Synthesis of Pyrazolines by Cascade Oxidation/Halogenoamino-cyclization Reaction of Homoallylhydrazides

Abstract

An efficient cascade oxidation/halogenoaminocyclization reaction of homoallylhydrazides with N-halogensuccinimide was developed without addition of other additives under mild reaction conditions to provide pyrazolines. Under the optimized conditions, a variety of highly substituted pyrazoline derivatives were obtained. Keywords oxidation/halogenoaminocyclization; pyrazolines; homoallylhydrazides; N-halogensuccinimide 2 Results and discussion Based on our previous reaction conditions, [15] N'-(1phenylbut-3-en-1-yl)benzohydrazide (1a) was taken as substrate to react with NIS (2a) in tetrahedron (THF) at room temperature. After 4 h, N-benzoyl-5-iodomethyl-3phenylpyrazoline (3a) was obtained in 91% yield (Table 1). In order to investigate the generalities of the substrates,

Brønsted acid-promoted hydroamination of unsaturated hydrazones: access to biologically important 5-arylpyrazolines

“…Based on the above experimental results and previous reports, 12–19 a plausible reaction mechanism is proposed ( Scheme 4 ). Initial electrophilic attack on the C–C double bond of hydrazone 1 by the proton generates carbocation A, which is deprotonated to afford olefin-isomerized intermediate B.…”

“… 11 Recently, the elegant synthesis of pyrazolines from β,γ-unsaturated hydrazones has been accomplished via a novel C–N bond-forming cyclization strategy by the groups of Loh, Xiao, Han, and others. 12–16 Despite recent impressive advances, the examples of the hydroamination of β,γ-unsaturated hydrazones for the construction of pyrazolines are rare. 16 In 2014, Xiao and Chen et al disclosed a novel visible-light-driven photocatalytic hydroamination of β,γ-unsaturated hydrazones, in which the generation of N-centered hydrazonyl radicals has been achieved for the first time by a visible-light photocatalytic oxidation strategy ( Scheme 1a , method A).…”

“…Based on these observations and considering the biological significance of 5-arylpyrazolines, we decided to explore new synthetic methods for the construction of the scaffolds. Inspired by the above breakthrough 12–18 and following our continuous interest in the synthesis of N -heterocycles, 15 f , g we herein report a novel Brønsted acid-promoted hydroamination of β,γ-unsaturated hydrazones to afford a wide range of pyrazolines in generally excellent yields and with high chemo- and regioselectivities through an ionic pathway ( Scheme 1d ). It is noteworthy that the present method provides a facile, mild, efficient, and practical access to biologically significant 5-arylpyrazolines.…”

Strategies and Methods for the Synthesis of 2‐Pyrazolines: Recent Developments (2012–2022)

“…By using a halosuccinimide ( 305 ), via in situ generation of N ‐acylhydrazones, the final products contain a residual active haloalkyl group, which can be used to access more complex derivatives [101a] . This process has also been successfully applied to non‐trifluoromethylated reactants [101b] . A series of control experiments were conducted in order to investigate the reaction mechanism and determine whether or not this process follows a radical pathway.…”

Anionic Chiral Co(III) Complexes Mediated Asymmetric Halocyclization─Synthesis of 5-Halomethyl Pyrazolines and Isoxazolines

“…Moreover, 5-halomethyl isoxazolines can be easily transformed into antibacterial (II) and antimalarial (III) agents (Scheme a) . Conventional methods to synthesize racemic 5-halomethyl pyrazolines and isoxazolines include halocyclizations of β,γ-unsaturated hydrazones and ketoximes, , 1,3-dipolar cycloadditions of nitrile oxides with allyl halide, , oxyhalogenations of allylic oximes and hydrazones, as well as copper-catalyzed radical processes . Despite efficient routes to access these racemic structural motifs, the development of catalytic asymmetric versions has severely been restricted by the rapid background reaction rate of halofunctionalization, , and only few strategies have been explored so far.…”