molecules Review Modern Approaches to the Synthesis and Transformations of Practically Valuable Benzothiazole Derivatives Larisa V. Zhilitskaya, Bagrat A. Shainyan * and Nina O. Yarosh E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, 1 Favorsky Street, 664033 Irkutsk, Russia; [email protected] (L.V.Z.); [email protected] (N.O.Y.) * Correspondence: [email protected] Abstract: The review is devoted to modern trends in the chemistry of 2-amino and 2-mercapto substituted benzothiazoles covering the literature since 2015. The reviewed heterocycles belong to biologically active and industrially demanded compounds. Newly developed synthesis methods can be divided into conventional multistep processes and one-pot, atom economy procedures, realized using green chemistry principles and simple reagents. The easy functionalization of the 2-NH2 and 2-SH groups and the benzene ring of the benzothiazole moiety allows considering them as highly reactive building blocks for organic and organoelement synthesis, including the synthesis of pharmacologically active heterocycles. The review provides a summary of findings, which may be useful for developing new drugs and materials and new synthetic approaches and patterns of reactivity. Keywords: benzothiazole; 2-aminobenzothiazole; 2-mercaptobenzothiazole; synthesis; reactivity; biological activity Citation: Zhilitskaya, L.V.; Shainyan, B.A.; Yarosh, N.O. Modern Approaches to the Synthesis and 1. Introduction Transformations of Practically Benzothiazoles, as a bicyclic heterocycles with fused benzene and thiazole rings con- Valuable Benzothiazole Derivatives. taining electron-rich heteroatoms, nitrogen and sulfur, attract great interest from researchers Molecules 2021, 26, 2190. https:// for drug design due to their high biological and pharmacological activity [1–5]. The present doi.org/10.3390/molecules26082190 review covers the literature from 2015. We consider modern trends in synthesizing bi- ologically active and industrially demanded compounds based on the C-2-substituted Academic Editor: Enrico Millo benzothiazole derivatives. The reactions of 2-amino- and 2-mercaptothiazole derivatives provide a powerful, modern tools for the design of a wide variety of aromatic azoles. Received: 17 March 2021 Their synthesis methods can be divided into two main groups: “one-pot” synthesis and Accepted: 9 April 2021 Published: 10 April 2021 sequential multistep synthesis. Along with conventional approaches, effective and ecologically friendly alternative reactions are being developed based on commercially available reagents and the principles Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in of green chemistry. These avoid the use of toxic solvents and minimize the formation of side published maps and institutional affil- products. Many reactions are performed in water as the solvent, making the process much iations. cheaper. Multistep one-pot reactions of the C-2-substituted benzothiazoles play a special role in the design of biologically active compounds. The advantages of these reactions are atom-economy, simple experimental implementation and high yields. The effectiveness and selectivity of multistep reactions can often be increased by using catalysts in the absence of solvents. In addition, the methods based on the combined use of microwave Copyright: © 2021 by the authors. irradiation and multicomponent reaction in ecologically safe solvents or in the solvent-free Licensee MDPI, Basel, Switzerland. This article is an open access article mode are actively used nowadays. distributed under the terms and 2. Aminobenzothiazoles conditions of the Creative Commons Attribution (CC BY) license (https:// 2-Aminobenzothiazoles demonstrate high antiviral activity [6–14], which is espe- creativecommons.org/licenses/by/ cially important in this period of global COVID-19 pandemic. They also possess antimi- 4.0/). crobial [14–20], antioxidant [20], anti-inflammatory [21–24], analgesic [24], antidepres- Molecules 2021, 26, 2190. https://doi.org/10.3390/molecules26082190 https://www.mdpi.com/journal/molecules Molecules 2021, 26, x FOR PEER REVIEW 2 of 38 2. Aminobenzothiazoles Molecules 2021, 26, 2190 2-Aminobenzothiazoles demonstrate high antiviral activity [6–14], which is 2espe- of 35 cially important in this period of global COVID-19 pandemic. They also possess antimi- crobial [14–20], antioxidant [20], anti-inflammatory [21–24], analgesic [24], antidepressant sant[25,26] [25,, 26anticonvulsant], anticonvulsant [27– [29]27–, 29anti], anti-diabetic-diabetic [21, [30]21,,30 antitumor], antitumor [31– [3135]–,35 antituberculosis], antitubercu- losis[14,36] [14 ,36activity.] activity. Their Their derivatives derivatives show show also also antimalarial antimalarial [[3737,,3838]],, insecticideinsecticide [ 39[39]and] and herbicideherbicide effect effect [ 40[40]].. They They are are also also used used as as key key intermediates intermediates in in fine fine organic organic synthesis synthesis and and thethe resins’ resins' components components [ 41[41].]. 2.1.2.1. Synthesis Synthesis SeveralSeveral approaches approaches to to the the thiazole thiazole ring ring formation formation are are based based on transitionon transition metal metal cataly- ca- sistalysi usings using a one-pot a one process,-pot process either, either solvent-free solvent- orfree in or green in green solvents. solvents. Thus,Thus,direct direct synthesis synthesis of theof substitutedthe substituted 2-aminobenzothiazoles 2-aminobenzothiazoles1a–t via 1a the–t via RuCl the3- catalyzedRuCl3-catalyzed intramolecular intramolecular oxidative oxidative coupling coupling of N-arylthioureas of N-arylthioureas in up toin 91%up to yield 91% wasyield proposedwas proposed (Scheme (Scheme1)[ 42 ].1) The[42]. electron-rich The electron substrates-rich substrates demonstrate demonstrate higher hig reactivityher reactivity than theirthan electron-deficient their electron-deficient analogs. analogs. SchemeScheme 1. 1.Ru(III)-catalyzed Ru(III)-catalyzed synthesis synthesis of of substituted substituted 2-aminobenzothiazoles 2-aminobenzothiazoles from fromN N-arylthioureas.-arylthioureas. 0 0 TheThe Pd(OAc) Pd(OAc)2-catalyzed2-catalyzed intramolecular intramolecular oxidative cyclizationoxidative of N-aryl-cyclizationN ,N -dialkylt- of hioureasN-aryl-N proceeds′,N′-dialkylthioureas similarly, resulting proceeds in the similarly, formation ofresulting 2-(dialkylamino)benzothiazoles in the formation of 2a2-–(dialkylamino)benzothiazolesp in the same yields (Scheme2 )[2a–43p ].in No the products same yields of the (Scheme intermolecular 2) [43]. No coupling products were of formed.the intermolecular However, in coupling view of preactivation,were formed. more However expensive, in view catalyst of preactivation and its larger, more amount, ex- thepensive method cataly is morest and costly. its larger amount, the method is more costly. SchemeScheme 2. 2.Pd-catalyzed Pd-catalyzed synthesis synthesis of 2-(dialkylamino)benzothiazolesof 2-(dialkylamino)benzothiazoles from fromN-aryl- N’,N’-dialkylthioureas. N-aryl-N’,N’-dialkylthioureas. Very recently, Ni(II) salts were shown to be very good catalysts for the same reac- tion [44]. The method is more advantageous as it uses a cheaper and less toxic catalyst in a much lower concentration, and the reaction is carried out under mild conditions in a very short time resulting in up to 95% product yield (Scheme3). The method can be applied to N-arylthioureas containing both electron-donating or electron-withdrawing substituents in the benzene ring and is scalable without any loss of the yield, which makes it promising for industrial application. Molecules 2021, 26, x FOR PEER REVIEW 3 of 38 Molecules 2021, 26, x FOR PEER REVIEW 3 of 38 Very recently, Ni(II) salts were shown to be very good catalysts for the same reaction [44]. VeryThe method recently is, Ni( moreII) salts advantageous were shown as to it beuses very a cheapergood catalysts and less for toxic the same catalyst reaction in a much[44]. The lower method concentration is more ,advantageous and the reaction as isit carrieduses a cheaperout under and mild less conditions toxic catalyst in a veryin a shortmuch tim lowere resulting concentration in up to, and 95% the product reaction yield is carried (Scheme out 3). under The method mild conditions can be applied in a very to Nshort-arylthioureas time resulting containing in up to both 95% electronproduct- donatingyield (Scheme or electron 3). The-withdrawing method can be substituents applied to inN- thearylthioureas benzene ring containing and is scalable both electron without-donating any loss or of electron the yield-withdrawing, which makes substituents it promis- Molecules 2021, 26, 2190 3 of 35 iinng the for benzene industrial ring application. and is scalable without any loss of the yield, which makes it promis- ing for industrial application. Scheme 3. Ni(II)-catalyzed synthesis of 2-aminobenzothiazoles 3a–t from N- arylthioureas. SchemeScheme 3.3. Ni(II)-catalyzedNi(II)-catalyzed synthesissynthesis ofof 2-aminobenzothiazoles2-aminobenzothiazoles3a 3a––ttfrom fromN N-arylthioureas.-arylthioureas. An alternative intermolecular approach to 2-aminobenzothiazoles 4a–m is based on the reactionAnAn alternativealternative of 2-haloanilines intermolecularintermolecular with approach approachdithiocarbamates toto 2-aminobenzothiazoles2-aminobenzothiazoles (Scheme 4) [45]. The 4a4a––m mmetalis is basedbased-free on