Synthesis of 4-substituted pyrazole-3,5-diamines via Suzuki–Miyaura coupling and iron-catalyzed reduction

Abstract

A general and efficient synthesis of 4-substituted-1H-pyrazole-3,5-diamines was developed to access derivatives with an aryl, heteroaryl, or styryl group, which are otherwise relatively difficult to prepare. The first step is based on the Suzuki-Miyaura cross-coupling reaction utilizing the XPhos Pd G2 precatalyst. The coupling reactions of 4-bromo-3,5-dinitro-1H-pyrazole with the electron-rich/deficient or sterically demanding boronic acids enabled the production of the corresponding dinitropyrazoles. The subsequent iron-catalyzed reduction of both nitro groups with hydrazine hydrate accomplished the synthesis. The additional demethylation of the 4-methoxystyryl derivative allowed the production of the carboanalog of CAN508 reported as a selective CDK9 inhibitor.

Alkyl-Substituted N,S-Embedded Heterocycloarenes with a Planar Aromatic Configuration for Hosting Fullerenes and Organic Field-Effect Transistors

“…The treatment of 2- n ( n = 2, 3, 4) with n-BuLi followed by the reaction with N , N -dimethylformamide (DMF) gave the respective dialdehyde compounds 3-n ( n = 2, 3, 4) in high yields (70–75%), which then underwent bromination using Br 2 to afford monomers 4- n ( n = 2, 3, 4) in nearly quantitative yields. The three key macrocyclic intermediates 6- n ( n = 2, 3, 4) with four aldehyde groups were prepared by an efficient Suzuki coupling reaction between 4- n ( n = 2, 3, 4) and 5 using the XPhos Pd G2 catalyst in 12–14% yields after separation by preparative recycling GPC using CHCl 3 as the solvent. After the Wittig reaction, the corresponding tetramethoxyethenylated precursors 7- n ( n = 2, 3, 4) with four vinyl ether groups were obtained in high yields (81–85%).…”

Modification of Boc-Protected CAN508 via Acylation and Suzuki-Miyaura Coupling

“…In order to extend the diversity of pharmacologically relevant amino benzoylated pyrazoles 12b – c , we used our previously reported SMC conditions for dinitropyrazoles [ 26 ]. Preliminary deprotection experiments with tripotassium phosphate showed that already two thirds of 11c were converted after 30 min into 12c and after 1 h the cleavage was almost complete.…”

“…In the last decade, the development of ligands and their use as pre-catalysts significantly broaden the scope of the SMC coupling with various nitrogen-containing heterocyclic systems [ 23 , 24 , 25 ]. Recently, we have taken an advantage of these scope extensions and reported studies with the challenging aminopyrazole substrates [ 20 , 21 , 26 ], which encourage us to attempt to synthesize pyrazoles 12 via Route A .…”

Synthesis and structural optimization of 2,7,9-trisubstituted purin-8-ones as FLT3-ITD inhibitors

“…Buchwald-Hartwig amination was used with piperazineaniline 11 to substitute the chlorine atom at position 2 (Scheme 2) since no general and high yielded method for conventional aromatic nucleophilic substitution was found. The reaction was efficiently performed with precatalyst XPhos Pd G2 under microwave irradiation [25][26][27]. Only derivatives 13 with R 1 = H were more problematic.…”