Fluoroalkyl‐Substituted Diazomethanes and Their Application in a General Synthesis of Pyrazoles and Pyrazolines

Abstract

A novel continuous-flow approach for the synthesis of fluoroalkyl-substituted diazomethanes has been developed. Utilizing a cheap, self-made microreactor fluoroalkyl-substituted amines were transformed into the corresponding diazomethanes using tert-butyl nitrite and acetic acid as catalyst. These diazomethanes were employed in [2+3] cycloaddition reactions with olefins and alkynes, yielding valuable pyrazolines and pyrazoles in good to excellent yields.

Batch and Continuous‐Flow One‐Pot Processes using Amine Diazotization to Produce Silylated Diazo Reagents

“…[17] Under previously reported reaction conditions [see Equation (1)], [14][15][16] the formation of TMSCHN 2 was observed; however, it instantaneously reacted with the acetic acid to form the corresponding ester.T om itigate this undesired byproduct, we applied ad initrite reagent, propyldinitrite [Pr(ONO) 2 ], in 2-MeTHF to afford TMSCHN 2 in 62 %yield using AcOH (Table 1, entry 1). [17] Under previously reported reaction conditions [see Equation (1)], [14][15][16] the formation of TMSCHN 2 was observed; however, it instantaneously reacted with the acetic acid to form the corresponding ester.T om itigate this undesired byproduct, we applied ad initrite reagent, propyldinitrite [Pr(ONO) 2 ], in 2-MeTHF to afford TMSCHN 2 in 62 %yield using AcOH (Table 1, entry 1).…”

The Generation of Diazo Compounds in Continuous‐Flow

“…In 2016, Koenigs and co‐workers described this concept using flow chemistry protocols . In this context, difluoro diazoethane ( 50 a ) proved to be a particularly useful reagent for flow protocols as it readily decomposes under aqueous conditions and suffers from low stability ,.…”

“…employed a pre‐mixed solution of fluoroalkyl‐substituted methylamines, tert ‐butyl nitrite and catalytic amounts of acetic acid. Heating this solution in a microreactor furnished fluoroalkyl‐substituted diazoalkanes ( 50 ) that provide pyrazoles ( 51 , 52 ) and pyrazolines in a consecutive batch dipolar cycloaddition reaction (Scheme ) …”

“…[57] In 2016, Koenigs and co-workersd escribed this concept using flow chemistry protocols. [58] In this context, difluoro diazoethane (50 a)p rovedt ob eap articularly usefulr eagent for flow protocols as it readily decomposesu nder aqueous conditions and suffers from low stability. [10a,g, 59] In af irst report, Koenigs et al employed ap re-mixeds olution of fluoroalkyl-substituted methylamines, tert-butyl nitrite and catalytic amountso f acetic acid.…”

Difluoroacetaldehyde N‐Triftosylhydrazone (DFHZ‐Tfs) as a Bench‐Stable Crystalline Diazo Surrogate for Diazoacetaldehyde and Difluorodiazoethane

“…Despite several attempts since 1971, CF 2 HCHN 2 was first prepared in situ in 2015 by Mykhailiuk by heating a solution of commercially available difluoroethylamine with tert ‐butyl nitrite under oxidative acidic conditions (Figure b, right side) . Subsequently, the research groups of Koenigs and Jamison have improved the technology by generating CF 2 HCHN 2 by using continuous‐flow technology. Later, the group of Han and Chen described an ex situ generation of CF 2 HCHN 2 by using the double‐chamber system .…”