluorodiazoethane compared with the oxidation of trifluoroethylamine [22]. Subsequently, they studied the utility of DFHZ-Tfs in Doyle-Kirmse reaction, which afforded the corresponding difluoromethylated or formylated homoallyl and α-allenyl sulfides (46 and 47) in moderate to good yields (Scheme 15b) [72].…”

“…Fluoroalkyl diazo compounds have been recognized as a versatile reagent for introducing fluorinated groups over the last decade, and their synthetic potential has attracted continuous interest, particularly in asymmetric synthesis. However, the potential toxicity and explosiveness of fluoroalkylsubstituted diazo compounds limit their safe and scalable applications [20][21][22][23][24]. Fluoroalkyl N-sulfonyl hydrazones have been developed and used as operationally safe diazo surrogates in carbene transfer reactions in this context.…”

“…Although first described in 1943 [19], the synthetic applicability of trifluorodiazoethane has started emerging only in the past decade. Many exciting new reactivities and fluoroalkyl-substituted diazo compounds have been developed as valuable reagents for the quick introduction of fluorinated side chains [20][21][22][23][24]. However, these reagents' safe and scalable applications have generally been hampered by their potential toxicity, explosive properties, and abnormal reactivity.…”