Modiﬁed Algar–Flynn–Oyamada Reaction for the Synthesis of 3-Hydroxy-2-styryl-chromen-4-ones under Solvent-Free Conditions †

: The simple and efﬁcient conditions for a Algar–Flynn–Oyamada reaction for the synthesis of 3-hydroxy-2-styryl-chromen-4-ones involving the grinding of different 1-(2 (cid:48) -hydroxy-phenyl)-5- aryl-penta-2,4-dien-1-ones with UHP (urea–hydrogen peroxide), pulverized potassium hydroxide and a few drops of ethanol at room temperature under solvent-free conditions are described. A presented protocol offers a faster reaction and a higher yield compared to conventional methods. The structure of the synthesized compounds was identiﬁed from their spectral data (IR, 1 H-NMR)

2-Styrylchromones, because of their conjugated diene structure, in which one of the double bonds is part of the heterocyclic ring, undergo a Diels-Alder reaction with different dienophiles to afford the condensed heterocyclic system, which otherwise are difficult to prepare [18,19].
However, the above-mentioned conditions suffer from one or the other limitations, as hydrogen peroxide is only available as aqueous solution (30-40 %) and its use increases the amount of water in the reaction mixture, the result makes 1-(2 -hydroxy-phenyl)-5aryl-penta-2,4-dien-1-ones insoluble. Further addition of a sufficient amount of pyridine is required to homogenize the reaction mixture and as a result increases the bulk of the reaction mixture [35]. Additionally, as the reaction is carried out under heating conditions, the formation of 2-cinnamylidene-3(2H)-benzofuranones may also accompany the reaction, making the purification of the required 3-hydroxy-2-styrylchromones difficult and lowering the yield.
These shortcomings led us to develop a rapid, safe, and environmentally friendly method for the synthesis of 3-hydroxy-2-styrylchromones using UHP (urea-hydrogen peroxide), avoiding the use of pyridine, a highly toxic substance when using the grinding technique.
In the last few years, the grinding technique has increasingly been used in organic synthesis. It has received much attention due to its operational simplicity. However, it is recognized as an important tool to carry out the reactions under solvent-free conditions with minimal cost and maximum yield compared to conventional methods [36,37]. Moreover, this technique has been used on an industrial scale, using an electric food mixer with stainless-steel rotors, or by using a ball mill [38]. Therefore, in continuation of our work on the synthesis of organic compounds using the grinding technique [39], here we developed an efficient method for the synthesis of 3-hydroxy-2-styrylchromones using UHP (ureahydrogen peroxide) under solvent-free conditions using the grinding technique (Scheme 1).
However, the above-mentioned conditions suffer from one or the other limita as hydrogen peroxide is only available as aqueous solution (30-40 %) and its use inc the amount of water in the reaction mixture, the result makes 1-(2′-hydroxy-phen aryl-penta-2,4-dien-1-ones insoluble. Further addition of a sufficient amount of py is required to homogenize the reaction mixture and as a result increases the bulk reaction mixture [35]. Additionally, as the reaction is carried out under heating cond the formation of 2-cinnamylidene-3(2H)-benzofuranones may also accompany the tion, making the purification of the required 3-hydroxy-2-styrylchromones difficu lowering the yield.
These shortcomings led us to develop a rapid, safe, and environmentally fr method for the synthesis of 3-hydroxy-2-styrylchromones using UHP (urea-hyd peroxide), avoiding the use of pyridine, a highly toxic substance when using the gri technique.
In the last few years, the grinding technique has increasingly been used in o synthesis. It has received much attention due to its operational simplicity. Howeve recognized as an important tool to carry out the reactions under solvent-free cond with minimal cost and maximum yield compared to conventional methods [36,37]. over, this technique has been used on an industrial scale, using an electric food mixe stainless-steel rotors, or by using a ball mill [38]. Therefore, in continuation of our on the synthesis of organic compounds using the grinding technique [39], here we oped an efficient method for the synthesis of 3-hydroxy-2-styrylchromones using (urea-hydrogen peroxide) under solvent-free conditions using the grinding tech (Scheme 1). Scheme 1. Synthesis of 3-hydroxy-2-styrylchromones using the grinding technique.

Results and Discussion
Herein, we wish to report a facile and efficient protocol for the synthesis of droxy-2-styrylchromones (Scheme 1) making use of UHP [40] as a source of hyd peroxide, which avoids increasing the bulk of the reaction mixture and using pyrid toxic reagent under grinding conditions. A mixture of 1-(2′-hydroxy-phenyl)-5 penta-2,4-dien-1-ones, UHP, and moist potassium hydroxide with a few drops of e was ground with a mortar and pestle at room temperature, affording 3-hydr styrylchromones with excellent yield in one step (Scheme 1). The compound was ext after acidification of the reaction mixture in cold concentrated HCl. As the reactio carried out at room temperature, the formation of 2-cinnamylidene-3(2H)-benzofura as side products, generally formed at elevated temperatures, was suppressed; conf

Results and Discussion
Herein, we wish to report a facile and efficient protocol for the synthesis of 3-hydroxy-2-styrylchromones (Scheme 1) making use of UHP [40] as a source of hydrogen peroxide, which avoids increasing the bulk of the reaction mixture and using pyridine, a toxic reagent under grinding conditions. A mixture of 1-(2 -hydroxy-phenyl)-5-aryl-penta-2,4-dien-1ones, UHP, and moist potassium hydroxide with a few drops of ethanol was ground with a mortar and pestle at room temperature, affording 3-hydroxy-2-styrylchromones with excellent yield in one step (Scheme 1). The compound was extracted after acidification of the reaction mixture in cold concentrated HCl. As the reaction was carried out at room temperature, the formation of 2-cinnamylidene-3(2H)-benzofuranones as side products, generally formed at elevated temperatures, was suppressed; confirmed by thin-layer chromatography, thus resulting in higher yields of 3-hydroxy-2-styrylchromones. An IR spectrum of the formed product showed an absorption peak at 3250 cm −1 due to O-H stretching and absorption at 1610 cm −1 due to C=O stretching. An 1 H-NMR spectrum showed a singlet at δ 9.60, a doublet at δ 8.05, and a multiplet at δ 7.85-7.55, due to the presence of OH, -CH=CH-, and aromatic protons, respectively. Further, the formation of 3hydroxy-2-styrylchromones was confirmed by comparing the melting point with literature values [33,35] (Table 1). The present method is simple, as UHP is used as a source of hydrogen peroxide, which avoids increasing the bulk volume of the reaction and makes handling easy. Moreover, the present method avoids the use of hazardous and toxic solvents, making the reaction eco-friendly.

Experimental Section
Melting points were determined in open capillaries. The IR spectra were recorded on a Perkin-Elmer spectrum BX series FT-IR spectrophotometer with KBr pellets. 1 H-NMR and 13 C-NMR spectra were recorded on Bruker Avance (400 MHz & 100 MHz) instruments, respectively, using TMS as the internal standard. All the chemicals were obtained commercially and used without further purification. 1-(2 -Hydroxy-phenyl)-5aryl-penta-2,4-dien-1-ones required for the present study were prepared using the method available in the literature [26].

General Procedure for the Synthesis of 3-Hydroxy-2-styrylchromones 2a-2k
A mixture of 1-(2 -Hydroxy-phenyl)-5-aryl-penta-2,4-dien-1-ones (1 mmol), ureahydrogen peroxide complex (UHP) (2 mmol), and pulverized potassium hydroxide was homogenized with 5-10 drops of ethanol (approx. 0.1-0.2 mL) and ground with a mortar and pestle at room temperature for 5 min. The completion of the reaction was monitored by thin-layer chromatography, confirming the presence of a single product. The reaction mixture was left at room temperature for 10 min to allow digestion. The mixture was subsequently diluted with ice-cold water, and then acidified with concentrated HCl. The solid obtained was filtered, washed with water, and recrystallized from ethanol to give 3-hydroxy-2-styrylchromones.

Conclusions
The present approach for the synthesis of 3-hydroxy-2-styrylchromones using UHP via the Algar-Flynn-Oyamada reaction is highly efficient and eco-friendly as it avoids the use of organic solvents at any stage of the reaction. This is a clean, mild, high-yield and expeditious method, avoiding the formation of any 2-cinnamylidene-3(2H)-benzofuranones byproducts.
Funding: This research received no external funding from any agency.
Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.