Synthesis of Functionalized 4‐Fluoropyridazines

Abstract

Ar oute to 4-fluoropyridazines by a[ 2 + +1]/[3+ +2] cycloaddition sequence betweena na cetylenic derivative, ad ifluorocarbenes ource,a nd ad iazo compound is reported. This approach is highly modulara nd compatiblew ith ab road range of functional groups. The protocol does not require the isolation of any reactive intermediates and,t hus, allows for access to aw ide range of 4-fluoropyridazines in as ingle synthetics tep from simple alkynes. Furthermore, these fluorinated compounds can be easily diversified by nucleophilic aromatic substitution (S N Ar) to displace the fluoro group to give aw ider range of 3,4,6-trisubstituted pyridazines. As ar esult of increasing interest in functionalized pyridazines as wella sf luorinated derivatives, this efficient and concise approacht o4 -fluoropyridazines should be of value to medicinal chemists. Scheme1.(1) Synthesis of 5-fluoropyridazinesb ya[ 2 + +1]/[3+ +2] cycloaddition sequencew ith alkyl diazoacetates;(2) Synthesis of 4-fluoropyridazines by a[ 2 + +1]/[3+ +2] cycloaddition sequence with other diazo compounds (TMS = trimethylsilyl, TFDA = trimethylsilyl fluorosulfonyldifluoroacetate, Nu = nucleophile).Scheme2.Mechanism of the [2+ +1]/[3+ +2] cycloaddition sequence with (trimethylsilyl)diazomethane (E).

Trifluorodiazoethane: A versatile building block to access trifluoromethylated heterocycles

“…In 2017, Cossy and coworkers reported a [3 + 2]‐cycloaddition of CF 3 CHN 2 with difluorocyclopropenes 100 to access functionalized 4‐fluoropyridazines 101 (Scheme 47) [64]. This base‐catalyzed protocol was compatible with several difluorocyclopropenes 100 to deliver the targeted products in good to excellent yields efficiently.…”

“…Multicomponent synthesis of trifluoromethylated isoquinolinonesusing o-(trimethylsilyl)phenyl triflate 97 as an aryne precursor in the presence of CsF and TEBAC ([Et 3 NBn] + Cl À ) in high yields under mild reaction conditions.4.13 | Synthesis of CF 3 -substituted pyridazinesIn 2017, Cossy and coworkers reported a [3 + 2]cycloaddition of CF 3 CHN 2 with difluorocyclopropenes 100 to access functionalized 4-fluoropyridazines 101 (Scheme 47)[64]. This base-catalyzed protocol was compatible with several difluorocyclopropenes 100 to deliver the targeted products in good to excellent yields efficiently.Mechanistically, [3 + 2]cycloaddition of 1 with difluorocyclopropenes gives the pyrazoline I.…”

Synthesis of α‐(Trifluoromethyl)pyridazine Derivatives

“…Recently, our group reported the synthesis of α-(trifluoromethyl)pyridazines 68 by using a [2+1]/[3+2]-cycloaddition sequence between a terminal alkyne, a difluorocarbene and (trifluoromethyl)diazomethane. [17] More specifically, in the presence of a difluorocarbene, alkynes 64 underwent a [2+1]-cycloaddition to form 3,3-difluorocyclopropenes 65. These cyclopropenes reacted in a [3+2]-cycloaddition with (trifluoromethyl)diazomethane to afford cyclopropanopyrazolines 66.…”

“…In addition, due to the presence of a fluorine atom at the C4 position of the pyridazine ring, pyridazines 68 could be further functionalized by applying a nucleophilic aromatic substitution (S N Ar), giving access to a wide diversity of (trifluoromethyl)pyridazines 69 (Scheme 23). [17] Scheme 23. Functionalization of α-(trifluoromethyl)pyridazines 68 using a S N Ar to access α-(trifluoromethyl)pyridazines 69.…”

Zinc-Enabled Annulation of Trifluorodiazoethane with 2H-Azirines to Construct Trifluoromethyl Pyrazolines, Pyrazoles, and Pyridazines

“…4 In 2017, Cossy and coworkers found that the reaction of CF 3 CHN 2 with strained alkenes such as difluorocyclopropenes proceeds in a [3 + 2] cycloaddition/cyclopropane ring-opening process, thus providing a novel entry to 6-CF 3 -pyridazines (Scheme 1b). 5 Recently, our group disclosed a silver-catalyzed [3 + 3] cycloaddition of glycine imines with CF 3 CHN 2 for the synthesis of CF 3 -(tetrahydro)triazines (Scheme 1c). 6 On this basis, we envisioned that 2H-azirines, as highly versatile and strained imines, may undergo a [3 + 3] annulation reaction with CF 3 CHN 2 to furnish the dihydrotriazines, which would be sequentially oxidized to afford CF 3 -triazines (Scheme 1d, top).…”