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A Facile Microwave-Assisted Synthesis of 3-hydroxy-2-phenyl-4H-chromen-4-one and its Derivatives via a Novel Approach.

Byline: Shahana Ehsan, Saniya Faisal and Wajiha Akbar

Summary: The presented research work demonstrates a new methodology for generating a petite library of novel flavonol derivatives via Algar-Flynn-Oyamada reaction. Amongst oxygen- containing heterocycles, flavonoids are versatile scaffolds due to their manifestation as crucial components in various natural products and encompassing massive biological activities. Thus, in view of the immense significance of flavonols and the pronounced effect of microwave-assisted protocol, a systematic and efficient scheme is put together for constructing the target motive and its derivatives by both classical and novel method. Initially, 2-hydroxy chalcones are assembled through an innovative conventional technique, later followed by the formation of flavonols. This methodical protocol results in enhanced yield with reduced reaction times under benign and environmental friendly conditions.

Keywords: Flavonol, Algar-Flynn-Oyamada reaction, 2-hydroxy chalcones, Microwave-assisted protocol, Biological activities.

Introduction

Microwave heating, an accessible technology for drug discovery and development, is an accomplishment for sustainable chemistry when coupled with synthetic organic research and is a fertile field for ardent researchers to explore, synthesize and design yet more structurally modified moieties. The start of the rapid growth of microwave- assisted schemes of organic synthesis was ignited in 1986 and during the last decade, the activity in this innovative technique has experienced exponential growth [1]. Being a valuable, non-conventional energy resource, it is considered as a green chemical approach, overhauling the cumbersome methods of synthesis by providing rapid heating and thus increasing the pace of reaction, the selectivity of the multifaceted compound and the overall yield of the products.

Besides these, high purity of the products, limited side-reactions, uncomplicated and enhanced synthetic procedure, modular systems and wider useable range of temperature is also ascertained by the dielectric heating associated with microwave technology [2].

As the world has modernized and awareness spread, a struggle for a greener environment has commenced. Green chemistry, a chemical philosophy liable to revolutionize the universe encourages the design and discovery of new compounds while eliminating the hazardous effects in an environmental friendly mode. An exceptional example in this regard are the oxidation reactions which though are potentially hazardous and extremely polluting but can be improved by exploiting greener oxidants such as hydrogen peroxide as it releases simply water as the by-product [3].

Multi-step procedures have always been considered a weakness associated with organic synthesis. However, multi-component reactions (MCRs) constitute an especially attractive synthetic strategy since they provide easy and rapid access to large libraries of organic compounds with diverse substitution patterns through one-pot protocol. MCRs have been considered as a major breakthrough in the drug discovery in context of rapid identification and optimization of biologically active compounds [4].

The forestalling and therapeutics of infectious diseases has developed a global public health dilemma. Moreover, the emergences of drug- resistance and exotic contagions have further worsened this situation. Thus, in order to overcome this state of crisis, a collective effort for the augmentation and synthesis of new drugs has spurred the chemists to search and formulate novel pharmacophores encompassing significant biological activities [5].

Oxygen-containing heterocycles, notably flavonol and its derivatives, are imperative synthetic targets due to their manifestation in multifarious natural products, cavernous biological activities and efficacy as versatile intermediates in organic synthesis [6].

Flavonoids, as polyphenolic compounds are based on a C15 (C6-C3-C6) framework that possess a chroman ring with a second aromatic ring at the C-2, C-3, or C-4 position that renders them hydrogen and electron donors [7]. The chromone moiety outlines an essential component of pharmacophores of a number of biologically active molecules of synthetic as well as natural origin [8]. Over 9,000 flavonoids have been identified and categorized according to chemical structure into nine leading subgroups as chalcones, flavones, flavonols, flavanones, flavanediols, anthocyanins, isoflavones, aurones and tannins (Fig. 1) [9].

Flavonoids are ubiquitous in photosynthesizing cells and occur widely in the plant kingdom. Their polyphenolic nature equates with ready oxidation and the formation of stable radicals [10]. In addition, they possess interesting biological and pharmacological activities including anti- mycobacterial, anti-convalescent, anti-microbial, anti-bacterial, anti-tuberculosis, anti-fungal, anti- arrhythmic, anti-viral, anti-hypertensive, cardioprotective, anti-oxidant, anti-inflammatory, cytotoxic, anti-protozoal, anti-carcinogenic and anti- microbial mushroom tyrosinase inhibition activities [11, 12].

Flavonols are most versatile naturally occurring plant components that are generally photochemically inert as indicated by their reported use as photosensitizers, photoquenchers and ultraviolet absorption filters. Moreover, as a result of this photostability, they are also used as food additives for health purposes [13].

On the other hand, biological connotation includes activity against both metabolic and infective diseases specifically anti-diabetic, anti-cancer, anti-inflammatory, anti-microbial, anti-allergic, anti-oxidant and cytotoxic activities [14].

A substantial role of flavonols is established not only in drug design but also in physical chemistry. Flavonols are naturally available compounds with physiological as well as biological functions in plants and animals. They are solvatochromic fluorescent dyes that become handy in biomolecular fluorescence intersection studies and they can also be applied as molecular fluorescence sensors [15].

Presence of a single hydroxyl group in the position 3 of the molecule renders the flavonols to sense pH in the range from 8 to 12. Their special photophysical properties yield optical applications such as biosensors, hydrogen-bonding sensors, fluorescent probes in lipid bilayers and dyes for protein labeling [16]. Flavonols were also envisaged as candidates for the development of fluorescent chemosensors for cation detection [17].

Thus, taking into account the immense versatility of these compounds and owing to their vast importance especially in drug chemistry and as building blocks in various biological and pharmacological active compounds, a series of flavonols was formulated [18].

Due to the availability of the starting material and comparative ease with which reaction can be run, one of the most recurrently used means of establishing the flavonol nucleus involves the Claisen-Schmidt reaction flanked by 2-hydroxy acetophenone and aromatic aldehyde derivatives. However, under certain conditions, applied during the conventional heating process as reported in this research work resulted in the speedy, contamination free product of 2-hydroxy chalcone and its derivatives. In a successive step, the subsequent oxidative cyclization of 2-hydroxy chalcones intermediate via Algar-Flynn-Oyamada reaction results into flavonol and its derivatives. Chalcones and 2-hydroxy chalcones are core intermediates in flavonoid synthesis and biosynthesis.

Experimental

Chemicals

All chemicals used in the synthesis were of analytical grade from Merck and Fluka.

Instrumentation

Microwave oven DW-180, 2450 MHz, 950 W was used for synthetic purpose. Melting points were uncorrected and determined using Gallenkamp melting point apparatus.

The assembling of the compounds was accomplished in two successive steps. In the first step, 2-hydroxy chalcones were fashioned by a unique conventional protocol that consumed less time than the reported methods of chalcone synthesis (Scheme-1).

In the second step, novel derivatives of flavonols were synthesized by using both conventional and microwave-assisted scheme (Scheme-2).

General procedure for the synthesis of (E)-1-(2- hydroxyphenyl)-3-phenyl-prop-2-en-1-one and its derivatives (1a-5a)

2-hydroxy acetophenone (1 mmol) was mixed with ethanolic KOH (40%, 2.0 mL) in a round bottom flask and stirred for 20 mins at 25 degC. Aromatic aldehyde (1 mmol) was added dropwise and the contents of the flask were again stirred for 15 mins to 1 hour and 20 mins. The reaction mixture was neutralized with ice-cold 5N HCl and poured in freezing-cold distilled water. TLC using n-hexane and ethyl acetate (9:1) was employed as the supervising factor for reaction's completion. Bright precipitates formed that were filtered, washed with ice-cold distilled water, dried and recrystallized from ethyl acetate. The melting points of the formulated compounds were compared and found to be in close proximity with the reported values (Table-1).

Compound 1a-5a (1 mmol) and ethanol (5.0 mL) were taken in a round bottom flask. Ethanolic KOH (40%, 1.0 mL) was added to it along with H2O2 (20%, 1.8 mL) at 30 degC and stirred for 3 hours and 5 mins to 3 hours and 30 mins until the completion of the reaction was determined by TLC (chloroform and methanol in 9:1). The reaction mixture was neutralized with 5N HCl and the contents of the flask were allowed to stand for half an hour. Bright precipitates appeared that were filtered, dried and recrystallized from methanol to obtain the pure product, 1b-5b (Fig. 2). The physical and spectroscopic analysis of the fabricated compounds confirmed the formation of flavonol and its derivatives (Table-2, Table-4 and Table-5).

Table-1: Physical appearance, percentage yield, reaction time and melting points of fabricated 2-hydroxy chalcones.

###Percentage###Melting point

Compound###Name###Physical appearance###Reaction time

###yield (%)###(degC)

###1a###(E)-1-(2-hydroxyphenyl)-3-phenyl-prop-2-en-1-one###Yellow crystal###50 mins.###85###88 (lit: 88)

###2a###(E)-1-(2-hydroxyphenyl)-3-(4-methoxyphenyl)prop-2-ene-1-one###Reddish-orange crystal###1 hr. 30 mins.###88###92 (lit: 93)

###3a###(E)-3-(furan-2-yl)-1-(2-hydroxyphenyl)prop-2-en-1-one###Brownish-orange powder###1 hr. 20 mins.###89###95 (lit: 97)

###4a###(E)-3-(4-bromophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one###Bright-yellow crystal###55 mins.###76###148.5 (lit: 149.1)

###5a###(E)-3-(4-chlorophenyl)-1-(2-hydroxyphenyl)prop-2-en-1-one###Brownish-yellow crystal###35 mins.###75###143 (lit: 144)

Table-2: Physical appearance, percentage yield, reaction time and melting points of the cyclized flavonols.

###Conventional###Microwave-assisted

###Compounds###Name of compounds###Physical appearance###methodology###protocol

###Reaction Yield Melting###Reaction###Yield###Melting

###Time###%###point (degC)###Time###%###point (degC)

###3 hrs.###1 min

###1 (b, c)###3-hydroxy-2-phenyl-4H-chromen-4-one###Yellow crystal###20 mins.

###76###171

###25 secs.

###80###170

###3 hrs.###1min

###2 (b, c)###2-(4-methoxyphenyl)-3-hydroxy-4H-chromen-4-one Brownish-orange crystal 10 mins. 87###225.5

###15 secs.

###90###225

###3 hrs.###1 min

###3 (b, c)###2-(furan-2-yl)-3-hydroxy-4 H-chromen-4-one Brownish-yellow crystal 5 mins. 86###170

###5 secs.

###92###169

###3 hrs.###1 min

###4 (b, c)###2-(4-bromophenyl)-3-hydroxy-4H-chromen-4-one Light-yellow crystal###30 mins.

###72###211

###35 secs.

###80###210.5

###3 hrs.###1 min

###5 (b, c)###2-(4-chlorophenyl)-3-hydroxy-4H-chromen-4-one Brownish-yellow crystal 15 mins. 76###203

###30 secs.

###85###202

Table-3: UV/Vis and FT-IR data of synthesized 2-hydroxy chalcones.

###Compound###max (nm)###Wave number (cm-1) Absorption intensity

###1a###211, 244 and 355###1110 (sec. C-O), 1445 (>C=CC=CC=CC=CC=CC=CC=CC=CC=CC=CC=C<), 1627 (C=O), 1637 (Ar.

###4 (b, c)###229 and 377###conjugation), 3082 (Ar. C-H), 619 (C-Br), 3355###230 and 376###conjugation), 3092 (Ar. C-H), 616 (C-Br),

###(O-H) and 1124 (sec. C-O)###3335 (O-H) and 1084 (sec. C-O)

###3212 (Ar-str), 1629 (C=O), 1635 (C=C str),

###3202 (Ar-str), 1619 (C=O), 1625 (C=C str), 800

###5 (b, c)###231 and 374###230 and 375###830 (C-Cl str), 3010 (C-H str) and 1248 (OH

###(C-Cl str), 3000 (C-H str) and 1238 (OH str)

Table-5: GC-MS values of the formulated flavonols.

###GC-MS values

###Compounds

###Conventional methodology###Microwave-assisted methodology

###1 (b, c)###75, 93, 211, 222, 237###77, 96, 209, 221, 235

###2 (b, c)###65, 77, 92, 108, 225, 253, 268###67, 76, 93, 111, 229, 255, 270

###3 (b, c)###77, 94, 134, 244, 264, 209###76, 95, 129, 240, 269, 219

###4 (b, c)###68, 76, 93, 157, 229, 242, 304###70, 78, 94, 158, 230, 241, 307

###5 (b, c)###77, 94, 112.5, 209, 237, 272###79, 95, 114, 211, 239, 273

Conclusion

The research work presented illustrates a new methodology of organic synthesis i.e. the microwave-assisted technique along with the conventional process. Derivatives of flavonol were prepared by the oxidative cyclization of 2-hydroxy chalcone and its derivatives with the help of hydrogen peroxide in the presence of 40% ethanolic solution of a base. All the fabricated compounds showed exceptionally good yields via microwave technique and had the added advantage of reduced reaction time and purity of products as no side- reactions had occurred. This scheme of synthesis offers an authenticated and valuable route for the prompt synthesis of these biologically active precursors that also have prominence in pharmaceutical industries.

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Author:Ehsan, Shahana; Faisal, Saniya; Akbar, Wajiha
Publication:Journal of the Chemical Society of Pakistan
Article Type:Report
Geographic Code:9PAKI
Date:Dec 31, 2016
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