Menadione: a platform and a target to valuable compounds synthesis

Abstract

Naphthoquinones are important natural or synthetic compounds belonging to the general class of quinones. Many compounds in this class have become drugs that are on the pharmaceutical market for the treatment of various diseases. A special naphthoquinone derivative is menadione, a synthetic naphthoquinone belonging to the vitamin K group. This compound can be synthesized by different methods and it has a broad range of biological and synthetic applications, which will be highlighted in this review.

Keywords: 2-methyl-1,4-naphthoquinone; cancer; chemical reactions; quinone; synthetic platform; vitamin K.

Figure 1

Natural bioactive naphthoquinones.

Figure 2

Chemical structures of vitamins K.

Figure 3

Redox cycle of menadione.

Scheme 1

Selected approaches for menadione synthesis using silver(I) as a catalyst.

Scheme 2

Methylation approaches for the preparation of menadione from 1,4-naphthoquinone using tert-butyl hydroperoxide or hydrogen peroxide.

Scheme 3

Methylation approach of 1,4-naphthoquinone using i) rhodium complexes/methylboronic acid and ii) bismuth(III) triflate and tert-butyl hydroperoxide.

Scheme 4

Synthesis of menadione (10) from itaconic acid.

Scheme 5

Menadione synthesis via Diels–Alder reaction.

Scheme 6

Synthesis of menadione (10) using p-cresol as a synthetic precursor.

Scheme 7

Synthesis of menadione (10) via demethoxycarbonylating annulation of methyl methacrylate.

Scheme 8

Furan 34 used as a diene in a Diels–Alder reaction for the synthesis of menadione (10).

Scheme 9

o-Toluidine as a dienophile in a Diels–Alder reaction for the synthesis of menadione (10).

Scheme 10

Representation of electrochemical synthesis of menadione.

Figure 4

Reaction sites and reaction types of menadione as substrate.

Scheme 11

DBU-catalyzed epoxidation of menadione (10).

Scheme 12

Phase-transfer catalysis for the epoxidation of menadione.

Scheme 13

Menadione epoxidation using a hydroperoxide derived from (+)-norcamphor.

Scheme 14

Enantioselective Diels–Alder reaction for the synthesis of asymmetric quinone 50 catalyzed by a chiral oxazaborolidinium cation.

Scheme 15

Optimized reaction conditions for the synthesis of anthra[9,1-bc]pyranone.

Scheme 16

Synthesis of anthra[9,1-bc]furanone, anthra[9,1-bc]pyridine, and anthra[9,1-bc]pyrrole derivatives.

Scheme 17

Synthesis of derivatives employing protected trienes.

Scheme 18

Synthesis of cyclobutene derivatives of menadione.

Scheme 19

Menadione reduction reactions using sodium hydrosulfite.

Scheme 20

Green methodology for menadiol synthesis and pegylation.

Scheme 21

Menadione reduction by 5,6-O-isopropylidene-ʟ-ascorbic acid under UV light irradiation.

Scheme 22

Selected approaches of menadione hydroacetylation to diacetylated menadiol.

Scheme 23

Thiele–Winter reaction catalyzed by Bi(OTf)₃.

Scheme 24

Carbonyl condensation of menadione using resorcinol and a hydrazone derivative.

Scheme 25

Condensation reaction of menadione with thiosemicarbazide.

Scheme 26

Condensation reaction of menadione with acylhydrazides.

Scheme 27

Menadione derivatives functionalized with organochalcogens.

Scheme 28

Synthesis of selenium-menadione conjugates derived from chloromethylated menadione 84.

Scheme 29

Menadione alkylation by the Kochi–Anderson method.

Scheme 30

Menadione alkylation by diacids.

Scheme 31

Menadione alkylation by heterocycles-substituted carboxylic acids.

Scheme 32

Menadione alkylation by bromoalkyl-substituted carboxylic acids.

Scheme 33

Menadione alkylation by complex carboxylic acids.

Scheme 34

Kochi–Anderson method variations for the menadione alkylation via oxidative decarboxylation of carbonyl substrates.

Scheme 35

Copper-catalyzed menadione alkylation via free radicals.

Scheme 36

Nickel-catalyzed menadione cyanoalkylation.

Scheme 37

Iron-catalyzed alkylation of menadione.

Scheme 38

Selected approaches to menadione alkylation.

Scheme 39

Menadione acylation by photo-Friedel–Crafts acylation reported by Waske and co-workers.

Scheme 40

Menadione acylation by Westwood procedure.

Scheme 41

Synthesis of 3-benzoylmenadione via metal-free TBAI/TBHP system.

Scheme 42

Michael-type addition of amines to menadione reported by Kallmayer.

Scheme 43

Synthesis of amino-menadione derivatives using polyalkylamines.

Scheme 44

Selected examples for the synthesis of different amino-substituted menadione derivatives.

Scheme 45

Selected examples of Michael-type addition of complex amines to menadione (10).

Scheme 46

Addition of different natural α-amino acids to menadione.

Scheme 47

Michael-type addition of amines to menadione using silica-supported perchloric acid.

Scheme 48

Indolylnaphthoquinone or indolylnaphthalene-1,4-diol synthesis reported by Yadav et al.

Scheme 49

Indolylnaphthoquinone synthesis reported by Tanoue and co-workers.

Scheme 50

Indolylnaphthoquinone synthesis from menadione by Escobeto-González and co-workers.

Scheme 51

Synthesis of menadione analogues functionalized with thiols.

Scheme 52

Synthesis of menadione-derived symmetrical derivatives through reaction with dithiols.

Scheme 53

Mercaptoalkyl acids as nucleophiles in Michael-type addition reaction to menadione.

Scheme 54

Reactions of menadione (10) with cysteine derivatives for the synthesis of quinoproteins.

Scheme 55

Synthesis of menadione-glutathione conjugate 152 by Michael-type addition.