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. 2020 May 21;10(33):19454-19462.
doi: 10.1039/d0ra01519a. eCollection 2020 May 20.

Oxidative radical coupling of hydroquinones and thiols using chromic acid: one-pot synthesis of quinonyl alkyl/aryl thioethers

T P Adarsh Krishna  1 , Sakthivel Pandaram  1 , Suresh Chinnasamy  1 , Andivelu Ilangovan  1
Affiliations

Oxidative radical coupling of hydroquinones and thiols using chromic acid: one-pot synthesis of quinonyl alkyl/aryl thioethers

T P Adarsh Krishna et al. RSC Adv. .

Abstract

An efficient, simple and practical protocol for one-pot sequential oxidative radical C-H/S-H cross-coupling of thiols with hydroquinones (HQs) and oxidation leading to the formation of quinonyl alkyl/aryl thioethers using H2CrO4 was developed. This cross-coupling of thiyl and aryl radicals offers mono thioethers in good to moderate yield and works well with a wide variety of thiols. Similarly, this method works well for coupling of 2-amino thiophenol and HQs to form phenothiazine-3-ones 5a-c. C-S bond formation via thioether synthesis was observed using a chromium reagent for the first time. Theoretical studies on the pharmacokinetic properties of compounds 5a-c revealed that due to drug-like properties, compound 5b strongly binds with Alzheimer's disease (AD) associated AChE target sites.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1
Fig. 1. Bioactive molecules containing a thioether linkage.
Scheme 1
Scheme 1. Quinonyl thioethers from thiol and hydroquinone.
Scheme 2
Scheme 2. Scope of C–H/S–H cross-coupling between HQ and thiols.a,b aReaction conditions: hydroquinone (1.0 equiv., 100 mg), thiol (1.5 equiv.), CrO3 (3.0 equiv.), DCM : H2O (4 mL, 1 : 1) at rt, bisolated yield; cexpected product.
Scheme 3
Scheme 3. One-pot C–H difunctionalization of HQ.
Scheme 4
Scheme 4. Synthesis of Hep3B inhibitor.
Scheme 5
Scheme 5. Domino reaction for phenothiazine-3-one. Reaction conditions: hydroquinone (1.0 equiv., 100 mg), 2-aminothiolphenol (1.5 equiv.), CrO3 (3.0 equiv.), DCM : H2O (4 mL, 1 : 1) at rt, isolated yield.
Fig. 2
Fig. 2. (A) Acetylcholinesterase target; (B) 3D structure of protein–ligand interaction; (C) 2D structure of protein–ligand interaction.
Scheme 6
Scheme 6. Conversion of HQ to BQ.
Scheme 7
Scheme 7. Verification experiments for the mechanism.
Scheme 8
Scheme 8. A Plausible mechanism.
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