A Brief Review: Some Interesting Methods of Synthesis Chromene Derivatives as Bioactive Molecules

Chromene is considered a fused pyran ring with a benzene ring, which is found in many plants and is part of many important compounds such as anthocyanidins, anthocyanins, catechins, and flavanones. These compounds are included under the headings "flavonoids" and "iso-flavonoids." These compounds are well known as bioactive molecules with wide medicinal uses. According to these pharmacokinetic characteristics, many researchers are giving more attention to this type of compound and its derivatives. Many chromene derivatives have been synthesized to study their biological effects for the treatment of many diseases. Furthermore, the researcher displayed wide interest in finding new methods for synthesizing chromene derivatives. These methods depend on utilizing a new catalyst to increase the yield of this reaction or reduce the time of the reaction. On the other hand, new methods were found by using a new reactant and a new substrate. This review will present the most recent important methods for the synthesis of chromene derivatives as well as an examination of their biological activity.


Introduction
2H-1-benzopyran and 4H-1-benzopyrean are commonly known as chromene, and they can be realized as a fused result from merging the benzene ring with pyran, as depicted in Figure 1. Chromene and its derivatives exist in many plants [1]. For instance, Koeberlinia spinosa was found to contain nine compounds containing chromene as bioactive compounds [2]. Furthermore, chromene structure was found in polyphenolic compounds, which are known for their biological activity. Hesperidine derivatives, for example, demonstrated antitumor [3] and antioxidant activity [4,5]. Furthermore, flavonoids demonstrated a broad range of biological activity [6,7], with antioxidant being one of the major bioactivities. Chromene derivatives have also shown anticancer [8,9], antioxidant [9], antibacterial [10], anticonvulsant [11], antiinflammatory [12], and antitubercular [13] properties. Figure 2 displayed some natural and synthetic chromene known for their biological activity [14]. These interesting and variable biological activities inspire the researcher to find new methods for the synthesis of chromene derivatives using either a new catalyst to increase the yield of these derivatives and reduce the time of synthesis or a new substrate and new conditions. This work will review the recently developed methods for synthesizing chromene derivatives and the biological activity of these compounds.

Methods of Synthesis of chromene
A large number of synthesis methods was found to synthesize 2H-chromene and 4H-chromene. These methods reflected the value of these derivatives. This section will discuss the most important methods for synthesis of chrome as well as the most intriguing catalysts that have been used.
i-Oxo-chromenyl xanthenone and indolyl xanthenone derivatives were synthesized and tested for anti-HIV-1 RT inhibitory activity using an ionic liquid ([Hmim] HSO4 as a catalyst) [15]. This reaction took 45-60 minutes at room temperature to produce a high yield, as shown in Scheme 1.
iii-The green method has been implemented by utilizing reactions between four compounds as displayed in Scheme 3. In this method, catalytic amounts of Ag@KF/Natrolite NPs were used as catalysts, and the reaction was performed at water and ambient temperature for two hours. These compounds were tested as antioxidants and antimicrobial agents [17]. Scheme 3. Synthesis chromene derivatives by using Ag@KF/Natrolite NPs as catalyst iv-Chromene derivatives were synthesized by a pot reaction utilizing nanoporous Na+montmorillonite perchloric acid as an improved natural soil, as shown in Scheme 4. The antioxidant capacity was investigated. These compounds had significant antioxidant properties [18]. v-2-amino-4H-chromene-3-carbonitriles containing a 5-hydroxypyrazol ring were synthesized from the reaction of four compounds with a free catalyst. As shown in Scheme 5, this reaction was carried out in water at 30 °C for 5-10 mints [19].
vii-A new one-pot method of synthesis of 3,4-dihydrocoumarin derivatives utilizing salicylaldehyde, Meldrum's acid, and isocyanides This condensation reaction is accomplished by a free catalyst in dichloromethane at room temperature [21], as displayed in Scheme 7. viii-2-amino-4H-chromene derivatives were synthesized using silica gel-supported polyamine as a heterogeneous catalyst [22]. This reaction was performed in aqueous ethanol with reflux for 2-3 hours to obtain a high yield. As displayed in Scheme 8. ix-Indolyl-4H-chromene derivatives were synthesized in a pot reaction using triethylamine as a catalyst, and the reaction was achieved under microwaves in the absence of solvent. The reactions accord was between 2-hydroxybenzaldehyde, N-methyl-1-(methylsulfanyl)-2-nitroethenamine, and indoles [23], as depicted in Scheme 9.
xi-As shown in Scheme 11, 2-amino-4H-chromene derivatives were synthesized in one-pot reactions between three compounds derived from 4-hydroxycoumarin using recyclable nanocatalyst (MNPs@Cu) in the absence of solvent [25]. Scheme 11. Synthesis chromene derivatives by using nano catalyst (MNPs@Cu) in free of solvent. xii-[3,2-c] chromenes were synthesized in two steps, the first one by refluxing 4-Hydroxy coumarin, Aryl aldehydes and Malononitrile in ethanol for one hour, and the second step was accomplished by treating the resulting product with N-chlorosuccinimide in ethyl alcohol at ambient temperature [26], as depicted in Scheme 12. The antimicrobial activity of compounds was screened, and most of these compounds showed extraordinary antimicrobial activity. xiii-New 2-Amino-4H-chromene-3-carboxylate derivatives were synthesized by a reaction substituting salicylaldehyde with ethyl cyanoacetate in ethanol at room temperature in the presence of 3A molecular sieves [27], as depicted in Scheme 13. These compounds exhibited anticancer activity. Scheme 13. Synthesis chromene derivatives by using 3A molecular sieves. xiv-In an aqueous medium, thiourea dioxide was used as a catalyst to synthesize new 3,4dihydropyrano[c]chromene and 6-amino-substituted-4H-pyrans [28]. as depicted in Scheme 14. Scheme 14. Synthesis chromene derivatives by using thiourea dioxide in aqueous medium.

Conclusion
Seventeen methods were exhibited for the synthesis of either 2H-chromene or 4H-chromene or both of them. Most of these methods depend on reacted three or four components in one pot or in stages. The majority of these methods made use of a new catalyst to increase the yield of the reaction or shorten the reaction time.