Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Mar 26;27(7):2150.
doi: 10.3390/molecules27072150.

Insight on Mercapto-Coumarins: Synthesis and Reactivity

Eslam Reda El-Sawy  1 , Ahmed Bakr Abdelwahab  2 , Gilbert Kirsch  3
Affiliations
Review

Insight on Mercapto-Coumarins: Synthesis and Reactivity

Eslam Reda El-Sawy et al. Molecules. .

Abstract

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.

Keywords: Newman–Kwart; biological activity; diazosulfuration; fluorescence; mercapto-coumarins.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The four common mercapto-coumarin derivatives.
Scheme 1
Scheme 1
The synthesis of 3-mercapto-coumarin (4). Reagents and conditions: (a) EtOH, reflux, TEA, 80% yield; (b) EtOH, NaOH, reflux, 88% yield.
Scheme 2
Scheme 2
Catalyst-free conditions for the synthesis of 3-mercapto-coumarins (4): Reagents and conditions: water; reflux; 8–10 h; 8 outputs with 82–97% yield.
Scheme 3
Scheme 3
Michael addition and Mannich reaction of 3-mercapto-coumarins (4). Reagents and conditions: (a) water, NaOH 10%, 50–56 °C, 4–12 h, four outputs with 40–92% yield; (b) formaldehyde, ethanol; (c) diphenyl amine, AcOH.
Scheme 4
Scheme 4
Benzothiophen-2-carboxylic (9) acid via phase-transfer catalyst: Reagents and conditions: high-pressure vessel, 0.8–1.2 MPa; aq. KOH 37%; tetrabutyl ammonium hydroxide; 135 °C, 10 h; conc. HCl; 41.6% yield.
Scheme 5
Scheme 5
Synthesis of N-acetyl-S-(3-coumarinyl)cysteine. Reagents and conditions: TEA, acetonitrile, N2, 4 h, stirring, 47% yield.
Scheme 6
Scheme 6
The synthesis of 4-mercapto-coumarin (14). Reagents and conditions: (a) POCl3, reflux, 2 h, 55% yield; (b) KSH generated from (KOH, MeOH saturated with H2S), reflux, 90% yield.
Scheme 7
Scheme 7
The synthesis of 4-mercapto-coumarin (14) according to Ghosh’s work. Reagents and conditions: (a) TsCl, pyridine, 30 min, stirring, 90% yield; (b) NaSH, EtOH, 0–10 °C, 2 h, stirring, no yield was recorded as the product was used in the subsequent reaction without further purification.
Scheme 8
Scheme 8
The reaction of 4-mercapto-coumarin (14) with 2,2-diphenylethen-1-one. Reagents and conditions: (a) 2,2-diphenylethen-1-one, benzene, 16 h, reflux, 59% yield; (b) 2,2-diphenylethen-1-one, benzene, 5 h, 6.2% yield.
Scheme 9
Scheme 9
Utilization of 4-mercapto-coumarin (14) in the synthesis of 2H-thiopyrano[3,2-c][1]benzopyran-5-ones. Reagents and conditions: (a,c) CHCl3, 1% aqueous NaOH, r.t., stirring, benzyltriethyl ammonium chloride (BTEAC) or tetrabutylammonium bromide (TBAB); (b,d) chlorobenzene, reflux, 30 min–4 h, six derivatives of 79–85% yield.
Scheme 10
Scheme 10
Regioselective synthesis of coumarin-annulated sulfur heterocycles. Reagent and conditions: (a) 1% aq. NaOH–CHCl3, benzyltriethyl ammonium chloride (BTEAC), 1 h, r.t., R=H 83% yield, R=OCH3 85% yields; (b) Bu3SnH, AIBN, benzene, N2, reflux, 1 h, R=H 72% yield, R=OCH3 75% yield.
Scheme 11
Scheme 11
Regioselective synthesis of thieno[3,2-c][1]benzopyran-4-ones (27). Reagent and conditions: (a) 1% aq. NaOH-CHCl3, benzyltriethyl ammonium chloride (BTEAC), stirring, 4 h, r.t., four products, 75–85% yield; (b) reflux, 0.5 h, HCl, four products, 65–80% yield.
Scheme 12
Scheme 12
Synthetic pathways for the reaction of catechol with 4-mercapto-coumarin. Reagents and conditions: (a) sodium acetate solution (c = 0.2 M) in water/acetonitrile (50/50), undivided cell equipped with graphite anode, a large stainless steel gauze cathode, 25 °C, R=CH3 isomer ratio with 52.5%/47.5% yield, R=OCH3 isomer ratio with 96.5%3.5% yield; (b) sodium acetate solution (0.2 M)/acetonitrile (70/30), stirring, r.t., 20–30 min, R=CH3 75% yield, R=OCH3 70% yield.
Scheme 13
Scheme 13
4-Mercapto-coumarin in the synthesis 3-chloro-azetidin-2-one derivatives (36). Reagents and conditions: (a) iodine, thiourea, ethanol, 2–3 h; (b) bromine, acetic acid reflux, 2 h; (c) aromatic aldehyde, acetic acid, ethanol, reflux, 6 h; (d) ethanol, reflux, 5 h; (e) chloroacetyl-chloride, triethylamine, 1,4-dioxane, reflux 7 h, 10 outputs 70–78% yields.
Scheme 14
Scheme 14
The synthesis of 6-mercapto-coumarin (33). Reagents and conditions: (a) HCl/NaNO2; potassium ethyl xanthate, EtOH–KOH, 65% yield; (b) Zn/6 N H2SO4, AcOH, no yield was recorded for compound 30 as the product was used in the subsequent reaction without further purification; (c) Me2CO, K2CO3, NaI, 2 h, reflux, five outputs 85–91% yield.
Scheme 15
Scheme 15
The synthesis of 7-mercapto-coumarin (46). Reagents and conditions: (a) THF, NaH, then (CH3)2NCSCl; (b) DMA, MW, 250 W, 260 °C; (c) KOH, MeOH, r.t., 7 h, then HCl, the product was obtained as a viscous mustard liquid, which could not be recrystallized or purified due to its tackiness.
Scheme 16
Scheme 16
Synthesis of 7-mercapto-4-coumarin (50, MMC). Reagents and conditions: (a) dimethylthiocarbamoyl chloride, DMAP/CH2Cl2, 86% yield; (b) heating, 87% yield; (c) (i) NaOCH3/MeOH, (ii) HCl, 74% yield.
Scheme 17
Scheme 17
Synthesis of conjugated coumarin and piperazine derivatives. Reagents and conditions: (a) Br(CH2)nBr (n = 2–4), K2CO3, acetone, 4 h, reflux, five outputs 61–70% yield; (b) CH3CN, K2CO3, 8 h, reflux, five derivatives of 16–42% yield.
Scheme 18
Scheme 18
Synthesis of bacterial enzyme DNA gyrase inhibitor. Reagents and conditions: (a) (i) TBDMSCl, imidazole, DMF, 12 h, r.t.; (ii) (BOC)2O, Et3N, DMAP, MeCN, 3 h, r.t.; (iii) NBS, (PhCO2)2, CCl4, 4.5 h, 78 °C, 72% yield; (b) Et3N, CH2Cl2, 4 h, r.t., 90% yield; (c) (i) BnBr or p-tBu-BnBr, KF, DMF, 4 h, r.t.; (ii) TFA, CH2Cl2, 4 h, r.t., 90% yield.
Scheme 19
Scheme 19
Synthesis of anti-AIDS agents. Reagents and conditions: (a) 3-bromo-1-propyne or 3-chloro-1-butyne, K2CO3, KI, acetone, N2, 58a: R=H 89.13%, 58b: R=CH3 75% yield; (b) N,N-diethylaniline, reflux, 59a: R=H 77.6%, 59b: R=CH3 56% yield; (c) (i) K2OsO2(OH)4, K3Fe(CN)6, (DHQ)2–PHAL, K2CO3, (ii) Na2SO3, 60a: R=H 51.3% yield, 60b: R=CH3 (S configuration) 52% yield; (d) camphanic chloride, DMAP/CH2Cl2, 61a: R=H 95%, 61b: R=CH3 78% yield.
Scheme 20
Scheme 20
Synthesis of S-substituted 7-mercapto-4-methyl coumarin analogs. Reagents and conditions: (a) halides, K2CO3, KI, acetone/N2; (b) 2,6-dichloropyridine N-oxide, pyridine, r.t., 48% yield; (c) PCl3, CHCl3, reflux, 48% yield.
Scheme 21
Scheme 21
Furoxan-based nitric oxide (NO) releasing S-coumarin. Reagents and conditions: (a) chloroethanol, K2CO3, acetone or DMF, reflux, 89% yield; (b) CH2Cl2, DBU, −15 °C, 3 h, 83% yield.
Scheme 22
Scheme 22
Direct photocatalytic S–H Bond cyanation with green “CN” source. Reagents and conditions: Rose Bengal (1 mol%), CH3CN, r.t., 12 h, white light (10 W), 52% yield.
Scheme 23
Scheme 23
Synthesis of fluorescent probe based on monosulfanyl-coumarin-BODIPY. BODIPY is the technical common name of a chemical compound with the formula C9H7BN2F2.
Scheme 24
Scheme 24
Synthesis of fluorescent chemosensor for some transition metals. Reagents and conditions: (a) MeOH, (E,E)-dichloroglyoxime DCGO, reflux, NaHCO3, 47% yield; (b) MX2·6H2O (M = NiII, CuII, CoII, UO2+2). X = NO3, Et3N, THF, 28–35% yield.
Scheme 25
Scheme 25
The fluorescent tag, 7-mercapto-4-methyl coumarin. Reagents and conditions: CHCl3, NEt3, r.t., 77% yield.
Scheme 26
Scheme 26
Thiol-Michael reaction between maleimide-CNF and 7-mercapto-4-methyl coumarin. Reagents and conditions: DMSO, phosphate buffer (pH = 7), stirring, 24 h, r.t.
Scheme 27
Scheme 27
Structures of fluorogenic phosphatidylcholine analogs.
Scheme 28
Scheme 28
Gold(III)–thiolato complex. Reagents and conditions: (i) K2CO3, acetone, 18 h; (ii) potassium t-butoxide, N2, dry toluene, 6 h, stirring, 84% yield.
Scheme 29
Scheme 29
(A). The synthesis of the naphthalimide coumarins (NCs). Reagents and conditions: DMF, K2CO3, N2, 90 °C, stirring 3 h, 74% yield. (B). Photographs were taken under 365 nm UV-light in different THF/H2O mixtures (50 μM).
Scheme 30
Scheme 30
7-Mercapto-4-methyl coumarin as a photodimerizable and healable reactant.
Scheme 31
Scheme 31
Synthesis of new fluorogenic substrates for neuramidase. Reagents and conditions: (a) NaOH (1.0 N), MeOH, 60% yield; (b) DMF, overnight, r.t., stirring, three outputs 60–88% yield; (c) NaOH (1.0 N), MeOH, three outputs 90% yield.
Scheme 32
Scheme 32
Enzymatic synthesis of S-glycosides. Reagents and conditions: (a) DtGlcA-E396Q, dichlorodiphenyltrichloroethane (DDT), 37 °C, o/n.
Scheme 33
Scheme 33
MMC-labeled sugars. Reagents and conditions: TEA, CH3CN/H2O (1/1), 1.5 h, 0 °C, 46% yield.
Scheme 34
Scheme 34
Diironcarbonyl–coumarin complex. Reagents and conditions: THF, stirring, r.t., overnight, 77.5% yield.
Scheme 35
Scheme 35
Bis(coumarin thiolate) complex. Reagents and conditions: (a) DMF, reflux, 20 h, 53% yield; (b) KOH, MeOH, 5 min, stirring, 69% yield.
Scheme 36
Scheme 36
[Au(bipydmb-H)(MeQS)][PF6] (3-PF6) complex. Reagents and conditions: dichloromethane, stirring, r.t., 24 h, 88% yield.
Scheme 37
Scheme 37
Synthesis of metallophthalocyanines. Reagents and conditions: (a) DMF, K2CO3, r.t., 93.3% yield; (b) (i) heat 145 °C, sealed tube, M = H (92a) with 63% yield; (ii) heat at 195 °C, dry quinolone, sealed tube, stirring, 24 h, M = Zn (92b) 95.1% yield, M = Cu (92c) 95.2% yield, M = Ni (92d) 96% yield, M = Co (92e) 96% yield.
See this image and copyright information in PMC

Similar articles

  • Coumarins as antioxidants.
    Kostova I, Bhatia S, Grigorov P, Balkansky S, Parmar VS, Prasad AK, Saso L. Kostova I, et al. Curr Med Chem. 2011;18(25):3929-51. doi: 10.2174/092986711803414395. Curr Med Chem. 2011. PMID: 21824098 Review.
  • A review: Biologically active 3,4-heterocycle-fused coumarins.
    Salehian F, Nadri H, Jalili-Baleh L, Youseftabar-Miri L, Abbas Bukhari SN, Foroumadi A, Tüylü Küçükkilinç T, Sharifzadeh M, Khoobi M. Salehian F, et al. Eur J Med Chem. 2021 Feb 15;212:113034. doi: 10.1016/j.ejmech.2020.113034. Epub 2020 Nov 25. Eur J Med Chem. 2021. PMID: 33276991 Review.
  • Semisynthesis of Selenoauraptene.
    Fiorito S, Epifano F, Marchetti L, Genovese S. Fiorito S, et al. Molecules. 2021 May 10;26(9):2798. doi: 10.3390/molecules26092798. Molecules. 2021. PMID: 34068532 Free PMC article.
  • New insights into the chemistry and antioxidant activity of coumarins.
    Torres FC, Brucker N, Andrade SF, Kawano DF, Garcia SC, Poser GL, Eifler-Lima VL. Torres FC, et al. Curr Top Med Chem. 2014;14(22):2600-23. doi: 10.2174/1568026614666141203144551. Curr Top Med Chem. 2014. PMID: 25478878 Review.
  • Synthetic and natural coumarins as antioxidants.
    Kostova I. Kostova I. Mini Rev Med Chem. 2006 Apr;6(4):365-74. doi: 10.2174/138955706776361457. Mini Rev Med Chem. 2006. PMID: 16613573 Review.
See all similar articles

Cited by

References

    1. Lončar M., Jakovljević M., Šubarić D., Pavlić M., Buzjak Služek V., Cindrić I., Molnar M. Coumarins in Food and Methods of Their Determination. Foods. 2020;9:645. doi: 10.3390/foods9050645. - DOI - PMC - PubMed
    1. Ballin N.Z., Sørensen A.T. Coumarin Content in Cinnamon Containing Food Products on the Danish Market. Food Control. 2014;38:198–203. doi: 10.1016/j.foodcont.2013.10.014. - DOI
    1. Coumarin Perfume Ingredient, Coumarin Fragrance and Essential Oils Benzopyrone. [(accessed on 25 February 2022)]. Available online: https://www.fragrantica.com/notes/Coumarin-259.html.
    1. Stiefel C., Schubert T., Morlock G.E. Bioprofiling of Cosmetics with Focus on Streamlined Coumarin Analysis. ACS Omega. 2017;2:5242–5250. doi: 10.1021/acsomega.7b00562. - DOI - PMC - PubMed
    1. Agić D., Karnaš M., Šubarić D., Lončarić M., Tomić S., Karačić Z., Bešlo D., Rastija V., Molnar M., Popović B.M., et al. Coumarin Derivatives Act as Novel Inhibitors of Human Dipeptidyl Peptidase III: Combined In Vitro and In Silico Study. Pharmaceuticals. 2021;14:540. doi: 10.3390/ph14060540. - DOI - PMC - PubMed