Huisgen [3 + 2] Dipolar Cycloadditions of Phthalazinium Ylides to Activated Symmetric and Non-Symmetric Alkynes.

Vasilichia Antoci,Ramona Danac,Costel Moldoveanu,Gheorghita Zbancioc,Violeta Mangalagiu

doi:10.3390/molecules25194416

Vasilichia Antoci, Ramona Danac + Show 3 more

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https://doi.org/10.3390/molecules25194416

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Journal: Molecules (Basel, Switzerland)	Publication Date: Sep 25, 2020
Citations: 5	License type: CC BY 4.0

Affiliation: Alexandru Ioan Cuza University

Abstract

We present herein a straightforward and efficient pathway for the synthesis of pyrrolophthalazine cycloadducts via Huisgen [3 + 2] dipolar cycloaddition reactions of phthalazinium ylides to methyl propiolate or dimethyl acetylenedicarboxylate (DMAD). A thoroughly comparative study concerning the efficiency of synthesis, conventional thermal heating (TH) versus microwave (MW) and ultrasound (US) irradiation, has been performed. The cycloaddition reactions of phthalazinium ylides to methyl propiolate occur regiospecific, with a single regioisomer being obtained. Under conventional TH, the cycloaddition reaction of phthalazinium ylides with DMAD occurs to a mixture of inseparable partial and fully aromatized pyrrolophthalazine cycloadducts, while MW or US irradiation are leading only to fully aromatized compounds, with the reactions becoming selective. A feasible mechanism for formation of fully aromatized compounds is presented. Besides selectivity, it has to be noticed that the reaction setup under MW or US irradiation offer a number of other certain advantages: higher yields, decreasing of the amount of used solvent comparative with TH, decreasing of the reaction time from hours to minutes and decreasing of the consumed energy; consequently, these reactions could be considered environmentally friendly.

Highlights

We studied the synthesis under conventional thermal heating and under US or MW irradiation of a series of new pyridazinium/phthalazinium derivatives with a dihydroxyacetophenone skeleton as well as their antimicrobial and/or anticancer activity [32,34,38]
The general approach used for the synthesis of pyrrolophthalazine derivatives, 5 and 6, is straightforward and efficient and involves two steps: the in situ generation of the phthalazinium ylides with dihydroxyacetophenone skeleton 2a–e (from the corresponding phthalazinium salts 1a–e, in the presence of triehtylamine (TEA) as base), followed by a Huisgen [3 + 2] dipolar cycloaddition of phthalazinium ylides 2a–e to the corresponding dipolarophiles, Scheme 1
A comparative study concerning the efficiency of synthesis, conventional thermal heating (TH) versus microwave (MW) and ultrasound (US) irradiation, has been performed

Summary

Introduction

The Huisgen [3 + 2] dipolar cycloaddition reactions of cycloimmonium ylides to variously symmetric and non-symmetric substituted dipolarophiles, represent a facile and convenient way to obtain fused azaheterocycles compounds, which are otherwise very difficult or even impossible to obtain [13,14]. These reactions are still widely discussed because of their theoretical and practical interest. In comparison with conventional thermal heating (TH), both microwave and ultrasound irradiation have several important advantages: improved yields, high purity of the compounds, increased selectivity, decreases of reaction time, lower costs and simplicity in handling and processing. Considering all these advantages, reactions under MW and US irradiation could be considered environmentally friendly [36,37]

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Conclusion