Metal-free synthesis of 3,5-disubstituted 1H- and 1-aryl-1H-pyrazoles from 1,3-diyne-indole derivatives employing two successive hydroaminations

Abstract

A robust and efficient atom-economic one-pot synthesis of 3,5-disubstituted 1H-and 1-aryl-1Hpyrazoles under base, acid and metal-free reaction conditions, is reported. The transformation conveniently takes place between 1,4-disubstituted 1,3-diynes and hydrazines in PEG-400 as an ecofriendly solvent, and involves two successive hydroaminations. The reaction was optimized for both, symmetric and non-symmetric 1,3-diyne-indole derivatives, as well as for hydrazine and substituted 10 phenylhydrazines. The scope and limitatons of the transformation were examined, observing that it is not sensitive to moisture or atmospheric oxygen, and that it tolerates a variety of functional groups. Even sterically hindered substrates afforded the expected pyrazoles in good to excellent yields, under mild conditions. A detailed reaction mechanism, which explains its regioselectivity, was also proposed.

Hydroelementation of diynes

“…301,302 Additionally, N-substituted products were obtained by the application of arylhydrazines 665a-d (Schemes 128 and 129). 302 3,5-Disubstituted pyrazoles 674a-d were synthesised using the Cope-type hydroamination in a sustainable manner by the application of a continuous flow process, starting from terminal alkynes 518a and 672a-c and hydrazine 633. Two coil reactors were combined, the temperature, the volume of the coils, and reagent flow rates, which influence the residence times, which were carefully chosen to obtain high product yields of 1a, 1c, 27c, and 258a in the Glasser coupling of alkynes and hydroamination process.…”

“…Applying PEG-400 as a solvent, it was possible to shorten the reaction time from 20 h to 2-6 h, and to carry out the reactions under milder conditions. 301,302 Additionally, N-substituted products were obtained by the application of arylhydrazines 665a-d (Schemes 128 and 129). 302 3,5-Disubstituted pyrazoles 674a-d were synthesised using the Cope-type hydroamination in a sustainable manner by the application of a continuous flow process, starting from terminal alkynes 518a and 672a-c and hydrazine 633.…”

Catalytic Hydrofunctionalization Reactions of 1,3-Diynes

“…In addition to the examples just commented upon, Bertrand and colleagues successfully achieved the catalytic hydroamination of 1,4-diphenylbuta-1,3-diyne with parent ammonia and hydrazine to afford the N-unsubstituted pyrrole 65 [94] and the pyrazole derivative 67 [95], respectively, employing the cationic gold(I) complexes 64 and 66 having a bulky cyclic (alkyl)(amino)carbene ligand (Scheme 37). Within this context, we must mention that access to substituted pyrazoles through metal-free Cope-type hydroamination of 1,3-diynes with hydrazine derivative H 2 NNHR (R = H, alkyl or aryl group) under thermal or base-promoted conditions has been amply reported [96][97][98][99][100][101][102]. Similarly, catalyst-free protocols for the construction of isoxazole [96,100,101,103,104] and pyrimidine [105][106][107] scaffolds by Cope-type hydroamination of 1,3-diynes with hydroxylamine and guanidines, respectively, can also be found in the literature.…”

Fast and Efficient Continuous Flow Method for the Synthesis of Ynones and Pyrazoles

“…The general synthetic method for accessing a pyrazole ring is through [3+2] cycloaddition of a 1,3‐dielectrophile derivative (an α,β‐unsaturated aldehyde/ketone, an allenic ketone, or a β‐alkynyl ketone) with hydrazine . Because of their wide biological activity, the challenge remains to develop new synthetic routes for the rapid and regioselective assembly of substituted pyrazoles from simple and readily available starting materials . In this context, when compared with batch techniques, continuous flow chemistry has many attractive features: enhancing mass‐ and heat‐transfer, minimizing reaction volumes, and improving the degrees of sample‐ and reagent‐mixing .…”