A Convenient Synthesis of Substituted Pyrazolidines and Azaproline Derivatives through Highly Regio- and Diastereoselective Reduction of 2-Pyrazolines

Abstract

The synthesis of substituted N-acetyl- and N-aroyl-2-pyrazolines via intramolecular Michael addition of alpha,beta-unsaturated hydrazones generated through olefination of phosphinyl and phosphonyl hydrazones with carbonyl compounds is reported. The regioselective reduction of the C-N double bond in these 2-pyrazolines using Superhydride (Et3BHLi) gives pirazolidine derivatives with excellent levels of cis-diastereoselectivity. These 2-pyrazolines can also be obtained in one-pot reaction from allenes, hydrazides, and aldehydes; and pyrazolidines, after reduction, from allenes, hydrazides, and aldehydes. This synthetic route was developed to provide a new approach to substituted azaproline derivatives in a diastereoselective fashion.

Mild, Stereoselective, and Highly Efficient Synthesis of N‐Acylhydrazones Mediated by CeCl3·7H2O in a Broad Range of Solvents

“…Compound 27 (see Table 3) involved an α,β‐unsaturated ketone as the starting material, which is an acid‐sensitive reactant, the hydrazones of which cannot be synthesized in presence of protic acids. In this case, the synthetic approach required a different strategy, and 27 and its analogues were prepared through a multistep synthetic route 22. Using 10 % of CeCl 3 catalyst, the condensation between benzohydrazide and benzalacetone easily proceeded under very mild conditions with a good time reaction to give 27 in excellent yield and stereoselectivity.…”

“…Using 10 % of CeCl 3 catalyst, the condensation between benzohydrazide and benzalacetone easily proceeded under very mild conditions with a good time reaction to give 27 in excellent yield and stereoselectivity. Such α,β‐unsaturated N ‐acylhydrazones are important building blocks in the synthesis of nitrogen‐containing heterocycles, which are important in both medicinal and synthetic chemistry 22…”

Ultrasonics Promoted Synthesis of 5-(Pyrazol-4-yl)-4,5-Dihydropyrazoles Derivatives

“…They have been reported in literature procedures for the design and development of new heterocycles (pyrazole and pyrazoline derivatives) by means of multistep reactions [26][27][28], metal-catalyzed synthesis [29,30], domino reaction of 2-acylaziridines with the Huisgen zwitterions [31] and 1,3-dipolar cycloaddition reactions [32] to access important heterobiaryls.…”

Catalytic Synthesis of Nonracemic Azaproline Derivatives by Cyclization of β‐Alkynyl Hydrazines under Kinetic Resolution Conditions

“…[10] The pyrazolidine ring of azaprolines has also been prepared by palladium-catalyzed cyclizations of optically active allenylic hydrazines [11] or hydrazine adducts produced from racemic allenyl phosphine oxides. [12] However, herein we report related cyclization reactions catalyzed by nonmetal cations, which have allowed for an exciting class of chiral ammonium phase-transfer catalysts to be brought to bear to produce nonracemic azaproline derivatives (Scheme 1).Based on our previous experience with g-silyl allenyl esters, [13] we hypothesized that base-catalyzed addition of dinitrogen-containing electrophiles such as azidodicarboxylates should lead to b-alkynyl hydrazine intermediates. Indeed, with substrates 1 and 2 (EWG = CO 2 tBu and CO 2 Et) DBU catalyzed this transformation but the reactions were sluggish especially with larger a-substituents (Table 1).…”

“…[10] The pyrazolidine ring of azaprolines has also been prepared by palladium-catalyzed cyclizations of optically active allenylic hydrazines [11] or hydrazine adducts produced from racemic allenyl phosphine oxides. [12] However, herein we report related cyclization reactions catalyzed by nonmetal cations, which have allowed for an exciting class of chiral ammonium phase-transfer catalysts to be brought to bear to produce nonracemic azaproline derivatives (Scheme 1).…”