Microwave‐Assisted Solution‐Phase Synthesis of 1,4,5‐Trisubstituted Pyrazoles

Abstract

A small parallel library of 1,4,5-trisubstituted pyrazoles was prepared in solution using a three-step procedure starting from Meldrum acid. The Meldrum acid was acylated with different acyl chlorides and the products opened with different alcohols and amines to give substituted β-keto esters and β-keto amines. Further reaction with N,N-dimethylformamide dimethylacetal and the final cyclisation were effectivelyThe current development of new methods for the parallel synthesis of libraries of organic molecules has led to renewed interest in a technique in which individual organic molecules are prepared in solution. The advantages of this technique are the standard solution-phase reactivity of the organic molecules, and easy analysis of the reaction using conventional methods without any need for linker chemistry. A particularly important aspect is that the operational time for the preparation of a new library can be shorter than the time necessary to develop a reaction on solid phase. On the other hand, in order to automate the preparation of the library, all the steps must give pure compounds after simple workup, involving exclusively filtration or evaporation under vacuum. To reach this goal, polymersupported reagents have been employed frequently, and recently the developments in the field have been reviewed extensively.[1Ϫ5] The main drawbacks of polymer-assisted solution-phase synthesis are related to the use of polymers that show low loading values and difficulty in swelling in several solvents. Moreover, the prices of several polymersupported reagents or scavengers are sometimes very high.In order to prepare a library of pharmacologically relevant heterocyclic scaffolds with a good level of potential molecular diversity in solution phase, we decided to optimize the synthesis of a trisubstituted pyrazole to obtain a protocol that could be easily automated. We wanted to improve the efficiency of each step to avoid purification and reduce the work-up procedures for a limited number of expensive [a]

Controlled Microwave Heating in Modern Organic Synthesis

“…[141] Numerous reports of the use of DMFDMA as a building block for the rapid synthesis of a large variety of heterocyclic ring systems by MAOS have also appeared. [144][145][146][147] The Bohlmann-Rahtz synthesis of trisubstituted pyridines from b-aminocrotonates and an ethynyl ketone has found application in the preparation of a variety of heterocycles containing this structural motif. [148] Bagley et al have developed a microwave-assisted modification of this heteroannulation method, which is best conducted in DMSO at 170 8C for 20 minutes, and provides the desired pyridine derivatives in 24-94 % yield (Scheme 23).…”

Benign Approaches for the Microwave‐assisted Synthesis of Five‐membered 1,2‐N,N‐heterocycles

“…The use of hydroxylamine instead of hydrazine brought about the formation of isoxazole ( 86 ). The cyclocondensation of mono‐substituted hydrazines with N , N ‐dialkyl enaminones or N , N ‐dialkyl enamino‐ β ‐keto esters (derived from ketones or β ‐keto esters, respectively, and DMF–DMA) ( 83 ) has been widely employed both in the solution phase and in the polymer‐supported synthesis of substituted pyrazoles. Thus, the attachment of enamino‐ β ‐keto esters ( 83 ) to cellulose beads was accomplished through the enamine moiety, which is a leaving group in the subsequent reaction with phenylhydrazine or hydroxylamine.…”

“…3-Methyl-1H-pyrazolones (57) were synthesized from substituted hydrazides using various solid supports under MWI. Inspired by the high yields obtained using formic acid, a further study of 4(3H)quinazolinones synthesis, as a possible Niementowski reaction, was carried out using different aromatic and heteroaromatic carboxylic acid (51); amine (53) and carboxylic acid (52) were mixed and irradiated under microwaves to yield 2,3-disubstituted-4 (3H)quinazolinones (54). Good yields were obtained in less irradiation time compared with the conventional procedure [44], requiring 5-substituted anthranilic acid, acetyl chloride, pyridine, amino acids, and long refluxing time.…”

Five‐Membered Heterocycles: 1,2‐Azoles. Part 1. Pyrazoles

“…The use of microwave irradiation in this type of chemistry allows the formation of pyrazole derivatives in a few minutes while it requires several hours under conventional heating [149]. The formation of pyrazoles from polymer-bound 2-acyl-3-aminopropenoates has also been described [150,151].…”