A robust protocol for Pd(ii)-catalyzed C-3 arylation of (1H) indazoles and pyrazoles: total synthesis of nigellidine hydrobromide

Abstract

C3-arylated indazole and pyrazoles are privileged structural motifs in agrochemicals and pharmaceuticals. C-3 C-H arylation of (1H) indazole and pyrazole has been a significant challenge due to the poor reactivity of the C-3 position. Herein, we report a practical Pd(II)/Phen catalyst and conditions for direct C-3 arylation of indazole and pyrazole with ArI or ArBr without using Ag additives as halide scavengers. The use of toluene, chlorobenzene, trifluoromethylbenzene and mesitylene as the solvent was found to be crucial for the selectivity and reactivity. We further demonstrate the robustness of this protocol through the first total synthesis of Nigellidine hydrobromide as well as expedient preparation of heterocycles structurally related to pesticides and drug molecules.

Directing/Protecting‐Group‐Free Synthesis of Tetraaryl‐Substituted Pyrazoles through Four Direct Arylations on an Unsubstituted Pyrazole Scaffold

“…Yu conditions were then examined for the coupling reaction (Figure 5). 17h In the case of Ar 2 and/or Ar 3 as electron‐donating groups (methoxy phenyl group), the coupling yields tended to decrease ( 9 g : 62 % yield vs. 9 j : 35 % yield, 9 d : 68 % yield vs. 9 k : 41 % yield). In the case of Ar 1 as an electron‐withdrawing group (fluorophenyl group), the coupling yields also tended to decrease ( 9 d : 68 % yield vs. 9 a : 51 % yield, 9 g : 62 % yield vs. 9 b : 35 % yield) probably due to the undesired CH direct arylation reaction on the Ar 1 ring.…”

“…Regioselective CH direct arylation at the C4‐position of 1,5‐diaryl‐substituted pyrazole was examined (Figure 4). Method C (Figure 3) was not effective for this coupling reaction, whereas the modified Yu’s conditions reported for the CH direct arylation at the C‐3 position of 1,4,5‐triphenylpyrazole were useful 17h. Although the introduction of a strong electron‐donating Ar 3 group (methoxyphenyl group) resulted in low yields ( 8 c : 35 % yield, 8 i : 21 % yield), weak electron‐donating, electron‐withdrawing, and heteroatom‐containing Ar 3 groups were introduced in moderate to good yields (43–76 %).…”

Synthesis of indazole motifs and their medicinal importance: An overview

“…The derivatives of indazoles such as Nigellidine hydrobromide are synthesized using Pb(OAc) 2 / CS 2 CO 3 in toluene (Scheme-72) [86]. Similarly another reagent Br-(CH 2 ) 4 -Br in acetonitrile is reported in good yield (Scheme-73) [87].…”

Synthesis of Natural Products and Pharmaceuticals via Catalytic CH Functionalization

“…In 2013, Yu and coworkers also discovered the reactivity of simple 1H-indazoles and pyrazoles using a Pd(OAc) 2 /phen/Cs 2 CO 3 catalytic system in toluene [87]. This catalytic reaction was successfully applied to the C-H arylation of indazole 190 with 4-bromoanisole to synthesize a biologically active compound, nigellidine hydrobromide (Scheme 16.43b).…”