Development of the Traceless Phenylhydrazide Linker for Solid‐Phase Synthesis

Abstract

The hydrazide group is a new oxidatively cleavable traceless linker for solid-phase chemistry. It can be readily introduced by hydrazide formation between a carboxy-functionalized resin and different substituted hydrazines. In order to achieve high yields in this step, new carboxylic acid resins were developed that are not prone to undesired imide formation upon activation of the carboxylic acid. The polymer-bound acyl hydrazides were successfully employed in various transformations, namely Heck, Suzuki, Sonogashira, and Stille couplings, as well as Wittig and Grignard reactions. Traceless release of the coupling products from the solid support is achieved selectively under mild conditions and in high purity by oxidation of the aryl hydrazides to acyl diazenes with Cu(II) salts or N-bromosuccinimide (NBS) and subsequent nucleophilic attack of the acyl diazene intermediates. Traceless cleavage by oxidation with NBS can be carried out as a two-step process in which stable acyl diazenes are first generated by treatment with NBS in the absence of a nucleophile. After removal of the reagents by simple resin washing, the traceless release is effected by the addition of methanol, which leads to products of high purity without any additional separation steps.

The Clinically Used Iron Chelator Deferasirox Is an Inhibitor of Epigenetic JumonjiC Domain-Containing Histone Demethylases

“…The synthetic route employed (Scheme 1) followed that of reported syntheses of this structural class and the commercial deferasirox process. [52][53][54][55][56] This efficient two-step protocol started with condensation of appropriately substituted salicylamides 4 The substituted derivatives 3b-f were tested in the in vitro assays against JMJD2A (Table 1) and found to be active in a concentration range similar to 3a. In order to investigate the relevance of the tridentate iron-binding motif composed of triazole-N and two phenol-O atoms in deferasirox 3a for potent inhibition, we designed two structural analogues 12a and 12b…”

1,3-Dipolar Cycloaddition of Nitrile Imines with Functionalized Acetylenes: Regiocontrolled Sc(OTf)3-Catalyzed Synthesis of 4- and 5-Substituted Pyrazoles

“…NaNO 2 /HCl and then by treatment with methyl-2-chloroacetoacetate in MeOH gave 3a in 96% yield after crystallization. 17 With the same procedure the unknown hydrazonoyl chloride 3b was obtained starting from methyl-4-aminobenzoate 18 while compound 3c 19 was obtained from 4-methoxyaniline using as solvent a mixture 1:1 of pyridine and water (Scheme 1).…”

A boronate prochelator built on a triazole framework for peroxide-triggered tridentate metal binding

“…Methyl 4-hydrazinylbenzoate ( 2 ), 2-(2-hydroxyphenyl)-4H-benzo[ e][1,3]oxazin-4-one ( 1 ) and 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid (deferasirox) were synthesized by following previously published procedures [13,20]. NMR spectra were collected on a Varian Inova 400 or Varian Unity 500 spectrometer with chemical shifts reported in ppm and J values in Hz.…”