Formal [4+1] Annulation of Azoalkenes with CF₃-Imidoyl Sulfoxonium Ylides and Dual Double Bond Isomerization Cascade: Synthesis of Trifluoromethyl-Containing Pyrazole Derivatives

Abstract

A straightforward strategy for the metal-free construction of trifluoromethyl-containing pyrazole derivatives has been achieved from readily available α-halo hydrazones and CF 3 -imidoyl sulfoxonium ylides. The cascade transformation proceeds through the formal [4+1] cycloaddition followed by an unexpected dual double bond isomerization. The protocol features mild conditions, easy operation, excellent substrate compatibility, and good regioselectivity. The synthetic utility is demonstrated by scale-up reaction and further elaboration of the obtained pyrazole products.A s one of the most ubiquitous five-membered N-heterocycles, pyrazole scaffolds have received considerable attention because of their broad spectrum of biological activities, which have been extensively applied in the fields of pharmaceuticals, agrochemicals, organic functional materials, and ligands. 1 Several commercially available drugs contain pyrazole fragments, such as celecoxib, rimonabant, lonazolac, acomplia, fluazolate, and insecticide fipronil (Figure 1). 1b,2 The pyrazole moiety is also used as a directing group for C−H bond functionalizations. 3 Therefore, the development of direct and efficient methods for preparing pyrazole compounds is highly desirable.

Construction of trifluoromethyl-containing heterocycles from trifluoroacetimidoyl chlorides and derivatives

“…Wu, Chen and co-workers disclosed a formal [4+1] cycloaddition of azoalkenes and CF 3 –imidoyl sulfoxonium ylides for the metal-free synthesis of trifluoromethyl-containing pyrazole derivatives under mild conditions (Scheme 45). 58 Different from the previous [4+1] annulation of azoalkenes with other C1 synthons for forming dihydropyrazoles, the present method provides a direct access to specifically functionalized pyrazole products with an unexpected dual double bond isomerization. The reaction was initiated from base-mediated generation of azoalkene 45-A from α-bromo hydrazone, which underwent [4+1] cycloaddition with TFISYs to furnish the isolatable pyrazoline intermediate 45-B bearing an imine moiety.…”

Enantioselective Access to C-N Axially Chiral Isoquinolones via Dynamic Kinetic Transformation of Carbene Reagents: Unique Chiral Induction Enabled by Dual Role of the Catalyst

“…Our design boils down to development of new coupling reagents that are both bulky and reactive. To reconcile these seemingly contradictive criteria, we employed a bifunctional carbene reagent such as CF3-imidoyl sulfoxonium ylides (TFISYs) [57][58][59][60][61][62][63][64][65] bearing a proximal nucleophilic imine nitrogen as well as a bulkyl N-aryl group (Scheme 1c). Consequently, a secondary amide bearing an electrophilic directing group [66][67][68][69][70][71] was applied as the C-H substrate.…”

“…The absolution configuration of product 51 has been confirmed to be (R) by X-Ray crystallography (CCDC2211789). The CF3 group in the imidoyl sulfoxonium ylide was also successfully extended to C2F5 and other difluoalkyls(61)(62)(63)(64) with no loss of enantioselectivity (89-94% ee).In contrast, no reaction occurred when the CF3 was replaced by a Ph group, suggesting necessity of EWG-activation of the carbene reagent. The rotational barrier of representative products (3, 51 and 59) along the C-N axis has been determined, with the ∆ ranging from 28.7 to > 37 kcal/mol and a bulkier o-substituent results in higher barrier (Scheme 2).…”

Divergent Synthesis of Trifluoromethyl-Substituted 1,2-Dihydroquinoxalines and Diimines by Cascade Reactions of CF3–Imidoyl Sulfoxonium Ylides with Azo Compounds

“…Our group has disclosed a formal [4 + 1] cycloaddition of azoalkenes with TFISYs as C1 synthons and the subsequent dual double bond isomerization for the synthesis of trifluoromethyl-decorated pyrazoles. 10 As a C3 synthon, various cascade annulation reaction involving TFISYs with suitable partners have been developed to forge trifluoromethylsubstituted heterocycles. 11 As a C5 synthon, the [5 + 1] annulation of TFISYs with isothiocyanates or difluorocarbene/ amines readily produce 2-trifluoromethyl quinolines.…”

“…TFISYs can be used as C1, C3, and C5 building blocks in diverse chemical transformations. Our group has disclosed a formal [4 + 1] cycloaddition of azoalkenes with TFISYs as C1 synthons and the subsequent dual double bond isomerization for the synthesis of trifluoromethyl-decorated pyrazoles . As a C3 synthon, various cascade annulation reaction involving TFISYs with suitable partners have been developed to forge trifluoromethyl-substituted heterocycles .…”