Insight on Mercapto-Coumarins: Synthesis and Reactivity

Mercapto (or sulfanyl)-coumarins are heterocycles of great interest in the development of valuable active structures in material and biological domains. They represent a highly exploitable class of compounds that open many possibilities for further chemical transformations. The present review aims to draw focus toward the synthetic applicability of various forms of mercapto-coumarins and their representations in pharmaceuticals and industries. This work covers the literature issued from 1970 to 2021.


Introduction
Coumarins (2H-1-benzopyran-2-ones) are an elite class of compounds present in various natural products, and they have wide applications, viz., as additives in food [1,2], perfumes [3], cosmetics [4], and pharmaceuticals [5,6], as well as in the preparation of optical brighteners [7], dispersed fluorescent [8][9][10] and laser dyes [11], and useful medicinal products [12,13]. On the other hand, the carbon-sulfur bond formation plays an important role in organic synthesis [14][15][16][17]. The introduction of the thiol group to organic structures has emerged as an important tool in medicinal chemistry and chemical biology [18][19][20][21]. It plays a distinguished role in the fabrication of applicable substances in the field of advanced functional materials [22], structural frameworks of natural products [23], and the pharmaceutical industry [24][25][26]. Therefore, there is an increasing demand to investigate thiol-based coupling reactions focusing on their chemoselectivity and their tolerance of various functional groups in order to provide feasible access to new chemical architectures [27,28].
The incorporation of a thiol functional group into coumarin results in mercaptocoumarins. Although mercapto-coumarins have been relatively less extensively studied [18][19][20][21], their chemistry and bioactivity appear to be interesting. This functionalization of coumarin allows a special reactivity due to the implication of the thiol group in different types of organic reactions. This facilitates access to various series of derivatives that may have special applications or biological activities.
By exploring mercapto-coumarin derivatives, we found that four common forms of functional thiol group integrate into the coumarin moiety that occupies different positions, either on the pyrone ring or on the benzene ring. The common four mercapto-coumarins are 3-mercapto-coumarin, 4-mercapto-coumarin, 6-mercapto-coumarin, and 7-mercaptocoumarin ( Figure 1).
The present review is concerned with the period from 1970 to 2021 to shed light on the different pathways of mercapto-coumarin synthesis, while also covering their broad applications at both industrial and biological levels. In addition, it is a groundbreaking release on these compounds, to open a platform for researchers to progress the development of this chemistry. The present review is concerned with the period from 1970 to 2021 to shed light the different pathways of mercapto-coumarin synthesis, while also covering their bro applications at both industrial and biological levels. In addition, it is a groundbreaki release on these compounds, to open a platform for researchers to progress the dev opment of this chemistry.

3-Mercapto-Coumarin
By analyzing the synthesis of 3-mercapto-coumarin, we found that the source sulfur was a heterocyclic compound not an inorganic reagent. In addition, the couma was formed in situ from primary sources, which were salicylaldehydes.

3-Mercapto-Coumarin
By analyzing the synthesis of 3-mercapto-coumarin, we found that the source of sulfur was a heterocyclic compound not an inorganic reagent. In addition, the coumarin was formed in situ from primary sources, which were salicylaldehydes.
Qiyi et al. reported the synthesis of 3-mercapto-coumarin (4) from 2-hydroxybenzylide nerhodanine (3). The latter was produced in situ from salicylaldehyde (1) and 2-thioxothiazo lidin-4-one (2). The reaction proceeded to the final target by refluxing of compound 3 in diluted ethanolic sodium hydroxide solution (Scheme 1) [18]. The present review is concerned with the period from 1970 to 2021 to shed light on the different pathways of mercapto-coumarin synthesis, while also covering their broad applications at both industrial and biological levels. In addition, it is a groundbreaking release on these compounds, to open a platform for researchers to progress the development of this chemistry.

3-Mercapto-Coumarin
By analyzing the synthesis of 3-mercapto-coumarin, we found that the source of sulfur was a heterocyclic compound not an inorganic reagent. In addition, the coumarin was formed in situ from primary sources, which were salicylaldehydes.
In 2009, a green catalyst-free synthetic protocol for synthesizing varieties of the target 3-mercapto-coumarins was reported. In this protocol, refluxing of 2-methyl-2-phenyl-1,3oxa-thiolan-5-one (5) and salicylaldehyde derivatives in water afforded the formation of corresponding 3-mercapto-coumarins (4) in excellent yields (82-97%) (Scheme 2) [22]. The present review is concerned with the period from 1970 to 2021 to shed light on the different pathways of mercapto-coumarin synthesis, while also covering their broad applications at both industrial and biological levels. In addition, it is a groundbreaking release on these compounds, to open a platform for researchers to progress the development of this chemistry.

3-Mercapto-Coumarin
By analyzing the synthesis of 3-mercapto-coumarin, we found that the source of sulfur was a heterocyclic compound not an inorganic reagent. In addition, the coumarin was formed in situ from primary sources, which were salicylaldehydes.
In the previous example of Ghosh's work, 4-mercapto-coumarin served as a transitional compound to produce different coumarin-fused heterocycles employing 4-hydroxycoumarin (12) as a starting reactant. As the compound (14) was produced, it converted immediately to the final products (Scheme 7).
In the previous example of Ghosh's work, 4-mercapto-coumarin served as a transitional compound to produce different coumarin-fused heterocycles employing 4-hydroxycoumarin (12) as a starting reactant. As the compound (14) was produced, it converted immediately to the final products (Scheme 7).
In the previous example of Ghosh's work, 4-mercapto-coumarin served as a transitional compound to produce different coumarin-fused heterocycles employing 4-hydroxycoumarin (12) as a starting reactant. As the compound (14) was produced, it converted immediately to the final products (Scheme 7).

6-Mercapto-Coumarin
The structure creation of 6-mercapto-coumarin was performed following the synthesis of 3-SH and 4-SH-coumarin. This 6-SH-coumarin is an unstable compound that reacts directly with halo-compounds to give S-alkyl coumarin derivatives.

6-Mercapto-Coumarin
The structure creation of 6-mercapto-coumarin was performed following the synthesis of 3-SH and 4-SH-coumarin. This 6-SH-coumarin is an unstable compound that reacts directly with halo-compounds to give S-alkyl coumarin derivatives.

6-Mercapto-Coumarin
The structure creation of 6-mercapto-coumarin was performed following the synthesis of 3-SH and 4-SH-coumarin. This 6-SH-coumarin is an unstable compound that reacts directly with halo-compounds to give S-alkyl coumarin derivatives.

Utilization of 7-Mercapto-4-Methyl Coumarin in the Synthesis of Bioactive Compounds
Novel 7-mercapto-coumarin derivatives (53) were designed starting from 7-mercapto-4-methyl coumarin (50). Most of compounds in 53 exhibited strong α1 an tagonistic activity [65]. In particular, compound 53c showed excellent activity, which was better than that of the reference compound prazosin [65] 7-((4-(4-(2-Methoxyphenyl)piperazin-1-yl)butyl) thio)-4-methyl-2H-chromen-2-one (53c was synthesized via the reaction of 7-mercapto-4-methyl coumarin (50) with 1,2-dibromoethane to give 51, which in turn reacted with 1-(2-methoxyphenyl)piperazine (52c) (Scheme 17) [65]. In an effort to find inhibitors of the bacterial enzyme DNA gyrase, Miller and his co-workers developed a potential low-molecular-weight inhibitor o 7-[4-(4-tert-butyl-benzyloxy)-1H-indazol-3-ylmethylsulfanyl] 4-methylcoumarin (57 (Scheme 18) [67]. The protected and brominated product (56) was involved in thioether formation with MMC (50) by nucleophilic substitution to give 56. The phenolic protection of 56 was removed and formed ether linkage simultaneously with BnBr or p-tBu-BnBr in presence of fluoride ion. The removal of the Boc protection was performed simply in acidic condition to give 57. Compound 57 was 10 times more potent than the reference drug, novobiocin as a DNA gyrase inhibitor [67]. Lee and his co-workers synthesized analogs of DCK, which was known to be active against HIV. In these new structures (thia-DCK), the sulfur atom was the isosteric equivalent to the oxygen atom in the original structure. These derivatives (61a and 61b) were synthesized by fusing the derivatized thiane ring within the benzene moiety of coumarin through a four-step reaction (Scheme 19) [21,64]. They proved to be potent as an anti-HIV agent with an EC 50 value of 0.14 and 0.039 µM and a remarkable therapeutic index of 1110 and 1000 for 61a and 61b, respectively [21,64]. Lee and his co-workers synthesized analogs of DCK, which was known to be acti against HIV. In these new structures (thia-DCK), the sulfur atom was the isoste equivalent to the oxygen atom in the original structure. These derivatives (61a and 61 were synthesized by fusing the derivatized thiane ring within the benzene moiety coumarin through a four-step reaction (Scheme 19) [21,64]. They proved to be potent an anti-HIV agent with an EC50 value of 0.14 and 0.039 µM and a remarkable therapeu index of 1110 and 1000 for 61a and 61b, respectively [21,64]. Another 12 antiviral agents of S-substituted 7-mercapto-4-methyl coumarin analo (62) were synthesized and evaluated against HBV in HepG2 cells (Scheme 20) [62]. The series of derivatives were prepared from reaction between MMC and halo compoun assisted by K2CO3/KI. The IC50 of 62a and 62b as anti-HBsAg activities was (0.01 µmol/ which was 16-fold more potent than the reference (3TC). Compounds 62c-f exhibit interesting inhibitory activity toward both HBsAg and HBeAg [62]. Another approa belonging to Chen et al. was to prepare and evaluate the effectiveness of 63 as an an tumor agent [68]. This compound, which afforded by reduction of 62b, showed a bro spectrum of activity against four tumor cells, as well as remarkably increased cellu apoptosis in a concentration-dependent manner. Furthermore, it induced A549 cell cy arrest at the G2/M phase [68].
Another 12 antiviral agents of S-substituted 7-mercapto-4-methyl coumarin analogs (62) were synthesized and evaluated against HBV in HepG2 cells (Scheme 20) [62]. These series of derivatives were prepared from reaction between MMC and halo compounds assisted by K 2 CO 3 /KI. The IC 50 of 62a and 62b as anti-HBsAg activities was (0.01 µmol/L), which was 16-fold more potent than the reference (3TC). Compounds 62c-f exhibited interesting inhibitory activity toward both HBsAg and HBeAg [62]. Another approach belonging to Chen et al. was to prepare and evaluate the effectiveness of 63 as an antitumor agent [68]. This compound, which afforded by reduction of 62b, showed a broad spectrum of activity against four tumor cells, as well as remarkably increased cellular apoptosis in a concentration-dependent manner. Furthermore, it induced A549 cell cycle arrest at the G2/M phase [68].
Lee and his co-workers synthesized analogs of DCK, which was known to be active against HIV. In these new structures (thia-DCK), the sulfur atom was the isosteric equivalent to the oxygen atom in the original structure. These derivatives (61a and 61b) were synthesized by fusing the derivatized thiane ring within the benzene moiety of coumarin through a four-step reaction (Scheme 19) [21,64]. They proved to be potent as an anti-HIV agent with an EC50 value of 0.14 and 0.039 µM and a remarkable therapeutic index of 1110 and 1000 for 61a and 61b, respectively [21,64]. Another 12 antiviral agents of S-substituted 7-mercapto-4-methyl coumarin analogs (62) were synthesized and evaluated against HBV in HepG2 cells (Scheme 20) [62]. These series of derivatives were prepared from reaction between MMC and halo compounds assisted by K2CO3/KI. The IC50 of 62a and 62b as anti-HBsAg activities was (0.01 µmol/L), which was 16-fold more potent than the reference (3TC). Compounds 62c-f exhibited interesting inhibitory activity toward both HBsAg and HBeAg [62]. Another approach belonging to Chen et al. was to prepare and evaluate the effectiveness of 63 as an antitumor agent [68]. This compound, which afforded by reduction of 62b, showed a broad spectrum of activity against four tumor cells, as well as remarkably increased cellular apoptosis in a concentration-dependent manner. Furthermore, it induced A549 cell cycle arrest at the G2/M phase [68].  (65). This linker was established by the reaction of chloroethanol with MMC in a K 2 CO 3 -containing solvent. The resulting intermediate (64) reacted with compound 65 in DCM, while DBU acted as a catalyst to deliver compound 66. This latter showed antiproliferation activity on A549, HeLa, A2780, A2780/CDDP, and HUVEC cell lines with IC 50 (µM) of 0.12, 0.024, 0.036, 0.14, 0.22, respectively [69].
A specific fluorescent probe based on monosulfanyl-coumarin-BODIPY for the selective detection of cysteine in living cells and artificial urine has been synthesized via a simple substitution reaction on the 5-position of XDS-BOD-XDS:BODIPY-Cl2 (68) with the thiol group generated from 7-mercapto-4-methyl coumarin (50) to yield MC-BOD-XDS (69), XDS-BOD-XDS (70) (Scheme 23) [75]. The reactivity could be attributed to the free SH-coumarin, which quickly binds to another MC-BOD-XDS and produces strong red fluorescent XDS-BOD-XDS (70) [75].  (67), which may be used as an inhibitor of monoamine oxidase A or anti-influenza drug [70]. Cutting off the C-S bond through a photocatalysis of inorganic thiocyanates salt delivered the green "CN", which transformed 7-SH group of 7-mercapto-4-methyl coumarin (50) in the presence of a 10 W white light and 1 mol% Rose Bengal to 7-SCN (67) (Scheme 22) [70].  (67), which may be used as an inhibitor of monoamine oxidase A or anti-influenza drug [70]. Cutting off the C-S bond through a photocatalysis of inorganic thiocyanates salt delivered the green "CN", which transformed 7-SH group of 7-mercapto-4-methyl coumarin (50) in the presence of a 10 W white light and 1 mol% Rose Bengal to 7-SCN (67) (Scheme 22) [70].
A specific fluorescent probe based on monosulfanyl-coumarin-BODIPY for the selective detection of cysteine in living cells and artificial urine has been synthesized via a simple substitution reaction on the 5-position of XDS-BOD-XDS:BODIPY-Cl2 (68) with the thiol group generated from 7-mercapto-4-methyl coumarin (50) to yield MC-BOD-XDS (69), XDS-BOD-XDS (70) (Scheme 23) [75]. The reactivity could be attributed to the free SH-coumarin, which quickly binds to another MC-BOD-XDS and produces strong red fluorescent XDS-BOD-XDS (70) [75]. Özer et al. presented a new fluorescent chemosensor for some transition metals, which was obtained by conjugating two molecules of 7-mercapto-4-methyl coumarin (50) through a glyoxime bridge. This dimer was formed by a refluxing mixture of mercapto-coumarin, (E,E)-dichloroglyoxime DCGO, and NaHCO 3 in MeOH. The coumarin collaborates in this conjugate by its fluorophore property while vic-dioxime acts as a metal-chelating moiety. This chelating capability was expressed in the last step of the following scheme to deliver 72 (Scheme 24) [76]. Özer et al. presented a new fluorescent chemosensor for some transition metals, which was obtained by conjugating two molecules of 7-mercapto-4-methyl coumarin (50) through a glyoxime bridge. This dimer was formed by a refluxing mixture of mercapto-coumarin, (E,E)-dichloroglyoxime DCGO, and NaHCO3 in MeOH. The coumarin collaborates in this conjugate by its fluorophore property while vic-dioxime acts as a metal-chelating moiety. This chelating capability was expressed in the last step of the following scheme to deliver 72 (Scheme 24) [76]. Navarro et al. labeled the modified cellulose nanofibrils (CNFs) with furan and maleimide moieties by the fluorescent probe, 7-mercapto-4-methyl coumarin, through the thiol-Michael reaction (Scheme 26) [78]. The fluorescein/coumarin labeled cellulose nano-fibrils (FC-CNFs) avoid a dye-to-dye interaction (for the same molecule) with an expected wide biological application such as multimodality molecular imaging [78]. Özer et al. presented a new fluorescent chemosensor for some transition metals, which was obtained by conjugating two molecules of 7-mercapto-4-methyl coumarin (50) through a glyoxime bridge. This dimer was formed by a refluxing mixture of mercapto-coumarin, (E,E)-dichloroglyoxime DCGO, and NaHCO3 in MeOH. The coumarin collaborates in this conjugate by its fluorophore property while vic-dioxime acts as a metal-chelating moiety. This chelating capability was expressed in the last step of the following scheme to deliver 72 (Scheme 24) [76]. Navarro et al. labeled the modified cellulose nanofibrils (CNFs) with furan and maleimide moieties by the fluorescent probe, 7-mercapto-4-methyl coumarin, through the thiol-Michael reaction (Scheme 26) [78]. The fluorescein/coumarin labeled cellulose nano-fibrils (FC-CNFs) avoid a dye-to-dye interaction (for the same molecule) with an expected wide biological application such as multimodality molecular imaging [78].  [78]. The fluorescein/coumarin labeled cellulose nano-fibrils (FC-CNFs) avoid a dye-to-dye interaction (for the same molecule) with an expected wide biological application such as multimodality molecular imaging [78]. Özer et al. presented a new fluorescent chemosensor for some transition metals, which was obtained by conjugating two molecules of 7-mercapto-4-methyl coumarin (50) through a glyoxime bridge. This dimer was formed by a refluxing mixture of mercapto-coumarin, (E,E)-dichloroglyoxime DCGO, and NaHCO3 in MeOH. The coumarin collaborates in this conjugate by its fluorophore property while vic-dioxime acts as a metal-chelating moiety. This chelating capability was expressed in the last step of the following scheme to deliver 72 (Scheme 24) [76].  [78]. The fluorescein/coumarin labeled cellulose nano-fibrils (FC-CNFs) avoid a dye-to-dye interaction (for the same molecule) with an expected wide biological application such as multimodality molecular imaging [78]. Hajdu and his co-workers reported the synthesis and enzymological characterization of three fluorogenic phosphatidylcholine analogs PC-1 (77), PC-2 (78), and PC-3 (79), targeting the detection and the quantitative assays of phospholipase A2 (sPLA2) [79]. Each demonstrated molecule contained a 7-mercapto-4-methyl coumarin fluorophore and 2,4dinitroaniline quencher on both tails (Scheme 27) [79]. The small size of these molecules helps to not disrupt the natural membrane. Scheme 26. Thiol-Michael reaction between maleimide-CNF and 7-mercapto-4-methyl co Reagents and conditions: DMSO, phosphate buffer (pH = 7), stirring, 24 h, r.t.

7-Mercapto-4-Methyl Coumarin as Photodimerizable and Healable Reactant
Zhao et al. exploited the photodimerization character of 7-mercapto-coumarin to introduce a novel bio-sourced self-healing technique. The epoxidized cottonseed oil was used as the main reagent, and it was photocrosslinked in the presence of 0.25 equivalents of 7-mercapto-4-methyl coumarin (50) as a photodimerizable and healable reactant. The reaction was initiated with 2 wt.% of a photo-based generator porphobilinogen (PBG) (Scheme 30) [82].
A diironhexacarbonyl cluster covalently linked to S-4-methyl coumarin (93) was synthesized (Scheme 34) [90]. The complex, 93, is electrochemically unstable and exhibited photoinduced intramolecular electron transfer from coumarin to the iron-carbonyl unit [90].  (50) is characterized by its ability to accept transition metals and form metal chelates that play a prominent role in the development of coordination chemistry [88,89].

R PEER REVIEW
16 of 20 2-N,N-dimethylaminoethanol in a sealed tube afforded 2,9,16,23-tetrakis(7-coumarinthio-4-methyl)-phthalocyanine (101a). The latter chelated various metals in a reaction with their salts, Zn(CH3COO)2.2H2O, NiCl2.6H2O, CuCl, and CoCl2.6H2O, and gave the corresponding metallophthalocyanines 101b-e (Scheme 37) [92]. Mercapto (or sulfanyl)-coumarins represent an interesting class of compounds that open many possibilities for further chemical transformations. As a nucleophile, mercapto-coumarin can be used to prepare derivatives with halides, activated halides, and in nucleophilic aromatic substitutions with the appropriate aromatic halides. They can also be used in Michael addition and Mannish reactions. Additionally, they can serve as an intermediate for the synthesis of thiophenes fused to coumarin as well as for the preparation of a thiocoumarin or a thiochromone ring.
Remarkably, 7-mercapto-4-methyl coumarin (MMC) shows the most useful structure for different applications. This substrate is considered as a starting compound to synthesize varieties of bioactive compounds. In addition, it plays an important role in materials science, where it serves as a reporter molecule, fluorescent probe, sugar acceptor, metal chelator (complex formation), and Raman reporter.
Finally, 5 and 8 mercapto-coumarins leave a lot of space for further investigation as there are not described in the literature. Even 8-mercapto-4,6-dimethyl coumarin was claimed to have been obtained [93], no proof of this structure was given.

Conclusions
Coumarins are one of the heterocyclic structures of great interest in the development of valuable structures with both biological and industrial applications.
Mercapto (or sulfanyl)-coumarins represent an interesting class of compounds that open many possibilities for further chemical transformations. As a nucleophile, mercaptocoumarin can be used to prepare derivatives with halides, activated halides, and in nucleophilic aromatic substitutions with the appropriate aromatic halides. They can also be used in Michael addition and Mannish reactions. Additionally, they can serve as an intermediate for the synthesis of thiophenes fused to coumarin as well as for the preparation of a thiocoumarin or a thiochromone ring.
Remarkably, 7-mercapto-4-methyl coumarin (MMC) shows the most useful structure for different applications. This substrate is considered as a starting compound to synthesize varieties of bioactive compounds. In addition, it plays an important role in materials science, where it serves as a reporter molecule, fluorescent probe, sugar acceptor, metal chelator (complex formation), and Raman reporter.
Finally, 5 and 8 mercapto-coumarins leave a lot of space for further investigation as there are not described in the literature. Even 8-mercapto-4,6-dimethyl coumarin was claimed to have been obtained [93], no proof of this structure was given. Funding: The APC was funded by MDPI.

Conflicts of Interest:
The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are not available from the authors.