C-H bonds as ubiquitous functionality: a general approach to complex arylated pyrazoles via sequential regioselective C-arylation and N-alkylation enabled by SEM-group transposition

Abstract

Pyrazoles are important azole heteroarenes frequently found in pharmaceuticals and protein ligands, and there has been a growing interest in new synthetic methods for their preparation. We report the first catalytic intermolecular C-H arylation of pyrazoles, namely SEM-protected pyrazoles and N-alkylpyrazoles, which lays the foundation for a new approach to the synthesis of complex arylated pyrazoles, where new arene rings are directly attached to predetermined positions of the heteroarene nucleus ("topologically obvious synthesis"). Through a systematic search, we identified a palladium-pivalate catalytic system as the most effective protocol and mapped the reactivity of all three C-H bonds of the pyrazole (C-5 > C-4 >> C-3). To circumvent the low reactivity of the C-3 position, we developed a "SEM switch", which transposes the SEM-protecting group from one nitrogen to the other in one step, and in the process transforms the unreactive C-3 position to the reactive C-5 position. The SEM switch thus enables sequential arylation of C-5 and C-3 position, providing rapid access to protected or free 3,4,5-triarylpyrazoles (the C-4 arene ring is readily introduced by bromination and Suzuki coupling). Furthermore, N-alkylation of SEM-protected pyrazoles allows for regioselective introduction of the amine substituent, addressing the low regioselectivity of N-alkylation of pyrazoles lacking sufficient steric bias. Thus, the catalytic C-H arylation combined with the protecting group transposition and N-alkylation provides a rapid route to fully substituted pyrazoles with complete regiocontrol of all substituents. The particular strength of this strategy is the ability to commence the synthesis from either the parent pyrazole or practically any pyrazole intermediate.

Figure 1

A new approach to synthesis of complex pyrazoles via direct C-H arylation

Figure 2

A/ General reactivity properties of pyrazole. B/ Reactivity profile of pyrazoles toward palladium-catalyzed C-H arylation. The C-5 position exhibits the highest reactivity. (a) Reaction conditions: Pyrazole, PhBr (1.5 equiv), Pd(OAc)₂ (5 mol %), P(n-Bu)Ad₂ (7.5 mol %), K₂CO₃ (3 equiv), HOPiv (25 mol %), 2.5 M DMA, 140 °C for 12 hours. Isolated yields are shown except for substrate 1, where the substrate conversion and the product ratio was determined by ¹H NMR of the crude mixture. All product ratios were confirmed by ¹H NMR of crude mixtures.

Scheme 1

Sequential C-arylation enabled by SEM group switch provides a rapid access to triarylpyrazoles with complete control of regioselectivity. The SEM group also allows for regioselective N-alkylation.

Scheme 2

SEM group transposition (SEM switch)

Scheme 3

Synthesis of triarylpyrazoles via sequential C-arylation Conditions: (a) Pyrazole, SEMCl (10 mol %), MeCN, 95°C, 24 hr, 84% yield. (b) Pyrazole, ArBr (1.5 equiv), Pd(OAc)₂ (5 mol %), P(n-Bu)Ad₂ (7.5 mol %), K₂CO₃ (3 equiv), HOPiv (25 mol %), 2.5 M DMA, 140°C, 12 hours; 77% yield. (c) 3N HCl, EtOH, reflux, 3 h, 75% yield. In DMSO-d₆, compound 24 exists as a mixture of tautomers. Yields are an average of at least two separate isolated yields.

Scheme 4

Sequential C-arylation and N-methylation provides a rapid access to 1-methyl-3,4,5-triarylpyrazoles with complete regioselectivity control Conditions: (a) Pyrazole, Me₃O-BF₄ (1.2 equiv), CH₂Cl₂, RT, 1 hr. (b) 3N HCl, EtOH, reflux, 1 h; 70% yield over 2 steps. (c) Pyrazole, ArBr (1.5 equiv), Pd(OAc)₂ (5 mol %), P(n-Bu)Ad₂ (7.5 mol %), K₂CO₃ (3 equiv), HOPiv (25 mol %), 2.5 M DMA, 140 °C for 12 hours; 70% yield. Yields are an average of at least two separate isolated yields.