AN OVERVIEW OF QUANTITATIVE AND QUALITATIVE APPROACHES ON THE SYNTHESIS OF HETEROCYCLIC KOJIC ACID SCAFFOLDS THROUGH THE MULTI-COMPONENT REACTIONS

– Multi-component reactions as powerful synthetic methods were developed to provide efficient complex scaffolds, including kojic acid, through the one-pot one-step fashion. This review highlights the progress of multicomponent reactions covering kojic acid under different conditions through, short reaction time, higher yields, and environmental friendliness via producing various molecules. The aim of this paper is to review the literature from 2015 to 2020 via quantitative and qualitative approaches.


INTRODUCTION
In 1912, Yabuta described the steamed rice were inoculated with Aspergillus oryzae and some acid was extracted through petroleum ether named koji acid.In 1916, Yabuta used the name kojic acid, and corrected the molecular formula to C6H6O4. 1 Saito 2 discovered kojic acid, as the demanding inhibitor of tyrosinase, which was used in food such as crab, shrimp, and vegetables in the food industry due to antioxidant activity and natural antibiotic. 3,4Kojic acid is a fungal metabolite which was produced by various species such as Aspergillus, Acetobacter, and Penicillium.Another source of kojic acid is through fermentation of glucose, sucrose, acetate, ethanol, arabinose, and xylose because of carbon sources by Aspergillus falavus. 5,6Another source of kojic acid or 5-hydroxy-2-hydroxymethyl-(4H)-pyran-4-one is from leaves of common bearberry, to protect skin via lightening properties. 7Among all compounds of kojic acid scaffold, pyranopyranes as a fused oxygenated structures 8 are one of the essential classes which have biological activities, like antibacterial, 9 anti-cancer, 10 antianaphylactic. 11The kojic acid derivativrs have many applications in cosmetic, 12 medicine, 13 food, 14 agriculture, 15 and chemical productions. 16Kojic acid 1 is a well-known tyrosinase inhibitor, 17 due to its structural similarity to phenolic substrates. 18This compound could chelate copper through the active site of the enzyme; therefore, the reasonable inhibitory effect has been expected. 19There are most commercially available tyrosinase inhibitors such as arbutin 2 and hydroquinone 3, which were shown in Figure 1.In terms of natural resources limititation, it is necessary to be synthesized. 4gure 1.The structure of some tyrosinase inhibitors The three-component reaction of kojic acid, aldehyde or 1,3-dicarbonyl motifs, and malononitrile is one of the most important process to provide heterocyclic motifs using different catalysts such as InCl3, 20 CAN, 21 Al2O3, 22 Bi(OTf)3, 23 CeCl3•7H2O/SiO2, 24 FeCl3-SiO2, 25 Fe3O4@SiO2, 26 imidazole, 27 piperidine, 28 Et3N, 29 and NH4VO3. 30This reaction can be accomplished under ultrasonic irradiation. 32In continuous our previous work [32][33][34][35] in multicomponent reaction in organic compounds, kojic acid was reviewed through quantitave and qualitative approaches.
Based on Scopus database, there are about 288 research papers related to kojic acid from 2015-2020, which demonstrates the publication rate of kojic acid.The chart of documents related to kojic acid by subject area was shown in Figure 2.  Three-Fields Plot on the "kojic acid" research area was shown in Figure 4, which demonstrated the relationship title (right column), top keywords plus (middle column), and abstract (left column).The words accounted as Keywords Plus are words or phrases that frequently appear in the titles of an article's references, and appear in the title of the article itself.The keywords plus in Figure illustrates "kojic acid," "tyrosinase inhibitor", "synthesis" or "molecular docking" which papers in middle column.The attractive keyword plus for the title of the selected papers are "kojic acid", "synthesis", "derivatives", "tyrosinase", "activity", "inhibitors", "molecular".In the abstract column, kojic acid as a keyword was selected in all papers with the title of kojic, tyrosinase, inhibitors, synthesis with tyrosinase and kojic, and acid due to the strong relation between tyrosinase and kojic acid as an inhibitor.The evolution of the title words in "kojic acid" from 2015 to 2020 as shown in Figure 5 indicates a clear increasing trend of the title words in the bioorganic chemistry by the time.

Abstract
Top Keywords Plus Title Figure 5. Title Words Growth occurrences by year in "kojic acid"

2-Substituted aryl(amino)kojic acid derivatives
Magnetic nanoparticle-supported molybdate sulfuric acid (MNPs-MSA) was synthesized to be used as a catalyst in the one-pot synthesis of the 2-substituted aryl(amino)kojic acid scaffolds 6 from various aldehydes 5, aniline 4, and kojic acid 1 at room temperature without using solvent as shown in Scheme 1. 36 Scheme 1.The synthesis of 2-substituted aryl(amino)kojic acid scaffolds 6

Dihydropyranopyran derivatives
The dihydropyranopyran derivatives 8 as the corresponding compounds were programmed through three-

Bis-2-aminodihydropyrano[3,2-b]pyran-3-carbonitrile derivatives
In this process, terephthalaldehyde 9 was applied to treat with malononitrile shown in Scheme 4. The catalyst Bi2O3-ZnO was synthesized by a sol-gel method by Bi 3+ which was supported on ZnO nanoparticles to yield Bi2O3 26 as heterogeneous catalysis with metal oxides. 27,28,37ere are other reports related to this method under different conditions, as illustrated in Table 2.
Scheme 4. The synthesis of pyranochromene structures 12 free condition as shown in Scheme 5. 36 This method was also accomplished in the presence of the different catalysts such as nano SiO2-OSO3H, FAU-Zeolite, and InCl3 through various conditions which were illustrated in Table 3. 24 Scheme 5.The synthesis of 2-substituted aryl(indolyl)kojic acid scaffolds 14

MISCELLANEOUS DERIVATIVES
In another work, Asghari and co-workers designed the novel catalyst by pyridine-4-carboxylic acid (PYCA) functionalized Fe3O4 nanoparticles as a magnetic hybrid heterogeneous catalyst to provide pyrano [3,2-b]pyranones 17 through the one-pot three-component reactions by various aromatic aldehydes 5, kojic acid 1, and ethyl cyanoacetate 16 under solvent-free conditions.The pros of this method were to be benign, simple by high yields and the catalyst was readily separated by the external magnet (Scheme 7). 53try Solvent Catalyst Temp.

Figure 2 .
Figure 2. The chart of documents related to kojic acid by subject area

Figure 3 .
Figure 3.The chart of documents related to kojic acid by source title

Figure 4 .
Figure 4. Three-Fields Plot of Top abstracts, Top Keywords Plus, and Top titles on "Kojic Acid."

Table 2 .
The synthesis of pyranochromene structures 12 under different conditions

Substituted aryl(indolyl)kojic acid derivatives
Magnetic nanoparticle-supported molybdate sulfuric acid (MNPs-MSA) was synthesized to be used as catalyst in the one-pot synthesis of the 2-substituted aryl(indolyl)kojic acid scaffolds 14 as the target compounds from various aldehydes 5, indole 13 and kojic acid 1 at room temperature under the solvent-

Table 3 .
The synthesis of the 2-substituted aryl(indolyl)kojic acid derivatives 14 under different