Modular radical cross-coupling with sulfones enables access to sp ³ -rich (fluoro)alkylated scaffolds

Abstract

Cross-coupling chemistry is widely applied to carbon-carbon bond formation in the synthesis of medicines, agrochemicals, and other functional materials. Recently, single-electron-induced variants of this reaction class have proven particularly useful in the formation of C(sp)-C(sp) linkages, although certain compound classes have remained a challenge. Here, we report the use of sulfones to activate the alkyl coupling partner in nickel-catalyzed radical cross-coupling with aryl zinc reagents. This method's tolerance of fluoroalkyl substituents proved particularly advantageous for the streamlined preparation of pharmaceutically oriented fluorinated scaffolds that previously required multiple steps, toxic reagents, and nonmodular retrosynthetic blueprints. Five specific sulfone reagents facilitate the rapid assembly of a vast set of compounds, many of which contain challenging fluorination patterns.

Nonconjugated Hydrocarbons as Rigid‐Linear Motifs: Isosteres for Material Sciences and Bioorganic and Medicinal Chemistry

“…[200] Most recently,r edoxa ctive esters have been employed to synthesize sp 3 -rich(fluoro)alkylated scaffolds. [201] This is made possible through modular radicalc ross-coupling with sulfones in the presenceo f[ Ni(acac) 2 ]f ollowed by the reactionw ith (4fluorophenyl)zinc chloride. This methodw as shown to be applicable with the BCO scaffold 143.C opper catalysis and photoredoxc atalysis were coupled together to develop an ew methodt oi ncorporate alkyl substrates by sp 3 CÀNb ond formation.…”

Transition‐Metal‐Free Electrophilic Fluoroalkanesulfinylation of Electron‐Rich (Het)Arenes with Fluoroalkyl Heteroaryl Sulfones via C(Het)−S and S=O Bond Cleavage

“…[14] Fluoroalkyl heteroaryl sulfones 1 are easy to prepare, bench-stable and non-hygroscopic solid, allowing for widespread use in the pharmaceutical and fluorine chemical fields. [19] However, despite great advances in nucleophilic and radical fluoroalkylation with fluoroalkyl heteroaryl sulfones 1, while to the best of our knowledge, compound 1 as electrophile has not yet been reported. [17] Hu's group also reported the visible light mediated radical fluoroalkylation of isocyanides with 2-BTSO 2 R f (Scheme 2c).…”

“…[18] In addition, the ironcatalyzed difluoromethylation of ArM (M = Mg, Zn) with 2-PySO 2 CF 2 H was disclosed more recently (Scheme 2d). [19] However, despite great advances in nucleophilic and radical fluoroalkylation with fluoroalkyl heteroaryl sulfones 1, while to the best of our knowledge, compound 1 as electrophile has not yet been reported. Consistent with our ongoing research on this field, we herein report an efficient method for the direct electrophilic fluoroalkanesulfinylation of electron-rich (het)arenes with 2-BTSO 2 R f (R f = C 4 F 9 , CF 2 Cl, CF 2 Br, and CF 2 COOEt) (Scheme 2e).…”

“…Simply heating 2-BTSO 2 CF 3 1 a and Ph 2 P(O)Cl in acetonitrile at 60°C for 1 h gave CF 3 SOCl (21%, δ =-À 77.32 ppm), CF 3 SO 2 Cl (19%, δ = À 76.13 ppm) and CF 3 SCl (10%, δ = À 46.56 ppm), respectively, which were detected by 19 F NMR spectroscopic analysis (Scheme 4). Simply heating 2-BTSO 2 CF 3 1 a and Ph 2 P(O)Cl in acetonitrile at 60°C for 1 h gave CF 3 SOCl (21%, δ =-À 77.32 ppm), CF 3 SO 2 Cl (19%, δ = À 76.13 ppm) and CF 3 SCl (10%, δ = À 46.56 ppm), respectively, which were detected by 19 F NMR spectroscopic analysis (Scheme 4).…”

“…Simply heating 2-BTSO 2 CF 3 1 a and Ph 2 P(O)Cl in acetonitrile at 60°C for 1 h gave CF 3 SOCl (21%, δ =-À 77.32 ppm), CF 3 SO 2 Cl (19%, δ = À 76.13 ppm) and CF 3 SCl (10%, δ = À 46.56 ppm), respectively, which were detected by 19 F NMR spectroscopic analysis (Scheme 4). Furthermore, the formation of CF 3 SOCl is also supported by the on line 19 F NMR analysis (see the Supporting Figure 2). Furthermore, the formation of CF 3 SOCl is also supported by the on line 19 F NMR analysis (see the Supporting Figure 2).…”