Chiral Thioureas—Preparation and Significance in Asymmetric

molecules

Review Chiral Thioureas—Preparation and Signiﬁcance in Asymmetric Synthesis and Medicinal Chemistry

Franz Steppeler 1 , Dominika Iwan 1, El˙zbietaWojaczy ´nska 1,* and Jacek Wojaczy ´nski 2

1 Faculty of Chemistry, Wrocław University of Science and Technology, Wybrze˙zeWyspia´nskiego 27, 50 370 Wrocław, Poland; [email protected] (F.S.); [email protected] (D.I.) 2 Faculty of Chemistry, University of Wrocław, 14 F. Joliot-Curie St., 50 383 Wrocław, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-71-320-2410

Academic Editors: Zbigniew Czarnocki and Joanna Szawkało Received: 29 December 2019; Accepted: 16 January 2020; Published: 18 January 2020

Abstract: For almost 20 years, thioureas have been experiencing a renaissance of interest with the emerged development of asymmetric organocatalysts. Due to their relatively high acidity and strong hydrogen bond donor capability, they differ significantly from ureas and offer, appropriately modified, great potential as organocatalysts, chelators, drug candidates, etc. The review focuses on the family of chiral thioureas, presenting an overview of the current state of knowledge on their synthesis and selected applications in stereoselective synthesis and drug development.

Keywords: asymmetric synthesis; chirality; isothiocyanates; organocatalysis; stereoselectivity; thioureas

1. Introduction The replacement of the electronegative oxygen atom of urea by sulfur (with electronegativity comparable to carbon) results in a significant change of properties. Thioureas (thiocarbamides) exhibit higher acidity and are stronger hydrogen bond donors [1–3]. This ability to participate in hydrogen bonding, which can be further modified by the appropriate substitution of nitrogen atoms, is essential for numerous applications of this class of organic compounds, mainly in organocatalysis and molecular recognition. Thioureas are also widely applied in agriculture and medicine [4–7], and as corrosion inhibitors [8–11]. For almost 20 years they have been used as catalysts in organic synthesis, especially in stereoselective reactions [12–14]. They also serve as valuable starting materials for the synthesis of heterocycles [15–17], and are used as ligands in coordination chemistry (particularly when additional donors are present in their molecules) [18–22], as well as in the field of anion binding and recognition [2,23]. Structurally thioureas can be classified depending on the number of substituents of nitrogen atom (Figure1)[ 6,7]. Not surprisingly, derivatives with one and two organic groups (either 1,1 or 1,3-disubstituted) are most common, though trisubstituted (with limited, but still preserved possibility to act as hydrogen bond donors) and fully substituted (mainly cyclic) thioureas are also prepared and used for various purposes. The first thiocarbamides were prepared ca. 150 years ago [24,25], and their chiral derivatives have been long known [26,27], but a great interest in the latter has arisen with the development of enantioselective organocatalysis.

Molecules 2020, 25, 401; doi:10.3390/molecules25020401 www.mdpi.com/journal/molecules Molecules 2020, 25, x 2 of 57 Molecules 2020, 25, 401x 22 of of 57 56

(a) (b) (c) (d) (e) (a) (b) (c) (d) (e)

Figure 1. TypesTypes of of thioureas; thioureas; (a) ( amonosubstituted;) monosubstituted; (b) (b1,1-disubstituted;) 1,1-disubstituted; (c) 1,3-disubstituted; (c) 1,3-disubstituted; (d) (Figuretrisubstituted;d) trisubstituted; 1. Types (e )of tetrasubstituted. (e )thioureas; tetrasubstituted. (a) monosubstituted; (b) 1,1-disubstituted; (c) 1,3-disubstituted; (d) trisubstituted; (e) tetrasubstituted. 2. Synthesis of Chiral Thioureas 2. SynthesisSince the of thioureaChiral Thioureas skeleton is notnot intrinsicallyintrinsically chiral, the existence of enantiomersenantiomers typically originatesSince fromthe thiourea its substituents.substituents. skeleton isExamples Examples not intrinsicall of of va variousriousy chiral, groups the bearingexistence stereogenic of enantiomers centers typically will be presentedoriginates ininfrom thethe subsequentitssubsequent substituents. section. section. Examples Desymmetrisation Desymmetrisation of various resulting groupsresulting bearing from from less less stereogenic common common axial centersaxial (biphenyl (biphenyl will be or binaphthylpresentedor binaphthyl in derivatives) the derivatives) subsequent [28 [28–30]– 30section.] or or planar planarDesymmetrisation chirality chirality [ 31[31–33]–33 resulting] is is also also from worth worth less mentioning.mentioning. common axial Consequently, (biphenyl theor binaphthyl methods of derivatives) synthesis of [28–30] chiral or thioureas planar chiral are essentiallyesseityntially [31–33] the is alsosame worth as for mentioning. their achiral Consequently, counterparts, but,the methods typically, of thethe synthesis reactants reactants of fromchiral from a thioureas achiral chiral pool pool are are esse are usedntially used in inenantiomerically the enantiomerically same as for their pure pure achiral form. form. However,counterparts, However, the thebut,preparation preparation typically, of the the of reactants thedesired desired productfrom product a chiral as asracemic racemicpool are mixture mixtureused in followed followedenantiomerically by by separation separation pure ofform. of enantiomers enantiomers However, was the reportedpreparation in selectedof the desired cases, e.g.,product bis-thiourea as racemic derivativesderiva mixturetives offollowed Tröger’s by base separation werewere obtained of enantiomers as racemates was andreported resolved in selected on a chiralchiral cases, stationarystationary e.g., bis-thiourea phasephase [[34].34 deriva]. Similarly,tives of enantiomersenantiomers Tröger’s base ofof we norbornanenorbornanere obtained thiocarbamidethiocarbamide as racemates formedand resolved as 1:1 on mixture a chiral in astationary two-step phase protocol [34]. from Similarly, norbornene enantiomers were separated of norbornane either by thiocarbamide chiral HPLC orformed by crystallizationcrystallization as 1:1 mixture of in diastereomericdiastere a two-stepomeric protocol salts ofoffrom thethe norbornene amineamine intermediatesintermediates were separated [[35].35]. Theeither advantage by chiral ofHPLC this approachor by crystallization lays in the of fact diastere that bothomeric optical salts antipodes of the amine of chiral intermediates thiourea can[35]. be The isolated advantage and used of this as organocatalystsapproach lays in or the for fact chiralchiral that recognition.recognition. both optical antipodes of chiral thiourea can be isolated and used as organocatalystsThe choice ofofor a afor particularparticular chiral recognition. method method of of preparation preparation of of the the desired desired stereoisomer stereoisomer depends depends mainly mainly on on its structureits structureThe choice (number (number of a and particular typeand oftype substituents)method of substituents) of preparation and availability and of availabilitythe ofdesired necessary stereoisomerof necessary startingmaterials. dependsstarting mainlymaterials. Certainly, on oneitsCertainly, structure should one also (number should consider andalso possible typeconsider of inconveniences substituents) possible inco (bothandnveniences availability for the (both person of for conductingnecessary the person starting the conducting synthesis materials. andthe forCertainly,synthesis the environment) and one for should the environment) connectedalso consider with connected possible the use withinco of certain nveniencesthe use reactants:of certain (both reactants:for their the limited person their stability, limitedconducting stability, toxicity, the flammability,synthesistoxicity, flammability, and orfor simply the environment) or an simply unpleasant an connected unpleasant odor. In withmost odor. the preparations, In use most of certainpreparations, reactants reactants: containingreactants their limited containing C=S bondstability, C=S are used—mainlytoxicity,bond are flammability, used—mainly isothiocyanates, or isothiocyanates, simply but an alsounpleasant dithiocarbamates, but also od or.dithiocarbamates, In most carbon preparations, disulfide, carbon reactants disulfide, thiophosgene containing thiophosgene and their C=S equivalents.bondand theirare used—mainly equivalents. Less frequently, isothiocyanates,Less inorganic frequently, sources but inorga also of sulfurdithiocarbamates,nic sources are useful of forsulfur carbon a given are disulfide, transformation—P useful thiophosgenefor a given4S10 orandtransformation—P Lawesson’s their equivalents. reagent4S10 toor Less convertLawesson’s frequently, urea intoreagent thioureainorga to nicconvert [ 36sources,37] sulfidesurea of intosulfur or elementalthiourea are useful [36,37] sulfur. for Aminessulfides a given areor thetransformation—Pelemental most usual sulfur. source Amines4S10 ofor thiourea areLawesson’s the mo nitrogenst usualreagent atoms; source tohowever, ofconvert thiourea isocyanidesurea nitrogen into thioureaatoms; and azides however, [36,37] are also isocyanidessulfides found or in variouselementaland azides protocols. sulfur. are also Amines An found alternative are in variou the mo routesst protocols. usual involves source An modification alternativeof thiourea ofroute nitrogen already involves atoms; constructed modification however, achiral isocyanides of thiourea already withandconstructed azides optically are achiral activealso foundthiourea groups. in variouwith opticallys protocols. active An groups. alternative route involves modification of already constructed achiral thiourea with optically active groups. 2.1. Reaction of Isothiocyanates with Amines 2.1. ReactionFor manymany of years,Isothiocyanates years, the the most most with common Aminescommon method method of preparation of preparation of thiourea, of includingthiourea, chiralincluding derivatives, chiral hasderivatives, beenFor basedmany has on years,been the based reactionthe moston ofthe alkylcommon reaction or aryl methodof isothiocyanate alkyl orof arylpreparation isothiocyanate with amine of orthiourea, with ammonia amine including (Scheme or ammonia 1chiral)[ 1]. Thisderivatives,(Scheme way, 1) unsymmetrical [1]. has This been way, based unsymmetrical mono-, on the di- reaction or trisubstituted mono-, of al di-kyl or or productstrisubstituted aryl isothiocyanate are formed, products dependingwith are amineformed, onor depending theammonia amine (which(Schemeon the amine can 1) be[1]. either(which This way, aliphatic can unsymmetrical be oreither aromatic). aliphatic mono-, This or substratearomatic). di- or trisubstituted typically This substrate serves products as typically a source are formed, ofserves chirality asdepending a insource most preparationsonof chiralitythe amine in of (whichmost chiral preparations thioureas,can be either while of aliphatic chiral the isocyanate thioureas, or aromatic). is while chosen This the to substrate isocyanate enhance thetypically is desired chosen serves properties to enhance as a source of the designedofdesired chirality properties catalyst, in most ligand, ofpreparations the ordesigned receptor of chiralcatalyst, (most thioureas, frequently ligand, whileor trifluoromethyl-substitutedreceptor the isocyanate (most frequently is chosen trifluoromethyl- aryl to enhance derivatives the aredesiredsubstituted used). properties However, aryl derivatives of chiralthe designed isothiocynatesare used ).catalyst, However, are liga used chiralnd, as or isothiocynates well, receptor as they (most can are befrequently used easily as well, obtained trifluoromethyl- as they from can the be respectivesubstitutedeasily obtained primary aryl fromderivatives amine the respective and are CS used2 [ 38primary). ].However, amine chiral and isothiocynates CS2 [38]. are used as well, as they can be easily obtained from the respective primary amine and CS2 [38].

Scheme 1. Preparation of thioureas from isothiocyanatesisothiocyanates and amines or ammonia. Scheme 1. Preparation of thioureas from isothiocyanates and amines or ammonia. Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, 401 3 of 56 Molecules 2020, 25, x 3 of 57

MoleculesThe method 2020, 25, x is versatile and convenient from the point of view of atom economy. Only one 3 of C–N57 bond has to be formed in the course of the reaction. Among Among drawbacks, drawbacks, limited long-term stability of isothiocyanateThe method reactants is versatile and theand possibility convenient of from format formation the ionpoint of ofside view products of atom (e.g., economy. uretanes Only in one case C–N when alcoholsbond has are to used be formed as solvents) in the course are often of the mentioned. reaction. Among drawbacks, limited long-term stability of isothiocyanate reactants and the possibility of formation of side products (e.g., uretanes in case when Recent examples of the application of this route to synthesize enantiomerically pure thioureas alcohols are used as solvents) are often mentioned. include the paper by Sureshbabu et al., who prepared 25 newnew NN-urethane-protected amino alkyl Recent examples of the application of this route to synthesize enantiomerically pure thioureas isothiocyanates [39]. [39]. A A CS CS22/trimethylamine/tosyl/trimethylamine/tosyl chloride chloride combination combination was was found found to to be be the most include the paper by Sureshbabu et al., who prepared 25 new N-urethane-protected amino alkyl efficienteﬃcient for the conversion of mono-N-protected chiral diamines, which in turn were obtained from isothiocyanates [39]. A CS2/trimethylamine/tosyl chloride combination was found to be the most the corresponding amino acids. The coupling of the isothiocyanates with amino acid esters in the theefficient corresponding for the conversion amino acids. of mono- The Ncoupling-protected of chiral the isothiocyanates diamines, which with in turn amino were acid obtained esters from in the presence of N,N-diisopropylethylamine resulted in formation of dithioureidopeptides in 65–74% presencethe corresponding of N,N-diisopropylethylamine amino acids. The coupling resulted of thein isothiocyanatesformation of dithioureidopeptides with amino acid esters in in65–74% the yield.presence Liu Liu et etof al. N ,Ndescribed described-diisopropylethylamine a a preparation preparation resultedof of five ﬁve new in formation chiral thiourea of dithioureidopeptides organocatalysts usingin 65–74% amines obtainedyield. Liu inin four etfour al. steps describedsteps from from da-mannitol preparationD-mannitol and of isocyanatesand five isocyanatesnew chiral (mainly thiourea(mainly those derivedorganocatalysts those derived from Cinchona usingfrom aminesalkaloids,Cinchona alkaloids,Schemeobtained2)[ 40Schemein ].four Isothiocyanates steps2) [40]. from IsothiocyanatesD were-mannitol also reacted and isocyanateswere with sulfoximinesalso (mainlyreacted [those41with] and derivedsulfoximines phosphoramides from Cinchona[41] [ 42and] to phosphoramidesgivealkaloids, the respective Scheme [42] thioureas. to2) give[40]. the Isothiocyanates respective thioureas. were also reacted with sulfoximines [41] and phosphoramides [42] to give the respective thioureas.

Scheme 2. ChiralChiral thiourea thiourea organocatalysts organocatalysts prepared prepared from from Dd-mannitol-mannitol derivative and Cinchona Scheme 2. Chiral thiourea organocatalysts prepared from D-mannitol derivative and Cinchona alkaloids [40]. [40]. alkaloids [40]. ModificationsModiﬁcations of typical reaction conditions havehave been recentlyrecently proposed.proposed. Possible application Modifications of typical reaction conditions have been recently proposed. Possible application of solvent-free protocols, with reactants in a gas- and/or solid state, and mechanochemical synthesis of ofsolvent-free solvent-free protocols, protocols, with with re reactantsactants in a gas- and/orand/or solid solid state, state, and and mechanochemical mechanochemical synthesis synthesis were explored [43–46]. As an example, neat grinding and liquid-assisted grinding were applied to werewere explored explored [43–46]. [43–46]. As As an an example,example, neat grinding andand liquid-assisted liquid-assisted grinding grinding were were applied applied to to the preparation of six (already known) chiral bis-thioureas in quantitative yields by Štrukil et al. thethe preparation preparation of of six six (already (already known)known) chiral bis-thioureasbis-thioureas in in quantitative quantitative yields yields by by Štrukil Štrukil et al.et al. (Scheme3)[ 47]. Bhattacharjee et al. demonstrated the utility of phosphinoselenoicamide-supported (Scheme(Scheme 3) 3) [47]. [47]. Bhattacharjee Bhattacharjee etet al.al. demonstrateddemonstrated thethe utilityutility of of phosphinoselenoicamide-supported phosphinoselenoicamide-supported titanium(IV)titanium(IV) complex complex complex as as a a apre-catalyst pre-catalyst pre-catalyst forfor for the the additionaddition addition of of amines amines of amines to to carbodiimides, carbodiimides, to carbodiimides, isocyanates, isocyanates, isocyanates, and and isothiocyanatesandisothiocyanates isothiocyanates [48]. [48]. [48 1,3-Disubstituted1,3-Disubstituted]. 1,3-Disubstituted derivative derivativesss werewere were preparedprepared prepared in in 75–99% in75–99% 75–99% yield. yield. yield. Arafa Arafa Arafa et etal. et al. al. reportedreported onon on the the the ultrasound-assisted ultrasound-assisted ultrasound-assisted synthesis synthesissynthesis of bis-thioureas ofof bis-thioureasbis-thioureas from from isocyanatesfrom isocyanates isocyanates and diamines; and and diamines; diamines; medium mediumandmedium high and reaction and high high yieldreaction reaction were yield yield observed werewere observed after several afterafter minutes severalseveral minutes ofminutes sonication of of sonication sonication [49]. [49]. [49].

SchemeScheme 3. 3. MechanochemicalMechanochemical synthesis synthesis of of axially axially chiral chiral thiourea thiourea [47]. [47 ]. Scheme 3. Mechanochemical synthesis of axially chiral thiourea [47]. MethodsMethods involving involving inorganicinorganic isothiocyanatesisothiocyanates are are less less commonly commonly used, used, but but can can be betreated treated as an as an Methods involving inorganic isothiocyanates are less commonly used, but can be treated as an interestinginteresting option option when when the the requiredrequired organicorganic isothiocyanateisothiocyanate is is not not available. available. Herr Herr and and co-workers co-workers interesting option when the required organic isothiocyanate is not available. Herr and co-workers showedshowed that that monosubstituted monosubstituted andand symmetricalsymmetrical 1,3-di 1,3-disubstitutedsubstituted thioureas thioureas can can be beprepared prepared in high in high showed that monosubstituted and symmetrical 1,3-disubstituted thioureas can be prepared in high yieldsyields from from amine amine hydrohalides hydrohalides (including (including chiral chiral ones) ones) and and KSCN KSCN [ 50[50].]. OnceOnce preparedprepared thiourea can be yields from amine hydrohalides (including chiral ones) and KSCN [50]. Once prepared thiourea can easilybe easily modiﬁed modified as discussed as discusse ind Section in Section 2.5 ,2.5, to achieveto achieve the the necessary necessary substitution substitution pattern. pattern. be easilyAn modified interesting as example discusse ofd stereosein Sectionlective 2.5, preparationto achieve the of chiralnecessary cyclic substitution thioureas in pattern.the reaction of organicAn interesting isothiocyanates example with of N stereose-tosylimineslective was preparation demonstrated of chiral by Wang cyclic and thioureas co-workers in the [51]. reaction The of organicreaction isothiocyanates was efficiently withcatalyzed N-tosylimines by another waschiral, demonstrated rosin-derived by thiourea Wang (see and Section co-workers 3.7). [51]. The reactionMolecules was 2020 ,efficiently 25, x; doi: catalyzed by another chiral, rosin-derived thiourea www.mdpi.com (see Section/journal/molecules 3.7). Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, 401 4 of 56

An interesting example of stereoselective preparation of chiral cyclic thioureas in the reaction of organic isothiocyanates with N-tosylimines was demonstrated by Wang and co-workers [51]. TheMolecules reaction 2020, 25 was, x eﬃciently catalyzed by another chiral, rosin-derived thiourea (see Section 3.7).4 of 57

2.2. Reaction of Amines with Dithiocarbamates Preparation of of thioureas thioureas from from dithiocarbamate dithiocarbamate de derivativesrivatives and and amines amines (Scheme (Scheme 4)4 can) can serve serve as alternativeas alternative to tothe the route route involving involving isothiocyanates isothiocyanates (which (which are, are, in in fact, fact, formed formed in in the the course course of the reaction). However, However, only in certain protocols isolated, stable dithiocarbamates are used, and in most cases, they are prepared in situsitu fromfrom CSCS22 and amines (see SectionSection 2.32.3).). In the recent years, several reports of of efficient efficient preparations preparations of of diverse diverse dithiocarbamates dithiocarbamates have have been been published. published. A reaction A reaction in water in waterinvolving involving also α, alsoβ-unsaturatedα,β-unsaturated compounds, compounds, and solvent- and solvent- and catalyst-free and catalyst-free protocol protocol with alkyl with halides alkyl bothhalides furnished both furnished appropriately appropriately substituted substituted dithiocarb dithiocarbamatesamates as reported as reported by byAzizi Azizi et etal. al. [52,53]. [52,53]. Similarly, hydroxylated derivatives were prepared byby Ziyaei-HalimjaniZiyaei-Halimjani and SaidiSaidi fromfrom amines,amines, CSCS22 and epoxidesepoxides [ 54[54].]. Vinyl Vinyl pyridines pyridines and and vinyl vinyl pyrazine pyrazine served served as Michael as Michael acceptors acceptors in another in protocolanother protocolfor efficient for synthesisefficient synthesis of dithiocarbamates of dithiocarbamates [55]. In turn, [55]. the In use turn, of DEADthe use or of DIAD DEAD resulted or DIAD in productsresulted inbearing products a sulfur-nitrogen bearing a sulfur-nitrogen bond, which bond, were which found towere be efoundfficient to intermediatesbe efficient intermediates in the synthesis in the of synthesisthioureas, of isothiocyanates thioureas, isothioc andyanates thiocarbamates and thiocarbamates [56]. [56].

Scheme 4. PreparationPreparation of thioureas from diacarbamates and amines.

The majoritymajority ofof publications publications concerning concerning transformations transformations of dithiocarbamatesof dithiocarbamates into thioureasinto thioureas focus focuson the on synthesis the synthesis of achiral of achiral derivatives. derivatives. For example, For example, various various di- and di- trisubstituted and trisubstituted thioureas thioureas were wereobtained obtained in 63–92% in yield63–92% via yield the reaction via the of trimethylaminereaction of trimethylamine or DABCO salts or of DABCO dithiocarbamates salts of dithiocarbamatesand primary or and secondary primary amines or secondary [57]. Ceriumamines [57]. ammonium Cerium ammonium nitrate was nitrate used was as a used catalyst, as a catalyst,and the and condensation the condensation was carried was carried out in out acetonitrile in acetonitrile at room at room temperature temperature for for 2–24 2–24 h. h. AA series of 1-aryl-3,3-dimethylthioureas were were prepared in 70–92% yield from aryl amines which were firstfirst treated withwith sodiumsodium hydridehydride in in DMSO DMSO and and then then heated heated with withS-aryl- S-aryl-N,NN-dimethyldithiocarbamates,N-dimethyldithiocarbamates for for3–5 3–5 h at h 90 at◦ 90C, °C, with with the the release release of thiophenol of thiophenol byproduct byproduct [58]. [58]. Recently published methods show that the reac reactiontion can be performed in water under mild conditions. For For example, thiazolidine-2-thiones and secondary amines stirred in aqueous solution at 80 ◦°CC for 3–5 h withoutwithout a catalystcatalyst yieldedyielded trisubstitutedtrisubstituted thioureas in 60–90%60–90% yieldyield [[59].59]. In another preparation, unsymmetricalunsymmetrical thioureas thioureas were were formed formed when when primary primary or secondary or secondary amines, amines, either aliphatic either aliphaticor aromatic, or aromatic, were heated were with heated dithiocarbamates with dithiocarb (derivedamates from (derived primary from amines) primary at amines) 50–60 ◦C at and 50–60 under °C andsolvent-free under solvent-free conditions (Schemeconditions5)[ (Scheme60]. Yields 5) [60] ranged. Yields from ranged 64% to from 100%. 64% Among to 100%. various Among derivatives various derivativesobtained, three obtained, inherited three chirality inherited from chirality the amine, from and the fiveamine, from and the five dithiocarbamate. from the dithiocarbamate. The reaction can be also mediated by metals that are complexed with dithiocarbamate ligands. Dirksen et al. reported on the preparation of aH mixture of 1,3-disubstituted and trisubstituted thioureas S N S from bis(dimethyldithiocarbamato) zinc(II) and( )n primary amines [61]. Maddani and Prabhu used ( )n X * N N dioxomolybdenum dialkyl dithiocarbamates* N S and primary aminesH to prepareX eleven thioureas in 51–85% H o yield (Scheme6)[ 62]. The reaction was conductedneat, 60 C in refluxing toluene under nitrogen for 0.5–3 h. X = CH2, n = 1,2 quant. Four chiral derivatives were preparedX starting = O, n = 2 from methyl esters of l-phenylalanine, l-tyrosine, and l-leucine. NH2 R S S

R * N N * N S H H H neat, 60 oC R = H, OMe 70-85%

* S S NH2 R * R N N N S H H H neat, 60 oC 64-100% R = C5H11, 4-MeOC6H4, 1-adamantyl

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x 4 of 57

2.2. Reaction of Amines with Dithiocarbamates Preparation of thioureas from dithiocarbamate derivatives and amines (Scheme 4) can serve as alternative to the route involving isothiocyanates (which are, in fact, formed in the course of the reaction). However, only in certain protocols isolated, stable dithiocarbamates are used, and in most cases, they are prepared in situ from CS2 and amines (see Section 2.3). In the recent years, several reports of efficient preparations of diverse dithiocarbamates have been published. A reaction in water involving also α,β-unsaturated compounds, and solvent- and catalyst-free protocol with alkyl halides both furnished appropriately substituted dithiocarbamates as reported by Azizi et al. [52,53]. Similarly, hydroxylated derivatives were prepared by Ziyaei-Halimjani and Saidi from amines, CS2 and epoxides [54]. Vinyl pyridines and vinyl pyrazine served as Michael acceptors in another protocol for efficient synthesis of dithiocarbamates [55]. In turn, the use of DEAD or DIAD resulted in products bearing a sulfur-nitrogen bond, which were found to be efficient intermediates in the synthesis of thioureas, isothiocyanates and thiocarbamates [56].

Scheme 4. Preparation of thioureas from diacarbamates and amines.

The majority of publications concerning transformations of dithiocarbamates into thioureas focus on the synthesis of achiral derivatives. For example, various di- and trisubstituted thioureas were obtained in 63–92% yield via the reaction of trimethylamine or DABCO salts of dithiocarbamates and primary or secondary amines [57]. Cerium ammonium nitrate was used as a catalyst, and the condensation was carried out in acetonitrile at room temperature for 2–24 h. A series of 1-aryl-3,3-dimethylthioureas were prepared in 70–92% yield from aryl amines which were first treated with sodium hydride in DMSO and then heated with S-aryl-N,N-dimethyldithiocarbamates for 3–5 h at 90 °C, with the release of thiophenol byproduct [58]. Recently published methods show that the reaction can be performed in water under mild conditions. For example, thiazolidine-2-thiones and secondary amines stirred in aqueous solution at 80 °C for 3–5 h without a catalyst yielded trisubstituted thioureas in 60–90% yield [59]. In another preparation, unsymmetrical thioureas were formed when primary or secondary amines, either aliphatic or aromatic, were heated with dithiocarbamates (derived from primary amines) at 50–60 °C andMolecules under2020 solvent-free, 25, 401 conditions (Scheme 5) [60]. Yields ranged from 64% to 100%. Among various5 of 56 derivatives obtained, three inherited chirality from the amine, and five from the dithiocarbamate.

H S N S ( )n ( ) N N n * N S X * X H H neat, 60 oC

X = CH2, n = 1,2 quant. Molecules 2020, 25, x X = O, n = 2 5 of 57

NH2 R S Scheme 5. Solvent-free synthesisS of non-racemic thioureas from dithiocarbamates and amines [60]. Molecules 2020, 25, x 5 of 57 R * N N * N S H H The reaction can be also Hmediated by metals that are complexed with dithiocarbamate ligands. neat, 60 oC Scheme 5. Solvent-free synthesis of non-racemic thioureas from dithiocarbamates and amines [60]. Dirksen et al. reported on the preparationR = H, of OMe a mixture of 70-85%1,3-disubstituted and trisubstituted thioureas from bis(dimethyldithiocarbamato) zinc(II) and primary amines [61]. Maddani and Prabhu The reaction can be also mediated by metals that are complexed with dithiocarbamate ligands. used dioxomolybdenum dialkyl dithiocarbamates* and primaryS amines to prepare eleven thioureas Dirksen et al. reported on theS preparation of aNH mixture2 of 1,3-disubstituted and trisubstituted in 51–85% yield (Scheme 6) [62]. The reaction was conductedR in refluxing* toluene under nitrogen for thioureas from bis(dimethyldithiocarbamato)R zinc(II) and primaryN N amines [61]. Maddani and Prabhu 0.5–3 h. Four chiral derivativesN wereS prepared starting fromH methylH esters of L-phenylalanine, L- used dioxomolybdenum dialkylH dithiocarbamateso and primary amines to prepare eleven thioureas tyrosine, and L-leucine. neat, 60 C in 51–85% yield (Scheme 6) [62]. The reaction was conducted in64-100% refluxing toluene under nitrogen for The formation of thioureasR = uponC5H11, 4-MeOCself-condensat6H4, 1-adamantylion of trialkylammonium dithiocarbamates was 0.5–3 h. Four chiral derivatives were prepared starting from methyl esters of L-phenylalanine, L- reportedScheme as well 5. [63]. Moleculestyrosine, 2020 and, 25 L, -leucine.x;Solvent-free doi: synthesis of non-racemic thioureas from dithiocarbamates www.mdpi.com and amines/journal/molecules [60]. The formation of thioureas upon self-condensationNH of trialkylammonium dithiocarbamates was S S 2 2 S COOMe O O R reported as well [63].1 1 R Mo R COOMe R1 R2 N S S N N N H 1 1 toluene (reflux),NH2 N2 1 R S O O S R R2 R S COOMe 1 3-3.5 h 1 R = Me, Et 1 1 2 R 2Mo R COOMe R R N RS = iPr,S Pr, 4-HOCN 6H4 N 51-58%N toluene (reflux), N H R1 R1 2 R1 Scheme 6. The use of coordinated dithiocarabamate3-3.5 h in the preparation of chiral thiourea [62]. Scheme 6. The use Rof1 =coordinated Me, Et dithiocarabamate in the preparation of chiral thiourea [62]. R2 = iPr, Pr, 4-HOC H 51-58% 6 4 2.3. TheThe Use formation of Carbon of Disulfide thioureas upon self-condensation of trialkylammonium dithiocarbamates was reportedScheme as well 6. [63 The]. use of coordinated dithiocarabamate in the preparation of chiral thiourea [62]. Reactions of amines with carbon disulfide serve as a simple method for the preparation of 2.3.symmetrical, The Use of 1,3-disubstituted Carbon Disulfide Disulfide thioureas. Using a modified protocol with two different amines opens the route to unsymmetrical, mono-, di- or trisubstituted products (Scheme 7). Transient formation of Reactions of amines with carbon disulfidedisulfide serve as a simple method for the preparation of dithiocarbamates and isothiocyanates was suggested as a key step in the mechanism of the process symmetrical, 1,3-disubstituted thioureas. Using a mo modifieddified protocol with two different different amines opens [1]. Like other C=S transfer reagents, carbon disulfide is not free of drawbacks: it is flammable, volatile the route to unsymmetrical, mono-, di- or trisubstituted products (Scheme7 7).). TransientTransient formationformation ofof (which requires an excess to be used), and has an unpleasant smell. Atom economy suffers from the dithiocarbamates andand isothiocyanatesisothiocyanates was was suggested suggested as as a keya key step step in in the the mechanism mechanism of theof the process process [1]. formation of sulfur-containing by-product, usually hydrogen sulfide. The reaction is typically Like[1]. Like other other C= SC=S transfer transfer reagents, reagents, carbon carbon disulfide disulfide is is not not free free of of drawbacks: drawbacks: it it isis flammable,flammable, volatile performed in organic solvents at elevated temperature and is relatively slow; it can be accelerated by (which(which requires an an excess excess to to be be used), used), and and has has an an unpleasant unpleasant smell. smell. Atom Atom economy economy suffers suff ersfrom from the addition of bases or oxidants to remove H2S [1]. Furthermore, CBr4 was shown by Liang et al. to theformation formation of sulfur-containing of sulfur-containing by-product, by-product, usually usually hydrogen hydrogen sulfide. sulfide. The The reaction reaction is is typicallytypically efficiently promote the reaction [64]. performed in organic solvents at elevated temperature and is relatively slow; it can be accelerated by addition of basesbases oror oxidantsoxidants toto removeremove HH22S[S [1].1]. Furthermore, CBr4 was shown by LiangLiang etet al.al. to eefficientlyfficiently promote thethe reactionreaction [[64].64].

Scheme 7. Synthesis of symmetrical and unsymmetrical thioureas from carbon disulfide and amines.

Most recent modifications involve the use of water, a convenient and green solvent, as reaction mediumScheme [65]. 7. ASynthesis simple of condensation symmetrical and between unsymmetrical amines thioureas and carbon from disulfide carbon disulﬁdedisulfide in refluxing and amines. water was described by Maddani and Prabhu as a route to symmetrical and unsymmetrical di- and Most recent modifications involve the use of water, a convenient and green solvent, as reaction trisubstituted thiourea derivatives [66]. The method worked well with aliphatic amines: in the first medium [65]. A simple condensation between amines and carbon disulfide in refluxing water was step, a secondary or primary amine was treated with CS2 in aqueous NaOH under ambient conditions described by Maddani and Prabhu as a route to symmetrical and unsymmetrical di- and and thus prepared dithiocarbamates were heated under reflux with primary amines for 3–12 h; after trisubstituted thiourea derivatives [66]. The method worked well with aliphatic amines: in the first acidic work-up the desired thioureas were isolated in good to high yields (19 examples, 40–93%, step, a secondary or primary amine was treated with CS2 in aqueous NaOH under ambient conditions Scheme 8). The use of racemic 1-phenylethylamine and (1R,2R)-1,2-diaminocyclohexane illustrates and thus prepared dithiocarbamates were heated under reflux with primary amines for 3–12 h; after the possibility of using the protocol to the synthesis of chiral derivatives (Scheme 9). acidic work-up the desired thioureas were isolated in good to high yields (19 examples, 40–93%, Scheme 8). The use of racemic 1-phenylethylamine and (1R,2R)-1,2-diaminocyclohexane illustrates theMolecules possibility 2020, 25 ,of x; doi:using the protocol to the synthesis of chiral derivatives www.mdpi.com(Scheme 9). /journal/molecules

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, 401 6 of 56

Most recent modifications involve the use of water, a convenient and green solvent, as reaction medium [65]. A simple condensation between amines and carbon disulfide in refluxing water was described by Maddani and Prabhu as a route to symmetrical and unsymmetrical di- and trisubstituted thiourea derivatives [66]. The method worked well with aliphatic amines: in the first step, a secondary or primary amine was treated with CS2 in aqueous NaOH under ambient conditions and thus prepared dithiocarbamates were heated under reflux with primary amines for 3–12 h; after acidic work-up the desired thioureas were isolated in good to high yields (19 examples, 40–93%, Scheme8). The use of Moleculesracemic 2020 1-phenylethylamine, 25, x and (1R,2R)-1,2-diaminocyclohexane illustrates the possibility of6 using of 57 Molecules 2020, 25, x 6 of 57 theMolecules protocol 2020, 25 to, thex synthesis of chiral derivatives (Scheme9). 6 of 57

Scheme 8. Preparation of thioureas in refluxing water [66]. Scheme 8. Preparation of thioureas in refluxing reﬂuxing water [[66].66].

Scheme 9. Synthesis of a chiral, racemic thiourea from diamine and CS2 [66]. Scheme 9. Synthesis of a chiral, racemic thiourea from diamine and CS [66]. Scheme 9. Synthesis of a chiral, racemic thiourea from diamine and CS22 [66]. Two chiral Schemeand twenty-three 9. Synthesis achiralof a chiral, symmetrical racemic thiourea disubstituted from diamine thioureas and CS were2 [66]. prepared in 70– 97% yieldTwo chiral chiralby Azizi andand et twenty-three twenty-three al. from various achiral achiral primary symmetrical symmetrical amines disubstituted anddisubstituted CS2; the thioureas reaction thioureas was were were carried prepared prepared out in in 70–97% inwater 70– yieldTwo by Azizi chiral et al.and from twenty-three various primary achiral amines symmetrical and CS disubstituted; the reaction thioureas was carried were out inprepared water at in 60 70–C at97% 60 yield°C for by 1–12 Azizi h (aromaticet al. from amines various required primary a amines longer andreaction2 CS2; time)the reaction and purification was carried involved out in water only◦ 97% yield by Azizi et al. from various primary amines and CS2; the reaction was carried out in water filtration,for 1–12 h washing (aromatic with amines water required and recrystallization a longer reaction from time) ethanol and puriﬁcationor diethyl ether involved [67]. Six only years ﬁltration, later, at 60 °C for 1–12 h (aromatic amines required a longer reaction time) and purification involved only washingthe same with group water described and recrystallization an ultrasound-assisted from ethanol orsynthesis diethyl ether of [1,3-disubstituted,67]. Six years later, but the samealso filtration, washing with water and recrystallization from ethanol or diethyl ether [67]. Six years later, trisubstitutedgroup described thiourea an ultrasound-assisted derivatives (Scheme synthesis 10) of[68]. 1,3-disubstituted, The reaction butwas also performed trisubstituted in water thiourea or the same group described an ultrasound-assisted synthesis of 1,3-disubstituted, but also polyethylenederivatives (Scheme glycol, 10and)[68 in]. the The latter reaction yields was were performed higher in in water most or cases polyethylene (60–97% glycol,after 3–6 and min inthe of trisubstituted thiourea derivatives (Scheme 10) [68]. The reaction was performed in water or sonicationlatter yields at were30–35 higher °C). Among in most 27 cases products, (60–97% two afterenantiomers 3–6 min of of 1,3-bis(1-phenylethyl)thiourea sonication at 30–35 ◦C). Among were 27 polyethylene glycol, and in the latter yields were higher in most cases (60–97% after 3–6 min of prepared,products, twoboth enantiomers in 97% yield. of 1,3-bis(1-phenylethyl)thiourea were prepared, both in 97% yield. sonication at 30–35 °C). Among 27 products, two enantiomers of 1,3-bis(1-phenylethyl)thiourea were prepared, both in 97% yield.

Scheme 10. Ultrasound-assisted synthesis of chiral thioureas [68]. Scheme 10. Ultrasound-assisted synthesis of chiral thioureas [68].

Scheme 10. Ultrasound-assisted synthesis of chiral thioureas [68]. Seventeen N-N-sulfonylcyclothioureas,sulfonylcyclothioureas,Scheme 10. Ultrasound-assisted including including synthesis 1 chiral1 chiral derivative,of chiralderivative, thioureas were were prepared[68]. prepared in 60–87% in 60–87% yield by Wan et al. in the reaction of corresponding amines with carbon disulfide in water catalyzed by yieldSeventeen by Wan et N-al.sulfonylcyclothioureas, in the reaction of corresponding including amines 1 chiral with derivative, carbon disulfide were prepared in water in catalyzed 60–87% silicaSeventeen [69]. An effi N-cientsulfonylcyclothioureas, (90–99% yield), green including (water used 1 aschiral solvent), derivative, catalyst- were and chromatography-freeprepared in 60–87% byyield silica by Wan [69]. et al.An in efficientthe reaction (90–99% of corresponding yield), green amines (water with carbonused asdisulfide solvent), in watercatalyst- catalyzed and protocolyield by forWan symmetrical, et al. in the bis-aliphaticreaction of corresponding thioureas was alsoamines developed with carbon by Jangale disulfide et al. in [70 water]. Milosavljević catalyzed chromatography-freeby silica [69]. An protocolefficient for(90–99% symmetrical, yield), bis-aliphatic green (water thioureas used was as alsosolvent), developed catalyst- by Jangale and etby al.silica described [69]. theAn environmentallyefficient (90–99% friendly yield), methodology green (water involving used theas usesolvent), of oxidants catalyst- (sodium and etchromatography-free al. [70]. Milosavljevi protocolć et al. described for symmetrical, the environmentally bis-aliphatic thioureasfriendly methodology was also developed involving by Jangalethe use percarbonatechromatography-free+ EDTA protocol system for was symmetrical, most efficient, bis-aliphatic but also thioureas H O and was air also were developed tested) and by solventJangale ofet al.oxidants [70]. Milosavljevi (sodium percarbonateć et al. described + EDTA the environmentally system was most friendly 2efficient,2 methodology but also H involving2O2 and air the were use recyclinget al. [70]. [Milosavljevi71]. Other modificationsć et al. described of reactionthe environmentally conditions for friendly the reaction methodology of amines involving with CS the2 have use tested)of oxidants and (sodiumsolvent recyclingpercarbonate [71]. +Other EDTA modifications system was mostof reaction efficient, conditions but also forH2O the2 and reaction air were of beenof oxidants proposed, (sodium including percarbonate green variants: + EDTA the system use of solar was energymost efficient, [72], microwaves but also [H732O,742 ],and ionic air liquid were aminestested) andwith solvent CS2 have recycling been proposed,[71]. Other includingmodifications green of variants:reaction theconditions use of forsolar the energy reaction [72], of mediatested) [75and,76 solvent]. recycling [71]. Other modifications of reaction conditions for the reaction of microwavesamines with [73,74], CS2 have ionic been liquid proposed, media [75,76]. including green variants: the use of solar energy [72], amines with CS2 have been proposed, including green variants: the use of solar energy [72], Ten chiral thioureas were prepared byby VVázquezázquez etet al.al. in the reaction of enantiopure primary microwaves [73,74], ionic liquid media [75,76]. amines (including(including four four pairs pairs of enantiomers)of enantiomers) with carbonwith carbon disulfide disulfide under either under solvent-free either solvent-free conditions Ten chiral thioureas were prepared by Vázquez et al. in the reaction of enantiopure primary conditionsor using microwave or using irradiationmicrowave in irradiation ethanol (Scheme in ethanol 11)[77 (Scheme]. Simple 11) mixing [77]. of Simple liquid reactantsmixing of resulted liquid amines (including four pairs of enantiomers) with carbon disulfide under either solvent-free reactantsin immediate resulted and in high immediate yielding and (91–97%) high yielding reaction, (91–97%) though productreaction, isolation though product and purification isolation wasand conditions or using microwave irradiation in ethanol (Scheme 11) [77]. Simple mixing of liquid purificationrequired. Slightly was required. lower yields Slightly (81–95%) lower yields were noted(81–95%) for 5were min noted of MW for irradiation, 5 min of MW however, irradiation, pure reactants resulted in immediate and high yielding (91–97%) reaction, though product isolation and however, pure products crystallized from ethanol used as solvent. Conventional heating was found purification was required. Slightly lower yields (81–95%) were noted for 5 min of MW irradiation, time-consuming and less efficient (75–88% yield). however, pure products crystallized from ethanol used as solvent. Conventional heating was found time-consuming and less efficient (75–88% yield).

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x 6 of 57

Scheme 8. Preparation of thioureas in refluxing water [66].

Scheme 9. Synthesis of a chiral, racemic thiourea from diamine and CS2 [66].

Two chiral and twenty-three achiral symmetrical disubstituted thioureas were prepared in 70– 97% yield by Azizi et al. from various primary amines and CS2; the reaction was carried out in water at 60 °C for 1–12 h (aromatic amines required a longer reaction time) and purification involved only filtration, washing with water and recrystallization from ethanol or diethyl ether [67]. Six years later, the same group described an ultrasound-assisted synthesis of 1,3-disubstituted, but also trisubstituted thiourea derivatives (Scheme 10) [68]. The reaction was performed in water or polyethylene glycol, and in the latter yields were higher in most cases (60–97% after 3–6 min of sonication at 30–35 °C). Among 27 products, two enantiomers of 1,3-bis(1-phenylethyl)thiourea were prepared, both in 97% yield.

Scheme 10. Ultrasound-assisted synthesis of chiral thioureas [68].

Seventeen N-sulfonylcyclothioureas, including 1 chiral derivative, were prepared in 60–87% yield by Wan et al. in the reaction of corresponding amines with carbon disulfide in water catalyzed by silica [69]. An efficient (90–99% yield), green (water used as solvent), catalyst- and chromatography-free protocol for symmetrical, bis-aliphatic thioureas was also developed by Jangale et al. [70]. Milosavljević et al. described the environmentally friendly methodology involving the use of oxidants (sodium percarbonate + EDTA system was most efficient, but also H2O2 and air were tested) and solvent recycling [71]. Other modifications of reaction conditions for the reaction of amines with CS2 have been proposed, including green variants: the use of solar energy [72], microwaves [73,74], ionic liquid media [75,76]. Ten chiral thioureas were prepared by Vázquez et al. in the reaction of enantiopure primary amines (including four pairs of enantiomers) with carbon disulfide under either solvent-free conditions or using microwave irradiation in ethanol (Scheme 11) [77]. Simple mixing of liquid Molecules 2020, 25, 401 7 of 56 reactants resulted in immediate and high yielding (91–97%) reaction, though product isolation and purification was required. Slightly lower yields (81–95%) were noted for 5 min of MW irradiation, however,products crystallizedpure products from crystalliz ethanoled used from as ethanol solvent. used Conventional as solvent. heating Conventional was found heating time-consuming was found time-consumingand less eﬃcient and (75–88% less efficient yield). (75–88% yield).

Molecules 2020,, 25,, xx 7 of 57 Molecules 2020, 25, x 7 of 57

Scheme 11. Preparation of chiral, symmetrical thioureas from CS2 and amines [77]. Molecules 2020, 25Scheme, x; doi: 11. Preparation of chiral, symmetrical thioureas from CS2 www.mdpi.comand amines [77]./journal/molecules Scheme 11. Preparation of chiral, symmetrical thioureas from CS22 and amines [77]. [77]. In 2019, a route to unsymmetrical thioureas was proposed by Dutta et al. involving the reaction In 2019,2019, aa routeroute toto unsymmetrical unsymmetrical thioureas thioureas was was proposed proposed by by Dutta Dutta et et al. al. involving involvinginvolving the thethe reaction reactionreaction of of dithiocarbamate anions, generated in situ from secondary or primary amines and carbon disulfide ofdithiocarbamate dithiocarbamate anions, anions, generated generated in in situ situ from from secondary secondary or or primary primary amines amines andand carboncarbon disulﬁdedisulfide at low temperature, with aromatic nitro compounds (Scheme 12) [78]. DMF as solvent, potassium at lowlow temperature,temperature, withwith aromaticaromatic nitronitro compoundscompounds (Scheme(Scheme 1212))[ [78].78]. DMF asas solvent,solvent, potassiumpotassium carbonate as a base, and temperature of 100 °C were established as optimal conditions for the second carbonate as a base, and temperature of 100 °CC were were established as optimal conditions for the second step of the reaction. Among 22 derivatives obtained◦ in 77–93% yield after 4–6 h one was chiral, but step of of the the reaction. reaction. Among Among 22 22 derivatives derivatives obtained obtained in in77–93% 77–93% yield yield after after 4–6 4–6h one h onewas waschiral, chiral, but apparently racemic (Scheme 13). The postulated reaction mechanism involved the formation of apparentlybut apparently racemic racemic (Sch (Schemeeme 13). 13 The). The postulated postulated reaction reaction mechanism mechanism involved involved the the formation formation of 2 2 3 nitrosoaryl intermediate and release of SO2 (consumed(consumed byby KK2CO3) as a by-product resulting from nitrosoaryl intermediate and release of SOSO2 (consumed by KK2CO3)) as as a a by-product resulting from dithiocarbamate oxidation by nitroarene. 2 2 3 dithiocarbamate oxidation byby nitroarene.nitroarene.

Scheme 12. Preparation of thioureas from nitro compounds, carbon disulfide and amines [78]. Scheme 12. PreparationPreparation of of thioureas thioureas from nitro compou compounds,nds, carbon disulﬁdedisulfide and amines [[78].78].

Scheme 13. AA racemic thiourea prepared by Dutta et al [[78].78]. Scheme 13. A racemic thiourea prepared by Dutta et al [78]. Organic azides were also converted to the corresponding thioureas.thioureas. Kumar et al. reported on the Organic azides were also converted to the corresponding thioureas. Kumar et al. reported on the synthesis of thioureido peptidomimetics using N-protected amino alkyl azides and dithiocarbamoic synthesis of thioureido peptidomimetics using N-protected amino alkyl azides and dithiocarbamoic acids formed formed in in situ situ from from carbon carbon disulfide disulﬁde and and primary primary or secondary or secondary amines amines (Scheme (Scheme 14) [79].14)[ The79]. acids formed inin situsitu from carbon disulfide and primary or secondary amines (Scheme 14) [79]. The The reaction proceeded with the liberation of2 N and sulfur; it was performed in THF in the presence reaction proceeded with the liberation of N2 andand2 sulfur;sulfur; itit waswas performedperformed inin THFTHF inin thethe presencepresence ofof reaction proceeded with the liberation of N2 and sulfur; it was performed in THF in the presence of pyridineof pyridine at at0 °C 0 ◦ Cto toroom room temperature temperature under under inert inert atmosphere atmosphere for for 6 6 h. h. Fifteen Fifteen enantiomerically enantiomerically pure pyridine at 0 °C to room temperature under inert atmosphere for 6 h. Fifteen enantiomericallyenantiomerically purepure derivatives were isolated in 72–85% yield. derivatives were isolated in 72–85% yield.

Scheme 14. Azides in the syntheisis of thioureas [79]. [79]. Scheme 14. Azides in the syntheisis of thioureas [79]. 2.4. Application of Other Compounds Containing C=S Bond 2.4. Application of Other Compounds Containing C=S Bond 2.4. Application of Other Compounds Containing C=S Bond Less frequently, other thioorganic compounds ﬁnd their application in the synthesis of thioureas, Less frequently, other thioorganic compounds find their application in the synthesis of bothLess chiral frequently, and achiral other derivatives. thioorganic In the past,compounds a reaction find of thiophosgene their application with primaryin the orsynthesis secondary of thioureas, both chiral and achiral derivatives. In the past, a reaction of thiophosgene with primary or thioureas,aminesthioureas, was bothboth used chiralchiral in such andand preparations, achiralachiral derivatives.derivatives. though InIn this thethe source past,past, aa of reactionreaction C=S fragment ofof thiophosgenethiophosgene has not gained withwith primaryprimary popularity oror secondary amines was used in such preparations, though this source of C=S fragment has not gained secondary amines was used in such preparations, though this source of C=S fragment has not gained popularity due to its corrosive and toxic properties [80]. However, its reaction with diamines was a popularity due to its corrosive and toxic properties [80].[80]. However,However, itsits reactionreaction withwith diaminesdiamines waswas aa key step in the synthesis of chiral cyclic thiourea ligands for palladium-catalyzed reactions by Yang key step in the synthesis of chiral cyclic thiourea ligands for palladium-catalyzed reactions by Yang and co-workers (Scheme 15) [81,82]. 1-(Methyldithiocarbonyl)imidazole and its quaternary N- and co-workers (Scheme 15) [81,82]. 1-(Methyldithiocarbonyl)imidazole and its quaternary N- methylated salt were found by Mohanta et al. to be effective thiocarbonyl transfer agents which methylated salt were found by Mohanta et al. toto bebe effectiveeffective thiocarbonylthiocarbonyl transfertransfer agentsagents whichwhich allowed preparation of mono-, di- and trisubstituted thioureas (though not chiral) under mild allowed preparation of mono-, di- and trisubstituted thioureas (though not chiral) under mild conditions [83]. conditions [83].

Molecules 2020,, 25,, x;x; doi:doi: www.mdpi.com www.mdpi.com/journal/molecules/journal/molecules Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x 7 of 57

Scheme 11. Preparation of chiral, symmetrical thioureas from CS2 and amines [77].

In 2019, a route to unsymmetrical thioureas was proposed by Dutta et al. involving the reaction of dithiocarbamate anions, generated in situ from secondary or primary amines and carbon disulfide at low temperature, with aromatic nitro compounds (Scheme 12) [78]. DMF as solvent, potassium carbonate as a base, and temperature of 100 °C were established as optimal conditions for the second step of the reaction. Among 22 derivatives obtained in 77–93% yield after 4–6 h one was chiral, but apparently racemic (Scheme 13). The postulated reaction mechanism involved the formation of nitrosoaryl intermediate and release of SO2 (consumed by K2CO3) as a by-product resulting from dithiocarbamate oxidation by nitroarene.

Scheme 12. Preparation of thioureas from nitro compounds, carbon disulfide and amines [78].

Scheme 13. A racemic thiourea prepared by Dutta et al [78].

Organic azides were also converted to the corresponding thioureas. Kumar et al. reported on the synthesis of thioureido peptidomimetics using N-protected amino alkyl azides and dithiocarbamoic acids formed in situ from carbon disulfide and primary or secondary amines (Scheme 14) [79]. The reaction proceeded with the liberation of N2 and sulfur; it was performed in THF in the presence of pyridine at 0 °C to room temperature under inert atmosphere for 6 h. Fifteen enantiomerically pure derivatives were isolated in 72–85% yield.

Scheme 14. Azides in the syntheisis of thioureas [79].

2.4. Application of Other Compounds Containing C=S Bond Less frequently, other thioorganic compounds find their application in the synthesis of thioureas,Molecules 2020 both, 25, 401chiral and achiral derivatives. In the past, a reaction of thiophosgene with primary8 of or 56 secondary amines was used in such preparations, though this source of C=S fragment has not gained popularity due to its corrosive and toxic properties [80]. However, its reaction with diamines was a keydue step to its in corrosive the synthesis and toxic of chiral properties cyclic [ 80thiourea]. However, ligands its reactionfor palladium-catalyzed with diamines was reactions a key step by inYang the andsynthesis co-workers of chiral (Scheme cyclic thiourea 15) [81,82]. ligands 1-(Methyldithiocarbonyl)imidazole for palladium-catalyzed reactions byand Yang its andquaternary co-workers N- (Schememethylated 15)[ salt81, 82were]. 1-(Methyldithiocarbonyl)imidazole found by Mohanta et al. to be effective and its thiocarbonyl quaternary N- transfermethylated agents salt which were allowedfound by preparation Mohanta et of al. mono-, to be e ﬀdi-ective and thiocarbonyl trisubstituted transfer thioureas agents (though which not allowed chiral) preparation under mild of conditionsmono-, di- and[83]. trisubstituted thioureas (though not chiral) under mild conditions [83].

Molecules 2020, 25, x 8 of 57 Molecules 2020, 25, x 8 of 57 Molecules 2020, 25, x 8 of 57 Scheme 15. The use of thiophosgene in the preparation of a chiral cyclic thiourea [81]. Scheme 15. The use of thiophosgene in the preparation of a chiral cyclic thiourea [81]. Scheme 15. The use of thiophosgene in the preparation of a chiral cyclic thiourea [81]. Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Furthermore,Scheme 15.achiralThe use derivatives of thiophosgene were in prepar the preparationed in the of areaction chiral cyclic of thioureaamines [ 81with]. thiuram Furthermore, achiral derivatives were prepared in the reaction of amines with thiuram disulfides Furthermore, (Scheme achiral16) or monosulfidesderivatives were (in turnprepar obtaineded in thefrom reaction dithiocarbamates) of amines with[84]. Lithiuram et al. disulfides (Scheme 16) or monosulfides (in turn obtained from dithiocarbamates) [84]. Li et al. disulfidesdevelopedFurthermore, (Schemea protocol achiral 16) utilizing or derivatives monosulfides phenyl were chlorothionoformate (in prepared turn obtained in the reaction [85,86]. from of dithiocarbamates)Its amines reaction with with thiuram primary [84]. disulfidesLi amines et al. developed a protocol utilizing phenyl chlorothionoformate [85,86]. Its reaction with primary amines developed(Scheme(either aliphatic 16 a) protocol or monosulfidesor aromatic) utilizing in (inphenyl refluxing turn chlorothionoformate obtained water carried from dithiocarbamates) out [85,86].for 2–12 Its h reaction(though [84]. with2–3 Li eth primary were al. developed sufficient amines (either aliphatic or aromatic) in refluxing water carried out for 2–12 h (though 2–3 h were sufficient (eitherina protocolmost aliphatic cases) utilizing affordedor aromatic) phenyl a series chlorothionoformate in refluxing of 17 symmetr water carriedical, [85,86 1,3-disubstituted out]. Its for reaction 2–12 h (though with thioureas primary 2–3 hin were amines60–99% sufficient (either yield in most cases) afforded a series of 17 symmetrical, 1,3-disubstituted thioureas in 60–99% yield in(Schemealiphatic most cases)17) or aromatic)[85]. afforded Among in refluxing athem, series two waterof enantiomerically17 carriedsymmetr outical, for pure1,3-disubstituted 2–12 derivatives h (though were 2–3 thioureas h prepared. were suinffi 60–99% cientThe protocol in yield most (Scheme 17) [85]. Among them, two enantiomerically pure derivatives were prepared. The protocol (Schemewascases) also aff orded17)used [85]. to a series obtainAmong of thione 17them, symmetrical, he twoterocycles, enantiomerically 1,3-disubstituted however, pureit failed thioureas derivatives in the in attempts 60–99%were prepared. with yield a (Scheme mixture The protocol 17 of)[ two85]. was also used to obtain thione heterocycles, however, it failed in the attempts with a mixture of two wasAmongamines also aimed them, used totwoto obtain yield enantiomerically thioneunsymmetrically heterocycles, pure substitu derivatives however,ted wereproducts.it failed prepared. in Such the attempts Thecompounds protocol with coulda was mixture also be usedformed of two to amines aimed to yield unsymmetrically substituted products. Such compounds could be formed aminesusingobtain a thione aimedtwo-step heterocycles,to yieldroute: unsymmetrically amines however, were it first failed substitu reacte in thetedd with attemptsproducts. chloroformate with Such a mixturecompounds in water of two couldfor amines 1 beh atformed aimedroom using a two-step route: amines were first reacted with chloroformate in water for 1 h at room usingtemperatureto yield a unsymmetricallytwo-step [86]. route:Then, aminesthe substituted result wereing products. thiocarbamatefirst reacte Suchd with compoundswas chloroformate converted could into bein formedthewater desired for using 1thiourea h a two-stepat room by temperature [86]. Then, the resulting thiocarbamate was converted into the desired thiourea by temperatureheatingroute: amines with another[86]. were Then, first (more reactedthe reactive) result withing amine chloroformate thiocarbamate for 20–80 inmin was water at converted100 for °C 1 h(Scheme at into room 18).the temperature Thedesired yields thiourea [were86]. Then, high by heating with another (more reactive) amine for 20–80 min at 100 °C (Scheme 18). The yields were high heating(87–95%the resulting with for theanother thiocarbamate first (morestep, 75–97%reactive) was converted for amine the forsecond into 20–80 the one), desired min productsat 100 thiourea °C (Scheme(none by heatingof 18). them The with were yields another chiral) were (more werehigh (87–95% for the first step, 75–97% for the second one), products (none of them were chiral) were (87–95%isolatedreactive) byfor amine filtration the forfirst 20–80 andstep, washed min 75–97% at 100 with for◦C thewater, (Scheme second with 18 outone),). The the products yields need of were (nonefurther high of purification. (87–95%them were for theThechiral) first reaction were step, isolated by filtration and washed with water, without the need of further purification. The reaction isolatedcould75–97% be forby performed thefiltration second on and one), a gramwashed products scale. with (none water, of them with wereout the chiral) need were of further isolated purification. by filtration The and reaction washed couldwith water, be performed without theon a need gram of scale. further purification. The reaction could be performed on a gram scale.

Scheme 16. Thiuram disulfide as a reactant in preparation of thioureas [84]. Scheme 16. Thiuram disulfide as a reactant in preparation of thioureas [84]. Scheme 16. ThiuramThiuram disulfide disulﬁde as as a a reactant in preparation of thioureas [[84].84].

Scheme 17. Synthesis of symmetrical thioureas from phenyl chlorothionoformate and amine [85]. Scheme 17. SynthesisSynthesis of symmetrical thioureas from ph phenylenyl chlorothionoformate and amine [[85].85]. Scheme 17. Synthesis of symmetrical thioureas from phenyl chlorothionoformate and amine [85].

SchemeScheme 18. Two-stepTwo-step approach to unsymmetrical thiour thioureaseas from phenyl chlorothionoformate [[86].86]. Scheme 18. Two-step approach to unsymmetrical thioureas from phenyl chlorothionoformate [86]. Scheme 18. Two-step approach to unsymmetrical thioureas from phenyl chlorothionoformate [86]. 2.5. Preparation of Chiral Thioureas from Other Thioureas 2.5. Preparation of Chiral Thioureas from Other Thioureas 2.5. Preparation of Chiral Thioureas from Other Thioureas 2.5. PreparationThe thiocarbonyl of Chiral moiety Thioureas of chiralfrom Other thiourea Thioureas can also originate from achiral ones, subjected to an The thiocarbonyl moiety of chiral thiourea can also originate from achiral ones, subjected to an appropriateThe thiocarbonyl modiﬁcation. moiety In principle, of chiral it thiourea is possible can to also preserve originate the original from achiral skeleton ones, and subjected replace groups to an appropriateThe thiocarbonyl modification. moiety In principlof chirale, thiourea it is possible can also to originatepreserve fromthe original achiral skeletonones, subjected and replace to an attachedappropriate to the modification. nitrogen atom(s), In principl changinge, it theis possible substitution to preserve pattern. Forthe example,original skeleton the thiazolidine and replace motif appropriategroups attached modification. to the nitrogen In principl atom(s),e, it is chanpossibleging to the preserve substitution the original pattern. skeleton For example, and replace the wasgroups introduced attached via to the the reaction nitrogen of mono-aryl-substituted atom(s), changing the thioureas substitution and the appropriatepattern. For carboxylic example, acids the groupsthiazolidine attached motif to was the introducednitrogen atom(s), via the chanreactigingon ofthe mono-aryl-substi substitution pattern.tuted thioureasFor example, and the withthiazolidine boronic acidmotif catalyst was introduced (Scheme 19 via)[87 the]. Various reaction prepared of mono-aryl-substiN-acyl derivativestuted included thioureas chiral and ones the thiazolidineappropriate carboxylicmotif was acidsintroduced with boronic via the acid reacti catalyston of (Schememono-aryl-substi 19) [87]. Varioustuted thioureas prepared and N- acylthe appropriate carboxylic acids with boronic acid catalyst (Scheme 19) [87]. Various prepared N-acyl appropriatederivatives includedcarboxylic chiral acids withones boronicand were acid foun catalystd to (Schemeexhibit antioxidant19) [87]. Various activity. prepared Appropriate N-acyl derivatives included chiral ones and were found to exhibit antioxidant activity. Appropriate derivativesmodifications included of substituents chiral ones of thiourea and were derive found dfrom to exhibit1,2-phenylenediamine antioxidant activity. were describedAppropriate by modifications of substituents of thiourea derived from 1,2-phenylenediamine were described by modificationsLiang et al. resulting of substituents in the introduction of thiourea ofderive chirality,d from an d,1,2-phenylenediamine finally, isolation of atropoisomeric were described N,S- by Liang et al. resulting in the introduction of chirality, and, finally, isolation of atropoisomeric N,S- Liangdonating et al.ligands resulting bearing in the oxazoline introduction moiety of [88]. chirality, and, finally, isolation of atropoisomeric N,S- donating ligands bearing oxazoline moiety [88].

Scheme 19. Reaction of monosubstituted thiourea with a chiral carboxylic acid as a route to a chiral thiourea Scheme 19. Reaction of monosubstituted thiourea with a chiral carboxylic acid as a route to a chiral thiourea Scheme 19. Reaction of monosubstituted thiourea with a chiral carboxylic acid as a route to a chiral thiourea [87]. [87]. [87].Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x 8 of 57

Scheme 15. The use of thiophosgene in the preparation of a chiral cyclic thiourea [81].

Furthermore, achiral derivatives were prepared in the reaction of amines with thiuram disulfides (Scheme 16) or monosulfides (in turn obtained from dithiocarbamates) [84]. Li et al. developed a protocol utilizing phenyl chlorothionoformate [85,86]. Its reaction with primary amines (either aliphatic or aromatic) in refluxing water carried out for 2–12 h (though 2–3 h were sufficient in most cases) afforded a series of 17 symmetrical, 1,3-disubstituted thioureas in 60–99% yield (Scheme 17) [85]. Among them, two enantiomerically pure derivatives were prepared. The protocol was also used to obtain thione heterocycles, however, it failed in the attempts with a mixture of two amines aimed to yield unsymmetrically substituted products. Such compounds could be formed using a two-step route: amines were first reacted with chloroformate in water for 1 h at room temperature [86]. Then, the resulting thiocarbamate was converted into the desired thiourea by heating with another (more reactive) amine for 20–80 min at 100 °C (Scheme 18). The yields were high (87–95% for the first step, 75–97% for the second one), products (none of them were chiral) were isolated by filtration and washed with water, without the need of further purification. The reaction could be performed on a gram scale.

Scheme 16. Thiuram disulfide as a reactant in preparation of thioureas [84].

Scheme 17. Synthesis of symmetrical thioureas from phenyl chlorothionoformate and amine [85].

Scheme 18. Two-step approach to unsymmetrical thioureas from phenyl chlorothionoformate [86].

2.5. Preparation of Chiral Thioureas from Other Thioureas The thiocarbonyl moiety of chiral thiourea can also originate from achiral ones, subjected to an appropriate modification. In principle, it is possible to preserve the original skeleton and replace groups attached to the nitrogen atom(s), changing the substitution pattern. For example, the thiazolidineMolecules 2020, 25motif, 401 was introduced via the reaction of mono-aryl-substituted thioureas and9 ofthe 56 appropriate carboxylic acids with boronic acid catalyst (Scheme 19) [87]. Various prepared N-acyl derivatives included chiral ones and were found to exhibit antioxidant activity. Appropriate modificationsand were found of to substituents exhibit antioxidant of thiourea activity. derive Appropriated from 1,2-phenylenediamine modiﬁcations of substituents were described of thiourea by Liangderived et fromal. resulting 1,2-phenylenediamine in the introduction were of described chirality, by an Liangd, finally, et al. isolation resulting of in atropoisomeric the introduction N,S- of donatingchirality, and,ligands ﬁnally, bearing isolation oxazoline of atropoisomeric moiety [88]. N,S-donating ligands bearing oxazoline moiety [88].

SchemeScheme 19. Reaction 19. Reaction of monosubstituted of monosubstituted thiourea thiourea with a chiral with acarboxylic chiral carboxylic acid as a acid route as to a a route chiral to thiourea a chiral Molecules 2020, 25, x 9 of 57 [87].Molecules thiourea 2020, 25 [87, x]. 9 of 57 MoleculesQuite 2020 frequently,, 25, x; doi: a reaction at thiocarbonyl carbon atom of thiourea www.mdpi.com is performed,/journal/molecules resulting in Quite frequently, a reactionreaction atat thiocarbonylthiocarbonyl carbon atom of thiourea is performed, resulting in C–N bond cleavage and attachment of an amine nucleophile. Yin et al. reported on the application of C–N bond cleavage and attachment of an amine nucleophile. Yin et al. reported on the application of readily available and stable 1,3-bis-Boc-substituted thiourea as thioacylating agent of nucleophiles readily available and stable 1,3-bis-Boc-substituted1,3-bis-Boc-substituted thiourea as thioacylating agent of nucleophilesnucleophiles (amines, but also alcohols, thiols, thiophenolates, sodium malonates, Scheme 20) [89]. Thiocarbonyl (amines, but alsoalso alcohols,alcohols, thiols,thiols, thiophenolates,thiophenolates, sodiumsodium malonates,malonates, SchemeScheme 2020))[ [89].89]. Thiocarbonyl compounds were formed in reasonable yields (78–94% in case of thioureas) under mild conditions compounds were formed in reasonable yields (78–94% in case of thioureas) under mild conditions (sodium hydride as a base, trifluoroacetic acid anhydride (TFAA) as an activator, THF solvent, 0 °C (sodium hydridehydride asas aa base,base, triﬂuoroacetictrifluoroacetic acid acid anhydride anhydride (TFAA) (TFAA) as as an an activator, activator, THF THF solvent, solvent, 0 ◦ 0C °C to to RT). Amines bearing additional functional groups could be converted into desired products as toRT). RT). Amines Amines bearing bearing additional additional functional functional groups grou couldps could be converted be converted into desiredinto desired products products as well, as well, including two enantiomerically pure derivatives for which no epimerization was observed. well,including including two enantiomerically two enantiomerically pure derivatives pure deriva fortives which for no which epimerization no epimerization was observed. was observed. However, However, for hindered acyclic secondary amines, the procedure did not work. Bis-Boc thiourea was However,for hindered for acyclic hindered secondary acyclic amines,secondary the amines, procedure the did procedure not work. did Bis-Boc not work. thiourea Bis-Boc was thiourea also utilized was also utilized by Cohrt and Nielsen in their synthesis of N-terminally modified α-thiourea peptides alsoby Cohrt utilized and by Nielsen Cohrt in and their Ni synthesiselsen in their of N-terminally synthesis of modiﬁed N-terminallyα-thiourea modified peptides α-thiourea that were peptides further that were further converted into the respective thiazoles, which in turn were incorporated into 15- to thatconverted were further into the converted respective into thiazoles, the respective which thiazo in turnles, were which incorporated in turn were into incorporated 15- to 17-membered into 15- to 17-membered macrocycles bearing up to three stereocenters [90]. 17-memberedmacrocycles bearing macrocycles up to threebearing stereocenters up to three [ 90stereocenters]. [90].

Scheme 20. Conversion of bis-Boc thiourea into other thioureas.[89] Scheme 20. Conversion of bis-Boc thiourea into other thioureas.[89] thioureas.[89] Thiourea derivatives bearing heterocyclic substituents were also found to be useful thioacylating Thiourea derivatives bearing heterocyclic substituentssubstituents were also found to be useful thioacylating agents. 1-(Alkyl/Arylthiocarbamoyl)benzotriazoles were applied by Katritzky et al. as stable agents. 1-(Alkyl/Arylthiocarbamoyl)benzotriazoles 1-(Alkyl/Arylthiocarbamoyl)benzotriazoles were were applied applied by by Katritzky et al.al. as as stable isothiocyanate equivalents (Scheme 21) [91]. Among di- and trisubstituted thioureas, three (R)-1- isothiocyanate equivalents equivalents (Scheme (Scheme 21) 21 )[[91].91 ].Among Among di- and di- trisubstituted and trisubstituted thioureas, thioureas, three ( threeR)-1- phenylethyl derivatives were formed in 92–99% yield (Scheme 22). Kang et al. used 1,1′- (phenylethylR)-1-phenylethyl derivatives derivatives were wereformed formed in 92–99% in 92–99% yield yield (Scheme (Scheme 22). 22Kang). Kang et al. et used al. used1,1′- thiocarbonyldiimidazole (Figure 2) for C=S transfer, and converted it into desired monosubstituted 1,1thiocarbonyldiimidazole0-thiocarbonyldiimidazole (Figure (Figure 2) 2for) for C=S C =transferS transfer,, and and converted converted it itinto into desired desired monosubstituted monosubstituted (achiral) thioureas in two subsequent reactions with primary amines (mainly fluorene derivatives) (achiral) thioureasthioureas in in two two subsequent subsequent reactions reactions with with primary primary amines amines (mainly (mainly ﬂuorene fluorene derivatives) derivatives) and and NH3 [92]. andNH3 NH[923]. [92].

Scheme 21. Benzotriazole derivative in the synthesis of appropriately substituted thioureas [91]. Scheme 21. BenzotriazoleBenzotriazole derivative in the synthesis of appropriately substituted thioureas [[91].91].

Scheme 22. PreparationPreparation of of chiral chiral thioureas from 1,3-bi 1,3-bis-benzotriazole-substituteds-benzotriazole-substituted derivative [[91].91]. Scheme 22. Preparation of chiral thioureas from 1,3-bis-benzotriazole-substituted derivative [91].

Figure 2. Bis-imidazole thiourea used in the synthesis of other derivatives [92]. Figure 2. Bis-imidazole thiourea used in the synthesis of other derivatives [92]. 2.6. C=S Bond Formation 2.6. C=S Bond Formation Less frequently, thioureas have been prepared via multi-component reactions in which Less frequently, thioureas have been prepared via multi-component reactions in which elementary sulfur or other sulfur-transfer agents are used to form the C=S bond. Hydrogen sulfide elementary sulfur or other sulfur-transfer agents are used to form the C=S bond. Hydrogen sulfide was used by Katritzky et al. as the source of sulfur and reacted with 1-cyanobenzotriazole and amines was used by Katritzky et al. as the source of sulfur and reacted with 1-cyanobenzotriazole and amines or with carboximidamides to give thioureas in reasonable to high yields (54–99%, with two or with carboximidamides to give thioureas in reasonable to high yields (54–99%, with two Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x 9 of 57

Quite frequently, a reaction at thiocarbonyl carbon atom of thiourea is performed, resulting in C–N bond cleavage and attachment of an amine nucleophile. Yin et al. reported on the application of readily available and stable 1,3-bis-Boc-substituted thiourea as thioacylating agent of nucleophiles (amines, but also alcohols, thiols, thiophenolates, sodium malonates, Scheme 20) [89]. Thiocarbonyl compounds were formed in reasonable yields (78–94% in case of thioureas) under mild conditions (sodium hydride as a base, trifluoroacetic acid anhydride (TFAA) as an activator, THF solvent, 0 °C to RT). Amines bearing additional functional groups could be converted into desired products as well, including two enantiomerically pure derivatives for which no epimerization was observed. However, for hindered acyclic secondary amines, the procedure did not work. Bis-Boc thiourea was also utilized by Cohrt and Nielsen in their synthesis of N-terminally modified α-thiourea peptides that were further converted into the respective thiazoles, which in turn were incorporated into 15- to 17-membered macrocycles bearing up to three stereocenters [90].

Scheme 20. Conversion of bis-Boc thiourea into other thioureas.[89]

Thiourea derivatives bearing heterocyclic substituents were also found to be useful thioacylating agents. 1-(Alkyl/Arylthiocarbamoyl)benzotriazoles were applied by Katritzky et al. as stable isothiocyanate equivalents (Scheme 21) [91]. Among di- and trisubstituted thioureas, three (R)-1- phenylethyl derivatives were formed in 92–99% yield (Scheme 22). Kang et al. used 1,1′- thiocarbonyldiimidazole (Figure 2) for C=S transfer, and converted it into desired monosubstituted (achiral) thioureas in two subsequent reactions with primary amines (mainly fluorene derivatives) and NH3 [92].

Scheme 21. Benzotriazole derivative in the synthesis of appropriately substituted thioureas [91].

Molecules 2020, 25, 401 10 of 56 Scheme 22. Preparation of chiral thioureas from 1,3-bis-benzotriazole-substituted derivative [91].

Figure 2. Bis-imidazoleBis-imidazole thiourea thiourea used in the synthesis of other derivatives [92]. [92].

2.6. C=S Bond Formation 2.6. C=S Bond Formation Less frequently, thioureas have been prepared via multi-component reactions in which elementary Less frequently, thioureas have been prepared via multi-component reactions in which sulfur or other sulfur-transfer agents are used to form the C=S bond. Hydrogen sulﬁde was used elementary sulfur or other sulfur-transfer agents are used to form the C=S bond. Hydrogen sulfide Moleculesby Katritzky 2020,, 25 et,, xx al. as the source of sulfur and reacted with 1-cyanobenzotriazole and amines10 of or57 wasMolecules used 2020 by, 25Katritzky, x et al. as the source of sulfur and reacted with 1-cyanobenzotriazole and amines10 of 57 with carboximidamides to give thioureas in reasonable to high yields (54–99%, with two exceptions, orexceptions, with carboximidamides Scheme 23) [93]. toThioureas give thioureas (and seleno in reasonableureas) were to also high prepared yields from(54–99%, cyanamides with two as exceptions,Scheme 23)[ Scheme93]. Thioureas 23) [93]. (and Thioureas selenoureas) (and seleno were alsoureas) prepared were also from prepared cyanamides from ascyanamides described byas Moleculesdescribed 2020 by, 25 Koketsu, x; doi: et al. [94]. The reaction with HCl in Et22O and then www.mdpi.comwith LiAlHSH/journal/molecules afforded 1,1- Koketsudescribed et by al. Koketsu [94]. The et reaction al. [94]. withThe reaction HCl in Et with2O andHCl then in Et with2O and LiAlHSH then with aﬀ ordedLiAlHSH 1,1-disubstituted afforded 1,1- disubstituted products in 52–89% yield (Scheme 24). Unfortunately, chiral derivatives were not disubstitutedproducts in 52–89% products yield in (Scheme 52–89% 24yield). Unfortunately, (Scheme 24). chiral Unfortunately, derivatives chiral were notderivatives prepared were by these not prepared by these two groups. preparedtwo groups. by these two groups.

Scheme 23. Utilization of hydrogen sulfide in the synthesis of thioureas [93]. Scheme 23. UtilizationUtilization of of hydrogen hydrogen sulfide sulﬁde in the synthesis of thioureas [[93].93].

Scheme 24. Cyanamide as a starting point for the preparation of thioureas [[94].94]. Scheme 24. Cyanamide as a starting point for the preparation of thioureas [94]. Tan etet al.al. describeddescribed anan applicationapplication of chloroformchloroform andand elementaryelementary sulfur actingacting asas thiocarbonylthiocarbonyl Tan et al. described an application of chloroform and elementary sulfur acting as thiocarbonyl surrogate (Scheme 25)25)[ [95].95]. Various Various primary primary amines amines we werere treated treated with with chloroform chloroform in inthe the presence presence of surrogate (Scheme 25) [95]. Various primary amines were treated with chloroform in the presence of ofa base a base followed followed by by addition addition of of sulfur sulfur and and a a second second primary amine. Optimal reaction conditionsconditions a base followed by addition of sulfur and a second primary amine. Optimal reaction conditions comprised t-BuOK used as a base, tert-butanol-butanol/1,4-dioxane/1,4-dioxane (1:1 mixture) solvent, 55 ◦°C,C, and reaction comprised t-BuOK used as a base, tert-butanol/1,4-dioxane (1:1 mixture) solvent, 55 °C, and reaction times varied from 66 toto 1515 h.h. Yields Yields ranged from 51% to 96%, and among 35 thioureasthioureas tenten chiralchiral times varied from 6 to 15 h. Yields ranged from 51% to 96%, and among 35 thioureas ten chiral derivatives were obtained withwith aa completecomplete preservationpreservation ofof opticaloptical puritypurity ofof thethe startingstarting amines.amines. derivatives were obtained with a complete preservation of optical purity of the starting amines. S 1) CHCl (10 eq), t-BuOK S 1) CHCl3 (10 eq), t-BuOK 1 S 2 1 2 3 R1 C R2 R1 NH 2 + R2 NH21) CHCl3 (10 eq), t-BuOK R C R R1NH 2 + R2NH2 2) S (3 eq.), t-BuOK 1 N N 2 R NH 2 + R NH2 2) S (3 eq.), t-BuOK R N C N R 2) S (3 eq.), t-BuOK HN HN 1 2 H H R1,, RR2 = alkyyll,, aarryyll R1, R2 = alkyl, aryl

Scheme 25. Reaction of amines with sulfur and ch chloroformloroform as a route to thioureas [[95].95]. Scheme 25. Reaction of amines with sulfur and chloroform as a route to thioureas [95]. Sulfuration of azoles connected with N-difluoromethylation-difluoromethylation yielding a family of appropriately Sulfuration of azoles connected with N-difluoromethylation yielding a family of appropriately substituted cyclic thioureas waswas reportedreported byby TangTang andand co-workersco-workers [96[96].]. The optimumoptimum reactionreaction substituted cyclic thioureas was reported by Tang and co-workers [96]. The optimum reaction conditions were established as 24 h atat 100100 ◦°CC inin DMADMA solventsolvent withwith sodiumsodium hydroxymethylsulfitehydroxymethylsulfite conditions were established as 24 h at 100 °C in DMA solvent with sodium hydroxymethylsulfite additive; elementary sulfur and ethyl 2-bromo-2,2-di 2-bromo-2,2-difluoroacetatefluoroacetate were used as as inexpensive inexpensive reagents. reagents. additive; elementary sulfur and ethyl 2-bromo-2,2-difluoroacetate were used as inexpensive reagents. Two products—derivativesproducts—derivatives ofof EconazoleEconazole (48%)(48%) and Ketoconazole (43%)—were chiral, and the latter Two products—derivatives of Econazole (48%) and Ketoconazole (43%)—were chiral, and the latter was obtainedobtained asas aa singlesingle enantiomerenantiomer (Figure(Figure3 3).). was obtained as a single enantiomer (Figure 3).

Figure 3. Ketoconazole thiourea derivative prepared by Tang and co-workers [96]. Figure 3. Ketoconazole thiourea derivative prepared by Tang and co-workers [96]. A relatively low explored synthetic strategy is based on the use of isocyanides. Zhu et al. A relatively low explored synthetic strategy is based on the use of isocyanides. Zhu et al. described a Co(II)-catalyzed insertion of isocyanides into active N-H bonds of amines under described a Co(II)-catalyzed insertion of isocyanides into active N-H bonds of amines under ultrasound irradiation; the amino methylidyneaminium intermediates reacted readily with various ultrasound irradiation; the amino methylidyneaminium intermediates reacted readily with various nucleophiles including sulfur (to give thioureas) or water (yielding ureas) [97]. A series of aniline nucleophiles including sulfur (to give thioureas) or water (yielding ureas) [97]. A series of aniline derivatives were tested with tert-butyl isocyanide to give 37–53% yield, and tryptamine with 4 derivatives were tested with tert-butyl isocyanide to give 37–53% yield, and tryptamine with 4 different isocyanides gave products in 53–67%. The optimal reaction conditions included 20 mol% of different isocyanides gave products in 53–67%. The optimal reaction conditions included 20 mol% of Molecules 2020,, 25,, x;x; doi:doi: www.mdpi.com www.mdpi.com/journal/molecules/journal/molecules Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x 10 of 57 exceptions, Scheme 23) [93]. Thioureas (and selenoureas) were also prepared from cyanamides as described by Koketsu et al. [94]. The reaction with HCl in Et2O and then with LiAlHSH afforded 1,1- disubstituted products in 52–89% yield (Scheme 24). Unfortunately, chiral derivatives were not prepared by these two groups.

Scheme 23. Utilization of hydrogen sulfide in the synthesis of thioureas [93].

Scheme 24. Cyanamide as a starting point for the preparation of thioureas [94].

Tan et al. described an application of chloroform and elementary sulfur acting as thiocarbonyl surrogate (Scheme 25) [95]. Various primary amines were treated with chloroform in the presence of a base followed by addition of sulfur and a second primary amine. Optimal reaction conditions comprised t-BuOK used as a base, tert-butanol/1,4-dioxane (1:1 mixture) solvent, 55 °C, and reaction times varied from 6 to 15 h. Yields ranged from 51% to 96%, and among 35 thioureas ten chiral derivatives were obtained with a complete preservation of optical purity of the starting amines.

S 1) CHCl (10 eq), t-BuOK 3 1 2 R1NH + R2NH R C R 2 2 2) S (3 eq.), t-BuOK N N H H R1, R2 = alkyl, aryl Scheme 25. Reaction of amines with sulfur and chloroform as a route to thioureas [95].

Sulfuration of azoles connected with N-difluoromethylation yielding a family of appropriately substituted cyclic thioureas was reported by Tang and co-workers [96]. The optimum reaction conditions were established as 24 h at 100 °C in DMA solvent with sodium hydroxymethylsulfite additive; elementary sulfur and ethyl 2-bromo-2,2-difluoroacetate were used as inexpensive reagents. MoleculesTwo products—derivatives2020, 25, 401 of Econazole (48%) and Ketoconazole (43%)—were chiral, and the11 latter of 56 was obtained as a single enantiomer (Figure 3).

Figure 3. Ketoconazole thiourea derivative preparedprepared by Tang andand co-workersco-workers [[96].96].

AA relativelyrelatively lowlow exploredexplored syntheticsynthetic strategystrategy isis basedbased onon thethe useuse ofof isocyanides.isocyanides. Zhu Zhu et al. describeddescribed aa Co(II)-catalyzed Co(II)-catalyzed insertion insertion of isocyanides of isocyanides into active into N-Hactive bonds N-H of bonds amines of under amines ultrasound under irradiation;ultrasound theirradiation; amino methylidyneaminium the amino methylidyneami intermediatesnium intermediates reacted readily reacted with variousreadily nucleophileswith various includingnucleophiles sulfur including (to give sulfur thioureas) (to give or water thioureas) (yielding or water ureas) (yielding [97]. A series ureas) of aniline[97]. A derivativesseries of aniline were Molecules 2020, 25, x 11 of 57 testedMoleculesderivatives with 2020 , tert25were, x-butyl tested isocyanide with tert to-butyl give 37–53%isocyanide yield, to andgive tryptamine 37–53% yield, with and 4 di fftryptamineerent isocyanides 11with of 574 gavedifferent products isocyanides in 53–67%. gave products The optimal in 53–67%. reaction The conditions optimal includedreaction conditions 20 mol% of included Co(acac) 202 mol%catalyst, of Co(acac)2 catalyst, two equivalents of Na2CO3 and one equivalent of TBHP in 1,4-dioxane and twoCo(acac) equivalents2 catalyst, of Natwo2CO equivalents3 and one of equivalent Na2CO3 ofand TBHP one inequivalent 1,4-dioxane of andTBHP ultrasound in 1,4-dioxane irradiation and ultrasoundMolecules 2020 ,irradiation 25, x; doi: at 75 °C. Chiral thioureas were not prepared, however, www.mdpi.com two enantiomers/journal/molecules of atultrasound 75 ◦C. Chiral irradiation thioureas at were75 °C. not Chiral prepared, thioureas however, were twonot prepared, enantiomers however, of urea two were enantiomers obtained from of enantiopureurea were obtained 1-phenylethylamines from enantiopure and 1-phenylethylaminestert-butyl isocyanide with and tert a complete-butyl isocyanide retention ofwith configuration, a complete suggestingretention ofa configuration, similar possibility suggesting for the a synthesis similar possibility of chiral thiourea. for the synthesis An efficient, of chiral three-component thiourea. An efficient, three-component reaction of isocyanides, aliphatic amines and elemental sulfur under mild reactionefficient, ofthree-component isocyanides, aliphatic reaction amines of isocyanides, and elemental aliphatic sulfur amines under and mild elemental conditions sulfur (RT under to 40 mild◦C, solvent-freeconditions (RT or toluene)to 40 °C, wassolvent-free also reported or toluene) by Nguyen was also et al. reported (Scheme by 26 Nguyen)[98]. et al. (Scheme 26) [98].

Scheme 26. PreparationPreparation of thioureas from isocyanides, amines and elementary sulfur [[98].98].

A three-component three-component reaction reaction of of isocyanides, isocyanides, in insitu situ formed formed N-chlorinatedN-chlorinated secondary secondary amines amines and andwater water or sodium or sodium sulfide sulﬁde was was reported reported on on by by Angyal Angyal et et al. [[99].99]. Sodium dichloroisocyanuratedichloroisocyanurate (NaDCC)(NaDCC) waswas usedused asas aa chlorinatingchlorinating agent.agent. The The reactions were performed in isopropanolisopropanol under microwave-assisted conditions conditions (100 (100 °C,◦C, 10 10 min, min, 250 250 W, W, Scheme Scheme 27). 27 ).Eight Eight thioureas thioureas were were prepared prepared in in27–68% 27–68% yield, yield, including including an anenantiopure enantiopure proline proline derivative derivative (30%). (30%). Singh Singh and and Sharma Sharma developed developed a amulticomponent multicomponent protocol protocol of ofthiourea thiourea preparation preparation utilizing utilizing aromatic aromatic isocyanides, isocyanides, amines amines and and1,2- 1,2-di(di(tert-butyl)disulfidetert-butyl)disulﬁde under under solventsolvent- and and catalyst-f catalyst-freeree conditions conditions (Scheme (Scheme 28) 28)[ [100].100]. Isocyanides were obtainedobtained byby formylationformylation ofof aromaticaromatic aminesamines followedfollowed byby dehydrationdehydration usingusing POClPOCl3.. All thethe were obtained by formylation of aromatic amines followed by dehydration using POCl33. All the ° ° reactions were heated for 5 hh atat 120120 ◦°C andand 11 hh atat 6060 ◦°CC afterafter thethe additionaddition ofof amines.amines. Twenty-seven thioureas werewere prepared prepared in in 56–99% 56–99% yield, yield, including includin ang optically an optically active active derivative derivative obtained obtained from phenyl from isocyanidephenyl isocyanideCinchona Cinchonamine (57%).mine (57%).

Scheme 27. Synthesis of thioureas from amines, isocyanides, and sodium sulﬁde [99]. Scheme 27. Synthesis of thioureas from amines, isocyanides, and sodium sulfide [99].

Scheme 28. Preparation of thioureas from isocyanides, amines and disulfide [100].

3. Types of Chiral Thioureas and Selected Applications in Asymmetric Synthesis Chiral thioureas can be classified taking into account a moiety introduced to its structure in order to induce chirality. Most structures contain a stereogenic center attached to a nitrogen atom of thiourea which typically derives from amine used as one of the reactants. In many cases, also additional elements of chirality are present, as well as functional groups designed to participate in desired interactions with target molecules (e.g., substrates of catalyzed reaction) or ions (metal ions in coordination compounds, anions bound by thiourea-based receptors). In particular, derivatives based on chiral diamines have attracted attention due to their possible application as bifunctional catalysts, with thiourea moiety acting as hydrogen bond donor and an amino group as a Brønsted base/Lewis base/nucleophile. Alternatively, systems consisting of an achiral thiourea together with components responsible for asymmetric induction are tested as well [101]. Several extensive reviews have been published on asymmetric organocatalysis and, in particular, the use of chiral ureas and thioureas in various stereoselective reactions [3,12–14,102–114]. Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x 11 of 57

Co(acac)2 catalyst, two equivalents of Na2CO3 and one equivalent of TBHP in 1,4-dioxane and ultrasound irradiation at 75 °C. Chiral thioureas were not prepared, however, two enantiomers of urea were obtained from enantiopure 1-phenylethylamines and tert-butyl isocyanide with a complete retention of configuration, suggesting a similar possibility for the synthesis of chiral thiourea. An efficient, three-component reaction of isocyanides, aliphatic amines and elemental sulfur under mild conditions (RT to 40 °C, solvent-free or toluene) was also reported by Nguyen et al. (Scheme 26) [98].

Scheme 26. Preparation of thioureas from isocyanides, amines and elementary sulfur [98].

A three-component reaction of isocyanides, in situ formed N-chlorinated secondary amines and water or sodium sulfide was reported on by Angyal et al. [99]. Sodium dichloroisocyanurate (NaDCC) was used as a chlorinating agent. The reactions were performed in isopropanol under microwave-assisted conditions (100 °C, 10 min, 250 W, Scheme 27). Eight thioureas were prepared in 27–68% yield, including an enantiopure proline derivative (30%). Singh and Sharma developed a multicomponent protocol of thiourea preparation utilizing aromatic isocyanides, amines and 1,2- di(tert-butyl)disulfide under solvent- and catalyst-free conditions (Scheme 28) [100]. Isocyanides were obtained by formylation of aromatic amines followed by dehydration using POCl3. All the reactions were heated for 5 h at 120 °C and 1 h at 60 °C after the addition of amines. Twenty-seven thioureas were prepared in 56–99% yield, including an optically active derivative obtained from phenyl isocyanide Cinchonamine (57%).

Molecules 2020, 25, 401 12 of 56 Scheme 27. Synthesis of thioureas from amines, isocyanides, and sodium sulfide [99].

Scheme 28. PreparationPreparation of of thioureas thioureas from isocya isocyanides,nides, amines and disulfide disulﬁde [[100].100].

3. Types Types of Chiral Thioureas and Selected Applications in Asymmetric SynthesisSynthesis Chiral thioureas thioureas can can be be classified classified taking taking into into acco accountunt a moiety a moiety introduced introduced to its tostructure its structure in order in toorder induce to induce chirality. chirality. Most Moststructures structures contain contain a stereogenic a stereogenic center center attached attached to a to nitrogen a nitrogen atom atom of thioureaof thiourea which which typically typically derives derives from from amine amine used used as as one one of of the the reactants. reactants. In In many many cases, also additional elements of chirality are present, as well as functional groups designed to participate in desired interactions withwith targettarget moleculesmolecules (e.g., (e.g., substrates substrates of of catalyzed catalyzed reaction) reaction) or or ions ions (metal (metal ions ions in incoordination coordination compounds, compounds, anions anions bound bound by thiourea-based by thiourea-based receptors). receptors). In particular, In particular, derivatives derivatives based basedon chiral on diamineschiral diamines have attracted have attracted attention attention due to their due possibleto their possible application application as bifunctional as bifunctional catalysts, withcatalysts, thiourea with moiety thiourea acting moiety as hydrogenacting as bondhydrogen donor bond and donor an amino and group an amino as a Brønstedgroup as basea Brønsted/Lewis base/Lewisbase/nucleophile. base/nucleophile. Alternatively, Alternatively, systems consisting systems of consisting an achiral of thiourea an achiral together thiourea with together components with componentsresponsible for responsible asymmetric for inductionasymmetric are induction tested as wellare tested [101]. as well [101]. Several extensive reviews have been published on asymmetric organocatalysis and, in particular, MoleculesSeveral 2020, 25extensive, x reviews have been published on asymmetric organocatalysis and,12 of in57 particular,the use of chiral the use ureas of chiral and thioureas ureas and in variousthioureas stereoselective in various stereoselective reactions [3,12 reactions–14,102–114 [3,12–14,102–114].]. Consequently, the following part is focused on the presentation of selected examples of compounds with only a Consequently,Molecules 2020, 25, thex; doi: following part is focused on the presentation of selected www.mdpi.com examples /journal/moleculesof compounds withshort only mention a short about mention their applications about their in applications the synthesis in and the functionalization synthesis and functionalization of one particular system,of one particulari.e., chroman system, scaff oldi.e., andchroman its derivatives scaffold and (Figure its de4rivatives). As an (Figure example 4). for As aan versatile example structure for a versatile with structurevarious pharmaceutically with various pharmaceutically active derivatives active [115 deri], itvatives has various [115], possible it has various medicinal possible usages medicinal [116,117]. usagesProchiral [116,117]. carbon atomsProchiral can carbon be substituted, atoms can yielding be substituted, structures yielding with several structures stereogenic with centers,several stereogenice.g., flavonoids centers, (Figure e.g.,4 flavonoids)[ 118,119 ].(Figure Preparation 4) [118,119]. of various Preparation chroman of various derivatives chroman with derivatives a defined withstereochemistry a defined challengedstereochemistry organic challenged chemists. Versatile,organic chemists. general methods Versatile, for general their asymmetric methods synthesisfor their asymmetrichave been found synthesis in recent have years been [fo117und,120 in– 122recent]. years [117,120–122].

(a) Chroman (b) Flavanoid scaffold

Figure 4. General structures of chroman and flavonoid scaffolds. Figure 4. General structures of chroman and flavonoid scaffolds. 3.1. Thioureas Containing trans-1,2-diaminocyclohexane (DACH) Skeleton and Other Chiral Diamines 3.1. ThioureasPioneering Containing works on trans-1,2-diaminocyclohexane application of chiral thioureas (DACH) in Skeleton enantioselective and Other organocatalysis Chiral Diamines came fromPioneering the laboratory works of on Jacobsen. application Three of chiral libraries thiour ofeas polystyrene-supported in enantioselective organocatalysis enantiopure ligands came fromcontaining the laboratory amino acid of residues,Jacobsen. urea Three or thiourealibraries moiety,of polystyrene-supported and Schiff bases (the enantiopure last two subunitsligands containinglinked with amino (R,R)-1,2-diamines) acid residues, were urea evaluated or thiourea as organocatalystsmoiety, and Schiff for asymmetricbases (the last Strecker two reactionssubunits (Figurelinked with5)[ 123 (R–,R125)-1,2-diamines)]. The optimized were catalyst evaluated and as its organocatalysts soluble analogues for showed asymmetric a broad Strecker substrate reactions scope. (FigureSimilar, appropriately5) [123–125]. The modified optimized Schiff basecatalyst catalysts and its were soluble found analogues optimal in showed other asymmetric a broad substrate reactions, scope.including Similar, hydrophosphonylation appropriately modi offied imines Schiff [126 base], intermolecularcatalysts were found addition optimal of indoles in other to cyclic asymmetricN-acyl reactions,iminium ions including [127], hydro- hydrophosphonylation and acylcyanation of iminesimines [128[126],–130 intermolecular]. Furthermore, addition imidazole of derivativesindoles to cyclicof Schi ffN-acylbases iminium were applied ions in [127], Strecker hydro- reaction and by acylcyanation Tsogoeva et al.of [ 131imines]. [128–130]. Furthermore, imidazole derivatives of Schiff bases were applied in Strecker reaction by Tsogoeva et al. [131].

Figure 5. Jacobsen’s thioureas derived from 1,2-diaminocyclohexane [123–125].

Later on, Jacobsen and co-workers developed other DACH-based thiourea organocatalysts (Figure 6) [132–134]. For example, pyrrole derivative appeared most efficient in acyl Pictet-Spengler reaction [133], and Cope-type hydroamination [134]. This type of catalyst was also applied by Bui et al. in asymmetric additions of oxoindoles to nitroolefins [135].

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x 12 of 57

Consequently, the following part is focused on the presentation of selected examples of compounds with only a short mention about their applications in the synthesis and functionalization of one particular system, i.e., chroman scaffold and its derivatives (Figure 4). As an example for a versatile structure with various pharmaceutically active derivatives [115], it has various possible medicinal usages [116,117]. Prochiral carbon atoms can be substituted, yielding structures with several stereogenic centers, e.g., flavonoids (Figure 4) [118,119]. Preparation of various chroman derivatives with a defined stereochemistry challenged organic chemists. Versatile, general methods for their asymmetric synthesis have been found in recent years [117,120–122].

(a) Chroman (b) Flavanoid scaffold

Figure 4. General structures of chroman and flavonoid scaffolds.

3.1. Thioureas Containing trans-1,2-diaminocyclohexane (DACH) Skeleton and Other Chiral Diamines Pioneering works on application of chiral thioureas in enantioselective organocatalysis came from the laboratory of Jacobsen. Three libraries of polystyrene-supported enantiopure ligands containing amino acid residues, urea or thiourea moiety, and Schiff bases (the last two subunits linked with (R,R)-1,2-diamines) were evaluated as organocatalysts for asymmetric Strecker reactions (Figure 5) [123–125]. The optimized catalyst and its soluble analogues showed a broad substrate scope. Similar, appropriately modified Schiff base catalysts were found optimal in other asymmetric reactions, including hydrophosphonylation of imines [126], intermolecular addition of indoles to cyclicMolecules N2020-acyl, 25 ,iminium 401 ions [127], hydro- and acylcyanation of imines [128–130]. Furthermore,13 of 56 imidazole derivatives of Schiff bases were applied in Strecker reaction by Tsogoeva et al. [131].

Figure 5. Jacobsen’sJacobsen’s thioureas thioureas derived derived from from 1,2-diaminocyclohexane [123–125]. [123–125].

Later on, Jacobsen and co-workers developed other DACH-based thioureathiourea organocatalysts (Figure 66))[ [132–134].132–134]. For example, pyrrole derivative appeared most efficient eﬃcient in acyl Pictet-Spengler reaction [[133],133], andand Cope-typeCope-type hydroaminationhydroamination [ 134[134].]. This This type type of of catalyst catalyst was was also also applied applied by by Bui Bui et al.et Moleculesal.in asymmetricin asymmetric 2020,, 25,, additionsxx additions of oxoindolesof oxoindoles to nitrooleﬁnsto nitroolefins [135 [135].]. 13 of 57

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Figure 6. ModifiedModiﬁed Jacobsen’s organocatalysts.[132–134] organocatalysts.[132–134]

DACH-based bisfunctional thiourea organocatalyst organocatalystss containing a tertiary amine function were developed by Takemoto andand co-workersco-workers (Figure(Figure7 7))... AAA dimethylaminedimethylaminedimethylamine derivativederivativederivative appearedappearedappeared tototo bebebe aaa versatile promoter,promoter, active active in in various various asymmetric asymmetric transformations: transformations: Michael Michael reaction reaction of nitrooleﬁns of nitroolefins and andmalonates malonates [136] or[136] 1,3-dicarbonyl or 1,3-dicarbonyl compounds compounds [137], active [137], methylene active methylene compounds compounds with α,β-unsaturated with α,,β- unsaturatedimides [138, imides139], aza-Henry [138,139], aza-Henry [140], Neber [140], reaction Neber (synthesisreaction (synthesis of azirine of azirine derivatives) derivatives) [141], [141], aldol aldolreaction reaction [142], [142], and others and others [110– 112[110–112].].

Figure 7. Takemoto’sTakemoto’s thiourea organocatalyst [[110–112].110–112].

Now commercially available (in both (R,R)- and (S,S) forms), Takemoto’s organocatalyst was also Now commercially available (in both (R,,R)- and (S,,S) forms), Takemoto’s organocatalyst was used by other groups, mainly to catalyze various stereoselective additions [135,143–150], and to control also used by other groups, mainly to catalyze various stereoselective additions [135,143–150], and to the ring-opening polymerization of racemic lactide leading to highly isotactic polylactide [151]. control the ring-opening polymerization of racemic lactide leading to highly isotactic polylactide Diverse modifications of Takemoto’s compound have been introduced, both in the parent group [151]. and by others (Figure8). A PEG-immobilized catalyst was e fficient in the enantioselective Michael Diverse modifications of Takemoto’s compound have been introduced, both in the parent group and tandem Michael reactions [152], while a hydroxylated derivative catalyzed a Petasis-type reaction and by others (Figure 8). A PEG-immobilized catalyst was efficient in the enantioselective Michael of quinolones and boronic acids [153]. A hybrid catalyst containing arylboronic acid was evaluated and tandem Michael reactions [152], while a hydroxylated derivative catalyzed a Petasis-type for asymmetric hetero-Michael addition to unsaturated carboxylic acids [154,155]. Various modified reaction of quinolones and boronic acids [153]. A hybrid catalyst containing arylboronic acid was derivatives of Takemoto’s catalyst were tested in the enantioselective reduction of ketones with borane; evaluated for asymmetric hetero-Michael addition to unsaturatedunsaturated carboxyliccarboxylic acidsacids [154,155].[154,155]. VariousVarious a benzyl-substituted catalyst led to the best outcomes [156]. A piperidine derivative showed the modified derivatives of Takemoto’s catalyst were tested in the enantioselective reduction of ketones with borane; a benzyl-substituted catalyst led to the best outcomes [156]. AA piperidinepiperidine derivativederivative showed the optimal performance among diamine-derived catalysts tested in inverse-electron- demand Diels-Alder cycloaddition [157], Mannich reaction of 2-substituted indolin-3-ones [158], and pyrrolidine-substituted thiourea, in conjugatedconjugated additionaddition ofof nitroacenitroacetates to unsaturated ketoesters [159], and in double Michael reaction used for the construction of a spiro-fused cyclohexanone-5- oxazolone system [160]. Schreiner and co-workers chose an imidazole-based catalyst (in cooperation with Brønsted acids) as the best one for cyanosilylation of various aldehydes [161]. An axially-chiral binaphthyl-derived amine was used for the synthesis of thioureas which catalyzed stereoselective Michael addition of 2,4-pentanodione and malononitrile to nitroolefins [162,163].

Molecules 2020,, 25,, x;x; doi:doi: www.mdpi.com www.mdpi.com/journal/molecules/journal/molecules Molecules 2020, 25, 401 14 of 56 optimal performance among diamine-derived catalysts tested in inverse-electron-demand Diels-Alder cycloaddition [157], Mannich reaction of 2-substituted indolin-3-ones [158], and pyrrolidine-substituted thiourea, in conjugated addition of nitroacetates to unsaturated ketoesters [159], and in double Michael reaction used for the construction of a spiro-fused cyclohexanone-5-oxazolone system [160]. Schreiner and co-workers chose an imidazole-based catalyst (in cooperation with Brønsted acids) as the best one for cyanosilylation of various aldehydes [161]. An axially-chiral binaphthyl-derived amineMolecules was 2020, used 25, x for the synthesis of thioureas which catalyzed stereoselective Michael addition14 of of57 2,4-pentanodioneMolecules 2020, 25, x and malononitrile to nitrooleﬁns [162,163]. 14 of 57

Figure 8. Various chiral DACH-based thioureas used as organocatalysts [153–163]. Figure 8. VariousVarious chiral DACH-based thiourea thioureass used as organocatalysts [[153–163].153–163]. A variety of thiourea organocatalysts based on chiral diaminocyclohexane skeleton have been prepared.A variety Selected of thioureathiourea examples organocatalystsorganocatalysts include thioureas based bearin on chiralgchiral primary diaminocyclohexanediaminocyclohexane amine functionalities skeleton that were have tested been prepared.in Michael Selected addition examples of active include methylene thioureas comp bearingbearinoundsg primary to enones amine functionalities [164–167] and thatof were ketones tested or indioxindoles MichaelMichael addition toaddition nitroolefins of activeof active (Figure methylene methylene 9) [168–171]. compounds comp ounds to enones to [enones164–167 [164–167]] and of ketones and of or dioxindolesketones or todioxindoles nitrooleﬁns to (Figurenitroolefins9)[168 (Figure–171]. 9) [168–171].

Figure 9. DACH-based thioureas bearing primary amine function [164–171]. Figure 9. DACH-based thioureas bearing pr primaryimary amine function [[164–171].164–171]. Introduction of additional chiral electron-withdrawing group in place of aryl moiety of Takemoto’sIntroduction catalyst ofof additional allowedadditional an chiral additionalchiral electron-withdrawing electron-wit stereocontrolhdrawing groupin Michael group in place additionin of plac aryle moiety reactionof aryl of Takemoto’s(Figuremoiety 10)of catalystTakemoto’s[172]. allowed catalyst an additional allowed an stereocontrol additional instereocontrol Michael addition in Michael reaction addition (Figure reaction 10)[172 ].(Figure 10) [172].

Figure 10. Thiourea derivative with three stereogenic centers [[172].172]. Figure 10. Thiourea derivative with three stereogenic centers [172]. The presence of two amino groups in 1,2-diaminocyclohexane opens the possibility to design and prepareThe presence dimeric of twostructures. amino Nagasawa’sgroups in 1,2-diaminocyclohexane group developed a chiral opens bis-thiourea the possibility organocatalyst to design andefficient prepare in enantioselective dimeric structures. Morita-Baylis-Hillman Nagasawa’s group reaction developed (Figure a chiral 11) [173], bis-thiourea and its analogues organocatalyst based efficienton other in enantioselectivediamines [174]. Morita-Baylis-Hillman The DACH-based reactionbis-thiourea (Figure was 11) [173],used andin itsother analogues asymmetric based ontransformations, other diamines e.g., in[174]. photochemical The DACH-based intramolec ularbis-thiourea [2+2] cycloaddition was used of 2,3-dihydropiridone-5-in other asymmetric transformations,carboxylates described e.g., in by photochemical Mayr et al. [175]. intramolec ular [2+2] cycloaddition of 2,3-dihydropiridone-5- carboxylates described by Mayr et al. [175].

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, 401 15 of 56

The presence of two amino groups in 1,2-diaminocyclohexane opens the possibility to design and prepare dimeric structures. Nagasawa’s group developed a chiral bis-thiourea organocatalyst eﬃcient in enantioselective Morita-Baylis-Hillman reaction (Figure 11)[173], and its analogues based on other diamines [174]. The DACH-based bis-thiourea was used in other asymmetric transformations, e.g., in photochemical intramolecular [2+2] cycloaddition of 2,3-dihydropiridone-5-carboxylates described by MoleculesMayr et 2020 al. [,, 17525,, xx]. 15 of 57

Figure 11. AA chiral chiral bis-thiourea bis-thiourea prepared by Nagasawa Nagasawa and and co-workers co-workers [[173].[173].173].

Other chiralchiral diamines diamines have have been been converted converted to thioureas to thioureasthioureas as well. asas Organocatalysts well.well. OrganocatalystsOrganocatalysts bearing multiplebearingbearing multiplehydrogen hydrogen bond donors—chiral bond donors—chiral diaminocyclohexane diaminocyclohexane and 1,2-diphenylethylenediamine and 1,2-diphenylethylenediamine fragments (Figurefragments 12 ),(Figure the latter 12), the converted latter converted into sulfonamide, into sulfonamide, were prepared were prepared by Wang by Wang and co-workersand co-workers and andappeared appeared highly highly eﬃcient efficient in asymmetric in asymmetric Michael Michael addition addition as well asas nitro-Mannichwell as nitro-Mannich reaction [176reaction,177]. Among[176,177]. chiral Among thioureas chiral containingthioureas containing tertiary amines tertiary tested amines in Michaeltested in additions Michael ofadditions 3-substituted of 3- substitutedoxindoles to maleimides,oxindoles andto cyanoacetatesmaleimides, to vinyland sulfones, cyanoacetates 1,2-diphenylethylenediamine to vinyl sulfones, derivatives 1,2- diphenylethylenediamineled to the highest yields derivatives and stereoselectivities led to the highest (Figure yields12)[178 and,179 stereoselectivities]. In turn, primary (Figure amines 12) [178,179].of this kind In turn, (Figure primary 12) amines were found of this most kind (F eﬃigurecient 12) in were asymmetric found most additions efficient to in unsaturatedasymmetric additionsketones [ 180to unsaturated,181] and a ketones stereoselective [180,181] construction and a stereoselective of α,α-disubstituted construction cycloalkanones of α,,α-disubstituted [182]. Acycloalkanones catalyst bearing [182]. two A catalyst 1,2-diphenylethylenediamine bearing two 1,2-diphenylethylenediamine fragments (Figure 12 fragments) was used (Figure in a tandem12) was usedasymmetric in a tandem Michael asymmetric/cyclization Michael/cyclization reaction of 4-hydroxycoumarin reaction of 4-hydroxycou and nitroalkanes,marin albeit and with nitroalkanes, moderate albeityields with [183]. moderate yields [183].

Figure 12. ChiralChiral thioureas thioureas based on 1,2- 1,2-diphenylethylenediaminediphenylethylenediamine [176–183]. [176–183].

1,2-Dinaphthylethylenediamine derivativesderivatives were applied by Tius and co-workers in asymmetric Nazorov cyclization of diketones (Figure 1313))[ [184184,,185].,185].185]. Berkessel Berkessel and and co-workersco-workers converted chiral isophoronediamine into into bis-thioureas and bis-ureasbis-ureas (Figure(Figure 1313))[ [186].186]. The derivativederivative containingcontaining trifluoromethyltriﬂuoromethyl groupsgroups appeared appeared the thethe optimum optimumoptimum catalyst catalystcatalyst for asymmetric forfor asymmetricasymmetric Morita-Baylis-Hillman Morita-Baylis-HillmanMorita-Baylis-Hillman reaction reactionof aldehydes of aldehydes with enones with or enonesenones acrylates. oror acrylates.acrylates.

Figure 13. Chiral thioureas preparaed by the groups of Tius (left) [184,185] and Berkessel (right) [186].

Molecules 2020,, 25,, x;x; doi:doi: www.mdpi.com www.mdpi.com/journal/molecules/journal/molecules Molecules 2020, 25, x 15 of 57

Figure 11. A chiral bis-thiourea prepared by Nagasawa and co-workers [173].

Other chiral diamines have been converted to thioureas as well. Organocatalysts bearing multiple hydrogen bond donors—chiral diaminocyclohexane and 1,2-diphenylethylenediamine fragments (Figure 12), the latter converted into sulfonamide, were prepared by Wang and co-workers and appeared highly efficient in asymmetric Michael addition as well as nitro-Mannich reaction [176,177]. Among chiral thioureas containing tertiary amines tested in Michael additions of 3- substituted oxindoles to maleimides, and cyanoacetates to vinyl sulfones, 1,2- diphenylethylenediamine derivatives led to the highest yields and stereoselectivities (Figure 12) [178,179]. In turn, primary amines of this kind (Figure 12) were found most efficient in asymmetric additions to unsaturated ketones [180,181] and a stereoselective construction of α,α-disubstituted cycloalkanones [182]. A catalyst bearing two 1,2-diphenylethylenediamine fragments (Figure 12) was used in a tandem asymmetric Michael/cyclization reaction of 4-hydroxycoumarin and nitroalkanes, albeit with moderate yields [183].

Figure 12. Chiral thioureas based on 1,2-diphenylethylenediamine [176–183].

1,2-Dinaphthylethylenediamine derivatives were applied by Tius and co-workers in asymmetric Nazorov cyclization of diketones (Figure 13) [184,185]. Berkessel and co-workers converted chiral isophoronediamine into bis-thioureas and bis-ureas (Figure 13) [186]. The derivative containing Moleculestrifluoromethyl2020, 25, 401 groups appeared the optimum catalyst for asymmetric Morita-Baylis-Hillman16 of 56 reaction of aldehydes with enones or acrylates.

MoleculesFigure 2020 13., 25 ,Chiral x thioureas preparaed by the groups of Ti Tiusus (left) [[184,185]184,185] and Berkessel (right) [[186].18616]. of 57

Other chiral thioureas bearing additional amino functionalities have been described as well (Figure 14). Ephedrine-based thioureas were obtained in Bolm’s group and tested in Michael (FigureMolecules 202014)., 25Ephedrine-based, x; doi: thioureas were obtained in Bolm’s group www.mdpi.com and tested/journal/molecules in Michael additions [[187].187]. Indane scaffold scaﬀold introduced into a structure of a catalyst resulted in good yields and stereochemical outcomeoutcome of cascadeof cascade Michael-oxa-Michael-tautomerization Michael-oxa-Michael-tautomerization process [188process]. A bifunctional [188]. A pyrrolidine-thioureabifunctional pyrrolidine-thiourea was applied bywas Tang applied and co-workersby Tang and to theco-workers diastereo- to and the enantioselectivediastereo- and Michaelenantioselective additions Michael of cyclohexanone additions of tocyclohexanone alkyl and aryl to nitrooleﬁns alkyl and aryl [189 nitroolefins]. In a study [189]. by Enders In a study and co-workers,by Enders and tertiary co-workers, amines tertiary (piperidine amines and (piper pyrrolidineidine and derivatives) pyrrolidine werederivatives) found thewere best found option the forbest dominooption for Michael–Mannich domino Michael–Ma cycloadditionsnnich cycloadditions [190]. Chen’s [190]. groupChen’s prepared group prepared a series a ofseries chiral of catalysts,chiral catalysts, including including thioureas, thioureas, using a chloramphenicolusing a chloramphenicol base skeleton, base andskeleton, used themand inused asymmetric them in transformationsasymmetric transformations [191–193]. [191–193].

Figure 14. Chiral thioureas based on various diamines [[187–193].187–193].

Chromans can bebe easilyeasily substitutedsubstituted usingusing thethe MichaelMichael additionaddition approach.approach. Various chiral organocatalysts have been used in asymmetric re reactionsactions of nitroalkenes with with malonates malonates [194–196]. [194–196]. Thiourea-based ones ones bearing bearing diamine diamine functions functions were were tested tested in inthe the Michael Michael addition addition by Yan by Yan and and coco-workersworkers (Scheme (Scheme 29) 29 [197].)[197 Tang’s]. Tang’s group group prepared prepared chroman chroman derivatives derivatives by by addition addition of of malonate malonate to the appropriate nitroolefinsnitroolefins inin highhigh yieldyield andand enantiomericenantiomeric excessexcess [[189].189]. Zhu and co-workers proposed a versatile method using vinylindols as dienophiles in an inverse electron demand Diels-Alder reaction (Scheme 30)[157,198]. This appeared an efficient method of preparation of new biochemically active flavonoids containing additional privileged structures such as pyran and indole [199]. Over recent years, asymmetric cascade reactions [200–205] have been developed into a powerful tool in asymmetric synthesis of such compounds; stereogenic quaternary all-carbon centers are especially challenging [206]. Spiro-substituted structures can be found in biologically active natural and synthetic compounds [207,208]. The study on the asymmetric synthesis of spiro centers has been recently intensified [209,210], and various asymmetric routes to chromans bearing this structural feature have been found [208,211]. Thiourea-based multivalent organocatalysts offer a great opportunity for preparation of substituted spiro-chroman structures, as exemplified by Michael-acetylation-cascade reaction of 2-oxocyclohexanecarbaldehyde derivatives (Scheme 31)[212].

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x 16 of 57

Other chiral thioureas bearing additional amino functionalities have been described as well (Figure 14). Ephedrine-based thioureas were obtained in Bolm’s group and tested in Michael additions [187]. Indane scaffold introduced into a structure of a catalyst resulted in good yields and stereochemical outcome of cascade Michael-oxa-Michael-tautomerization process [188]. A bifunctional pyrrolidine-thiourea was applied by Tang and co-workers to the diastereo- and enantioselective Michael additions of cyclohexanone to alkyl and aryl nitroolefins [189]. In a study by Enders and co-workers, tertiary amines (piperidine and pyrrolidine derivatives) were found the best option for domino Michael–Mannich cycloadditions [190]. Chen’s group prepared a series of chiral catalysts, including thioureas, using a chloramphenicol base skeleton, and used them in asymmetric transformations [191–193].

Figure 14. Chiral thioureas based on various diamines [187–193].

Chromans can be easily substituted using the Michael addition approach. Various chiral organocatalysts have been used in asymmetric reactions of nitroalkenes with malonates [194–196]. Thiourea-based ones bearing diamine functions were tested in the Michael addition by Yan and co- Moleculesworkers2020, 25 (Scheme, 401 29) [197]. Tang’s group prepared chroman derivatives by addition of malonate to17 of 56 the appropriate nitroolefins in high yield and enantiomeric excess [189].

Molecules 2020, 25, x 17 of 57

Scheme 29. Asymmetric Michael addition and a proposed mechanism of formation of nitrochroman [197].

Zhu and co-workers proposed a versatile method using vinylindols as dienophiles in an inverse electron demand Diels-Alder reaction (Scheme 30) [157,198]. This appeared an efficient method of preparation of new biochemically active flavonoids containing additional privileged structures such as pyran and indole [199].

Molecules 2020, 25, x 17 of 57

Scheme 29. Asymmetric Michael addition and a proposed mechanism of formation of nitrochroman [197].

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules

Scheme 30. Asymmetric DA reaction and proposed interactions in a transition state [157].

Over recent years, asymmetric cascade reactions [200–205] have been developed into a powerful tool in asymmetric synthesis of such compounds; stereogenic quaternary all-carbon centers are especially challenging [206]. Spiro-substituted structures can be found in biologically active natural and synthetic compounds [207,208]. The study on the asymmetric synthesis of spiro centers has been recently intensified [209,210], and various asymmetric routes to chromans bearing this structural feature have been found [208,211]. Thiourea-based multivalent organocatalysts offer a great opportunitySchemeScheme for 30. preparation Asymmetric30. Asymmetric of DA substitutedDA reaction reactionand andspiro-chroman proposed in interactionsteractions structures, in ina tran aas transitionsition exemplified state state [157]. [157by ].Michael- acetylation-cascade reaction of 2-oxocyclohexanecarbaldehyde derivatives (Scheme 31) [212]. Over recent years, asymmetric cascade reactions [200–205] have been developed into a powerful tool in asymmetric synthesis of such compounds; stereogenic quaternary all-carbon centers are especially challenging [206]. Spiro-substituted structures can be found in biologically active natural and synthetic compounds [207,208]. The study on the asymmetric synthesis of spiro centers has been recently intensified [209,210], and various asymmetric routes to chromans bearing this structural feature have been found [208,211]. Thiourea-based multivalent organocatalysts offer a great opportunity for preparation of substituted spiro-chroman structures, as exemplified by Michael- acetylation-cascade reaction of 2-oxocyclohexanecarbaldehyde derivatives (Scheme 31) [212].

Scheme 31. Cont.

Molecules 2020, 25, x; doi: www.mdpi.com /journal/molecules

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, 401x 1818 of of 57 56 Molecules 2020, 25, x 18 of 57

SchemeScheme 31. 31. Asymmetric Asymmetric Michael-acetylation-cascade Michael-acetylation-cascade reactionreaction andand proposed proposed reaction reaction mechanism mechanism of of spiro-centerspiro-center formation formation [[212].212 [212].].

A A non-spiro non-spiro stereogenic stereogenic quaternary quaternary all-carbonall-carbon center was was formed formed in in an an oxa-Michael oxa-Michaeloxa-Michael addition addition followedfollowed by by an an intramolecular intramolecular Michael Michael addition addition as as reported reported byby by Lu Lu Lu and and and co-workers co-workers co-workers (Scheme (Scheme (Scheme 32) 32)32 [213].)[ [213].213 ].

Scheme 32. Formation of all-carbon quarternary centers catalyzed by a chiral thiourea and its postulated interactions with the reactant [213]. Scheme 32.32.Formation Formation of of all-carbon all-carbon quarternary quarternary centers center catalyzeds catalyzed by a chiral by a thiourea chiral andthiourea its postulated and its postulatedinteractions interactions with the reactant with the [213 reactant]. [213]. 3.2. Thioureas Containing Cinchona Alkaloids 3.2. Thioureas Containing Cinchona Alkaloids 3.2. ThioureasCinchona Containi alkaloids,ng Cinchona a privileged Alkaloids motif of various structures useful in asymmetric synthesis [214,215],Cinchona werealkaloids, also combined a privileged with motif thioureas, of various typically structures by usefulconversion in asymmetric of hydroxyl synthesis group [ 214at ,C2159 ], Cinchona alkaloids, a privileged motif of various structures useful in asymmetric synthesis position into amine and its reaction with an appropriate isothiocyanate [17]. Such derivatives, were also combined with thioureas, typically by conversion of hydroxyl group at C9 position into [214,215], were also combined with thioureas, typically by conversion of hydroxyl group at C9 amineintroduced and its by reaction the groups with anof appropriateConnon and isothiocyanateSoós (Figure 15), [17 were]. Such first derivatives, applied in introducedenantioselective by the position into amine and its reaction with an appropriate isothiocyanate [17]. Such derivatives, groupsaddition of Connon of malonates and So ótos (Figurenitroalkenes 15), were[216] first and applied nitroalkanes in enantioselective to chalcones addition[217]. Later of malonates on, these to introduced by the groups of Connon and Soós (Figure 15), were first applied in enantioselective nitroalkenesbifunctional [216 organocatalysts] and nitroalkanes were tofound chalcones efficient [217 in]. Latera variety on, theseof asymmetric bifunctional transformations, organocatalysts additionincluding of Michaelmalonates and to combined nitroalkenes Michael–Henry [216] and reactionnitroalkanes [218–238], to chalcones sulfa-Michael [217]. and Later retro-sulfa- on, these were found efficient in a variety of asymmetric transformations, including Michael and combined bifunctionalMichael reaction organocatalysts [239,240], aldol were reaction found [241], efficient Mannich in a reaction variety [242], of asymmetric Strecker reaction transformations, [243,244], Michael–Henry reaction [218–238], sulfa-Michael and retro-sulfa-Michael reaction [239,240], aldol includinghydrophosphonylation Michael and combined [245,246], Michael–Henrydecarboxylative protonreactionation [218–238], [247], fluorination sulfa-Michael of ketoesters and retro-sulfa- [248], reaction [241], Mannich reaction [242], Strecker reaction [243,244], hydrophosphonylation [245,246], Michaelarylation reaction of cyclic [239,240], ketoamides aldol with reaction quinone [241], monoamine Mannich [249] reaction and others.[242], Strecker reaction [243,244], decarboxylative protonation [247], fluorination of ketoesters [248], arylation of cyclic ketoamides with hydrophosphonylation [245,246], decarboxylative protonation [247], fluorination of ketoesters [248], quinone monoamine [249] and others. arylationMolecules of2020 cyclic, 25, x; ketoamidesdoi: with quinone monoamine [249] and others. www.mdpi.com /journal/molecules

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020,, 25,, 401x 1919 of of 5657 Molecules 2020, 25, x 19 of 57

Figure 15. Thioureas derived from Cinchona alkaloids [216,217,250]. Figure 15. ThioureasThioureas derived derived from Cinchona alkaloids [216,217,250]. [216,217,250]. Thiourea was also introduced in place of methoxy group of quinine by Hiemstra and co-workers (FigureThiourea 16), and was the also resulting introduced catalysts in place used of methoxy in enantioselective group of quinine Henry by reaction Hiemstra Hiemstra [250], and and though co-workers co-workers they (Figurewere less 16),16 ),efficient and the in resulting other asymmetric catalysts used transfor in enantioselectiveenmationsantioselective [221,243–245]. Henry Bis-alkaloid reaction [250], [250 thioureas], though werethey wereprepared less by eefficientﬃ Songcient inandin otherother co-workers asymmetricasymmetric and were transformationstransfor shownmations to exhibit [[221,243–245].221,243 high–245 enantioselectivity]. Bis-alkaloid thioureas in a dynamic were preparedkinetic resolution by Song of and race co-workersmic azlactone and derived were shown from valine to exhibit (Figure high 16) enantioselectivity [251]. in a dynamic kinetic resolution of racemicracemic azlactone derived from valine (Figure 1616))[ [251].251].

Figure 16. Bis-alkaloid thioureas prepared by Song’ group [251]. Figure 16. Bis-alkaloidBis-alkaloid thioureas thioureas prep preparedared by Song’ group [251]. [251]. One can choose among stereoisomers (quinine/quinidine, cinchonidine/cinchonine and their epimers),One can and choosetheir modified among derivatives, stereoisomers which (quinine(quinine/q often/ quinidine,allowsuinidine, obtaining cinchonidine both optical/cinchonine/cinchonine antipodes and oftheir the epimers),product of and the their catalytical modified modified reaction derivatives, [228,232,238,252] which often . However, allows obtaining other bisfunctional both optical catalysts antipodes seem of the to productoffer more of thepossibilities catalytical of reaction fine tuning [[228,232,238,252]228 ,of232 catalytic,238,252 ].properties.. However, Ce otherrtain bisfunctional problems are catalysts connected seem with to offerolimitedffer more thermal possibilities stability of [217] finefine and tuningtuning dimerization ofof catalyticcatalytic of properties.properties. alkaloid-thiourea Ce Certainrtain conjugates problems arein solution connected through with limitedintermolecular thermal hydrogen stability [217] [bonds217] and which dimerization can limit theirof alkaloid-thiourea activity [253,254]. conjugates in solution through intermolecularGu and co-workers hydrogen prepared bonds which a series can limitof chroman theirtheir activityactivity derivatives [[253,254].253,254 in]. a double Michael reaction of commerciallyGu and co-workers available startingprepared materials, a series ofchalcone chroman enolates derivatives and in nitromethane, a double Michael using reaction Cinchona of - commerciallyalkaloid thioureas availableavailable as catalysts starting starting materials,(Scheme materials, 33) chalcone [255].chalcone enolatesThree enolates stereogenic and nitromethane,and nitromethane,centers were using formed Cinchonausing withCinchona-alkaloid high- alkaloidthioureasstereoselectivity. thioureas as catalysts In as a catalysts proposed (Scheme (Scheme mechanism,33)[255 33)]. [255]. both Three Three Si stereogenic(not stereogenic observed) centers centers and wereRe were face formed formedapproaches withwith werehigh stereoselectivity.included, which wouldIn In a a proposed proposed result in mechanism, mechanism,a completely both bothdiverse SiSi (not (nothydrogen observed) observed) bonding and and interactionsReRe face approaches in a transient were included,state. whichwhich wouldwould result result in in a completelya completely diverse diverse hydrogen hydrogen bonding bonding interactions interactions in a transientin a transient state. state.

Scheme 33. Cont.

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, 401 20 of 56 Molecules 2020, 25, x 20 of 57

Scheme 33.33. AsymmetricAsymmetric doubledouble Michael Michael reaction reaction catalyzed catalyzed by byCinchona Cinchonaalkaloid-derived alkaloid-derived thiourea thiourea and aand proposed a proposed reaction reaction mechanism mechanism [255 ].[255].

Cinchona alkaloid-basedalkaloid-based organocatalysts organocatalysts were were also also applied applied by bySingh Singh and andco-workers co-workers in their in theirsynthesis synthesis of chiral of chiralchroman chroman derivatives derivatives from chalcones from chalcones and α,β-unsaturated and α,β-unsaturated nitroalkenes nitroalkenes (Scheme (Scheme34) [256]. 34 )[Reasonable256]. Reasonable yields yieldswere wereaccompanied accompanied by a by modest a modest diastereoselectivity diastereoselectivity and and high enantioselectivity, andand thethe reactionreaction waswas completedcompleted inin 8–488–48 h.h.

Scheme 34. Synthesis of chiral chroman derivatives catalyzed by a thiourea obtained from Cinchona alkaloidalkaloid.[256] [256]. 3.3. Thioureas Derived from Amino Acids and Peptides 3.3. Thioureas Derived from Amino Acids and Peptides As already demonstrated by Jacobsen’s catalyst (described in part 3.2.) [123], naturally occurring As already demonstrated by Jacobsen’s catalyst (described in part 3.2.) [123], naturally occurring amino acids and their derivatives can serve as chirality source in the construction of chiral amino acids and their derivatives can serve as chirality source in the construction of chiral thioureas thioureas [62,257–260]. Jacobsen’s group described the application of amide-thiourea catalyst [62,257–260]. Jacobsen’s group described the application of amide-thiourea catalyst obtained in three obtained in three steps from valine and N-methylbenzylamine in Pictet-Spengler reaction [261,262], steps from valine and N-methylbenzylamine in Pictet-Spengler reaction [261,262], and tert-leucine- derived amides in iso-Pictet-Spengler reaction (both reactions were co-catalyzed with benzoic acid;

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, 401 21 of 56

Molecules 2020,, 25,, xx 21 of 57 and tert-leucine-derived amides in iso-Pictet-Spengler reaction (both reactions were co-catalyzed Figurewith benzoic 17) [263]. acid; Thioureas Figure 17)[ bearing263]. Thioureas tt-leucine-leucine bearing arylpyrrolidinoarylpyrrolidinot-leucine arylpyrrolidinoamideamide componentcomponent amide catalyzedcatalyzed component thethe stereoselectivecatalyzed the stereoselective indole addition indole to γ addition-pyrone-pyrone toderivativesderivativesγ-pyrone derivatives[264].[264]. tt-Leucine-derived-Leucine-derived [264]. t-Leucine-derived thioureasthioureas werewere thioureas alsoalso efficientwere also in e ffithecient enantioselective in the enantioselective dearomatization dearomatization of isoquinolinesisoquinolines of isoquinolines [265],[265], anan [265d the], and synthesis the synthesis of furan of derivativesfuran derivatives with a with trifluoromethyl a trifluoromethyl at a atstereogeni a stereogenicc center center [266]. [266 ].Valine Valine de derivativerivative prepared prepared by by Pedrosa and co-workers was applied in nitro-Michaelnitro-Michael additions; a supported catalyst was also prepared [[267–269].267–269]. Fullerene Fullerene was was also also introduced introduced intointo into chiralchiral chiral thioureasthioureas thioureas derivedderived derived fromfrom from valine,valine, valine, phenylalanine and and tertterttert-leucine,-leucine,-leucine, andand and thethe the resultingresulting resulting hybridshybrids hybrids appearappear appeareded efficient, efficient, recyclable recyclable catalysts catalysts for stereoselectivefor stereoselective nitro-Mi nitro-Michaelchael reaction reaction [270]. [270 ].

Figure 17. ExamplesExamples of of chiral chiral thioureas thioureas de derivedrivedrived fromfrom amino amino acids acids [263–269]. [[263–269].263–269].

Thioureas derived derived from from L-proline-prolinel-proline werewere were reportedreported reported byby variousvarious by various groups groups (Figure (Figure 18) [271–273]. 18)[271 These–273]. derivativesThese derivatives were wereapplied applied in asymmetric in asymmetric direct direct aldol aldol reaction reaction of ofcyclohexanone cyclohexanone and and aldehydes aldehydes or or enantioselective MichaelMichael addition addition of of 1,3-diones 1,3-diones to to nitrooleﬁns, nitroolefins,nitroolefins, both bothboth proceeding proceedingproceeding in high inin highhigh yields yieldsyields and withandand withexcellent excellent stereoselectivity stereoselectivity [271, 273[271,273].].

Figure 18. ChiralChiral thioureas thioureas obtained obtained from from Ll-proline-proline [271–273]. [[271–273].271–273].

A series series of of thioureas thioureas was was obtained obtained by by Bolm Bolm and and co-workers co-workers starting starting from from L-aspartic-asparticl-aspartic acidacid acid andand and L-- glutamicl-glutamic acid acid which which were were converted converted into into cyclic cyclic amines amines and and reacted reacted with with organic isothiocyanatesisothiocyanates (Figure(Figure 1919)19))[ [274].[274].274]. TheThe The resultingresulting resulting coco compoundsmpounds provided provided excellent excellent yields yields and stereoselectivities of Michael additions.

FigureFigure 19. AnAn example example of of chiral chiral thiourea thiourea prepared prepared in Bolm’s group [274]. [274].

InIn 2007, 2007, Lattanzi Lattanzi prepared prepared thioureasthioureas fromfrom commerciallycommercially availableavailable enantiopureenantiopure aminoalcoholsaminoalcohols and used used them them in stereoselective in stereoselective Morita–Baylis– Morita–Baylis–HillmanHillman reaction reaction of cyclohexanone of cyclohexanone and aldehydes and [275].aldehydes[275]. VariousVarious [275 peptidomimeticspeptidomimetics]. Various peptidomimetics containingcontaining thioureathiourea containing fragmentfragment thiourea werewere fragmentpreparedprepared wereasas wellwell prepared [39,79,90].[39,79,90]. as Peptidicwell [39 ,79derivatives,90]. Peptidic containing derivatives adamantyl containing moiety adamantyl were found moiety efficient were catalysts found of eﬃ Morita–Baylis–cient catalysts Hillmanof Morita–Baylis–Hillman reactions (Figure 20) reactions [276]. (Figure 20)[276].

Molecules 2020,, 25,, x;x; doi:doi: www.mdpi.com www.mdpi.com/journal/molecules/journal/molecules Molecules 2020, 25, 401 22 of 56 Molecules 20202020,, 2525,, xx 2222 ofof 5757

Figure 20. AA peptide-like peptide-like chiral thiourea [276]. [276].

Amino acid-derived thiourea organocatalysts were were used used by by Zhao’s group in a tandem thia/oxa thia/oxa Michael-Michael reactionreaction yielding yielding optically optically pure pu chromansrere chromanschromans containing containingcontaining the pharmaceutically thethe pharmaceuticallypharmaceutically important importantoxindoleimportant sca oxindoleoxindoleﬀold (Scheme scaffoldscaffold 35 (Scheme(Scheme)[277]. Spiro 35) [277]. products Spiro were products isolated were in isolated high yields in high and yields good up and to good very uphigh to enantiomeric very high enantiomeric excess. excess.

Scheme 35. AsymmetricAsymmetric tandem tandem Michael–Michael Michael–Michael reaction reaction reported reported by by Zhao Zhao et et al. al. and and its its proposed proposed mechanism [277]. [277].

Excellent yield, yield, diastereomeric diastereomeric and and enantiomeric enantiomeric excess excess were were reported reported in ina domino a domino reaction reaction of oxa-Michaelof oxa-Michael and and 1,6-addition 1,6-addition by Enders by Enders et al. et (Scheme(Scheme al. (Scheme 36)36) [278]. [278].36)[ 278AsAs ]. privilegedprivileged As privileged substratessubstrates substrates ortho-ortho- hydroxyphenylortho-hydroxyphenyl derivatives derivatives were used were [279], used introducing [279], introducing a nucleophilic a nucleophilic group para- groupquinonepara- methidesquinone thatmethidesthat becamebecame that suitablesuitable became donor-Michaeldonor-Michael suitable donor-Michael acceptorsacceptors acceptors[280–287].[280–287]. [ 280–287].

Molecules 20202020,, 2525,, x;x; doi:doi: www.mdpi.com www.mdpi.com/journal/molecules/journal/molecules Molecules 2020, 25, x 23 of 57 Molecules 2020, 25, 401 23 of 56 Molecules 2020, 25, x 23 of 57

Scheme 36. Asymmetric domino oxa-Michael-1,6-addition and the proposed interactions in the transient state [278]. Scheme 36.36. AsymmetricAsymmetric domino domino oxa-Michael-1,6-addition oxa-Michael-1,6-addition and and the the proposed interactions in the transient state [[278].278]. 3.4. Carbohydrate-Based Chiral Thioureas 3.4. Carbohydrate-Based Chiral Thioureas 3.4. Carbohydrate-BasedChiral thioureas can Chiral bear Thioureas enantiopure carbohydrates. Quite frequently, they are combined with otherChiral functionalities. thioureas thioureas can canFor bear bearexample, enantiopure enantiopure Liu et carbohydra al. carbohydrates. preparedtes. Quitefive Quite novel frequently, frequently, D-mannitol-derived theythey are combined are combined thiourea with with other functionalities. For example, Liu et al. prepared ﬁve novel d-mannitol-derived thiourea organocatalystsother functionalities. containing For example,Cinchona alkaloidsLiu et al. as preparedwell and usedfive themnovel for D -mannitol-derivedasymmetric Henry thioureareaction organocatalysts[40]. containingcontainingCinchona Cinchonaalkaloids alkaloids as as well well and and used used them them for for asymmetric asymmetric Henry Henry reaction reaction [40]. [40]. Ma and co-workers introduced bifunctionalbifunctional organocatalystsorganocatalysts containing multiple stereogenic centersMa inin and bothboth co-workers primary primary amine amine introduced derived derived frombifunctional from DACH DACH andor ganocatalystsand various various carbohydrate carbohydrate containing moieties multiple moieties (Figure stereogenic(Figure 21)[288 21)]. With[288].centers theseWith in both these promoters, primary promoters, Michaelamine Michael derived addition addition from of DACH ketonesof ketones and to to nitroalkenesvarious nitroalkenes carbohydrate proceeded proceeded moieties with with highhigh(Figure yields 21) and[288]. stereoselectivities. With these promoters, Similar Similar Michael catalysts catalysts addition (also (also of containing ketones to 1,2-phenylenediamine)nitroalkenes proceeded were werewith highapplied yields in otherand stereoselectivities. Michael additions Similar [[194,289],194,289 catalysts], Mannich (also reaction containing [[290,291],290,291 1,2-phenylenediamine)], and conjugateconjugate additionaddition/dearomative were/dearomative applied in

ﬂuorinationfluorinationother Michael [292[292,293]. additions,293]. ThioureasThioureas [194,289], containing containingMannich a reaction glycosyla glycosyl [290,291], scaﬀ scaffoldold were and were also conjugate applied also appliedaddition/dearomative in aza-Henry in aza-Henry reaction betweenreactionfluorination betweenN-Boc [292,293]. imines N-Boc andThioureas imines nitromethane and containing nitromethane [294 ].a glycosyl [294]. scaffold were also applied in aza-Henry reaction between N-Boc imines and nitromethaneAcO [294]. (R,R)or(S,S) AcOAcO O S (R,R)or(S,S) AcO * AcO O N S N * H H OAc * NR2 AcO N N * R=H,Me,BuH H OAc NR2 NR = R=H,Me,Bu2 N N NR = 2 N N

Figure 21. Carbohydrate-derived chiral thiourea [[288].288]. Figure 21. Carbohydrate-derived chiral thiourea [288].

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, 401 24 of 56 Molecules 2020, 25, x 24 of 57

Asymmetric tandem Michael–Michael additions of ketones and nitroalkenes were optimized by Miao and co-workersco-workers (Scheme 3737))[ [295].295]. A carbohydrate-basedcarbohydrate-based chiral thioureathiourea organocatalystorganocatalyst usedused together with benzenesulfonicbenzenesulfonic acid (BSA) aaffordedﬀorded high yields, excellent enantiomeric excess and high diastereoselectivity. The The resulting resulting spiro-compounds are are not only interesting due to possiblepossible biological activitiesactivities [ 296[296],], but but also also as enantiopureas enantiopure multi-functionalized multi-functionalized pyrazole pyrazole derivatives derivatives for further for synthesisfurther synthesis [211,212 [211,212,297–299].,297–299].

Scheme 37. Asymmetric synthesis of various spiro-co spiro-compoundsmpounds with mechanism proposed [[295].295].

3.5. Chiral Phosphine-Bearing Thioureas Bifunctional catalysts catalysts containing containing thiourea thiourea moiety moiety (hydrogen (hydrogen bond bond donor, donor, Brønsted Brønsted acid)acid) and andnucleophilic/basic nucleophilic/basic phosphine phosphine functi functionality,onality, both attached both attached to a chiral to a skeleton, chiral skeleton, have already have found already a foundvariety aof variety applications of applications in stereoselective in stereoselective reactions [113]. reactions The first [113 ].report The on first their report synthesis on theirwas synthesispublished wasby Shi published and Shi in by 2007 Shi andwho Shiprepared in 2007 thre whoe binaphthyl-based prepared three binaphthyl-based derivatives (Figure derivatives 22) [300]. (FigureA N-phenyl-substituted 22)[300]. A N-phenyl-substituted catalyst was most catalyst efficien wast in most aza-Morita-Baylis-Hillman efficient in aza-Morita-Baylis-Hillman reaction of N- reactionsulfonated of Nimines-sulfonated and vinyl imines ketones and vinylor acrolein: ketones (S or)-products acrolein: were (S)-products formed werein moderate formed to in high moderate yield toand high stereoselectivities. yield and stereoselectivities. Shi and co-workers Shi and used co-workers modified used thioureas modified belonging thioureas to the belonging same class to the in samethe reaction class in of the MBH reaction adducts of MBH with adductsoxazolones with [301]. oxazolones [301].

Figure 22. Axially chiral ph phosphine-containingosphine-containing thiourea [[300].300].

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x 25 of 57 Molecules 2020, 25, 401x 2525 of of 57 56 MoleculesAn 2020 active, 25, catalystx bearing a diphenylphosphine moiety was introduced by Wu and co-workers25 of 57 and testedAn active for thecatalyst Morita–Baylis–Hillman bearing a diphenylphosphine reaction of moiety aromatic was aldehydes introduced with by methylWu and vinyl co-workers ketone and acrylatestestedAn active for (Figure thecatalyst Morita–Baylis–Hillman 23) bearing [302,303]. a diphenylphosphine Slightly reaction higher (and of moiety aromatic opposite) was aldehydes introduced enantioselectivities with by methylWu and were vinyl co-workers noted ketone for andvaline-derived acrylates tested for (Figure thephosphinothiourea, Morita–Baylis–Hillman 23) [302,303]. Slightlyhowever, reaction higher the reaction (and of aromatic opposite) required aldehydes enantioselectivities more time with [304]. methyl were vinyl noted ketone for andvaline-derived acrylates (Figure phosphinothiourea, 2323))[ [302,303].302,303]. Slightlyhowever, higher the reaction (and (and opposite) required enantioselectivities more time [304]. were noted for valine-derived phosphinothiourea, however, thethe reactionreaction requiredrequired moremore timetime [[304].304].

Figure 23. Chiral thioureas with diphen ylphosphine moiety [302,303]. Figure 23. Chiral thioureas with diphen ylphosphine moiety [302,303]. Phosphinothiourea,Figure 23. described ChiralChiral thioureas by Mita with and diphen diphenylphosphine Jacoylphosphinebsen, catalyzed moiety enantioselective [302,303]. [302,303]. opening of aziridinesPhosphinothiourea, with hydrogen described chloride byto Mitayield andβ-chloroamine Jacobsen, catalyzed derivatives enantioselective (Figure 24) [305]. opening Chiral of aziridinesthioureaPhosphinothiourea, bearing with hydrogen a phosphine described described chloride moiety by to was Mita yield also andβ-chloroamine efficient Jacobsen,Jacobsen, in 1,6-conjugate catalyzed derivatives enantioselective addition(Figure 24) of para[305]. opening -quinone Chiral of aziridinesthioureamethides bearing withwith hydrogen dicyanoolefinshydrogen a phosphine chloride chloride moiety[306]. to yieldto Anwas yield βinteresting -chloroaminealso β-chloroamine efficient example derivatives in 1,6-conjugate derivatives of thioureas (Figure addition(Figure 24 bearing)[305 ].24) of Chiral apara[305]. stereogenic-quinone thiourea Chiral methidesthioureaphosphorusbearing a bearing phosphinewith atom, dicyanoolefins a preparedphosphine moiety by was moiety[306]. a alsostereoselective An ewasffi cientinteresting also inefficient reduction 1,6-conjugate example in 1,6-conjugateof theof addition thioureascorresp ofadditiononding parabearing-quinone aminophosphine of apara stereogenic methides-quinone withphosphorusmethidesoxides dicyanoolefins and with their atom, dicyanoolefins reaction prepared [306]. with An by interestingisothiocyanates,[306]. a stereoselective An interesting example wa reductions of describedexample thioureas of thebyof bearing Suthioureascorresp and a ondingTaylor stereogenic bearing (Figureaminophosphine a phosphorusstereogenic 24) [307]. oxidesphosphorusEpimericatom, prepared and catalysts their atom, by reaction a prepared stereoselectiveexhibited with by differentisothiocyanates, a stereoselective reduction activity of thewa reductionands corresponding described stereoselectivity of theby aminophosphineSucorresp and in ondingTaylor Morita-Baylis-Hillman (Figureaminophosphine oxides 24) and [307]. their Epimericoxidesreactionsreaction and with ofcatalysts theirmethyl isothiocyanates, reaction acrylateexhibited with and wasdifferentisothiocyanates, aromatic described activityaldehydes. by wa Su ands and described stereoselectivity Taylor (Figureby Su and 24 in)[ Taylor 307Morita-Baylis-Hillman]. Epimeric (Figure 24) catalysts [307]. reactionsEpimericexhibitedIn a of di2019catalysts ffmethylerent paper, activity acrylateexhibited amino and and acid-derived stereoselectivitydifferent aromatic activityaldehydes. thiourea in Morita-Baylis-Hillmanand -phosphonium stereoselectivity salts reactions inwere Morita-Baylis-Hillman explored of methyl as acrylatephase- reactionstransferand aromaticIn acatalysts of2019 methyl aldehydes. paper, for acrylate asymmetric amino and acid-derived aromatic Mannich aldehydes. reaction thiourea (Figure -phosphonium 24) [308]. salts were explored as phase- transferIn acatalysts 2019 paper, for asymmetric amino acid-derived Mannich reaction thiourea (Figure-phosphonium 24) [308]. salts were explored as phase- transfer catalysts for asymmetric Mannich reaction (Figure 24) [308].

Figure 24.24.Examples Examples of chiralof chiral thioureas thioureas bearing phosphinebearing phosphine functionalities[ functionalities[305,307]305,307] and a phosphonium and a Figurephosphoniumsalt [308 ].24. Examples salt [308]. of chiral thioureas bearing phosphine functionalities[305,307] and a Figurephosphonium 24. Examples salt [308]. of chiral thioureas bearing phosphine functionalities[305,307] and a phosphoniumAIn novel a 2019 chiral paper, salt ferrocenyl amino [308]. acid-derived bis-phosphine thiourea-phosphonium thiourea was introduced salts were by Zhang explored and asco-workers phase-transfer who describedcatalystsA novel for its asymmetricchiral use ferrocenyl in MannichRh-catalyzed bis-phosphine reaction hydrogenat (Figure thiourea 24ion)[ was308 of introduced]. nitroalkenes by Zhang with and high co-workers yields whoand describedenantioselectivities,A novel its chiral use ferrocenyl evenin Rh-catalyzedat low bis-phosphine catalyst loadinghydrogenat thiourea (Figureion was 25)of introduced [309,310].nitroalkenes byThis Zhang ligand,with and highnamed co-workers yields ZhaoPhos, who and enantioselectivities,describedeasily prepared itsits use use infrom Rh-catalyzed evenin Ugi’s Rh-catalyzedat low amine, hydrogenationcatalyst showed loadinghydrogenat ofhigh (Figure nitroalkenes ionefficiency 25)of [309,310].nitroalkenes with in highvarious This yields ligand,withhydrogen and enantioselectivities, highnamed bond-assisted yields ZhaoPhos, and easilyenantioselectivities,catalyticeven at prepared low hydrogenations catalyst from loadingeven Ugi’s atwith low (Figure amine, rhodium catalyst 25 )[showed 309loadingand,310 iridium high]. (Figure This efficiency complexes ligand, 25) [309,310]. named in [311–318]. various ZhaoPhos, This ligand, hydrogenThe easilysystem named preparedbond-assisted exemplified ZhaoPhos, from catalyticeasilytheUgi’s idea amine,prepared ofhydrogenations synergistic showed from high activationUgi’s with eﬃ ciencyamine, rhodium via in cooperatingshowed various and iridium hydrogenhigh transition efficiency complexes bond-assisted metal-catalyst in [311–318]. various catalytic and hydrogenThe organocatalyst hydrogenationssystem bond-assisted exemplified joined with thecatalyticinrhodium one idea bifunctional ofhydrogenations and synergistic iridium structure complexesactivation with [319]. rhodium [via311 cooperating–318 and]. The iridium system transition complexes exempliﬁed metal-catalyst [311–318]. the idea and The of organocatalyst synergistic system exemplified activation joined viainthe one cooperatingidea bifunctional of synergistic transition structure activation metal-catalyst [319]. via cooperating and organocatalyst transition metal-catalyst joined in one bifunctional and organocatalyst structure joined [319]. in one bifunctional structure [319].

Figure 25. ZhaoPhos, a chiral bis-phosphine thiourea organocatalyst [309,310]. Figure 25. ZhaoPhos,ZhaoPhos, a chiral bis-phosphine th thioureaiourea organocatalyst [[309,310].309,310]. Figure 25. ZhaoPhos, a chiral bis-phosphine thiourea organocatalyst [309,310].

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, 401x 2626 of of 57 56

Other chiral phosphorus derivatives of thioureas are also worth mentioning. Two phosphorylamideOther chiral phosphorus derivatives derivatives were prepared of thioureas by are Juaristi also worth and mentioning. co-workers Twophosphorylamide and utilized in stereoselectivederivatives were Michael prepared addition by Juaristi of and cyclohex co-workersanone and to utilized nitrostyrenes in stereoselective and chalcones Michael [42]. addition Chiral of thioureascyclohexanone containing to nitrostyrenes an aminophosphonate and chalcones moiety [42]. Chiral were thioureas investigated containing in context an aminophosphonate of their antiviral activitymoiety wereas well investigated [320]. in context of their antiviral activity as well [320]. In a chiral phosphine thiourea-mediated reaction of para-quinone methides with dicyanoolefins dicyanooleﬁns described by Yao etet al.al. excellent excellent diastereomeric diastereomeric excess excess in in combination combination with with good yield and enantioselectivity were observedobserved (Scheme 3838))[ [306].306].

Scheme 38. Asymmetric reaction of para-quinone methides catalyzed by chiral phosphine thiourea catalysts and a proposed transient state [[306].306]. 3.6. Thioureas and Bis-Thioureas with Axial, Planar or Helical Chirality 3.6. Thioureas and Bis-Thioureas with Axial, Planar or Helical Chirality Chirality of majority enantiopure thioureas used in asymmetric organocatalysis origins from Chirality of majority enantiopure thioureas used in asymmetric organocatalysis origins from the the presence of stereogenic center(s). However, one cannot neglect a group of derivatives which are presence of stereogenic center(s). However, one cannot neglect a group of derivatives which are characterized by the presence of other stereogenic elements. Some notable representatives include characterized by the presence of other stereogenic elements. Some notable representatives include eﬃcient organocatalysts and exciting examples of molecular motors from Feringa’s laboratory. efficient organocatalysts and exciting examples of molecular motors from Feringa’s laboratory. Most compounds belonging to this class exhibit axial chirality/helicity connected with the Most compounds belonging to this class exhibit axial chirality/helicity connected with the presence of biaryl fragment characterized by a restricted rotation around the Caryl–Caryl bond. presence of biaryl fragment characterized by a restricted rotation around the Caryl–Caryl bond. First First examples come from 2005, when, looking for optimal organocatalyst for the asymmetric examples come from 2005, when, looking for optimal organocatalyst for the asymmetric Morita- Morita-Baylis-Hillman reaction of cyclohexanone with aldehydes, Wang and co-workers decided Baylis-Hillman reaction of cyclohexanone with aldehydes, Wang and co-workers decided to combine to combine thiourea moiety with binaphthylamine (Figure 26)[28]. An axially chiral binaphthyl thiourea moiety with binaphthylamine (Figure 26) [28]. An axially chiral binaphthyl bis-thiourea was bis-thiourea was prepared by Connon and co-workers and proved useful in promotion of asymmetric prepared by Connon and co-workers and proved useful in promotion of asymmetric Friedel–Crafts Friedel–Crafts type addition of indole derivatives to nitroalkenes (Figure 26)[29]. Modiﬁed catalysts type addition of indole derivatives to nitroalkenes (Figure 26) [29]. Modified catalysts belonging to

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, 401 27 of 56 Molecules 2020,, 25,, xx 27 of 57 thisbelonging class obtained to this classin Shi’s obtained group were in Shi’s alsogroup efficient were in the also asymmetric efficient in Henry the asymmetric [30] and Morita-Baylis- Henry [30] Hillmanand Morita-Baylis-Hillman reactions [300,301,321]. reactions A multifunctional [300,301,321 ].organocatalyst A multifunctional containing organocatalyst quinine, thiourea containing and binaphthylaminequinine, thiourea moieties, and binaphthylamine capable of stereoselectiv moieties,e capable formation of stereoselectiveof three stereocenters formation in a ofdomino three Michael-aldolstereocenters in reaction a domino was Michael-aldol constructed reaction by Barbas was III constructed and co-workers by Barbas [322]. III andNovel co-workers bis-thioureas [322]. preparedNovel bis-thioureas by Rampalakos prepared and by RampalakosWulff from and commercially Wulff from commerciallyavailable enantiomerically available enantiomerically pure 1,1′′- binaphthyl-2,2pure 1,10-binaphthyl-2,2′′-diamine 0were-diamine tested were in aza-Henry tested in aza-Henryreactions (Figure reactions 26) (Figure[323]. A 26series)[323 of]. binaphthyl- A series of derivedbinaphthyl-derived thiourea catalysts thiourea catalystswere applied were applied by Kim by Kimand andco-workers co-workers in inasymmetric asymmetric Mannich-type Mannich-type reactions of fluorinatedfluorinated ketoestersketoesters [[324].324]. For For th thee asymmetric Henry reaction, bis-thioureas were prepared connected withwith 4,40′′-bisindanyl-bisindanyl [325], [325], and and substituted substituted biphenyl- biphenyl- and and bianthryl-based bianthryl-based linkers (Figure 2626))[ [326–328].326–328]. High yields and stereoselectivitiesstereoselectivitiesivities werewere observedobserved forforfor certaincertaincertain derivatives.derivatives.derivatives.

Figure 26. ExamplesExamples ofof thioureasthioureas andand bis-thiobis-thio bis-thioureasureas with axial chirality [28,29,323–328]. [28,29,323–328].

A combined point chirality and axial chirality chirality resu resultingltinglting fromfrom thethe restrictedrestricted rotationrotation waswas observedobserved for thiourea-oxazoline ligands used used for for palladium-ca palladium-catalyzedtalyzed asymmetric asymmetric reactions reactions (Figure (Figure 27)27)[ [82,88].82,88]. A seriesseries ofof enantiopureenantiopure atropisomeric atropisomeric thioxothiazol-substituted thioxothiazol-substitutedl-substituted derivatives derivativesderivatives prepared preparedprepared by byby Roussel RousselRoussel et al.etet wereal. were tested tested as enantioselectiveas enantioselective anion anion receptors receptors (Figure (Figure 27)[ 27)329 [329].].

Figure 27. ThioureasThioureasThioureas withwith axialaxial chirchir chiralityality resulting resulting from a restricted rotation [[82,329].82,329].

Bisfunctional, photoswitchable, dual stereoselective catalysts based on the idea of unidirectional unidirectional molecular motorsmotors werewere designeddesigned by by Feringa Feringa and and co-workers co-workers (Figure (Figure 28 28))[330 [330,331].,331]. The The cooperation cooperation of ofthiourea thiourea and and tertiary tertiary amine amine in cis instates cis statesstates wasfound waswas foundfound a key factoraa keykey forfactorfactor stereoselectivity for stereoselectivity of Henry of reaction Henry reactionof nitromethane of nitromethane and ﬂuorinated and fluorinated ketones and ketone Michaels and reaction Michael of bromonitrostyrene reaction of bromonitrostyrene and pentanedione. and pentanedione.

Molecules 2020,, 25,, x;x; doi:doi: www.mdpi.com www.mdpi.com/journal/molecules/journal/molecules Molecules 2020, 25, 401 28 of 56 Molecules 2020,, 25,, xx 28 of 57

FigureFigure 28. MolecularMolecular motorsmotors bearingbearing thioureathiourea moietymoiety [330,331].[330,331]. [330,331].

Enantiomerically pure pure planar-chiral planar-chiral thiourea thiourea derivatives derivatives based based on on [2.2]cyclophane were were first first prepared by by Paradies Paradies and and co-workers co-workers and andshowed showed ratherther rather limitedlimited limited efficiencyefficiency effi ininciency stereoselectivestereoselective in stereoselective Friedel–Friedel– CraftsFriedel–Crafts alkylation alkylation of indole of and indole transfer and transfer hydrogenation hydrogenation of nitroolefin of nitroolefin (Figure (Figure 29) [31]. 29)[ However,31]. However, the performancethe performance of cyclophane of cyclophane bis-thio bis-thioureasureas in asymmetric in asymmetric Henry reaction Henry reaction was much was improved much improved and also ledledand toto also highhigh led inductioninduction to high inductionofof chiralitychirality of (Figure(Figure chirality 29)29) (Figure [32].[32]. OtherOther 29)[ modificationsmodifications32]. Other modifications ofof thethe systemsystem of (the(the the introductionintroduction system (the ofintroduction amino group) of aminowere found group) useful were forfor found thethe catalysiscatalysis useful for ofof the aldolaldol catalysis reactionreaction of ofof aldol isatinesisatines reaction andand ketonesketones of isatines (Figure(Figure and 29)ketones [33]. (Figure 29)[33].

FigureFigure 29. ExamplesExamples ofof thioureasthioureas withwith planarplanar chiralitychirality [31–33].[31–33]. [31–33].

Thioureas were also incorporated to optically active helical polymers. Polymerized Polymerized enantiopure enantiopure N-propargylthioureas-propargylthioureas derived derived from from 1-phenylethylamine 1-phenylethylamine formed formed helices helices in in low low polaritypolarity solventssolvents andand showedshowed affinity aﬃnity to iron(III) ions [[332].332]. Polyacetylenes Polyacetylenes bearing bearing pendant pendant thiourea thiourea groups groups were were used as chiralchiral catalysts catalysts for for the the asymmetric asymmetric Michael Michael addition addition of of diethyl diethyl malonate malonate to to trans- trans-ββ-nitrostyrene-nitrostyrene-nitrostyrene [333].[333]. [333].

3.7. Thioureas Thioureas Containing Containing Other Other Functional Functional Groups Groups A variety ofof thioureathiourea organocatalystsorganocatalysts have have been been prepared prepared containing containing additional additional functionalities functionalities to totointroduce introduceintroduce chirality chiralitychirality or/and or/andor/and to actively toto participateactivelyactively participateparticipate in the catalytic inin thethe reaction. catalyticcatalytic For example,reaction.reaction. photochemically ForFor example,example, photochemicallyactive thioxanthone active was thioxanthone attached to was thiourea attached moiety to thioureathiourea with various moietymoiety chiral withwith variousvarious linkers andchiralchiral the linkerslinkers resulting andand thethecatalysts resultingresulting were catalystscatalysts employed werewere in employed theemployed photocyclization inin thethe photocyclizationphotocyclization of 2-aryloxycyclohex-2-enones ofof 2-aryloxycyclohex-2-enones2-aryloxycyclohex-2-enones (Figure 30)[334 (Figure(Figure]. 30) [334].

Molecules 2020,, 25,, x;x; doi:doi: www.mdpi.com www.mdpi.com/journal/molecules/journal/molecules Molecules 2020, 25, 401 29 of 56 Molecules 2020, 25, x 29 of 57

FigureFigure 30.30. Chiral thioureas bearing thioxanthone fragmentfragment.[334] [334].

Wang and co-workersco-workers reported a preparation of bifunctional rosin-derived catalysts (prepared from chiralchiral dehydroabietic dehydroabietic amine) amine) and and used used it in ait doubly in a doubly stereocontrolled stereocontrolled addition addition reactions, reactions, including includingthe stereoselective the stereoselective synthesis synthe of chiralsis of cyclic chiral thioureas cyclic thioureas (Figure (Figure31)[51, 17131) ,[51,171,335–341].335–341]. Wang’s Wang’s group groupmodiﬁed modified the original the original structure structure of their of catalyst their catalyst with Cinchona with Cinchonaalkaloids alkaloids as well as to well provide to provide a double a doublestereocontrol stereocontrol [342–344 [342–344].]. Rosin-derived Rosin-derived thioureas thioureas were were also also used used by by Reddy Reddy and and co-workersco-workers in asymmetric Michael-hemiketalization of allomaltol [[345].345].

Figure 31. Rosin-derived thiourea [51]. [51].

A series of chiral bis-thioureas bis-thioureas bearing a central guanidine motif were developed by Nagasawa's Nagasawa’s group andand appliedapplied as as catalysts catalysts of of Henry Henry reaction reaction of nitromethaneof nitromethane and and various vari aldehydesous aldehydes (Figure (Figure 32)[346 32)]. [346].Ricci’s Ricci's group group developed developed an indanol an indanol chiral chiral thiourea thiourea organocatalyst organocatalyst for enantioselective for enantioselective Friedel-Crafts Friedel- Craftsalkylation alkylation of indoles of indoles with nitroalkenes with nitroalkenes (Figure (Figure 32)[347 32)]. [347].

Figure 32. ChiralChiral thioureas thioureas with guanidine moie moietyty [346] [346] and indanol derivative [347]. [347].

Thioureas cancan be be equipped equipped with with additional additional sulfur sulfur functionalities. functionalities. In our In laboratory, our laboratory, chiral amino-chiral amino-and diaminosulﬁdes and diaminosulfides obtained obtained from cyclohexane-1,2-diol from cyclohexane-1,2-diol were converted were intoconverted mono- andinto bisthioureasmono- and whichbisthioureas were tested which in were Morita-Baylis-Hillman tested in Morita-Baylis-Hillman reaction (Figure reaction 33)[348 ].(Figure Bolm and33) co-workers[348]. Bolm designed and co- workersthe synthesis designed of a set the of chiralsynthesis sulfoximine-based of a set of chir thioureasal sulfoximine-based (Figure 33)[41 ].thioureas Interestingly, (Figure the optimum33) [41]. Interestingly,results of asymmetric the optimum Biginelli results reaction of asymmetric were obtained Biginelli for reaction the derivative were obtained bearing for only the sulfurderivative as a bearingstereogenic only center sulfur separated as a stereogenic from thiourea center separated moiety. from thiourea moiety.

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, 401 30 of 56 Molecules 2020, 25, x 30 of 57

Figure 33. ChiralChiral thioureas thioureas substituted with thio thioetherether groups [348] [348] and sulfoximine [[41].41].

Krasonvskaya etet al. al. described described a preparationa preparation of a of thiourea-modiﬁed a thiourea-modified doxorubicin doxorubicin as a pH-sensitive as a pH- sensitiveprodrug capableprodrug of capable releasing of cytotoxic releasing component cytotoxic component as well as anticonvulsant as well as anticonvulsant albutoin in a weaklyalbutoin acidic in a weaklymedium acidic [349]. medium Thioureas [349]. containing Thioureas a chiral containing isosteviol a chiral moiety isosteviol [350–352 moiety], terpenes [350–352], [77], camphor terpenes [[77],353] camphoror steroid [353] scaﬀ oldor steroid [354] have scaffold been [354] also have reported. been also reported.

4. Biological Biological Activity Activity of of Chiral Thioureas Thioureas represent represent an an important important class class of ofcompound compoundss that that attracted attracted a lot a of lot attention of attention due to due their to bioactivity,their bioactivity, e.g., in e.g., medicinal in medicinal chemistry, chemistry, pharmaceutical pharmaceutical industry, industry, and agriculture. and agriculture. Derivatives Derivatives were werefound found to be efficient to be effi cientantiviral antiviral [72], antifungal [72], antifungal [355], [ 355antimicrobial], antimicrobial [356] [or356 anticancer] or anticancer agents agents [357]. [ 357The]. abilityThe ability of preparing of preparing thioureas thioureas containing containing various various scaffolds scaffolds allows allows their their use use as as potential potential inhibitors against numerous molecular target targets.s. Consequently, Consequently, these compounds have become an interesting material forfor further further investigations. investigations. In this In partthis of part the review, of the selected review, examples selected of chiralexamples thiocarbamides of chiral thiocarbamidesused in biomedical used studies in biomedical will be presented. studies will be presented. 4.1. Antiviral Thioureas 4.1. Antiviral Thioureas Aminophosphonates are structural analogues of amino acids. Likewise the aminophosphonic Aminophosphonates are structural analogues of amino acids. Likewise the aminophosphonic acids, they are able to inhibit enzymes involved in amino acids metabolism, and thus may generate acids, they are able to inhibit enzymes involved in amino acids metabolism, and thus may generate various physiological responses, e.g., neuromodulatory activity [358]. Cucumber mosaic virus (CMV) various physiological responses, e.g., neuromodulatory activity [358]. Cucumber mosaic virus (CMV) and tobacco mosaic virus (TMV) are plant virus diseases which have become a serious problem in and tobacco mosaic virus (TMV) are plant virus diseases which have become a serious problem in agriculture in recent years [359]. The commercially available product Ningnanmycin is commonly used agriculture in recent years [359]. The commercially available product Ningnanmycin is commonly against CMV and TMV, though with serious limitations resulting from its light and moisture sensitivity. used against CMV and TMV, though with serious limitations resulting from its light and moisture Thus, the design and preparation of novel antiviral agents constitutes a significant challenge. sensitivity. Thus, the design and preparation of novel antiviral agents constitutes a significant In 2009, Chen et al. reported the novel anti-TMV chiral thioureas and bis-thioureas bearing challenge. α-aminophosphonate moiety [320]. The evaluation of a tested series revealed that two derivatives are In 2009, Chen et al. reported the novel anti-TMV chiral thioureas and bis-thioureas bearing α- active against CMV and TMV comparable to Ningnanmycin (Figure 34). It was also found that the aminophosphonate moiety [320]. The evaluation of a tested series revealed that two derivatives are absolute configuration of isothiocyanates, used to form corresponding mono- and bis-thioureas, active against CMV and TMV comparable to Ningnanmycin (Figure 34). It was also found that the considerably affected the antiviral activity of tested compounds. Generally, mono-thiourea absolute configuration of isothiocyanates, used to form corresponding mono- and bis-thioureas, (S)-enantiomers were more effective against TMV than corresponding (R)-enantiomers [320], while the considerably affected the antiviral activity of tested compounds. Generally, mono-thiourea (S)- results for bis-thioureas against CMV appeared to be reversed: derivatives obtained from (R)-enantiomer enantiomers were more effective against TMV than corresponding (R)-enantiomers [320], while the of isothiocyanate were more active against the virus [359]. results for bis-thioureas against CMV appeared to be reversed: derivatives obtained from (R)- enantiomer of isothiocyanate were more active against the virus [359].

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, 401 31 of 56 Molecules 2020,, 25,, xx 31 of 57

Figure 34. NingnanmycinNingnanmycinNingnanmycin (left)(left) (left) andand and thethe themostmost most acactivetive active bis-thioureabis-thiourea bis-thiourea derivativesderivatives derivatives bearingbearing bearing α- aminophosphonateα-aminophosphonate functional functional group group [320,359]. [320,359 ].

Liu andand co-workers co-workers prepared prepared a series a of series chiral thioureasof chiral bearing thioureast-leucine bearing and α -aminophosphonatet-leucine and α- aminophosphonatemoieties and evaluated moieties their anti-TMVand evaluated activity their [360 anti-TMV]. Two compounds activity [360]. were Two identiﬁed compounds as the were most identifiedpotentidentified antiviral asas thetheagents mostmost potentpotent (Figure antiviralantiviral 35). It was agentsagents shown (Figur(Figur thate 35). the It derivatives was shown containing that the derivatives electron withdrawing containing electrongroups in withdrawingpara position ofgroups the aromatic in para ring positionposition revealed ofof better thethe activity.aromaticaromatic Stereoisomers ringring revealedrevealed with betterbetterl conﬁguration activity.activity. wereStereoisomers more active with than ll configurationconfiguration their d counterparts werewere moremore or the activeactive racemic thanthan form.theirtheir d counterparts or the racemic form.

Figure 35. TheThe most most active active fluorinated ﬂuorinatedfluorinated thiourea derivatives containing α-aminophosphonate moiety based on leucine [361]. [361].

Yan etet al. al. synthesized synthesized also also a newa new collection collection of chiral of chiral thioureas thioureas and evaluated and evaluated their activity their activity against againstTMV [361 TMV]. Novel [361]. compounds Novel compounds were prepared were in prepared ionic liquid, in ionic an eco-friendly liquid, an environment.eco-friendly environment. Among them, Amongan indane them, derivative an indane (Figure derivative 36) exhibited (Figure the best 36)antiviral exhibited properties: the best inantiviral vivo protection, properties: inactivation in vivo protection,and curative inactivation eﬀects against and curative TMV with effects inhibitory against eTMVﬀects with of 57.0%, inhibitory 96.4% effects and of 55.0%, 57.0%, respectively, 96.4% and 55.0%,at 500 µrespectively,g/mL. Moreover, at 500 it was μg/mL. more Moreover, active against it was TMV more than active the reference against compound TMV than Ningnanmycin. the reference compound Ningnanmycin.

Molecules 2020,, 25,, x;x; doi:doi: www.mdpi.com www.mdpi.com/journal/molecules/journal/molecules Molecules 2020, 25, x 32 of 57 Molecules 2020, 25, 401 32 of 56 Molecules 2020, 25, x 32 of 57

Figure 36. A set of new chiral thioureas (left) prepared by Yan et al.and the most active indane derivative (right) tested against TMV [361]. Figure 36.36. AA set set of of new new chiral chiral thioureas thioureas (left) (left) prepared prepared by Yan by et al.andYan et the al.and most the active most indane active derivative indane Besides(right)derivative tested the (right) agriculture, against tested TMV against various [361]. TMV thiourea [361]. derivatives are important for pharmaceutical industry. Several examples of structurally diverse derivatives that act on human viruses, e.g., human immunodeficiencyBesides the agriculture, agriculture, virus (HIV) various various or human thiourea thiourea cytomegalovirus derivatives derivatives are are (HCMV) important important can for for be pharmaceutical pharmaceutical found in the literatureindustry. industry. [362,363].Several examples of structurally diversediverse derivativesderivatives thatthat actact onon humanhuman viruses, e.g., human immunodeficiencyAfter extensive virus virus studies (HIV) (HIV) of or the humanor pharmacological human cytomegalovirus cytomegalovirus influence (HCMV) (HCMV) of novel can be 1,3-thiazepine-basedcan found be infound the literature in the literatureurea [362, 363and]. thiourea[362,363].After derivatives extensive studieson animal of thecentral pharmacological nervous system influence (CNS), of Struga novel and 1,3-thiazepine-based co-workers published urea andthe resultsthioureaAfter of derivativestheir extensive antiviral studies on activity animal of the centralassays pharmacological [364]. nervous The system compounds influence (CNS), ofwere Struga novel found and1,3-thiazepine-based useful co-workers in antiviral published urea therapy and the dueresultsthiourea to their of derivatives their specific antiviral structure: on activityanimal butterfly-like central assays [nervous364]. conformation The sy compoundsstem (CNS), formed were Struga by found the and hydrophilic usefulco-workers in antiviral center published and therapy two the hydrophobicdueresults to theirof their specific moieties. antiviral structure: Suchactivity a butterfly-like structureassays [364]. is conformationcharacteristic The compounds formedfor werenon-nucleoside by found the hydrophilic useful reverse in antiviral center transcriptase andtherapy two inhibitorshydrophobicdue to their (NNRTIs), specific moieties. structure: used Such as anti-HIV abutterfly-like structure agents is conformation characteristic [364,365]. formed for non-nucleoside by the hydrophilic reverse center transcriptase and two inhibitorshydrophobicFurthermore, (NNRTIs), moieties. the used 1,3-thiazepine Such as anti-HIVa structure ring agents isis an characteristic [ 364important,365]. system for non-nucleoside considering its reverse biological transcriptase activity. It isinhibitors a partFurthermore, of (NNRTIs), the Omapatrilat the used 1,3-thiazepine as structure, anti-HIV ring an agents isantihypertensive an important [364,365]. system drug considering currently in its stage biological IV of activity.clinical trials It is a [366,367].part ofFurthermore, the OmapatrilatAdditionally, the 1,3-thiazepine structure, seven-membered an antihypertensive ring is cyclican important thiourea drug currentlysystem derivatives considering in stage are IV used ofits clinical biological as a trials nitric activity. [366 oxide,367 It]. synthaseAdditionally,seven-memberedis a part ofinhibitors the Omapatrilat [366]. structure, cyclic thiourea an antihypertensive derivatives are used drug as currently a nitric oxide in stage synthase IV of inhibitors clinical trials [366]. [366,367].The 1,3-thiazepine-basedAdditionally, seven-membered isothiourea isothiourea cyclicderivatives derivatives thiourea were were derivatives tested tested against against are useddiverse diverse as avirus virus nitric classes: classes: oxide Retrovirussynthase inhibitors (HIV-1), [366].Hepadnavirus (HBV) and Flav Flaviridaeiridae (YFFV (YFFV and and BVDV, BVDV, both the single-stranded + RNAThe+ viruses;viruses; 1,3-thiazepine-based Figure Figure 37).37). In In spite spite isothiourea of of the the promising promising derivatives pharmacological pharmacological were tested action action against on on animal animaldiverse CNS, CNS, virus only only classes: three three compoundsRetrovirus (HIV-1), exhibited Hepadnavirus modest antiviral (HBV) activity and Flav [[364].364iridae]. (YFFV and BVDV, both the single-stranded RNA+ viruses; Figure 37). In spite of the promising pharmacological action on animal CNS, only three compounds exhibited modest antiviral activity [364].

Figure 37. 1,3-Thiazepine1,3-Thiazepine isothiourea isothiourea derivatives derivatives [364]. [364].

Figure 37. 1,3-Thiazepine isothiourea derivatives [364]. Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, 401 33 of 56 Molecules 20202020,, 2525,, xx 3333 ofof 5757

Venkatachalam et al. studiedstudied thethe impactimpact ofof the the stereochemistry stereochemistry ofof thioureas thioureas on on their their anti-HIV anti-HIV activity (Figure 38)38)[ [368].368]. Eleven Eleven chiral chiral naphthyl naphthyl thioureas thioureas were were testedtested inin vitro vitro againstagainst recombinant recombinant reversereverse transcriptase transcriptase (RT) (RT) [369]. [[369].369]. Generally, Generally, the the (R)-stereoisomers)-stereoisomers of of all all eleven eleven compoundscompounds werewere moremore active than their enantiomers. Five Five of of the the most most active active compounds were were further evaluated for their ability to inhibit HIV-1 replication in human peripheral blood mononuclear cells (PBMC). While the ((R)-stereoisomers)-stereoisomers werewere active active at at nanomolar nanomolar concen concentration,concentration,tration, theirtheir their enantiomersenantiomers enantiomers werewere were againagain again inactive.inactive. inactive. Furthermore, the most active active compound compound was was much much more more active active against against various various NNI-resistant NNI-resistant HIV-1 HIV-1 strains,strains, than than standard standard NNINNI drugsdrugsdrugs (nevirapine,(nevirapine,(nevirapine, delavirdinedelavirdine andand trovirdine).trovirdine). Molecular modelling studiesstudies confirmed conﬁrmedconfirmed thatthat thethe (( RR)-isomer)-isomer fitsfits ﬁts toto thethe targettarget NNINNI bindingbinding pocketpocket onon HIV-RTHIV-RT much much better better thanthan the the ( (S)-enantiomer)-enantiomer [368]. [[368].368].

FigureFigure 38. 38. AA seriesseriesA series ofof chiralchiral of chiral naphthylnaphthyl naphthyl thioureathiourea thioureasss testedtested tested asas anti-H asanti-H anti-HIVIVIV agentsagents agents [368,369].[368,369]. [368,369 ].

InIn the the 1990s,1990s, BellBell andand co-workersco-workersco-workers reportedreportedreported phenethylthiazolylthioureaphenethylthiazolylthioureaphenethylthiazolylthiourea (PETT) (PETT) compounds compounds as as potent anti-HIV agents; taking the structure-activity structure-activity relationship relationship into into account account various various substituents substituents in in theirtheir structures structures were were analyzed analyzed [3 [[337070,371].,371]. Later, Later, Venkatachalam’s Venkatachalam’s gr groupoup undertook the studies of the influenceinfluenceinfluence of of stereochemistry stereochemistry onon the the activity activity of of this this class class of of compoundscompounds [372]. [[372].372]. AA new new series series of of chiral chiral halopyridyl- and thiazolyl-substituted thioureas were synthesized (Figure 3939).). Molecular modelling suggestedsuggested thatthat that forfor for bothboth both groupsgroups groups ((R)) ( stereoisomersRstereoisomers) stereoisomers fitfit betterbetter fit better toto thethe to targettarget the target bindingbinding binding pocketpocket pocketofof HIVHIV reverse ofreverse HIV transcriptasereversetranscriptase transcriptase thanthan theirtheir than ((S their)) counterparts.counterparts. (S) counterparts. TheThe inin Thevitrovitroin teststests vitro confirmedconfirmedtests confirmed thisthis resultresult this result andand exhibitedexhibited and exhibited alsoalso thatalsothat thethe that leadlead the compoundscompounds lead compounds werewere severalseveral were several ordersorders orders ofof magnitude of magnitude more potent more than potent the than standard the standard NNRTI Nevirapine.NNRTI Nevirapine.

Figure 39. Figure 39. ChiralChiralChiral thioureasthioureas thioureas studiedstudied byby VankatachalamVankatachalam and and co-workers co-workers as as antiviral antiviral agents agents [372]. [[372].372]. 4.2. Anticancer Thioureas 4.2. Anticancer Thioureas Since cancer constitutes the second most common cause of death globally, the quest for the new Since cancer constitutes the second most common cause of death globally, the quest for the new anti-tumorSince cancer agents constitutes remains a the continuous second most interest common of numerous cause of death scientific globally, teams. the It quest has been for the proven new anti-tumor agents remains a continuous interest of numerous scientific teams. It has been proven that anti-tumorthat various agents groups remains of thioureas a continuous exhibit interest antiproliferative of numerous activity scientific [373– 375teams.]. Some It has compounds been proven reveal that various groups of thioureas exhibit antiproliferative activity [373–375]. Some compounds reveal dual variousdual biological groups eofff ects,thioureas e.g. anti-tumor exhibit antiproliferat together withive activity anti-oxidant [373–375]. or anti-inflammatory Some compounds activity reveal [dual376]. biological effects, e.g. anti-tumor together with anti-oxidant or anti-inflammatory activity [376]. biologicalDepending effects, on structure e.g. anti-tumor and content together of other biologicallywith anti-oxidant active fragmentsor anti-inflammatory they act on various activity types [376]. of Depending on structure and content of other biologically active fragments they act on various types Dependingcancer cells. on Herein, structure we presentand content chosen, of other promising biologic resultsally active of antiproliferative fragments they studies. act on various types of cancer cells. Herein, we present chosen, promising results of antiproliferative studies. of cancerChiral cells. thioureas Herein, we containing present chosen,α-aminophosphonate promising results moiety, of antiproliferative already mentioned studies. as potential Chiral thioureas containing α-aminophosphonate moiety, already mentioned as potential antiviralChiral agents, thioureas were containing also used byα-aminophosphonate Liu et al. as pseudo-peptides moiety, alre toady treat mentioned cancer (Figure as potential40)[377]. antiviral agents, were also used by Liu et al. as pseudo-peptides to treat cancer (Figure 40) [377]. antiviralSeveral derivativesagents, were revealed also used promising by Liu et activity al. as againstpseudo-peptides human tumor to treat cells cancer PC3 (Figure (prostate 40) cancer), [377]. Several derivatives revealed promising activity against human tumor cells PC3 (prostate cancer), SeveralBcap37 (breastderivatives cancer) revealed and BGC823 promising (stomach activity cancer). against In human a preliminary tumor incells vitro PC3assay (prostate the three cancer), most Bcap37 (breast cancer) and BGC823 (stomach cancer). In a preliminary in vitro assay the three most potent compounds emerged with IC50 values from 4.7 to 17.2 µM against the PC3 cell line; two of them potent compounds emerged with IC5050 valuesvalues fromfrom 4.74.7 toto 17.217.2 μM against the PC3 cell line; two of themthem exhibitedexhibited aa betterbetter antiproliferativeantiproliferative activityactivity thanthan thethe referencereference compound—acompound—a commerciallycommercially

Molecules 20202020,, 2525,, x;x; doi:doi: www.mdpi.com www.mdpi.com/journal/molecules/journal/molecules Molecules 2020, 25, x 34 of 57 available 6,7-dimethoxy-N-(3-bromophenyl)-4-aminoquiazoline (IC50 13.7 μM). Furthermore, one derivative exhibited higher activity than the reference drug against a stomach cancer cell line (IC50 values: 4.7 μM and 6.9 μM, respectively). Interestingly, a significant influence of the absolute configuration of tested compounds on the antiproliferative activity was observed. Generally, D-isomers revealed higher growth inhibition in comparison with L-isomer derivatives [376]. To enhance antiproliferative activity, another amino acid residue (glycine or more rigid fragment, e.g., L-proline) was introduced into the pseudo-peptide scaffold [378]. This new series of chiral thiourea derivatives was examined toward BGC-823 (human Molecules 2020, 25, 401 34 of 56 gastricMolecules cancer) 2020, 25, andx A-549 (human non-small cell lung cancer) cell lines. The basic SAR studies34 led of to57 the statement that the presence of the rigid L-proline fragment in the corresponding dipeptide structureexhibitedavailable increases a6,7-dimethoxy- better antiproliferative antiproliferatN-(3-bromophenyl)-4-aminoquiazolineive activity activity. than Moreover, the reference antitumor compound—a (IC properties50 13.7 μ commerciallyM). may Furthermore, be improved available one by introducing6,7-dimethoxy-derivative exhibited an Nelectron-withdrawing-(3-bromophenyl)-4-aminoquiazoline higher activity than group the inrefe therence para drug (ICposition50 against13.7 ofµ theM). a stomach terminal Furthermore, cancer phenyl one cell group derivativeline of(IC50 the dipeptideexhibitedvalues: 4.7 higherthioureas μM and activity 6.9[377]. μ thanM, respectively). the reference drug against a stomach cancer cell line (IC50 values: 4.7 µM and 6.9 Interestingly,µM, respectively). a significant influence of the absolute configuration of tested compounds on the antiproliferative activity was observed. Generally, D-isomers revealed higher growth inhibition in comparison with L-isomer derivatives [376]. To enhance antiproliferative activity, another amino acid residue (glycine or more rigid fragment, e.g., L-proline) was introduced into the pseudo-peptide scaffold [378]. This new series of chiral thiourea derivatives was examined toward BGC-823 (human gastric cancer) and A-549 (human non-small cell lung cancer) cell lines. The basic SAR studies led to the statement that the presence of the rigid L-proline fragment in the corresponding dipeptide structure increases antiproliferative activity. Moreover, antitumor properties may be improved by introducing an electron-withdrawing group in the para position of the terminal phenyl group of the dipeptide thioureas [377].

Figure 40. PotentialPotential lead lead compounds compounds displaying anti antiproliferativeproliferative activity in vitro [[376–378].376–378].

HuangInterestingly, et al. demonstrated a significant influence the results of of the anticanc absoluteer configurationactivity assays of of tested thioureas compounds containing on the αantiproliferative-aminophosphonate activity moiety was based observed. on dehydroabietic Generally, d-isomers acid (DHA, revealed Figu higherre 41) skeleton growth inhibition[379]. It was in foundcomparison that the with DHAl-isomer increases derivatives antiproliferative [376]. To action enhance of drugs antiproliferative on various cancer activity, cells another [380]. Hence, amino aacid new residue series (glycine of thioureas or more incorporating rigid fragment, the e.g., α-aminophosphonatel-proline) was introduced moiety into and the DHA pseudo-peptide core was synthesizedscaffold [378 and]. This tested new in series vitro ofagainst chiral NCI-H460 thiourea derivatives (lung), A549 was (lung examined adenocarcinoma), toward BGC-823 HepG2 (human (liver) andgastric SKOV3 cancer) (ovarian) and A-549 human (human cancer non-small cell lines. cell The lung compounds cancer) cell exhibited lines. The moderate basic SAR to studieshigh level led of to antiproliferativethe statement that activity. the presence The most of the active rigid derivativel-proline fragment revealed inbetter the correspondingresults against dipeptideA549 cell structureline than 5-fluorouracil,increases antiproliferative the medicine activity. commonly Moreover, used in antitumor cancer therapy properties (Figure may 41). be A improved preliminary by introducing analysis of mechanisman electron-withdrawingFigure of its 40. action Potential proved group lead compoundsthat in the thepara compou displayingpositionnd is anti ofcapable theproliferative terminal to induce activity phenyl cell in apoptosis groupvitro [376–378]. of [379]. the dipeptide thioureas [377]. Huang et al. demonstrated the results of anticanceranticancer activity assays of thioureas containing the α-aminophosphonate moiety based on dehydroabietic acid (DHA, FigureFigure 4141)) skeletonskeleton [[379].379]. It was found that the DHADHA increasesincreases antiproliferative action of drugs on various cancer cells [[380].380]. Hence, a newnew series series of thioureasof thioureas incorporating incorporating the α -aminophosphonatethe α-aminophosphonate moiety andmoiety DHA and core DHA was synthesized core was andsynthesized tested in and vitro testedagainst in vitro NCI-H460 against (lung), NCI-H460 A549 (lung), (lung adenocarcinoma), A549 (lung adenocarcinoma), HepG2 (liver) HepG2 and SKOV3 (liver) (ovarian)and SKOV3 human (ovarian) cancer human cell lines. cancer The cell compounds lines. The exhibited compounds moderate exhibited to high moderate level of antiproliferativeto high level of activity.antiproliferative The most activity. active derivativeThe most active revealed derivative better resultsrevealed against better A549results cell agai linenst than A549 5-fluorouracil, cell line than the5-fluorouracil, medicine commonly the medicine used commonly in cancer therapyused in cancer (Figure therapy 41). A preliminary(Figure 41). A analysis preliminary of mechanism analysis of itsmechanism action proved of its thataction the proved compound that the is capable compou tond induce is capable cell apoptosis to induce [ 379cell]. apoptosis [379].

Figure 41. Dehydroabietic acid and its most active thiourea derivative [379].

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules

Figure 41. Dehydroabietic acid and its most active thiourea derivative [[379].379].

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x 35 of 57 Molecules 2020, 25, 401x 3535 of of 57 56

The results of previous research on impact of stereochemistry of halopyridyl and thiazolyl thioureas on anti-HIV activity [372], prompted Venkatachalam’s group to extent studies toward anti- thioureasThe results on anti-HIV of previous activity research [372], on prompted impact of Venkatachalam’s stereochemistry ofgroup halopyridyl to extent and studies thiazolyl toward thioureas anti- onleukemic anti-HIV activity. activity They [372 designed], prompted and Venkatachalam’s synthesized five group series to of extent new chiral studies derivatives toward anti-leukemic (Figure 42) activity.[381]. Their They anticancer designed activity and was synthesized evaluated ﬁve against series human of new B-lineage chiral derivativesNalm-6 and (Figure T-lineage 42 )[Molt-3381]. Theiracute anticancerlymphoblastic activity leukemia was evaluated cell lines. againstPreliminar humany studies B-lineage proved Nalm-6 that the and stereochemistry T-lineage Molt-3 indeed acute lymphoblasticwas the factor leukemiathat determined cell lines. the Preliminary activity of studiestested compounds: proved that the(S) stereochemistryenantiomers performed indeed was better the factorin the thattests. determined the activity of tested compounds: (S) enantiomers performed better in the tests.

Figure 42. A new set of chiral halopyridyl and thiazolyl thioureas studied as antiproliferative agents Figure 42. 42. AA new new setset of chiral of chiral halopyridyl halopyridyl and thiazolyl and thiazolyl thioureas thioureas studied studied as antiproliferative as antiproliferative agents [381]. agents[381]. [381]. 4.3. Anti-Allergic Thioureas 4.3. Anti-Allergic Thioureas Venkatachalam et al. reported the synthesis and evaluation of anti-allergic activity of novel chiral Venkatachalam et al. reported the synthesis and evaluation of anti-allergic activity of novel heterocycle-based thioureas [382]. Referring to the fact that leukotrienes, chemical mediators released chiral heterocycle-based thioureas [382]. Referring to the fact that leukotrienes, chemical mediators by mast cells, play an important role in pathophysiology of allergy and asthma, they became a new released by mast cells, play an important role in pathophysiology of allergy and asthma, they became target for potential thiourea based anti-allergic agents [383]. a new target for potential thiourea based anti-allergic agents [383]. The set of indolyl-, naphthyl- and phenylethyl-substituted halopyridyl, thiazolyl and The set of indolyl-, naphthyl- and phenylethyl-substituted halopyridyl, thiazolyl and benzothiazolyl thiourea derivatives were tested in vitro for the mast cell inhibitory activity (Figure 43). benzothiazolyl thiourea derivatives were tested in vitro for the mast cell inhibitory activity (Figure Among them, naphthyl-substituted thiazolyl thioureas were found most promising. Based on the 43). Among them, naphthyl-substituted thiazolyl thioureas were found most promising. Based on the results obtained for (S)- and (R)-isomer of naphthyl thioureas it was concluded that the stereochemistry results obtained for (S)- and (R)-isomer of naphthyl thioureas it was concluded that the of studied thioureas did not greatly inﬂuence their activity. stereochemistry of studied thioureas did not greatly influence their activity.

Figure 43 43.. ChiralChiral naphthyl-substituted thioureas as potential anti-allergic agents [[383].383]. Figure 43. Chiral naphthyl-substituted thioureas as potential anti-allergic agents [383]. 4.4. Antimicrobial Thioureas 4.4. Antimicrobial Thioureas Pyrazole derivatives have been recognized as versatile compounds with multiple biological Pyrazole derivatives have been recognized as versatile compounds with multiple biological properties,Pyrazole e.g., derivatives antibacterial, have anti-inﬂammatory been recognized or as antiproliferative versatile compounds activity [with384,385 multiple]. Many biological scientiﬁc properties, e.g., antibacterial, anti-inflammatory or antiproliferative activity [384,385]. Many scientific groupsproperties, have e.g., been antibacterial, involved in anti the-inflammatory investigation and or antiproliferative development of novelactivity pyrazole [384,385]. derivatives, Many scientific facing groups have been involved in the investigation and development of novel pyrazole derivatives, thegroups problem have ofbeen their involved high toxicity. in the investigation and development of novel pyrazole derivatives, facing the problem of their high toxicity. facingThe the connection problem of of their thiourea high toxicity. functional group with these biologically active molecules led to a The connection of thiourea functional group with these biologically active molecules led to a discoveryThe connection of new compounds of thiourea with functional a potential group pharmaceutical with these biologically importance. active Bildirici molecules and co-workers led to a discovery of new compounds with a potential pharmaceutical importance. Bildirici and co-workers synthesizeddiscovery of novelnew compounds chiral pyrazole-based with a potential thioureas pharmaceutical (Figure 44)[ 383importance.]. The compounds Bildirici and were co-workers examined synthesized novel chiral pyrazole-based thioureas (Figure 44) [383]. The compounds were examined againstsynthesized three novel Gram-positive chiral pyrazole-based bacteria (Bacillus thioureas subtilis (Figure, Staphylococcus 44) [383]. The aureus compounds, Bacillus megaterium were examined) and against three Gram-positive bacteria (Bacillus subtilis, Staphylococcus aureus, Bacillus megaterium) and fouragainst Gram-negative three Gram-positive bacteria bacteria (Enterobacter (Bacillus aerogenes subtilis, Pseudomonas, Staphylococcus aeruginosa, aureus, KlebsiellaBacillus megaterium pneumoniae) and four Gram-negative bacteria (Enterobacter aerogenes, Pseudomonas aeruginosa, Klebsiella pneumoniae and Escherichiafour Gram-negative coli) and exhibited bacteria ( aEnterobacter desired activity, aerogenes one, of Pseudomonas them even higheraeruginosa, than Klebsiella amikacin pneumoniae and rifampicin and Escherichia coli) and exhibited a desired activity, one of them even higher than amikacin and andEscherichia similar coli to penicillin.) and exhibited Additionally, a desired they activity, were evaluated one of asthem antifungal even higher agents againstthan amikacin three fungal and rifampicin and similar to penicillin. Additionally, they were evaluated as antifungal agents against strainsrifampicin (Candida and similar albicans to, Saccharomyces penicillin. Additionally, cerevisiae and theyYarro werevia lipolyticaevaluated). as antifungal agents against three fungal strains (Candida albicans, Saccharomyces cerevisiae and Yarrovia lipolytica). Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, x 36 of 57

Molecules 2020, 25, 401 36 of 56 Molecules 2020, 25, x 36 of 57

Figure 44. Novel chiral pyrazole-based thioureas exhibiting antibacterial activity [383].

In the literature, there are several reports concerning thiourea functional group combined with heterobicyclic fused aromatic scaffolds, e.g., benzothiazole or benzimidazole rings [386,387]. Madabhushi et al. prepared two sets of chiral thioureas bearing benzimidazole ring based on natural and non-natural amino acids ((S)-alanine, (S)-phenylalanine, (S)-valine, (S)-leucine and (R)-alanine, (R)-phenylalanine,Figure 44. (NovelNovelR)-valine chiral andpyrazole-based (R)-leucine, thioureas respectively; exhibiting antibacterial Figure 45) activity[388]. [[383].383The]. obtained compounds were studied as potential antimicrobial agents against the Gram-positive strains StaphylococcusIn the the literature, literature, aureus, Bacillusthere there are subtilis are several several, Staphylococcus reports reports concer concerning aureusning andthiourea thioureaMicrococcus functional functional luteus group as well group combined as the combined Gram- with withnegativeheterobicyclic heterobicyclic strains fused Klebsiella fused aromatic aromaticplanticola scaffolds, sca, Escherichiaﬀolds, e.g., e.g., benzothiazole coli benzothiazole and Pseudomonas or orbenzimidazole benzimidazole aeruginosa rings. ringsAdditionally, [386,387]. [386,387]. antiproliferativeMadabhushi et al. activity prepared prepared was two examined sets of chiral against thioureas A549, MCF7, bearing DU145 benzimidazole and HeLa ring cell lines.based on natural and non-naturalInterestingly, amino the compounds acids ((S)-alanine, derived (fromS)-phenylalanine, natural amino ( (S acids)-valine,)-valine, exhibited ( (S)-leucine)-leucine antibacterial and and ( R)-alanine,)-alanine, activity, whereas(R)-phenylalanine, their isomers (R()-valineR turned)-valine andout and (toR )-leucine, be(R inactive)-leucine, respectively; against respectively; the Figuretested 45FigureGram-positive)[388 ].45) The [388]. obtained and Gram-negativeThe compounds obtained werestrains.compounds studied Thioureas were as potential substitutedstudied antimicrobial as withpotential isopropyl agents antimicrob againstor isobutylial the agents Gram-positiveand 3,5-(CF against3)2 C strainsthe6H3 Gram-positivegroupsStaphylococcus were the strains aureus most, potentBacillusStaphylococcus among subtilis aureus ,theStaphylococcus series., Bacillus It subtiliswas aureus considered, Staphylococcusand Micrococcus that aaureus suitable luteus and asMicrococcusstereochemistry well as the luteus Gram-negative and as well the aspresence the strainsGram- of lipophilicKlebsiellanegative planticola strainstrifluoromethyl Klebsiella, Escherichia groupsplanticola coli and which, PseudomonasEscherichia may increase coli aeruginosa andbioavailability Pseudomonas. Additionally, and aeruginosa antiproliferativebio-efficiency,. Additionally, were activity the wasfactorsantiproliferative examined that determined against activity A549, antibacterial was MCF7,examined DU145 activity. against and A549, HeLa MCF7, cell lines. DU145 and HeLa cell lines. Interestingly, the compounds derived from natural amino acids exhibited antibacterial activity, whereas their isomers turned out to be inactive against the tested Gram-positive and Gram-negative strains. Thioureas substituted with isopropyl or isobutyl and 3,5-(CF3)2C6H3 groups were the most potent among the series. It was considered that a suitable stereochemistry and the presence of lipophilic trifluoromethyl groups which may increase bioavailability and bio-efficiency, were the factors that determined antibacterial activity.

Figure 45. NovelNovel chiral chiral thioureas thioureas bearing benzimidazole fragmentfragment studied byby MadabhushiMadabhushi etet al.al [388]. [388].

ChiralInterestingly, thiophosphorylated the compounds thioureas derived have from attracted natural aminoan attention acids exhibiteddue to their antibacterial biological activity, activity, whereasand ability their to form isomers diverse turned complexes out to be with inactive transi againsttion metals. the tested Based Gram-positive on literature and reports Gram-negative Metlushka etstrains. al. synthesized Thioureas substitutednew coordinati withon isopropyl polymers or with isobutyl chiral and thiophosphorylated 3,5-(CF3)2C6H3 groups thioureas were thein mostboth racemicpotent among and enantiopure the series. It forms was considered and checked that their a suitable antimicrobial stereochemistry activity against and the S. presence aureus and of lipophilic B. cereus [22].triﬂuoromethyl FigureThey examined 45. Novel groups chiralboth which thioureasenantiopure may bearing increase and benzimidazole racemic bioavailability derivatives fragment and as studied bio-e wellﬃ as byciency, their Madabhushi complexes were the et al factorswith [388]. Ni(II) that (Figuredetermined 46). Neither antibacterial (R)- nor activity. (S)-ligands did exhibit valuable anti-microbial activity, while the racemic mixtureChiral was thiophosphorylated surprisingly active. thioureas thioureasIn case of have havecomplexes, attracted attracted (R an)-complex an attention attention was due due less to to activetheir their biologicalbiological than (S)-complex activity, activity, againstand abilityability S. toaureusto form form while diverse diverse the complexes complexes racemate with probablywith transition transi wastion metals. not metals. considered Based Based on literatureon in literaturethe research. reports reportsMetlushka In Metlushkaturn, both et al. isomersetsynthesized al. synthesized and the new racemic coordination new coordinatimixtur polymerse performedon polymers with similarly chiral with thiophosphorylatedagainstchiral thiophosphorylatedB. cereus. thioureas thioureas in both racemicin both racemicand enantiopure and enantiopure forms and forms checked and checked their antimicrobial their antimicrobial activity activity against againstS. aureus S. aureusand B. and cereus B. cereus[22]. They[22]. They examined examined both both enantiopure enantiopure and and racemic racemic derivatives derivatives as as well well as as their their complexescomplexes with Ni(II) (Figure 4646).). Neither Neither ( (R)-)- nor nor ( (SS)-ligands)-ligands did did exhibit exhibit valuable valuable anti-microbial anti-microbial activity, activity, while the racemic mixture was surprisingly active. In case of complexes, ( R)-complex was less active than ( S)-complex against S.S. aureusaureuswhile while the the racemate racemate probably probably was was not considerednot considered in the in research. the research. In turn, In both turn, isomers both isomersand the racemicand the mixtureracemic mixtur performede performed similarly similarly against B. against cereus. B. cereus.

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules

Molecules 2020, 25, x; doi: www.mdpi.com/journal/molecules Molecules 2020, 25, 401 37 of 56 Molecules 2020, 25, x 37 of 57

CH3 S S

P(OEt)2 N N Ph H H Ph Ph

H C NH S H3C NH S H3C NH S 3 CH S S 3 P(OEt) P(OEt)2 P(OEt)2 2 S N P(OEt)2 S N S N N N Ni N N Ni N N H H Ni N N N SH N SH N SH (EtO) P (EtO)2P (EtO)2P 2 CH3 S S S HN CH S HN CH3 S HN CH3 3 P(OEt)2 N N H H Ph Ph Ph n n n (R,R)/(S,S) rac FigureFigure 46. 46.Structures Structures of thiophosphorylated of thiophosphorylated thioureas thioureas and theirand Ni(II)their complexesNi(II) complexes forming forming coordination polymerscoordination studied polymers for their studied antimicrobial for their antimicrobial activity [22 ].activity [22].

5. Summary5. Summary A relativelyA relatively simple, simple, rigidrigid skeleton of of thiourea thiourea can can be combined be combined with withchiral chiralmoieties, moieties, yielding yieldinga system that is capable of strong and selective interactions with a variety of chiral molecules, including a system that is capable of strong and selective interactions with a variety of chiral molecules, compounds of biological importance. By an appropriate substitution we can suitably modify their includingproperties, compounds and, in principle, of biological there are importance. no limitations By in an preparation appropriate of desired substitution mono-, wedi-, cantri- or suitably modifytetrasubstituted, their properties, aliphatic and, or inaromatic, principle, unsymmetr there areical, no or limitations symmetrical in preparationthiocarbamides. of desiredRecently mono-, di-,published tri- or tetrasubstituted, synthetic methods aliphatic extend orthe aromatic, palette of unsymmetrical, possible reactants, or symmetricaland often focus thiocarbamides. on the Recentlymodification published of conditions: synthetic the methods reaction can extend be pe therformed palette in water, of possible with ul reactants,trasound-assistance, and often and focus on theeven modification without any of solvent conditions: and catalyst. the reaction can be performed in water, with ultrasound-assistance, and evenChiral without thioureas any solventhave already and catalyst.proven their utility in various stereoselective reactions, mainly as efficientChiral organocatalysts thioureas have and already chiral ligands. proven As their shown utility by numerous in various examples, stereoselective a proper reactions, choice of a mainly as echiralfficient component organocatalysts present in and the structure chiral ligands. of thiourea As and shown its configuration by numerous can examples,also result in a a proper desired choice biological activity. This is manifested in a considerable interest in the use of these compounds as of a chiral component present in the structure of thiourea and its configuration can also result in a pharmaceuticals and in agriculture, and biomedical applications of chiral thioureas should become desiredan important biological and activity. growing This area. is manifested in a considerable interest in the use of these compounds as pharmaceuticals and in agriculture, and biomedical applications of chiral thioureas should become an importantFunding: This and research growing was area.supported by a grant Harmonia, funded by the National Science Centre, Poland (grant number: 2018/30/M/ST5/00401). Funding: This research was supported by a grant Harmonia, funded by the National Science Centre, Poland Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the (grant number: 2018/30/M/ST5/00401). study, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the Conflictsresults. of Interest: The authors declare no conflict of interest. The funders had no role in the design of the study, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results. References References 1. Schroeder, D.C. Thioureas. Chem. Rev. 1955, 55, 181–228, doi:10.1021/cr50001a005. 1. 2. Schroeder,Gómez, D.E.; D.C. Fabbrizzi, Thioureas. L.;Chem. Licchelli, Rev. M.;1955 Monzani,, 55, 181–228. E. Urea vs. [CrossRef thiourea] in anion recognition. Org. Biomol. 2. Gómez,Chem. 2005 D.E.;, 3, Fabbrizzi,1495–1500, doi:10.1039/B500123D. L.; Licchelli, M.; Monzani, E. Urea vs. thiourea in anion recognition. 3. Org.Yu, Biomol. X.; Wang, Chem. W.2005 Hydrogen-bond-, 3, 1495–1500.mediated [CrossRef asymmetric][PubMed catalysis.] Chem. Asian J. 2008, 3, 516–532, 3. Yu,doi:10.1002/asia.200700415. X.; Wang, W. Hydrogen-bond-mediated asymmetric catalysis. Chem. Asian J. 2008, 3, 516–532. [CrossRef] 4. Ruder, F.J.; Guyer, W.; Benson, J.A.; Kayser, H. The thiourea insecticide/acaricide diafenthiuron has a novel [PubMed] mode of action: Inhibition of mitochondrial respiration by its carbodiimide product. Pestic. Biochem. Physiol. 4. Ruder, F.J.; Guyer, W.; Benson, J.A.; Kayser, H. The thiourea insecticide/acaricide diafenthiuron has a novel 1991, 41, 207–219, doi:10.1016/0048-3575(91)90075-W. 5. modeXiao, of S.; action: Wei, L.; Inhibition Hong, Z.; of Rao, mitochondrial L.; Ren, Y.; Wan, respiration J.; Feng, by L. its Design, carbodiimide synthesis product. and algicidesPestic. activities Biochem. of Physiol. 1991thiourea, 41, 207–219. derivatives [CrossRef as the] novel scaffold aldolase inhibitors. Bioorg. Med. Chem. 2019, 27, 805–812, 5. Xiao,doi:10.1016/J.BMC.2019.01.023. S.; Wei, L.; Hong, Z.; Rao, L.; Ren, Y.; Wan, J.; Feng, L. Design, synthesis and algicides activities 6. of thioureaShakeel, A.; derivatives Altaf, A.A.; as Qureshi, the novel A.M.; sca Badshah,ffold aldolase A. Thiourea inhibitors. derivativesBioorg. in drug Med. design Chem. and2019 medicinal, 27, 805–812. [CrossRefchemistry:] A short review. J. Drug Des. Med. Chem. 2016, 2, 10–20, doi:10.11648/j.jddmc.20160201.12. 6. 7. Shakeel,Choi, J.; A.; Jee, Altaf, J.-G. Repositioning A.A.; Qureshi, of A.M.;thiourea Badshah,-containing A. drugs Thiourea as tyrosinase derivatives inhibitors. in drug Int. designJ. Mol. Sci. and 2015 medicinal, chemistry:16, 28534–28548, A short doi:10.3390/ijms161226114. review. J. Drug Des. Med. Chem. 2016, 2, 10–20. [CrossRef] 7. Choi, J.; Jee, J.-G. Repositioning of thiourea-containing drugs as tyrosinase inhibitors. Int. J. Mol. Sci. 2015, Molecules16, 28534–28548. 2020, 25, x; doi: [CrossRef ] www.mdpi.com/journal/molecules 8. Subramanyam, N.C.; Sheshadri, B.S.; Mayanna, S.M. Thiourea and substituted thioureas as corrosion inhibitors for aluminium in sodium nitrite solution. Corros. Sci. 1993, 34, 563–571. [CrossRef] Molecules 2020, 25, 401 38 of 56

9. Edrah, S.; Hasan, S. Studies on thiourea derivatives as corrosion inhibitor for aluminum in sodium hydroxide solution. J. Appl. Sci. Res. 2010, 6, 1045–1049. 10. Loto, R.T.; Loto, C.A.; Popoola, A.P.I. Corrosion inhibition of thiourea and thiadiazole derivatives: A Review. J. Mater. Environ. Sci 2012, 3, 885–894. 11. Fatima, S.; Sharma, R.; Asghar, F.; Kamal, A.; Badshah, A.; Kraatz, H.-B.B. Study of new amphiphiles based on ferrocene containing thioureas as eﬃcient corrosion inhibitors: Gravimetric, electrochemical, SEM and DFT studies. J. Ind. Eng. Chem. 2019, 76, 374–387. [CrossRef] 12. Kotke, M.; Schreiner, P.R. Organocatalysts. In Hydrogen Bonding in Organic Synthesis; Pihko, P.M., Ed.; Wiley-VCH: Hoboken, NJ, USA, 2009; pp. 141–251. 13. Takemoto, Y. Recognition and activation by ureas and thioureas: Stereoselective reactions using ureas and thioureas as hydrogen-bonding donors. Org. Biomol. Chem. 2005, 3, 4299–4306. [CrossRef][PubMed] 14. Connon, S.J. Asymmetric catalysis with bifunctional Cinchona alkaloid-based urea and thiourea organocatalysts. Chem. Commun. 2008, 2499–2510. [CrossRef][PubMed] 15. Yuan, W.-K.; Liu, Y.F.; Lan, Z.; Wen, L.-R.; Li, M. Nickle catalysis enables access to thiazolidines from thioureas via oxidative double isocyanide insertion reactions. Org. Lett. 2018, 20, 7158–7162. [CrossRef][PubMed] 16. Pandey, G.; Bhowmik, S.; Batra, S. Synthesis of 4-substituted imino-4H-benzo[d][1,3] thiazin-2-amines via palladium-catalysed isocyanide insertion in 2-bromophenylthioureas. RSC Adv. 2014, 4, 41433–41436. [CrossRef] 17. Goncalves, I.L.; de Azambuja, G.O.; Kawano, D.F.; Eiﬂer-Lima, V.L. Thioureas as building blocks for the generation of heterocycles and compounds with pharmacological activity: An overview. Mini. Rev. Org. Chem. 2018, 15, 28–35. [CrossRef]

18. Koch, K.R. New chemistry with old ligands: N-alkyl- and N,N-dialkyl-N0-acyl(aroyl)thioureas in co-ordination, analytical and process chemistry of the platinum group metals. Coord. Chem. Rev. 2001, 216–217, 473–488. [CrossRef] 19. Mingji, D.; Liang, B.; Wang, C.; You, Z.; Xiang, J.; Dong, G.; Chen, J.; Yang, Z. A novel thiourea ligand applied in the Pd-catalyzed Heck, Suzuki and Suzuki carbonylative reactions. Adv. Synth. Catal. 2004, 346, 1669–1673. [CrossRef] 20. Li, J.; Shi, L.-L.; Chen, J.; Gong, J.; Yang, Z. Thioureas as ligands in organometallic reactions. Synthesis 2014, 46, 2007–2023. [CrossRef] 21. Saeed, A.; Flörke, U.; Erben, M.F. A review on the chemistry, coordination, structure and biological properties of 1-(acyl/aroyl)-3-(substituted) thioureas. J. Sulfur Chem. 2014, 35, 318–355. [CrossRef] 22. Metlushka, K.E.; Sadkova, D.N.; Shaimardanova, L.N.; Nikitina, K.A.; Ivshin, K.A.; Islamov, D.R.; Kataeva, O.N.; Alfonsov, A.V.; Kataev, V.E.; Voloshina, A.D. First coordination polymers on the bases of chiral thiophosphorylated thioureas. Inorg. Chem. Commun. 2016, 66, 11–14. [CrossRef] 23. Blažek Bregović,V.; Basarić,N.; Mlinarić-Majerski,K. Anion binding with urea and thiourea derivatives. Coord. Chem. Rev. 2015, 295, 80–124. [CrossRef] 24. Nencki, M. Zur Kenntniss des Sulfoharnstoffs. Ber. Dtsch. Chem. Ges. 1873, 6, 598–600. [CrossRef] 25. Brückner, A. Vorläufige Mittheilung. Ber. Dtsch. Chem. Ges. 1873, 6, 1103–1104. [CrossRef] 26. Brown, E.L.; Campbell, N. Studies in qualitative organic analysis. identification of alkyl halides, amines, and acids. J. Chem. Soc. 1937, 1699–1701. [CrossRef]

27. Luskin, L.S.; Gantert, G.E.; Craig, W.E. t-Carbinamines, RR’R”CNH2 IV. The addition of isothiocyanic acid to oleﬁnic compounds. J. Am. Chem. Soc. 1956, 78, 4965–4967. [CrossRef] 28. Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Chiral binaphthyl-derived amine-thiourea organocatalyst-promoted asymmetric Morita Baylis Hillman reaction. Org. Lett. 2005, 7, 4293–4296. [CrossRef] − − 29. Fleming, E.M.; McCabe, T.; Connon, S.J. Novel axially chiral bis-arylthiourea-based organocatalysts for asymmetric Friedel–Crafts type reactions. Tetrahedron Lett. 2006, 47, 7037–7042. [CrossRef] 30. Liu, X.-G.G.; Jiang, J.-J.J.; Shi, M. Development of axially chiral bis(arylthiourea)-based organocatalysts and their application in the enantioselective Henry reaction. Tetrahedron: Asymmetry 2007, 18, 2773–2781. [CrossRef] 31. Schneider, J.F.; Falk, F.C.; Fröhlich, R.; Paradies, J. Planar-chiral thioureas as hydrogen-bond catalysts. Eur. J. Org. Chem. 2010, 2265–2269. [CrossRef] 32. Kitagaki, S.; Ueda, T.; Mukai, C. Planar chiral [2.2]paracyclophane-based bis(thiourea) catalyst: Application to asymmetric Henry reaction. Chem. Commun. 2013, 49, 4030–4032. [CrossRef][PubMed] Molecules 2020, 25, 401 39 of 56

33. Lu, Y.; Ma, Y.; Yang, S.; Ma, M.; Chu, H.; Song, C. Synthesis of planar chiral [2.2]paracyclophane-based amino thioureas and their application in asymmetric aldol reactions of ketones with isatins. Tetrahedron: Asymmetry 2013, 24, 1082–1088. [CrossRef] 34. Didier, D.; Sergeyev, S. Thiourea derivatives of Tröger’s base: Synthesis, enantioseparation and evaluation in organocatalysis of Michael addition to nitrooleﬁns. Arkivoc 2009, 124–134. [CrossRef] 35. Caille, S.; Boni, J.; Cox, G.B.; Faul, M.M.; Franco, P.; Khattabi, S.; Klingensmith, L.M.; Larrow, J.F.; Lee, J.K.; Martinelli, M.J.; et al. Comparison of large-scale routes to manufacture ciral exo -2-norbornyl thiourea. Org. Process Res. Dev. 2010, 14, 133–141. [CrossRef] 36. Ozturk, T.; Ertas, E.; Mert, O. Use of Lawesson’s Reagent in Organic Syntheses. Chem. Rev. 2007, 107, 5210–5278. [CrossRef][PubMed]

37. Ozturk, T.; Ertas, E.; Mert, O. A Berzelius Reagent, Phosphorus Decasulfide (P4S10), in Organic Syntheses. Chem. Rev. 2010, 110, 3419–3478. [CrossRef][PubMed] 38. Hodgekins, J.E.; Ettlinger, M.G.; Hodgkins, J.E.; Ettlinger, M.G. The synthesis of isothiocyanates from amines. J. Org. Chem. 1956, 21, 404–405. [CrossRef] 39. Sureshbabu, V.V.; Naik, S.A.; Hemantha, H.P.; Narendra, N.; Das, U.; Guru Row, T.N. N-urethane-protected amino alkyl isothiocyanates: Synthesis, isolation, characterization, and application to the synthesis of thioureidopeptides. J. Org. Chem. 2009, 74, 5260–5266. [CrossRef] 40. Liu, M.; Ji, N.; Wang, L.; Liu, P.; He, W. d-Mannitol-derived novel chiral thioureas: Synthesis and application in asymmetric Henry reactions. Tetrahedron Lett. 2018, 59, 999–1004. [CrossRef] 41. Frings, M.; Thomé, I.; Bolm, C. Synthesis of chiral sulfoximine-based thioureas and their application in asymmetric organocatalysis. Beilstein J. Org. Chem. 2012, 8, 1443–1451. [CrossRef] 42. Cruz-Hernández, C.; Martínez-Martínez, E.; Hernández-González, P.E.; Juaristi, E. Synthesis of a new N-diaminophosphoryl-N’-[(2S)-2-pyrrolidinylmethyl]thiourea as a chiral organocatalyst for the stereoselective Michael addition of cyclohexanone to nitrostyrenes and chalcones—Application in cascade processes for the synthesis of Polyc. Eur. J. Org. Chem. 2018, 6890–6900. [CrossRef] 43. Kaupp, G.; Schmeyers, J.; Boy, J. Quantitative solid-state reactions of amines with carbonyl compounds and isothiocyanates. Tetrahedron 2000, 56, 6899–6911. [CrossRef] 44. Li, J.-P.P.; Wang, Y.-L.L.; Wang, H.; Luo, Q.-F.F.; Wang, X.-Y.Y. A new and efficient solid state synthesis of diaryl thioureas. Synth. Commun. 2001, 31, 781–785. [CrossRef] 45. Štrukil, V.; Igrc, M.D.; Fábián, L.; Eckert-Maksić,M.; Childs, S.L.; Reid, D.G.; Duer, M.J.; Halasz, I.; Mottillo, C.; Frišˇcić,T. A model for a solvent-free synthetic organic research laboratory: Click-mechanosynthesis and structural characterization of thioureas without bulk solvents. Green Chem. 2012, 14, 2462–2473. [CrossRef] 46. Štrukil, V. Mechanochemical synthesis of thioureas, ureas and guanidines. Beilstein J. Org. Chem. 2017, 13, 1828–1849. [CrossRef] 47. Štrukil, V.; Igrc, M.D.; Eckert-Maksić,M.; Frišˇcić,T. Click mechanochemistry: Quantitative synthesis of “ready to use” chiral organocatalysts by efficient two-fold thiourea coupling to vicinal diamines. Chem. Eur. J. 2012, 18, 8464–8473. [CrossRef] 48. Bhattacharjee, J.; Das, S.; Kottalanka, R.K.; Panda, T.K. Hydroamination of carbodiimides, isocyanates, and isothiocyanates by a bis(phosphinoselenoic amide) supported titanium(IV) complex. Dalton Trans. 2016, 45, 17824–17832. [CrossRef] 49. Arafa, W.A.A.; Ibrahim, H.M. A sustainable strategy for the synthesis of bis-2-iminothiazolidin-4-ones utilizing novel series of asymmetrically substituted bis-thioureas as viable precursors. RSC Adv. 2018, 8, 10516–10521. [CrossRef] 50. Herr, J.R.; Kuhler, J.L.; Meckler, H.; Opalka, C.J. A convenient method for the preparation of primary and symmetrical N,N’-disubstituted thioureas. Synthesis 2000, 1569–1574. [CrossRef] 51. Jiang, X.; Wang, Y.; Zhang, G.; Fu, D.; Zhang, F.; Kai, M.; Wang, R. Enantioselective synthesis of cyclic thioureas via mannich reaction and concise synthesis of highly optically active methylthioimidazolines: Discovery of a more potent antipyretic agent. Adv. Synth. Catal. 2011, 353, 1787–1796. [CrossRef] 52. Azizi, N.; Aryanasab, F.; Saidi, M.R. Straightforward and highly efficient catalyst-free one-pot synthesis of dithiocarbamates under solvent-free conditions. Org. Lett. 2006, 8, 5275–5277. [CrossRef][PubMed] 53. Azizi, N.; Aryanasab, F.; Torkiyan, L.; Ziyaei, A.; Saidi, M.R. One-pot synthesis of dithiocarbamates accelerated in water. J. Org. Chem. 2006, 71, 3634–3635. [CrossRef][PubMed] Molecules 2020, 25, 401 40 of 56

54. Ziyaei-Halimjani, A.; Saidi, M.R. Synthesis of β-hydroxy dithiocarbamate derivatives via regioselective addition of dithiocarbamate anion to epoxide in water. Can. J. Chem. 2006, 84, 1515–1519. [CrossRef] 55. Ziyaei Halimehjani, A.; Martens, J.; Schlüter, T. A one-pot three-component synthesis of dithiocarbamates starting from vinyl pyridines and vinyl pyrazine under solvent- and catalyst-free conditions. Tetrahedron 2016, 72, 3958–3965. [CrossRef] 56. Ziyaei Halimehjani, A.; Klepetáˇrová, B.; Beier, P. Synthesis of novel dithiocarbamates and xanthates using dialkyl azodicarboxylates: S–N bond formation. Tetrahedron 2018, 74, 1850–1858. [CrossRef] 57. Li, T.-T.T.; Song, X.-H.H.; Wang, M.-S.S.; Ma, N. Cerium ammonium nitrate-catalyzed aerobic oxidative coupling of dithiocarbamates: Facile synthesis of thioureas and bis(aminothiocarbonyl)disulfides. RSC Adv. 2014, 4, 40054–40060. [CrossRef] 58. Cao, Q.; Liu, F.; Wang, M.; Xu, W.; Zeng, M.-T.; Liu, M.; Li, Y.-S.; Dong, Z.-B. Facile synthesis of substituted arylthioureas in the presence of sodium hydride. J. Chem. Res. 2017, 41, 301–303. [CrossRef] 59. Gan, S.-F.; Wan, J.-P.; Pan, Y.-J.; Sun, C.-R. Highly efficient and catalyst-free synthesis of substituted thioureas in water. Mol. Divers. 2011, 15, 809–815. [CrossRef] 60. Ziyaei Halimehjani, A.; Pourshojaei, Y.; Saidi, M.R. Highly efficient and catalyst-free synthesis of unsymmetrical thioureas under solvent-free conditions. Tetrahedron Lett. 2009, 50, 32–34. [CrossRef] 61. Dirksen, A.; Nieuwenhuizen, P.J.; Hoogenraad, M.; Haasnoot, J.G.; Reedijk, J. New mechanism for the reaction of amines with zinc dithiocarbamates. J. Appl. Polym. Sci. 2001, 79, 1074–1083. [CrossRef] 62. Maddani, M.; Prabhu, K.R. A convenient method for the synthesis of substituted thioureas. Tetrahedron Lett. 2007, 48, 7151–7154. [CrossRef] 63. Üngören, ¸S.H.;Sırça, F. Novel self -condensation of ammonium dithiocarbamates leading to symmetrical substituted thioureas. Phosphorus. Sulfur. Silicon Relat. Elem. 2017, 192, 28–33. [CrossRef] 64. Liang, F.; Tan, J.; Piao, C.; Liu, Q. Carbon tetrabromide promoted reaction of amines with carbon disulfide: Facile and efficient synthesis of thioureas and thiuram disulfides. Synthesis 2008, 3579–3584. [CrossRef] 65. Fardpour, M.; Shafie, A.; Bahadorikhalili, S.; Larijani, B.; Mahdavi, M. Utilizing amines and carbon disulfide to obtain nitrogen- and sulfur-containing compounds under green conditions: A review. Curr. Org. Chem. 2018, 22, 2315–2380. [CrossRef] 66. Maddani, M.R.; Prabhu, K.R. A concise synthesis of substituted thiourea derivatives in aqueous medium. J. Org. Chem. 2010, 75, 2327–2332. [CrossRef] 67. Azizi, N.; Khajeh-Amiri, A.; Ghafuri, H.; Bolourtchian, M. Toward a practical and waste-free synthesis of thioureas in water. Mol. Divers. 2011, 15, 157–161. [CrossRef] 68. Azizi, N.; Rahimzadeh-Oskooee, A.; Yadollahy, Z.; Ourimi, A.G. Ultrasound-assisted rapid sustainable synthesis of substituted thiourea. Monatsh. Chem. 2014, 145, 1675–1680. [CrossRef] 69. Wan, G.-X.; Xu, L.; Ma, X.-S.; Ma, N. Silica gel promoted synthesis of N-sulfonylcyclothioureas in water. Tetrahedron Lett. 2011, 52, 6250–6254. [CrossRef] 70. Jangale, A.D.; Kumavat, P.P.; Wagh, Y.B.; Tayade, Y.A.; Mahulikar, P.P.; Dalal, D.S. Green process development

for the synthesis of aliphatic symmetrical N,N0-disubstituted thiourea derivatives in aqueous medium. Synth. Commun. 2015, 45, 236–244. [CrossRef] 71. Milosavljević,M.M.; Vukićević,I.M.; Drmanić,S.Ž.; Nikolić,J.B.; Marinković,A.D.; Krstić,S.S.; Petrović,S.D. Simple one-pot synthesis of thioureas from amines, carbon disulfide and oxidants in water. J. Serb. Chem. Soc 2016, 81, 219–231. [CrossRef] 72. Kumavat, P.P.; Jangale, A.D.; Patil, D.R.; Dalal, K.S.; Meshram, J.S.; Dalal, D.S. Green synthesis of symmetrical N,N’-disubstituted thiourea derivatives in water using solar energy. Environ. Chem. Lett. 2013, 11, 177–182. [CrossRef] 73. Ranu, B.C.; Dey, S.S.; Bag, S. A simple and green procedure for the synthesis of symmetrical N,N’-disubstituted thioureas on the surface of alumina under microwave irradiation. Arkivoc 2003, 14–20. [CrossRef] 74. Chau, C.-M.M.; Chuan, T.-J.J.; Liu, K.-M.M. A highly efficient one-pot method for the synthesis of thioureas and 2-imino-4-thiazolidinones under microwave conditions. RSC Adv. 2014, 4, 1276–1282. [CrossRef] 75. Ziyaei Halimehjani, A.; Farahbakhsh, F. Synthesis of thioureas in ionic liquid medium. J. Sulfur Chem. 2013, 34, 284–288. [CrossRef] 76. Azizi, N.; Farhadi, E. Rapid and highly efficient synthesis of thioureas in biocompatible basic choline hydroxide. J. Sulfur Chem. 2017, 38, 548–554. [CrossRef] Molecules 2020, 25, 401 41 of 56

77. Vázquez, J.; Bernès, S.; Reyes, Y.; Moya, M.; Sharma, P.; Alvarez, C.; Gutiérrez, R. Solvent-free synthesis of

chiral N,N0-disubstituted thioureas by ‘just mixing’ the reagents. Synthesis 2004, 1955–1958. [CrossRef] 78. Dutta, S.; Mondal, M.; Ghosh, T.; Saha, A. Unprecedented thiocarbamidation of nitroarenes a facile one-pot route to unsymmetrical thioureas. Org. Chem. Front. 2019, 6, 70–74. [CrossRef] 79. Kumar, L.R.; Panduranga, V.; Vishwanatha, T.M.; Shekharappa; Sureshbabu, V.V. Synthesis of thioureido peptidomimetics employing alkyl azides and dithiocarbamates. Org. Biomol. Chem. 2018, 16, 2258–2263. [CrossRef] 80. Sharma, S. Thiophosgene in organic synthesis. Synthesis 1978, 803–820. [CrossRef]

81. Dai, M.; Liang, B.; Wang, C.; Chen, J.; Yang, Z. Synthesis of a novel C2-symmetric thiourea and its application in the Pd-catalyzed cross-coupling reactions with arenediazonium salts under aerobic conditions. Org. Lett. 2004, 6, 221–224. [CrossRef] 82. Gao, Y.; Chang, L.; Shi, H.; Liang, B.; Wongkhan, K.; Chaiyaveij, D.; Batsanov, A.S.; Marder, T.B.; Li, C.; Yang, Z.; et al. A thiourea-oxazoline library with axial chirality: Ligand synthesis and studies of the palladium-catalyzed enantioselective bis(methoxycarbonylation) of terminal oleﬁns. Adv. Synth. Catal. 2010, 352, 1955–1966. [CrossRef] 83. Mohanta, P.K.; Dhar, S.; Samal, S.K.; Ila, H.; Junjappa, H. 1-(Methyldithiocarbonyl)imidazole: A useful thiocarbonyl transfer reagent for synthesis of substituted thioureas. Tetrahedron 2000, 56, 629–637. [CrossRef] 84. Ramadas, K.; Srinivasan, N. A convenient route to substituted thiocarbamides. Synth. Commun. 1995, 25, 3381–3387. [CrossRef] 85. Li, Z.; Liu, D.; Chen, Y.; Yin, Y.; Wang, Z.; Sun, X. Practical synthesis of symmetrical thioureas and heterocyclic thiones in water. J. Chem. Res. 2016, 40, 515–518. [CrossRef]

86. Li, Z.; Chen, Y.; Yin, Y.; Wang, Z.; Sun, X. Convenient synthesis of unsymmetrical N,N0-disubstituted thioureas in water. J. Chem. Res. 2016, 40, 670–673. [CrossRef] 87. da Silva, T.L.; Miolo, L.M.F.; Sousa, F.S.S.; Brod, L.M.P.; Savegnago, L.; Schneider, P.H. New thioureas based on thiazolidines with antioxidant potential. Tetrahedron Lett. 2015, 56, 6674–6680. [CrossRef] 88. Liang, B.; Liu, J.; Gao, Y.X.; Wongkhan, K.; Shu, D.X.; Lan, Y.; Li, A.; Batsanov, A.S.; Howard, J.A.H.; Marder, T.B.; et al. Synthesis of thiourea-oxazolines, a new class of chiral S,N-heterobidentate ligands: Application in Pd-catalyzed asymmetric bis(methoxycarbonylation) of terminal olefins. Organometallics 2007, 26, 4756–4762. [CrossRef] 89. Yin, B.-L.; Liu, Z.-G.; Zhang, J.-C.; Li, Z.-R. N,N-Di-Boc-substituted thiourea as a novel and mild thioacylating agent applicable for the synthesis of thiocarbonyl compounds. Synthesis 2010, 991–999. [CrossRef] 90. Cohrt, A.E.; Nielsen, T.E. Solid-phase synthesis of peptide thioureas and thiazole-containing macrocycles through Ru-catalyzed ring-closing metathesis. ACS Comb. Sci. 2014, 16, 71–77. [CrossRef] 91. Katritzky, A.R.; Ledoux, S.; Witek, R.M.; Nair, S.K. 1-(Alkyl/arylthiocarbamoyl)benzotriazoles as stable isothiocyanate equivalents: Synthesis of di- and trisubstituted thioureas. J. Org. Chem. 2004, 69, 2976–2982. [CrossRef] 92. Kang, I.-J.; Wang, L.-W.; Yeh, T.-K.; Lee, C.-C.; Lee, Y.-C.; Hsu, S.-J.; Wu, Y.-S.; Wang, J.-C.; Chao, Y.-S.; Yueh, A.; et al. Synthesis, activity, and pharmacokinetic properties of a series of conformationally-restricted thiourea analogs as novel hepatitis C virus inhibitors. Bioorg. Med. Chem. 2010, 18, 6414–6421. [CrossRef] [PubMed] 93. Katritzky, A.; Kirichenko, N.; Rogovoy, B.; Kister, J.; Tao, H. Synthesis of mono- and N,N-disubstituted thioureas and N-acylthioureas. Synthesis 2004, 1799–1805. [CrossRef] 94. Koketsu, M.; Fukuta, Y.; Ishihara, H. Preparation of N,N-unsubstituted selenoureas and thioureas from cyanamides. Tetrahedron Lett. 2001, 42, 6333–6335. [CrossRef] 95. Tan, W.; Wei, J.; Jiang, X. Thiocarbonyl surrogate via combination of sulfur and chloroform for thiocarbamide and oxazolidinethione construction. Org. Lett. 2017, 19, 2166–2169. [CrossRef][PubMed] 96. Deng, J.-C.C.; Gao, Y.-C.C.; Zhu, Z.; Xu, L.; Li, Z.-D.D.; Tang, R.-Y.Y. Sulfite-promoted synthesis of N-difluoromethylthioureas via the reaction of azoles with bromodifluoroacetate and elemental sulfur. Org. Lett. 2019, 21, 545–548. [CrossRef][PubMed] 97. Zhu, T.-H.H.; Xu, X.-P.P.; Cao, J.-J.J.; Wei, T.-Q.Q.; Wang, S.-Y.Y.; Ji, S.-J.J. Cobalt(II)-catalyzed isocyanide insertion reaction with amines under ultrasonic conditions: A divergent synthesis of ureas, thioureas and azaheterocycles. Adv. Synth. Catal. 2014, 356, 509–518. [CrossRef] Molecules 2020, 25, 401 42 of 56

98. Nguyen, T.B.; Ermolenko, L.; Al-Mourabit, A. Three-component reaction between isocyanides, aliphatic amines and elemental sulfur: Preparation of thioureas under mild conditions with complete atom economy. Synthesis 2014, 46, 3172–3179. [CrossRef] 99. Angyal, A.; Demjén, A.; Wölfling, J.; Puskás, L.G.; Kanizsai, I. A green, isocyanide-based three-component reaction approach for the synthesis of multisubstituted ureas and thioureas. Tetrahedron Lett. 2018, 59, 54–57. [CrossRef] 100. Singh, K.; Sharma, S. An isocyanide based multi-component reaction under catalyst- and solvent-free conditions for the synthesis of unsymmetrical thioureas. Tetrahedron Lett. 2017, 58, 197–201. [CrossRef] 101. Cui, H.-L.; Chouthaiwale, P.V.; Yin, F.; Tanaka, F. Reaction-based mechanistic investigations of asymmetric hetero-Diels-Alder reactions of enones with isatins catalyzed by amine-based three-component catalyst systems. Asian J. Org. Chem. 2016, 5, 153–161. [CrossRef] 102. Serdyuk, O.V.; Heckel, C.M.; Tsogoeva, S.B. Bifunctional primary amine-thioureas in asymmetric organocatalysis. Org. Biomol. Chem. 2013, 11, 7051–7071. [CrossRef][PubMed] 103. Pellissier, H. Asymmetric organocatalysis. Tetrahedron 2007, 63, 9267–9331. [CrossRef] 104. Gruttadauria, M.; Giacalone, F. (Eds.) Catalytic Methods in Asymmetric Synthesis: Advanced Materials, Techniques, and Applications; John Wiley & Sons: Hoboken, NJ, USA, 2011; ISBN 9781118087992. 105. Alemán, J.; Cabrera, S. Applications of asymmetric organocatalysis in medicinal chemistry. Chem. Soc. Rev. 2013, 42, 774–793. [CrossRef][PubMed] 106. Volla, C.M.R.R.; Atodiresei, I.; Rueping, M. Catalytic C–C bond-forming multi-component cascade or domino reactions: Pushing the boundaries of complexity in asymmetric organocatalysis. Chem. Rev. 2014, 114, 2390–2431. [CrossRef][PubMed] 107. Hong, L.; Sun, W.; Yang, D.; Li, G.; Wang, R. Additive effects on asymmetric catalysis. Chem. Rev. 2016, 116, 4006–4123. [CrossRef] 108. Tsogoeva, S.B. Recent advances in asymmetric organocatalytic 1,4-conjugate additions. Eur. J. Org. Chem. 2007, 1701–1716. [CrossRef] 109. Doyle, A.G.; Jacobsen, E.N. Small-molecule H-bond donors in asymmetric catalysis. Chem. Rev. 2007, 107, 5713–5743. [CrossRef] 110. Takemoto, Y.; Miyabe, H. The amino thiourea-catalyzed asymmetric nucleophilic reactions. Chimia 2007, 61, 269–275. [CrossRef] 111. Miyabe, H.; Takemoto, Y. Discovery and application of asymmetric reaction by multi-functional thioureas. Bull. Chem. Soc. Jpn. 2008, 81, 785–795. [CrossRef] 112. Takemoto, Y. Development of Chiral Thiourea Catalysts and Its Application to Asymmetric Catalytic Reactions. Chem. Pharm. Bull. 2010, 58, 593–601. [CrossRef] 113. Sun, Y.L.; Wei, Y.; Shi, M. Applications of chiral thiourea-amine/phosphine organocatalysts in catalytic asymmetric reactions. Chem. Cat. Chem. 2017, 9, 718–727. [CrossRef] 114. Ricci, P.; Khotavivattana, T.; Pfeifer, L.; Médebielle, M.; Morphy, J.R.; Gouverneur, V. The dual role of thiourea in the thiotrifluoromethylation of alkenes. Chem. Sci. 2017, 8, 1195–1199. [CrossRef][PubMed] 115. Ellis, G.P. (Ed.) Chromenes, Chromanones, and Chromones. In Chemistry of Heterocyclic Compounds; John Wiley & Sons: Hoboken, NJ, USA, 1977. [CrossRef] 116. Koufaki, M.; Kiziridi, C.; Alexi, X.; Alexis, M.N. Design and synthesis of novel neuroprotective 1,2-dithiolane/chroman hybrids. Bioorg. Med. Chem. 2009, 17, 6432–6441. [CrossRef][PubMed] 117. Shen, H.C. Asymmetric synthesis of chiral chromans. Tetrahedron 2009, 65, 3931–3952. [CrossRef] 118. Crozier, A.; Jaganath, I.B.; Clifford, M.N. Dietary phenolics: Chemistry, bioavailability and effects on health. Nat. Prod. Rep. 2009, 26, 1001–1043. [CrossRef][PubMed] 119. Crozier, A.; del Rio, D.; Clifford, M.N. Bioavailability of dietary flavonoids and phenolic compounds. Mol. Aspects Med. 2010, 31, 446–467. [CrossRef] 120. Wang, Y.; Lu, H.; Xu, P.-F. Asymmetric catalytic cascade reactions for constructing diverse scaffolds and complex molecules. Acounts Chem. Res. 2015, 48, 1832–1844. [CrossRef] 121. Sonsona, I.; Marqués-López, E.; Herrera, R.P. Enantioselective organocatalyzed synthesis of 2-amino-3-cyano-4H-chromene derivatives. Symmetry 2015, 7, 1519–1535. [CrossRef] 122. Núnez, M.G.; García, P.; Moro, R.F.; Díez, D. Asymmetric organocatalytic synthesis of six-membered oxygenated heterocycles. Tetrahedron 2010, 66, 2089–2109. [CrossRef] Molecules 2020, 25, 401 43 of 56

123. Sigman, M.S.; Jacobsen, E.N. Schiff base catalysts for the asymmetric Strecker reaction identified and optimized from parallel synthetic libraries. J. Am. Chem. Soc. 1998, 120, 4901–4902. [CrossRef] 124. Sigman, M.S.; Vachal, P.; Jacobsen, E.N. A general catalyst for the asymmetric Strecker reaction. Angew. Chem. Int. Ed. 2000, 39, 1279–1281. [CrossRef] 125. Vachal, P.; Jacobsen, E.N. Structure-based analysis and optimization of a highly enantioselective catalyst for the Strecker reaction. J. Am. Chem. Soc. 2002, 124, 10012–10014. [CrossRef][PubMed] 126. Joly, G.D.; Jacobsen, E.N. Thiourea-catalyzed enantioselective hydrophosphonylation of imines: Practical access to enantiomerically enriched α-amino phosphonic acids. J. Am. Chem. Soc. 2004, 126, 4102–4103. [CrossRef][PubMed] 127. Peterson, E.A.; Jacobsen, E.N. Enantioselective, thiourea-catalyzed intermolecular addition of indoles to cyclic N-acyl iminium ions. Angew. Chem. Int. Ed. 2009, 48, 6328–6331. [CrossRef] 128. Zuend, S.J.; Coughlin, M.P.; Lalonde, M.P.; Jacobsen, E.N. Scaleable catalytic asymmetric Strecker syntheses of unnatural α-amino acids. Nature 2009, 461, 968–970. [CrossRef] 129. Zuend, S.J.; Jacobsen, E.N. Mechanism of amido-thiourea catalyzed enantioselective imine hydrocyanation: Transition state stabilization via multiple non-covalent interactions. J. Am. Chem. Soc. 2009, 131, 15358–15374. [CrossRef] 130. Pan, S.C.; List, B. The catalytic acylcyanation of imines. Chem. Asian J. 2008, 3, 430–437. [CrossRef] 131. Tsogoeva, S.B.; Yalalov, D.A.; Hateley, M.J.; Weckbecker, C.; Huthmacher, K. Asymmetric organocatalysis with novel chiral thiourea derivatives: Bifunctional catalysts for the Strecker and nitro-Michael reactions. Eur. J. Org. Chem. 2005, 19, 4995–5000. [CrossRef] 132. Lalonde, M.P.; Chen, Y.; Jacobsen, E.N. A chiral primary amine thiourea catalyst for the highly enantioselective direct conjugate addition of α,α-disubstituted aldehydes to nitroalkenes. Angew. Chem. Int. Ed. 2006, 45, 6366–6370. [CrossRef] 133. Taylor, M.S.; Jacobsen, E.N. Highly enantioselective catalytic acyl-Pictet-Spengler reactions. J. Am. Chem. Soc. 2004, 126, 10558–10559. [CrossRef] 134. Brown, A.R.; Uyeda, C.; Brotherton, C.A.; Jacobsen, E.N. Enantioselective thiourea-catalyzed intramolecular Cope-type hydroamination. J. Am. Chem. Soc. 2013, 135, 6747–6749. [CrossRef][PubMed] 135. Bui, T.; Syed, S.; Barbas III, C.F. Thiourea-catalyzed highly enantio- and diastereoselective additions of oxindoles to nitroolefins: Application to the formal synthesis of (+)-physostigmine. J. Am. Chem. Soc. 2009, 131, 8758–8759. [CrossRef][PubMed] 136. Okino, T.; Hoashi, Y.; Takemoto, Y. Enantioselective Michael reaction of malonates to nitroolefins catalyzed by bifunctional organocatalysts. J. Am. Chem. Soc. 2003, 125, 12672–12673. [CrossRef][PubMed] 137. Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. Enantio- and diastereoselective Michael reaction of 1,3-dicarbonyl compounds to nitroolefins catalyzed by a bifunctional thiourea. J. Am. Chem. Soc. 2005, 127, 119–125. [CrossRef][PubMed] 138. Hoashi, Y.; Okino, T.; Takemoto, Y. Enantioselective Michael addition to α,β-unsaturated imides catalyzed by a bifunctional organocatalyst. Angew. Chem. Int. Ed. 2005, 44, 4032–4035. [CrossRef][PubMed] 139. Inokuma, T.; Hoashi, Y.; Takemoto, Y.Thiourea-catalyzed asymmetric Michael addition of activated methylene compounds to α,β-unsaturated imides: Dual activation of imide by intra- and intermolecular hydrogen bonding. J. Am. Chem. Soc. 2006, 128, 9413–9419. [CrossRef][PubMed] 140. Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Enantioselective aza-Henry reaction catalyzed by a bifunctional organocatalyst. Org. Lett. 2004, 6, 625–627. [CrossRef] 141. Sakamoto, S.; Inokuma, T.; Takemoto, Y. Organocatalytic asymmetric Neber reaction for the synthesis of 2H-azirine carboxylic esters. Org. Lett. 2011, 13, 6374–6377. [CrossRef] 142. Sakamoto, S.; Kazumi, N.; Kobayashi, Y.; Tsukano, C.; Takemoto, Y. Asymmetric synthesis of trisubstituted oxazolidinones by the thiourea-catalyzed aldol reaction of 2-isocyanatomalonate diester. Org. Lett. 2014, 16, 4758–4761. [CrossRef] 143. Wang, J.-J.; Lao, J.-H.; Hu, Z.-P.; Lu, R.-J.; Nie, S.-Z.; Du, Q.-S.; Yan, M. Organocatalytic asymmetric conjugate addition of cyclic 1,3-dicarbonyl compounds to β,γ-unsaturated α-ketoesters. Arkivoc 2010, 229–243. [CrossRef] 144. Zea, A.; Valero, G.; Alba, A.N.R.; Moyano, A.; Rios, R. Bifunctional thiourea-catalyzed asymmetric addition of anthrones to maleimides. Adv. Synth. Catal. 2010, 352, 1102–1106. [CrossRef] Molecules 2020, 25, 401 44 of 56

145. Enders, D.; Göddertz, D.P.; Beceño, C.; Raabe, G. Asymmetric synthesis of polyfunctionalized pyrrolidines via a thiourea catalyzed domino Mannich/aza-Michael reaction. Adv. Synth. Catal. 2010, 352, 2863–2868. [CrossRef] 146. Liao, Y.H.; Liu, X.L.; Wu, Z.J.; Du, X.L.; Zhang, X.M.; Yuan, W.C. Thiourea-catalyzed highly diastereo- and enantioselective conjugate additions of α-substituted cyanoacetates to maleimides: Eﬃcient construction of vicinal quaternary-tertiary stereocenters. Adv. Synth. Catal. 2011, 353, 1720–1728. [CrossRef] 147. Ma, C.H.; Kang, T.R.; He, L.; Liu, Q.Z. Highly enantioselective Michael addition of malonates to

β-CF3-β-(3-indolyl)nitroalkenes: Construction of trifluoromethylated all-carbon quaternary stereogenic centres. Eur. J. Org. Chem. 2014, 3981–3985. [CrossRef] 148. Monari, M.; Montroni, E.; Nitti, A.; Lombardo, M.; Trombini, C.; Quintavalla, A. Highly Stereoselective [4+2] and [3+2] Spiroannulations of 2-(2-Oxoindolin-3-ylidene)acetic Esters Catalyzed by Bifunctional Thioureas. Chem. Eur. J. 2015, 21, 11038–11049. [CrossRef] 149. Lutete, L.M.; Miyamoto, T.; Ikemoto, T. Tertiary amino thiourea-catalyzed asymmetric cross aldol reaction of aryl methyl ketones with aryl trifluoromethyl ketones. Tetrahedron Lett. 2016, 57, 1220–1223. [CrossRef] 150. Yang, J.; Sun, W.; He, Z.; Yu, C.; Bao, G.; Li, Y.; Liu, Y.; Hong, L.; Wang, R. Access to α, γ-diamino diacid derivatives via organocatalytic asymmetric 1,4-addition of azlactones and dehydroalanines. Org. Lett. 2018, 20, 7080–7084. [CrossRef] 151. Orhan, B.; Tschan, M.J.-L.; Wirotius, A.-L.; Dove, A.P.; Coulembier, O.; Taton, D. Isoselective ring-opening polymerization of rac-lactide from chiral Takemoto’s organocatalysts: Elucidation of stereocontrol. ACS Macro Lett. 2018, 7, 1413–1419. [CrossRef] 152. Miyabe, H.; Tuchida, S.; Yamauchi, M.; Takemoto, Y. Reaction of nitroorganic compounds using thiourea catalysts anchored to polymer support. Synthesis 2006, 3295–3300. [CrossRef] 153. Yamaoka, Y.; Miyabe, H.; Takemoto, Y. Catalytic enantioselective Petasis-type reaction of quinolines catalyzed by a newly designed thiourea catalyst. J. Am. Chem. Soc. 2007, 129, 6686–6687. [CrossRef] 154. Azuma, T.; Murata, A.; Kobayashi, Y.; Inokuma, T.; Takemoto, Y. A dual arylboronic acid-aminothiourea catalytic system for the asymmetric intramolecular hetero-Michael reaction of α,β-unsaturated carboxylic acids. Org. Lett. 2014, 16, 4256–4259. [CrossRef][PubMed] 155. Hayama, N.; Kuramoto, R.; Földes, T.; Nishibayashi, K.; Kobayashi, Y.; Pápai, I.; Takemoto, Y. Mechanistic insight into asymmetric hetero-Michael addition of α,β-unsaturated carboxylic acids catalyzed by multifunctional thioureas. J. Am. Chem. Soc. 2018, 140, 12216–12225. [CrossRef][PubMed] 156. Li, D.R.; He, A.; Falck, J.R. Enantioselective, organocatalytic reduction of ketones using bifunctional thiourea-amine catalysts. Org. Lett. 2010, 12, 1756–1759. [CrossRef][PubMed] 157. Mao, Z.; Lin, A.; Shi, Y.; Mao, H.; Li, W.; Cheng, Y.; Zhu, C. Chiral tertiary amine thiourea-catalyzed asymmetric inverse-electron-demand Diels-Alder reaction of chromone heterodienes using 3-vinylindoles as dienophiles. J. Org. Chem. 2013, 78, 10233–10239. [CrossRef][PubMed] 158. Ravi Kumar, G.; Ramesh, B.; Yarlagadda, S.; Sridhar, B.; Reddy, B.V.S. Organocatalytic enantioselective Mannich reaction: Direct access to chiral β-amino esters. ACS Omega 2019, 4, 2168–2177. [CrossRef] 159. Lu, R.J.; Wei, W.T.; Wang, J.J.; Nie, S.Z.; Zhang, X.J.; Yan, M. Organocatalytic conjugate addition of α-nitroacetates to β,γ-unsaturated α-keto esters and subsequent decarboxylation: Synthesis of optically active δ-nitro-α-keto esters. Tetrahedron 2012, 68, 9397–9404. [CrossRef] 160. Zhou, M.-Q.; Zuo, J.; Cui, B.-D.; Zhao, J.-Q.; You, Y.; Bai, M.; Chen, Y.-Z.; Zhang, X.-M.; Yuan, W.-C. Organocatalytic asymmetric double Michael reaction of Nazarov reagents with alkylidene azlactones for the construction of spiro-fused cyclohexanone/5-oxazolone system. Tetrahedron 2014, 70, 5787–5793. [CrossRef] 161. Zhang, Z.; Lippert, K.M.; Hausmann, H.; Kotke, M.; Schreiner, P.R. Cooperative thiourea-Brønsted acid organocatalysis: Enantioselective cyanosilylation of aldehydes with TMSCN. J. Org. Chem. 2011, 76, 9764–9776. [CrossRef] 162. Peng, F.-Z.; Shao, Z.-H.; Fan, B.-M.; Song, H.; Li, G.-P.; Zhang, H.-B. Addition of 2,4-pentandione to nitroalkenes promoted by bifunctional thioureas with central and axial chiral elements. J. Org. Chem. 2008, 73, 5202–5205. [CrossRef] 163. Guo, H.-M.; Li, J.-G.; Qu, G.-R.; Zhang, X.-M.; Yuan, W.-C. Organocatalytic enantioselective Michael addition of malononitrile to nitroolefins catalyzed by bifunctional thiourea. Chirality 2011, 23, 514–518. [CrossRef] Molecules 2020, 25, 401 45 of 56

164. Mei, K.; Jin, M.; Zhang, S.; Li, P.; Liu, W.; Chen, X.; Xue, F.; Duan, W.; Wang, W. Simple cyclohexanediamine-derived primary amine thiourea catalyzed highly enantioselective conjugate addition of nitroalkanes to enones. Org. Lett. 2009, 11, 2864–2867. [CrossRef][PubMed] 165. Dudziński, K.; Pakulska, A.M.; Kwiatkowski, P. An efficient organocatalytic method for highly enantioselective Michael addition of malonates to enones catalyzed by readily accessible primary amine-thiourea. Org. Lett. 2012, 14, 4222–4225. [CrossRef][PubMed] 166. Moritaka, M.; Miyamae, N.; Nakano, K.; Ichikawa, Y.; Kotsuki, H. Highly efficient asymmetric Michael addition reaction of malonates to α,β-unsaturated ketones promoted by a chiral thiourea/PPY dual-catalyst system. Synlett 2012, 23, 2554–2558. [CrossRef] 167. Miyamae, N.; Watanabe, N.; Moritaka, M.; Nakano, K.; Ichikawa, Y.; Kotsuki, H. Asymmetric organocatalytic desymmetrization of 4,4-disubstituted cyclohexadienones at high pressure: A new powerful strategy for the synthesis of highly congested chiral cyclohexenones. Org. Biomol. Chem 2014, 12, 5847–5855. [CrossRef] [PubMed] 168. Zhang, X.; Liu, S.; Lao, J.; Du, G.; Yan, M.; Chan, A.S.C.C. Asymmetric conjugate addition of carbonyl compounds to nitroalkenes catalyzed by chiral bifunctional thioureas. Tetrahedron: Asymmetry 2009, 20, 1451–1458. [CrossRef] 169. Li, B.-L.L.; Wang, Y.-F.F.; Luo, S.-P.P.; Zhong, A.-G.G.; Li, Z.-B.B.; Du, X.-H.H.; Xu, D.-Q.Q. Enantioselective Michael addition of aromatic ketones to nitroolefins catalyzed by bifunctional thioureas and mechanistic insight. Eur. J. Org. Chem. 2010, 656–662. [CrossRef] 170. Retini, M.; Bergonzini, G.; Melchiorre, P. Dioxindole in asymmetric catalytic synthesis: Direct access to 3-substituted 3-hydroxy-2-oxindoles via 1,4-additions to nitroalkenes. Chem. Commun. 2012, 48, 3336–3338. [CrossRef] 171. Guo, X.-T.; Sha, F.; Wu, X.-Y. Highly enantioselective Michael addition of aromatic ketones to nitrodienes and the application to the synthesis of chiral γ-aminobutyric acid. Synthesis 2017, 49, 647–656. [CrossRef] 172. Jiménez, E.I.; Vallejo Narváez, W.E.; Román-Chavarría, C.A.; Vazquez-Chavez, J.; Rocha-Rinza, T.; Hernández-Rodríguez, M. Bifunctional thioureas with α-trifluoromethyl or methyl groups: Comparison of catalytic performance in Michael additions. J. Org. Chem. 2016, 81, 7419–7431. [CrossRef] 173. Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K. Development of bis-thiourea-type organocatalyst for asymmetric Baylis-Hillman reaction. Tetrahedron Lett. 2004, 45, 5589–5592. [CrossRef] 174. Sohtome, Y.; Takemura, N.; Takagi, R.; Hashimoto, Y.; Nagasawa, K. Thiourea-catalyzed Morita-Baylis-Hillman reaction. Tetrahedron 2008, 64, 9423–9429. [CrossRef] 175. Mayr, F.; Brimioulle, R.; Bach, T. A chiral thiourea as a template for enantioselective intramolecular [2 + 2] photocycloaddition reactions. J. Org. Chem. 2016, 81, 6965–6971. [CrossRef][PubMed] 176. Wang, C.-J.; Zhang, Z.-H.; Dong, X.-Q.; Wu, X.-J. Chiral amine-thioureas bearing multiple hydrogen bonding donors: Highly efficient organocatalysts for asymmetric Michael addition of acetylacetone to nitroolefins. Chem. Commun. 2008, 1431–1433. [CrossRef][PubMed] 177. Wang, C.-J.; Dong, X.-Q.; Zhang, Z.-H.; Xue, Z.-Y.; Teng, H.-L. Highly anti-selective asymmetric nitro-mannich reactions catalyzed by bifunctional amine-thiourea-bearing multiple hydrogen-bonding donors. J. Am. Chem. Soc. 2008, 130, 8606–8607. [CrossRef] 178. Liao, Y.-H.; Liu, X.-L.; Wu, Z.-J.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Highly diastereo- and enantioselective Michael additions of 3-substituted oxindoles to maleimides catalyzed by chiral bifunctional thiourea-tertiary amine. Org. Lett. 2010, 12, 2896–2899. [CrossRef] 179. Liu, T.-Y.; Long, J.; Li, B.-J.; Jiang, L.; Li, R.; Wu, Y.; Ding, L.-S.; Chen, Y.-C. Enantioselective construction of quaternary carbon centre catalysed by bifunctional organocatalyst. Org. Biomol. Chem. 2006, 4, 2097–2099. [CrossRef] 180. Dong, L.-T.; Du, Q.-S.; Lou, C.-L.; Zhang, J.-M.; Lu, R.-J.; Yan, M. Asymmetric synthesis of nitrocyclopropanes catalyzed by chiral primary amines. Synlett 2010, 266–270. [CrossRef] 181. Mei, R.-Q.; Xu, X.-Y.; Li, Y.-C.; Fu, J.-Y.; Huang, Q.-C.; Wang, L.-X. Highly effective and enantioselective Michael addition of 4-hydroxycoumarin to α,β-unsaturated ketones promoted by simple chiral primary amine thiourea bifunctional catalysts. Tetrahedron Lett. 2011, 52, 1566–1568. [CrossRef] 182. Kang, J.Y.; Johnston, R.C.; Snyder, K.M.; Cheong, P.H.-Y.; Carter, R.G. Construction of stereogenic

α,α-disubstituted cycloalkanones via 1◦ amine thiourea dual catalysis: Experimental scope and computational analyses. J. Org. Chem. 2016, 81, 3629–3637. [CrossRef] Molecules 2020, 25, 401 46 of 56

183. Mei, R.-Q.Q.; Xu, X.-Y.Y.; Peng, L.; Wang, F.; Tian, F.; Wang, L.-X.X. Asymmetric Michael/cyclization tandem reaction of 4-hydroxycoumarin with β-nitroalkenes catalyzed by chiral bifunctional thioureas. Org. Biomol. Chem. 2013, 11, 1286–1289. [CrossRef] 184. Basak, A.K.; Shimada, N.; Bow, W.F.; Vicic, D.A.; Tius, M.A. An asymmetric organocatalytic Nazarov cyclization. J. Am. Chem. Soc. 2010, 132, 8266–8267. [CrossRef][PubMed] 185. Asari, A.H.; Lam, Y.-H.; Tius, M.A.; Houk, K.N. Origins of the stereoselectivity in a thiourea-primary amine-catalyzed Nazarov cyclization. J. Am. Chem. Soc. 2015, 137, 13191–13199. [CrossRef][PubMed] 186. Berkessel, A.; Roland, K.; Neudörﬂ, J.M. Asymmetric Morita-Baylis-Hillman reaction catalyzed by isophoronediamine-derived bis(thio)urea organocatalysts. Org. Lett. 2006, 8, 4195–4198. [CrossRef] [PubMed] 187. Flock, A.M.; Krebs, A.; Bolm, C. Ephedrine- and pseudoephedrine-derived thioureas in asymmetric Michael additions of keto esters and diketones to nitroalkenes. Synlett 2010, 1219–1222. [CrossRef] 188. Ren, Q.; Gao, Y.; Wang, J. Enantioselective synthesis of densely functionalized pyranochromenes via an unpredictable cascade Michael-oxa-Michael-tautomerization sequence. Chem. Eur. J. 2010, 16, 13594–13598. [CrossRef] 189. Cao, C.-L.; Ye, M.-C.; Sun, X.-L.; Tang, Y. Pyrrolidine—Thiourea as a bifunctional organocatalyst: Highly enantioselective Michael addition of cyclohexanone to nitrooleﬁns. Org. Lett. 2006, 8, 2901–2904. [CrossRef] 190. Zhi, Y.; Zhao, K.; von Essen, C.; Rissanen, K.; Enders, D. Thiourea-catalyzed domino Michael-Mannich [3+2]

cycloadditions: A strategy for the asymmetric synthesis of 3,30-pyrrolidinyl-dispirooxindoles. Synlett 2017, 28, 2876–2880. [CrossRef] 191. Yan, L.; Wang, H.; Xiong, F.; Tao, Y.; Wu, Y.; Chen, F. Chloramphenicol base chemistry. Part 11: Chloramphenicol base-derived thiourea-catalyzed enantioselective Michael addition of malononitrile to α,β-unsaturated ketones. Tetrahedron: Asymmetry 2017, 28, 921–929. [CrossRef] 192. Wang, S.-X.; Chen, F.-E. A novel cost-effective thiourea bifunctional organocatalyst for highly enantioselective alcoholysis of meso-cyclic anhydrides: Enhanced enantioselectivity by configuration inversion. Adv. Synth. Catal. 2009, 351, 547–552. [CrossRef] 193. Yan, L.-J.; Wang, H.-F.; Chen, W.-X.; Tao, Y.; Jin, K.-J.; Chen, F.-E. Development of bifunctional thiourea organocatalysts derived from a chloramphenicol base scaffold and their use in the enantioselective alcoholysis of meso cyclic anhydrides. Chem. Cat. Chem. 2016, 8, 2249–2253. [CrossRef] 194. Li, X.-J.; Liu, K.; Ma, H.; Nie, J.; Ma, J.-A. Highly enantioselective Michael addition of malonates to nitroolefins catalyzed by chiral bifunctional tertiary amine-thioureas based on saccharides. Synlett 2008, 3242–3246. [CrossRef] 195. Chen, F.-X.; Shao, C.; Liu, Q.; Gong, P.; Liu, C.-L.; Wang, R. Asymmetric Michael addition of trisubstituted carbanion to nitroalkenes catalyzed by sodium demethylquinine salt in water. Chirality 2009, 21, 600–603. [CrossRef][PubMed] 196. McGarraugh, P.G.; Brenner, S.E. Novel bifunctional sulfonamides catalyze an enantioselective conjugate addition. Tetrahedron 2009, 65, 449–455. [CrossRef][PubMed] 197. Nie, S.-Z.; Hu, Z.-P.; Xuan, Y.-N.; Wang, J.-J.; Li, X.-M.; Yan, M. Organocatalytic asymmetric conjugate addition of malonates to 3-nitro-2H-chromenes. Tetrahedron: Asymmetry 2010, 21, 2055–2059. [CrossRef] 198. Jiang, X.; Wang, R. Recent developments in catalytic asymmetric inverse-electron-demand Diels Alder − reaction. Chem. Rev. 2013, 113, 5515–5546. [CrossRef] 199. Johansson, H.; Jørgensen, T.B.; Gloriam, D.E.; Bräuner-Osborne, H.; Pedersen, D.S. 3-Substituted 2-phenyl-indoles: Privileged structures for medicinal chemistry. RSC Adv. 2013, 3, 945–960. [CrossRef] 200. Guo, H.-C.; Ma, J.-A. Catalytic asymmetric tandem transformations triggered by conjugate additions. Angew. Chem. Int. Ed. 2006, 45, 354–366. [CrossRef] 201. Pellissier, H. Asymmetric domino reactions. Part B: Reactions based on the use of chiral catalysts and biocatalysts. Tetrahedron 2006, 62, 2143–2173. [CrossRef] 202. Alba, A.-N.; Companyo, X.; Viciano, M.; Rios, R. Organocatalytic domino reactions. Curr. Org. Chem. 2009, 13, 1432–1474. [CrossRef] 203. Zu, L.; Zhang, S.; Xie, H.; Wang, W. Catalytic asymmetric oxa-Michael-Michael cascade for facile construction of chiral chromans via an aminal intermediate. Org. Lett. 2009, 11, 1627–1630. [CrossRef] 204. Moyano, A.; Rios, R. Asymmetric organocatalytic cyclization and cycloaddition reactions. Chem. Rev. 2011, 111, 4703–4832. [CrossRef][PubMed] Molecules 2020, 25, 401 47 of 56

205. Chanda, T.; Zhao, J.C.-G. Recent progress in organocatalytic asymmetric domino transformations. Adv. Synth. Catal. 2018, 360, 2–79. [CrossRef] 206. Bella, M.; Gasperi, T. Organocatalytic formation of quaternary stereocenters. Synthesis 2009, 1583–1614. [CrossRef] 207. Kumar, K.; Waldmann, H. Synthesis of natural product inspired compound collections. Angew. Chem. Int. Ed. 2009, 48, 3224–3242. [CrossRef][PubMed] 208. Deng, Y.; Chin, Y.-W.; Chai, H.; Keller, W.J.; Kinghorn, A.D. Anthraquinones with quinone reductase-inducing activity and benzophenones from morinda citrifolia (noni) roots. J. Nat. Prod. 2007, 70, 2049–2052. [CrossRef] [PubMed] 209. Singh, G.S.; Desta, Z.Y. Isatins as privileged molecules in design and synthesis of spiro-fused cyclic frameworks. Chem. Rev. 2012, 112, 6104–6155. [CrossRef][PubMed] 210. Dalpozzo, R.; Bartoli, G.; Bencivenni, G. Recent advances in organocatalytic methods for the synthesis of disubstituted 2- and 3-indolinones. Chem. Soc. Rev. 2012, 41, 7247–7290. [CrossRef] 211. Mao, H.; Lin, A.; Tang, Y.; Shi, Y.; Hu, H.; Cheng, Y.; Zhu, C. Organocatalytic oxa/aza-Michael–Michael cascade

strategy for the construction of spiro [chroman/tetrahydroquinoline-3,30-oxindole] scaffolds. Org. Lett. 2013, 15, 4062–4065. [CrossRef] 212. Hong, B.-C.; Kotame, P.; Lee, G.-H. Asymmetric synthesis of 3,4-dihydrocoumarin motif with an all-carbon quaternary stereocenter via a Michael–acetalization sequence with bifunctional amine-thiourea organocatalysts. Org. Lett. 2011, 13, 5758–5761. [CrossRef] 213. Wang, H.; Luo, J.; Han, X.; Lu, Y. Enantioselective synthesis of chromanones via a tryptophan-derived bifunctional thiourea-catalyzed oxa-Michael-Michael cascade reaction. Adv. Synth. Catal. 2011, 353, 2971–2975. [CrossRef] 214. Yoon, T.P.; Jacobsen, E.N. Privileged chiral catalysts. Science 2003, 299, 1691–1693. [CrossRef][PubMed] 215. Kacprzak, K.; Gawroński, J. Cinchona alkaloids and their derivatives: Versatile catalysts and ligands in asymmetric synthesis. Synthesis 2001, 961–998. [CrossRef] 216. McCooey, S.H.; Connon, S.J. Urea- and thiourea-substituted Cinchona alkaloid derivatives as highly efficient bifunctional organocatalysts for the asymmetric addition of malonate to nitroalkenes: Inversion of configuration at C9 dramatically improves catalyst performance. Angew. Chem. Int. Ed. 2005, 44, 6367–6370. [CrossRef][PubMed] 217. Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Highly enantioselective conjugate addition of nitromethane to chalcones using bifunctional Cinchona organocatalysts. Org. Lett. 2005, 7, 1967–1969. [CrossRef][PubMed] 218. Vakulya, B.; Varga, S.; Soós, T. Epi -Cinchona based thiourea organocatalyst family as an efficient assymmetric Michael addition promoter: Enantioselective conjugate addition of nitroalkanes to chalcones and α,β-unsaturated N-acylpyrroles. J. Org. Chem. 2008, 73, 3475–3480. [CrossRef] 219. Varga, S.; Jakab, G.; Drahos, L.; Holczbauer, T.; Czugler, M.; Soós, T. Double diastereocontrol in bifunctional thiourea organocatalysis: Iterative Michael-Michael-Henry sequence regulated by the configuration of chiral catalysts. Org. Lett. 2011, 13, 5416–5419. [CrossRef] 220. Li, P.; Wen, S.; Yu, F.; Liu, Q.; Li, W.; Wang, Y.; Liang, X.; Ye, J. Enantioselective organocatalytic Michael addition of malonates to α, β-unsaturated ketones. Org. Lett. 2009, 11, 753–756. [CrossRef] 221. Li, H.; Zhang, S.; Yu, C.; Song, X.; Wang, W. Organocatalytic asymmetric synthesis of chiral fluorinated quaternary carbon containing β-ketoesters. Chem. Commun. 2009, 2136–2138. [CrossRef] 222. Han, X.; Luo, J.; Liu, C.; Lu, Y. Asymmetric generation of fluorine-containing quaternary carbons adjacent to tertiary stereocenters: Uses of fluorinated methines as nucleophiles. Chem. Commun. 2009, 2044–2046. [CrossRef] 223. Fan, L.-P.; Li, P.; Li, X.-S.; Xu, D.-C.; Ge, M.-M.; Zhu, W.-D.; Xie, J.-W.W. Facile domino access to chiral mono-, bi-, and tricyclic 2,3-dihydrofurans. J. Org. Chem. 2010, 75, 8716–8719. [CrossRef] 224. Pham, T.S.; Balázs, L.; Petneházy, I.; Jászay, Z. Enantioselective Michael addition of diethyl cyanomethylphosphonate to chalcones using bifunctional Cinchona-derived organocatalysts: Synthesis of chiral precursors of α-substituted β-aminophosphonates. Tetrahedron: Asymmetry 2010, 21, 346–351. [CrossRef] 225. Mancheño, O.G.; Tangen, P.; Rohlmann, R.; Fröhlich, R.; Alemán, J. Synthesis of chiral cyclic nitrones by asymmetric addition of β-ketosulfones to nitroalkenes followed by reductive cyclization. Chem. Eur. J. 2011, 17, 984–992. [CrossRef][PubMed] Molecules 2020, 25, 401 48 of 56

226. Liu, Y.-Z.Z.; Cheng, R.-L.L.; Xu, P.-F.F. Asymmetric michael addition of 1-acetylindolin-3-ones to β-nitrostyrenes catalyzed by bifunctional thioureas: A simple access to 2-functionalized indoles. J. Org. Chem. 2011, 76, 2884–2887. [CrossRef][PubMed] 227. Wang, J.-J.; Hu, Z.-P.; Lou, C.-L.; Liu, J.-L.; Li, X.-M.; Yan, M. Asymmetric synthesis of trifluoromethyl substituted dihydropyrans via organocatalytic cascade Michael-hemiketalization reaction. Tetrahedron 2011, 67, 4578–4583. [CrossRef] 228. Chiarucci, M.; Lombardo, M.; Trombini, C.; Quintavalla, A. Enantioselective conjugate addition of nitroalkanes to alkylidenemalonates promoted by thiourea-based bifunctional organocatalysts. Adv. Synth. Catal. 2012, 354, 364–370. [CrossRef] 229. Curti, C.; Rassu, G.; Zambrano, V.; Pinna, L.; Pelosi, G.; Sartori, A.; Battistini, L.; Zanardi, F.; Casiraghi, G. Bifunctional Cinchona alkaloid/thiourea catalyzes direct and enantioselective vinylogous Michael addition of 3-alkylidene oxindoles to nitroolefins. Angew. Chem. Int. Ed. 2012, 51, 6200–6204. [CrossRef] 230. Guo, Z.-W.; Li, X.-S.; Zhu, W.-D.; Xie, J.-W. Construction of chiral multi-functionalized polyheterocyclic benzopyran derivatives by using an asymmetric organocatalytic domino reaction. Eur. J. Org. Chem. 2012, 6924–6932. [CrossRef] 231. Molleti, N.; Allu, S.; Ray, S.K.; Singh, V.K. Bifunctional chiral urea catalyzed highly enantioselective Michael addition of cyclic 1,3-dicarbonyl compounds to 2-enoylpyridines. Tetrahedron Lett. 2013, 54, 3241–3244. [CrossRef] 232. Kwiatkowski, J.; Lu, Y. Highly enantioselective preparation of fluorinated phosphonates by Michael addition of α-fluoro-β-ketophosphonates to nitroalkenes. Asian J. Org. Chem. 2014, 3, 458–461. [CrossRef] 233. Kwiatkowski, P.; Cholewiak, A.; Kasztelan, A. Efficient and highly enantioselective construction of trifluoromethylated quaternary stereogenic centers via high-pressure mediated organocatalytic conjugate addition of nitromethane to β,β-disubstituted enones. Org. Lett. 2014, 16, 5930–5933. [CrossRef] 234. Konda, S.; Zhao, J.C.-G. High enantioselective Michael addition of malonates to β,γ-unsaturated α-ketoesters catalyzed by bifunctional thioureas. Tetrahedron Lett. 2014, 55, 5216–5218. [CrossRef] 235. Chang, H.-H.; Chu, K.-T.; Chiang, M.-H.; Han, J.-L. Organocatalytic enantioselective Michael reaction of 1,3-dicarbonyls with α-substituted β-nitroacrylates. Tetrahedron 2017, 73, 727–734. [CrossRef] 236. Bhagat, U.K.; Peddinti, R.K. Asymmetric organocatalytic approach to 2,4-disubstituted 1,2,3-triazoles by N2-selective aza-Michael addition. J. Org. Chem. 2018, 83, 793–804. [CrossRef] 237. Reddy, S.N.; Reddy, V.R.; Dinda, S.; Nanubolu, J.B.; Chandra, R. Asymmetric reaction of p-quinone diimide: Organocatalyzed Michael addition of α-cyanoacetates. Org. Lett. 2018, 20, 2572–2575. [CrossRef] 238. Yuan, J.-N.; Liu, H.-X.; Tian, Q.-Q.; Ji, N.; Shen, K.; He, W. Highly enantioselective Michael addition of dithiomalonates to nitroolefins catalyzed by new bifunctional chiral thioureas. Synthesis 2018, 50, 2577–2586. [CrossRef] 239. Wang, Y.-F.; Wu, S.; Karmaker, P.G.; Sohail, M.; Wang, Q.; Chen, F.-X. Enantioselective synthesis of trifluoromethylated tertiary thioethers through organocatalytic sulfa-Michael addition of thiols to β-trifluoromethyl β,β-disubstituted enones. Synthesis 2015, 47, 1147–1153. [CrossRef] 240. Bacsó, A.; Szigeti, M.; Varga, S.; Soós, T. Bifunctional thiourea-catalyzed stereoablative retro-sulfa-Michael reaction: Concise and diastereoselective access to chiral 2,4-diarylthietanes. Synthesis 2017, 49, 429–439. [CrossRef] 241. Konda, S.; Guo, Q.-S.; Abe, M.; Huang, H.; Arman, H.; Zhao, J.C.-G. Organocatalyzed asymmetric aldol reactions of ketones and β,γ-unsaturated α-ketoesters and phenylglyoxal hydrates. J. Org. Chem. 2015, 80, 806–815. [CrossRef] 242. Ji, S.; Alkhalil, A.E.; Su, Y.; Xia, X.; Chong, S.; Wang, K.-H.; Huang, D.; Fu, Y.; Hu, Y. Bifunctional thiourea catalyzed asymmetric Mannich reaction using trifluoromethyl aldimine as trifluoromethyl building blocks. Synlett 2015, 26, 1725–1731. [CrossRef] 243. Liu, Y.-L.; Shi, T.-D.; Zhou, F.; Zhao, X.-L.; Wang, X.; Zhou, J. Organocatalytic asymmetric Strecker reaction of di- and trifluoromethyl ketoimines. Remarkable fluorine effect. Org. Lett. 2011, 13, 3826–3829. [CrossRef] 244. Xie, H.; Song, A.; Song, X.; Zhang, X.; Wang, W. Organocatalytic enantioselective Strecker reaction of cyclic trifluoromethyl-ketoimines. Tetrahedron Lett. 2013, 54, 1409–1411. [CrossRef] 245. Xie, H.; Song, A.; Zhang, X.; Chen, X.; Li, H.; Sheng, C.; Wang, W. Quinine-thiourea catalyzed enantioselective hydrophosphonylation of trifluoromethyl 2(1H)-quinazolinones. Chem. Commun. 2013, 49, 928–930. [CrossRef][PubMed] Molecules 2020, 25, 401 49 of 56

246. Du, F.; Zhou, J.; Peng, Y. Asymmetric reaction of α-diazomethylphosphonates with α-ketoesters to access optically active α-diazo-β-hydroxyphosphonate derivatives. Org. Lett. 2017, 19, 1310–1313. [CrossRef] [PubMed] 247. Amere, M.; Lasne, M.-C.; Rouden, J. Highly enantioselective decarboxylative protonation of α-aminomalonates mediated by thiourea Cinchona alkaloid derivatives: Access to both enantiomers of cyclic and acyclic α-aminoacids. Tetrahedron: Asymmetry 2007, 9, 2621–2624. [CrossRef] 248. Xu, J.; Hu, Y.; Huang, D.; Wang, K.-H.; Xu, C.; Niu, T. Thiourea-catalyzed enantioselective fluorination of β-keto esters. Adv. Synth. Catal. 2012, 354, 515–526. [CrossRef] 249. Hu, X.-Y.; Hu, F.-Z.; Chen, H.; Xu, X.-Y.; Yuan, W.-C.; Zhang, X.-M. Enantioselective α-arylation of cyclic β-ketoamides with a quinone monoimine. ChemistrySelect 2018, 3, 3975–3977. [CrossRef] 250. Marcelli, T.; van Der Haas, R.N.S.; van Maarseveen, J.H.; Hiemstra, H. Asymmetric organocatalytic Henry reaction. Angew. Chem. Int. Ed. 2006, 45, 929–931. [CrossRef] 251. Oh, J.-S.; Lee, J.-W.; Ryu, T.H.; Lee, J.H.; Song, C.E. Self-association free bifunctional thiourea organocatalysts: Synthesis of chiral α-amino acids via dynamic kinetic resolution of racemic azlactones. Org. Biomol. Chem. 2012, 10, 1052–1055. [CrossRef] 252. Dondoni, A.; Massi, A. Asymmetric organocatalysis: From infancy to adolescence. Angew. Chem. Int. Ed. 2008, 47, 4638–4660. [CrossRef] 253. Tárkányi, G.; Király, P.; Varga, S.; Vakulya, B.; Soós, T. Edge-to-face CH/π aromatic interaction and molecular self-recognition in epi-Cinchona-based bifunctional thiourea organocatalysis. Chem. Eur. J. 2008, 14, 6078–6086. [CrossRef] 254. Oh, S.H.; Rho, H.S.; Lee, J.W.; Lee, J.E.; Youk, S.H.; Chin, J.; Song, C.E. A highly reactive and enantioselective bifunctional organocatalyst for the methanolytic desymmetrization of cyclic anhydrides: Prevention of catalyst aggregation. Angew. Chem. Int. Ed. 2008, 47, 7872–7875. [CrossRef][PubMed] 255. Jia, Z.-X.; Luo, Y.-C.; Cheng, X.-N.; Xu, P.-F.; Gu, Y.-C. Organocatalyzed Michael–Michael cascade reaction: Asymmetric synthesis of polysubstituted chromans. J. Org. Chem. 2013, 78, 6488–6494. [CrossRef][PubMed] 256. Saha, P.; Biswas, A.; Molleti, N.; Singh, V.K. Enantioselective synthesis of highly substituted chromans via the oxa-Michael–Michael cascade reaction with a bifunctional organocatalyst. J. Org. Chem. 2015, 80, 11115–11122. [CrossRef][PubMed] 257. Andrés, J.M.; Manzano, R.; Pedrosa, R. Novel bifunctional chiral urea and thiourea derivatives as organocatalysts: Enantioselective nitro-Michael reaction of malonates and diketones. Chem. Eur. J. 2008, 14, 5116–5119. [CrossRef] 258. Chen, X.-K.; Zheng, C.-W.; Zhao, S.-L.; Chai, Z.; Yang, Y.-Q.; Zhao, G.; Cao, W.-G. Highly enantioselective Michael addition of cyclic 1,3-dicarbonyl compounds to β,γ-unsaturated α-keto esters. Adv. Synth. Catal. 2010, 352, 1648–1652. [CrossRef] 259. Cui, H.-F.; Li, P.; Wang, X.-W.; Zhu, S.-Z.; Zhao, G. Asymmetric Michael addition of α-fluoro-α-phenylsulfonyl ketones to nitroolefins catalyzed by phenylalanine-based bifunctional thioureas. J. Fluor. Chem. 2012, 133, 120–126. [CrossRef] 260. Massolo, E.; Benaglia, M.; Orlandi, M.; Rossi, S.; Celentano, G. Enantioselective organocatalytic reduction of β-trifluoromethyl nitroalkenes: An efficient strategy for the synthesis of chiral β-trifluoromethyl amines. Chem. Eur. J. 2015, 21, 3589–3595. [CrossRef] 261. Klausen, R.S.; Jacobsen, E.N. Weak Brønsted acid-thiourea co-catalysis: Enantioselective, catalytic protio-Pictet-Spengler reactions. Org. Lett. 2009, 11, 887–890. [CrossRef] 262. Klausen, R.S.; Kennedy, C.R.; Hyde, A.M.; Jacobsen, E.N. Chiral thioureas promote enantioselective Pictet-Spengler cyclization by stabilizing every intermediate and transition state in the carboxylic acid-catalyzed reaction. J. Am. Chem. Soc. 2017, 139, 12299–12309. [CrossRef] 263. Lee, Y.; Klausen, R.S.; Jacobsen, E.N. Thiourea-catalyzed enantioselective iso-pictet-spengler reactions. Org. Lett. 2011, 13, 5564–5567. [CrossRef] 264. Yeung, C.S.; Ziegler, R.E.; Porco, J.A.; Jacobsen, E.N. Thiourea-catalyzed enantioselective addition of indoles to pyrones: Alkaloid cores with quaternary carbons. J. Am. Chem. Soc. 2014, 136, 13614–13617. [CrossRef] [PubMed] 265. Choudhury, A.R.; Mukherjee, S. Enantioselective dearomatization of isoquinolines by anion-binding catalysis en route to cyclic a-aminophosphonates. Chem. Sci. 2016, 7, 6940–6945. [CrossRef][PubMed] Molecules 2020, 25, 401 50 of 56

266. Yang, G.-J.; Du, W.; Chen, Y.-C. Construction of furan derivatives with a trifluoromethyl stereogenic center: Enantioselective Friedel Crafts alkylations via formal trienamine catalysis. J. Org. Chem. 2016, 81, − 10056–10061. [CrossRef][PubMed] 267. Manzano, R.; Andrés, J.M.; Muruzábal, M.D.; Pedrosa, R. Stereocontrolled construction of quaternary stereocenters by inter- and intramolecular nitro-michael additions catalyzed by bifunctional thioureas. Adv. Synth. Catal. 2010, 352, 3364–3372. [CrossRef] 268. Manzano, R.; Andrés, J.M.; Álvarez, R.; Muruzábal, M.D.; de Lera, Á.R.; Pedrosa, R. Enantioselective conjugate addition of nitro compounds to α,β-unsaturated ketones: An experimental and computational study. Chem. Eur. J. 2011, 17, 5931–5938. [CrossRef][PubMed] 269. Andrés, J.M.; Ceballos, M.; Maestro, A.; Sanz, I.; Pedrosa, R. Supported bifunctional thioureas as recoverable and reusable catalysts for enantioselective nitro-Michael reactions. Beilstein J. Org. Chem. 2016, 12, 628–635. [CrossRef][PubMed] 270. Andrés, J.M.; González, M.; Maestro, A.; Naharro, D.; Pedrosa, R. Recyclable chiral bifunctional thioureas derived from [60]fullerene and their use as highly efficient organocatalysts for the asymmetric Nitro-Michael reaction. Eur. J. Org. Chem. 2017, 2683–2691. [CrossRef] 271. Li, Y.; Yang, Q.; Xu, X.-Y.; Zhou, Y.; Bai, J.; Wang, F.; Wang, L. A highly asymmetric direct aldol reaction catalyzed by chiral proline amide – thiourea bifunctional catalysts. Can. J. Chem. 2011, 89, 1312–1318. [CrossRef] 272. Vargas-Caporali, J.; Cruz-Hernández, C.; Juaristi, E. Synthesis of versatile bifunctional derivatives of chiral diamines obtained through anchimerically assisted nucleophilic substitution reactions on diastereomeric phenylprolinols. Heterocylces 2012, 86, 1275–1300. [CrossRef] 273. Vinayagam, P.; Vishwanath, M.; Kesavan, V. New class of bifunctional thioureas from l-proline: Highly enantioselective Michael addition of 1,3-dicarbonyls to nitroolefins. Tetrahedron: Asymmetry 2014, 25, 568–577. [CrossRef] 274. Hielkema, J.U.; Ticheler, J.; Jörres, M.; Schiffers, I.; Atodiresei, I.; Bolm, C. Asymmetric Michael additions of α-nitrocyclohexanone to aryl nitroalkenes catalyzed by natural amino acid-derived bifunctional thioureas. Org. Lett. 2012, 14, 4518–4521. [CrossRef] 275. Lattanzi, A. Asymmetric Morita-Baylis-Hillman reaction catalyzed by simple amino alcohol derived thioureas. Synlett 2007, 2106–2110. [CrossRef] 276. Wanka, L.; Cabrele, C.; Vanejews, M.; Schreiner, P.R. γ-aminoadamantanecarboxylic acids through direct C-H bond amidations. Eur. J. Org. Chem. 2007, 1474–1490. [CrossRef]

277. Huang, Y.; Zheng, C.; Chai, Z.; Zhao, G. Synthesis of spiro[chroman/tetrahydrothiophene-3,30-oxindole] scaﬀolds via heteroatom-Michael-Michael reactions: Easily controlled enantioselectivity via bifunctional catalysts. Adv. Synth. Catal. 2014, 356, 579–583. [CrossRef] 278. Zhao, K.; Zhi, Y.; Shu, T.; Valkonen, A.; Rissanen, K.; Enders, D. Organocatalytic domino oxa-Michael/1,6-addition reactions: Asymmetric synthesis of chromans bearing oxindole scaﬀolds. Angew. Chem. Int. Ed. 2016, 55, 12104–12108. [CrossRef] 279. Wang, L.; Jia, Y.-X.; Zhang, J.-M.; Qian, C.; Chen, X.-Z. Improved synthesis of 4-benzylidene-2,6-di-tert-butylcyclohexa-2,5-dienone and its derivatives. Monatsh. Chem. 2014, 145, 1941–1945. [CrossRef] 280. Hughes, B.; Howat, D.; Lisle, H.; Holbrook, M.; James, T.; Gozzard, N.; Blease, K.; Hughes, P.; Kingaby, R.; Warrellow, G.; et al. The inhibition of antigen-induced eosinophilia and bronchoconstriction by CDP840, a novel stereo-selective inhibitor of phosphodiesterase type 4. Br. J. Pharmacol. 1996, 118, 1183–1191. [CrossRef] 281. Rovner, E.S.; Wein, A.J. Once-daily, extended-release formulations of antimuscarinic agents in the treatment of overactive bladder: A review. Eur. Urol. 2002, 41, 6–14. [CrossRef] 282. Davidson, S.J.; Barker, D. Synthesis of various lignans via the rearrangements of 1,4-diarylbutane-1,4-diols. Tetrahedron Lett. 2015, 56, 4549–4553. [CrossRef] 283. Jiang, X.; Wu, S.; Wang, J.; Mei, G.; Shi, F. Catalytic Asymmetric [4+2] Cyclization of para-quinone methide derivatives with 3-alkyl-2-vinylindoles. Adv. Synth. Catal. 2018, 360, 4225–4235. [CrossRef] 284. Li, W.; Yuan, H.; Liu, Z.; Zhang, Z.; Cheng, Y.; Li, P. NHC-Catalyzed enantioselective [4 + 3] cycloaddition of ortho-hydroxyphenyl substituted para -quinone methides with isatin-derived enals. Adv. Synth. Catal. 2018, 360, 2460–2464. [CrossRef] Molecules 2020, 25, 401 51 of 56

285. Sun, M.; Ma, C.; Zhou, S.-J.; Lou, S.-F.; Xiao, J.; Jiao, Y.; Shi, F. Catalytic asymmetric (4 + 3) cyclizations of in situ generated ortho-quinone methides with 2-indolylmethanols. Angew. Chem. Int. Ed. 2019, 58, 8703–8708. [CrossRef][PubMed] 286. Wang, Z.-H.; Zhang, X.-Y.; You, Y.; Zhao, J.-Q.; Zhou, M.-Q.; Zhang, X.-M.; Xu, X.-Y.; Yuan, W.-C. Efficient construction of polycyclic chromans through 4-methylbenzenesulfonic acid mediated domino 1,6-addition/oxa-Mannich reaction of ortho-hydroxyphenyl substituted para-quinone methides and cyclic enamides. Tetrahedron 2019, 75, 3456–3462. [CrossRef] 287. Cheng, Y.-C.; Wang, C.-S.; Li, T.-Z.; Gao, F.; Jiao, Y.; Shi, F. Organocatalytic [4 + 2] cyclizations of para -quinone methide derivatives with isocyanates. Org. Biomol. Chem. 2019, 17, 6662–6670. [CrossRef] 288. Liu, K.; Cui, H.-F.; Nie, J.; Dong, K.-Y.; Li, X.-J.; Ma, J.-A. Highly enantioselective Michael addition of aromatic ketones to nitroolefins promoted by chiral bifunctional primary amine-thiourea catalysts based on saccharides. Org. Lett. 2007, 9, 923–925. [CrossRef] 289. Ma, H.; Liu, K.; Zhang, F.-G.; Zhu, C.-L.; Nie, J.; Ma, J.-A. Chiral bifunctional thiourea-catalyzed enantioselective Michael addition of ketones to nitrodienes. J. Org. Chem. 2010, 75, 1402–1409. [CrossRef] 290. Qiao, B.; Huang, Y.-J.; Nie, J.; Ma, J.-A. Highly regio-, diastereo-, and enantioselective Mannich reaction of allylic ketones and cyclic ketimines: Access to chiral benzosultam. Org. Lett. 2015, 17, 4608–4611. [CrossRef] 291. Liu, Y.-J.; Li, J.-S.; Nie, J.; Ma, J.-A. Organocatalytic asymmetric decarboxylative Mannich reaction of β-keto acids with cyclic α-ketiminophosphonates: Access to quaternary α-aminophosphonates. Org. Lett. 2018, 20, 3643–3646. [CrossRef] 292. Li, F.; Sun, L.; Teng, Y.; Yu, P.; Zhao, J.C.-G.; Ma, J.-A. Highly diastereo- and enantioselective organocatalytic one-pot sequential 1,4-addition/dearomative-fluorination transformation. Chem. Eur. J. 2012, 18, 14255–14260. [CrossRef] 293. Meng, W.-T.; Zheng, Y.; Nie, J.; Xiong, H.-Y.; Ma, J.-A. Organocatalytic asymmetric one-pot sequential conjugate addition/dearomative fluorination: Synthesis of chiral fluorinated isoxazol-5(4H)-ones. J. Org. Chem. 2013, 78, 559–567. [CrossRef] 294. Wang, C.; Zhou, Z.; Tang, C. Novel bifunctional chiral thiourea catalyzed higly enantioselective aza-Henry reaction. Org. Lett. 2008, 10, 1707–1710. [CrossRef][PubMed]

295. Zheng, W.; Zhang, J.; Liu, S.; Yu, C.; Miao, Z. Asymmetric synthesis of spiro[chroman-3,30-pyrazol] scaﬀolds with an all-carbon quaternary stereocenter via a oxa-Michael–Michael cascade strategy with bifunctional amine-thiourea organocatalysts. RSC Adv. 2015, 5, 91108–91113. [CrossRef] 296. V. Kouznetsov, V.; R. Merchan Arenas, D.; Arvelo, F.; S. Bello Forero, J.; Sojo, F.; Munoz, A. 4-Hydroxy-3-methoxyphenyl substituted 3-methyl-tetrahydroquinoline derivatives obtained through imino Diels-Alder reactions as potential antitumoral agents. Lett. Drug Des. Discov. 2010, 7, 632–639. [CrossRef] 297. Breschi, M.C.; Calderone, V.; Martelli, A.; Minutolo, F.; Rapposelli, S.; Testai, L.; Tonelli, F.; Balsamo, A. New benzopyran-based openers of the mitochondrial ATP-sensitive potassium channel with potent anti-ischemic properties. J. Med. Chem. 2006, 49, 7600–7602. [CrossRef][PubMed] 298. Rapposelli, S.; Da Settimo, F.; Digiacomo, M.; La Motta, C.; Lapucci, A.; Sartini, S.; Vanni, M. Synthesis and

biological evaluation of 20-oxo-2,3-dihydro-30H- spiro[chromene-4,50-[1,3]oxazolidin]-30yl]acetic acid derivatives as aldose reductase inhibitors. Arch. Pharm. 2011, 344, 372–385. [CrossRef][PubMed] 299. Ramachary, D.B.; Madhavachary, R.; Prasad, M.S. Observation of neighboring ortho-hydroxyl group participation in organocatalytic asymmetric sequential Michael-lactonization reactions: Synthesis of highly substituted chiral spirodihydrocoumarins. Org. Biomol. Chem. 2012, 10, 5825–5829. [CrossRef][PubMed] 300. Shi, Y.-L.; Shi, M. Chiral thiourea-phosphine organocatalysts in the asymmetric aza-Morita-Baylis-Hillman reaction. Adv. Synth. Catal. 2007, 349, 2129–2135. [CrossRef] 301. Yang, Y.-L.; Pei, C.-K.; Shi, M. Multifunctional chiral phosphines-catalyzed highly diastereoselective and enantioselective substitution of Morita-Baylis-Hillman adducts with oxazolones. Org. Biomol. Chem. 2011, 9, 3349–3358. [CrossRef] 302. Yuan, K.; Zhang, L.; Song, H.-L.; Hu, Y.; Wu, X.-Y. Chiral phosphinothiourea organocatalyst in the enantioselective Morita-Baylis-Hillman reactions of aromatic aldehydes with methyl vinyl ketone. Tetrahedron Lett. 2008, 49, 6262–6264. [CrossRef] 303. Yuan, K.; Song, H.-L.; Hu, Y.; Wu, X.-Y. Chiral phosphinothiourea-catalyzed asymmetric Morita-Baylis-Hillman reactions of acrylates with aromatic aldehydes. Tetrahedron 2009, 65, 8185–8190. [CrossRef] Molecules 2020, 25, 401 52 of 56

304. Gong, J.-J.; Yuan, K.; Wu, X.-Y. Valine-derived phosphinothiourea as organocatalyst in enantioselective Morita-Baylis-Hillman reactions of acrylates with aromatic aldehydes. Tetrahedron: Asymmetry 2009, 20, 2117–2120. [CrossRef] 305. Mita, T.; Jacobsen, E. Bifunctional asymmetric catalysis with hydrogen chloride: Enantioselective ring opening of aziridines catalyzed by a phosphinothiourea. Synlett 2009, 1680–1684. [CrossRef] 306. Li, X.; Xu, X.; Wei, W.; Lin, A.; Yao, H. Organocatalyzed asymmetric 1,6-conjugate addition of para-quinone methides with dicyanoolefins. Org. Lett. 2016, 18, 428–431. [CrossRef][PubMed] 307. Su, H.Y.; Taylor, M.S. P-Stereogenic β-aminophosphines: Preparation and applications in enantioselective organocatalysis. J. Org. Chem. 2017, 82, 3173–3182. [CrossRef][PubMed] 308. Zhang, J.; Zhao, G. Enantioselective Mannich reaction of γ-malonate-substituted α,β-unsaturated esters with N-Boc imines catalyzed by chiral bifunctional thiourea-phosphonium salts. Tetrahedron 2019, 75, 1697–1705. [CrossRef] 309. Zhao, Q.; Li, S.; Huang, K.; Wang, R.; Zhang, X. A novel chiral bisphosphine-thiourea ligand for asymmetric hydrogenation of β,β-disubstituted nitroalkenes. Org. Lett. 2013, 15, 4014–4017. [CrossRef] 310. Zhao, Q.; Wen, J.; Tan, R.; Huang, K.; Metola, P.; Wang, R.; Anslyn, E.V.; Zhang, X. Rhodium-catalyzed asymmetric hydrogenation of unprotected NH imines assisted by a thiourea. Angew. Chem. Int. Ed. 2014, 53, 8467–8470. [CrossRef] 311. Han, Z.; Li, P.; Zhang, Z.; Chen, C.; Wang, Q.; Dong, X.Q.; Zhang, X. Highly enantioselective synthesis of chiral succinimides via Rh/bisphosphine-thiourea-catalyzed asymmetric hydrogenation. ACS Catal. 2016, 6, 6214–6218. [CrossRef] 312. Li, P.; Hu, X.; Dong, X.Q.; Zhang, X. Rhodium/bisphosphine-thiourea-catalyzed enantioselective hydrogenation of α,β-unsaturated N-acylpyrazoles. Chem. Commun. 2016, 52, 11677–11680. [CrossRef] 313. Li, P.; Huang, Y.; Hu, X.; Dong, X.-Q.; Zhang, X. Access to chiral seven-member cyclic amines via Rh-catalyzed asymmetric hydrogenation. Org. Lett. 2017, 19, 3855–3858. [CrossRef] 314. Han, Z.; Wang, R.; Gu, G.; Dong, X.-Q.; Zhang, X. Asymmetric hydrogenation of maleic anhydrides catalyzed by Rh/bisphosphine-thiourea: Efficient construction of chiral succinic anhydrides. Chem. Commun. 2017, 53, 4226–4229. [CrossRef][PubMed] 315. Huang, Y.; Li, P.; Dong, X.-Q.; Zhang, X. Synthesis of chiral seven-membered β-substituted lactams via Rh-catalyzed asymmetric hydrogenation. Org. Biomol. Chem. 2018, 16, 8819–8823. [CrossRef][PubMed] 316. Liu, G.; Han, Z.; Dong, X.-Q.; Zhang, X. Rh-catalyzed asymmetric hydrogenation of β-substituted-β-thio-α,β-unsaturated esters: Expeditious access to chiral organic sulfides. Org. Lett. 2018, 20, 5636–5639. [CrossRef][PubMed] 317. Liu, Y.; Huang, Y.; Yi, Z.; Liu, G.; Dong, X.-Q.; Zhang, X. Enantioselective access to chiral cyclic sulfamidates through iridium-catalyzed asymmetric hydrogenation. Adv. Synth. Catal. 2019, 361, 1582–1586. [CrossRef] 318. Han, Z.; Liu, G.; Wang, R.; Dong, X.-Q.; Zhang, X. Highly efficient Ir-catalyzed asymmetric hydrogenation of benzoxazinones and derivatives with a Brønsted acid cocatalyst. Chem. Sci. 2019, 10, 4328–4333. [CrossRef] [PubMed] 319. Dong, X.-Q.; Zhao, Q.; Li, P.; Chen, C.; Zhang, X. Metalorganocatalysis: Cooperating transition metal catalysis and organocatalysis through a covalent bond. Org. Chem. Front. 2015, 2, 1425–1431. [CrossRef] 320. Chen, M.-H.; Chen, Z.; Song, B.-A.; Bhadury, P.S.; Yang, S.; Cai, X.-J.; Hu, D.-Y.; Xue, W.; Zeng, S. Synthesis and antiviral activities of chiral thiourea derivatives containing an α-aminophosphonate moiety. J. Agric. Food Chem. 2009, 57, 1383–1388. [CrossRef] 321. Shi, M.; Liu, X.-G. Asymmetric Morita-Baylis-Hillman reaction of arylaldehydes with 2-cyclohexen-1-one catalyzed by chiral bis(thio)urea and DABCO. Org. Lett. 2008, 10, 1043–1046. [CrossRef] 322. Tan, B.; Candeias, N.R.; Barbas, C.F. Construction of bispirooxindoles containing three quaternary stereocentres in a cascade using a single multifunctional organocatalyst. Nat. Chem. 2011, 3, 473–477. [CrossRef] 323. Rampalakos, C.; Wulff, W.D.D. A novel bis-thiourea organocatalyst for the asymmetric aza-Henry reaction. Adv. Synth. Catal. 2008, 350, 1785–1790. [CrossRef] 324. Kang, Y.K.; Yoon, S.J.; Kim, D.Y. Asymmetric Mannich-type reactions of fluorinated ketoesters with binaphthyl-modified thiourea catalysts. Bull. Korean Chem. Soc. 2011, 32, 1195–1200. [CrossRef] 325. Nakayama, Y.; Hidaka, Y.; Ito, K. Asymmetric Henry reactions of aldehydes using chiral biaryl-based bis(thiourea) organocatalysts. Synlett 2013, 24, 883–885. [CrossRef] Molecules 2020, 25, 401 53 of 56

326. Otevrel, J.; Bobal, P. Biphenyl-based bis(thiourea) organocatalyst for asymmetric and syn-selective Henry reaction. Synthesis 2017, 49, 593–603. [CrossRef] 327. Otevrel, J.; Bobal, P. Diamine-tethered bis(thiourea) organocatalyst for asymmetric Henry reaction. J. Org. Chem. 2017, 82, 8342–8358. [CrossRef] 328. Otevrel, J.; Svestka, D.; Bobal, P. Bianthryl-based organocatalysts for the asymmetric Henry reaction of fluoroketones. Org. Biomol. Chem. 2019, 17, 5244–5248. [CrossRef] 329. Roussel, C.; Roman, M.; Andreoli, F.; del Rio, A.; Faure, R.; Vanthuyne, N. Non-racemic atropisomeric (thio)ureas as neutral enantioselective anion receptors for amino-acid derivatives: Origin of smaller Kass with thiourea than urea derivatives. Chirality 2006, 18, 762–771. [CrossRef] 330. Vlatković,M.; Bernardi, L.; Otten, E.; Feringa, B.L. Dual stereocontrol over the Henry reaction using a light- and heat-triggered organocatalyst. Chem. Commun. 2014, 50, 7773–7775. [CrossRef] 331. Pizzolato, S.F.; Collins, B.S.L.; van Leeuwen, T.; Feringa, B.L. Bifunctional molecular photoswitches based on overcrowded alkenes for dynamic control of catalytic activity in Michael addition reactions. Chem. Eur. J. 2017, 23, 6174–6184. [CrossRef] 332. Song, C.; Li, L.; Wang, F.; Deng, J.; Yang, W. Novel optically active helical poly(N-propargylthiourea)s: Synthesis, characterization and complexing ability toward Fe(III) ions. Polym. Chem. 2011, 2, 2825–2829. [CrossRef] 333. Zhang, H.; Yang, W.; Deng, J. Optically active helical polymers with pendent thiourea groups: Chiral organocatalyst for asymmetric Michael addition reaction. J. Polym. Sci. Part A Polym. Chem. 2015, 53, 1816–1823. [CrossRef] 334. Mayr, F.; Mohr, L.-M.; Rodriguez, E.; Bach, T. Synthesis of chiral thiourea-thioxanthone hybrids. Synthesis 2017, 49, 5238–5250. [CrossRef] 335. Jiang, X.; Zhang, Y.; Chan, A.S.C.; Wang, R. Highly enantioselective synthesis of γ-nitro heteroaromatic ketones in a doubly stereocontrolled manner catalyzed by bifunctional thiourea catalysts based on dehydroabietic amine: A doubly stereocontrolled approach to pyrrolidine carboxylic acids. Org. Lett. 2009, 11, 153–156. [CrossRef][PubMed] 336. Jiang, X.; Zhang, Y.; Liu, X.; Zhang, G.; Lai, L.; Wu, L.; Zhang, J.; Wang, R. Enantio- and diastereoselective asymmetric addition of 1,3-dicarbonyl compounds to nitroalkenes in a doubly stereocontrolled manner catalyzed by bifunctional rosin-derived amine thiourea catalysts. J. Org. Chem. 2009, 74, 5562–5567. [CrossRef][PubMed] 337. Jiang, X.; Zhang, Y.; Wu, L.; Zhang, G.; Liu, X.; Zhang, H.; Fu, D.; Wang, R. Doubly stereocontrolled asymmetric aza-Henry reaction with in situ generation of N-Boc-imines catalyzed by novel rosin-derived amine thiourea catalysts. Adv. Synth. Catal. 2009, 351, 2096–2100. [CrossRef] 338. Jiang, X.; Fu, D.; Zhang, G.; Cao, Y.; Liu, L.; Song, J.; Wang, R. Highly diastereo- and enantioselective Mannich reaction of lactones with N-Boc-aldimines catalyzed by bifunctional rosin-derived amine thiourea catalysts. Chem. Commun. 2010, 46, 4294–4296. [CrossRef] 339. Jiang, X.; Zhang, G.; Fu, D.; Cao, Y.; Shen, F.; Wang, R. Direct organocatalytic asymmetric aldol reaction of α-isothiocyanato imides to α-ketoesters under low ligand loading: A doubly stereocontrolled approach to cyclic thiocarbamates bearing chiral quaternary stereocenters. Org. Lett. 2010, 12, 1544–1547. [CrossRef] 340. Liu, L.; Zhong, Y.; Zhang, P.; Jiang, X.; Wang, R. Core scaffold-inspired stereoselective synthesis of spiropyrazolones via an organocatalytic Michael/cyclization sequence. J. Org. Chem. 2012, 77, 10228–10234. [CrossRef] 341. Shi, X.M.; Dong, W.P.; Zhu, L.P.; Jiang, X.X.; Wang, R. Asymmetric vinylogous Michael addition/cyclization cascade reaction for the construction of diversely structured spiro-oxindole skeletons. Adv. Synth. Catal. 2013, 355, 3119–3123. [CrossRef] 342. Zhang, G.; Zhang, Y.; Jiang, X.; Yan, W.; Wang, R. Highly enantioslective synthesis of multisubstituted polyfunctional dihydropyrrole via an organocatalytic tandem Michael/cyclization sequence. Org. Lett. 2011, 13, 3806–3809. [CrossRef] 343. Zhang, G.; Zhang, Y.; Yan, J.; Chen, R.; Wang, S.; Ma, Y.; Wang, R. One-pot enantioselective synthesis of functionalized pyranocoumarins and 2-amino-4H-chromenes: Discovery of a type of potent antibacterial agent. J. Org. Chem. 2012, 77, 878–888. [CrossRef] 344. Jiang, X.; Wang,L.; Kai, M.; Zhu, L.; Yao,X.; Wang,R. Asymmetric inverse-electron-demand hetero-Diels-Alder reaction for the construction of bicyclic skeletons with multiple stereocenters by using a bifunctional Molecules 2020, 25, 401 54 of 56

organocatalytic strategy: An efficient approach to chiral macrolides. Chem. Eur. J. 2012, 18, 11465–11473. [CrossRef][PubMed] 345. Reddy, B.V.S.; Swain, M.; Reddy, S.M.; Yadav, J.S.; Sridhar, B. Asymmetric Michael/hemiketalization of 5-hydroxy-2-methyl-4H-pyran-4-one to β,γ-unsaturated α-ketoesters catalyzed by a bifunctional rosin-indane amine thiourea catalyst. RSC Adv. 2014, 4, 42299–42307. [CrossRef] 346. Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. Guanidine-thiourea bifunctional organocatalyst for the asymmetric Henry (nitroaldol) reaction. Adv. Synth. Catal. 2005, 347, 1643–1648. [CrossRef] 347. Herrera, R.P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Catalytic enantioselective Friedel-Crafts alkylation of indoles with nitroalkenes by using a simple thiourea organocatalyst. Angew. Chem. Int. Ed. 2005, 44, 6576–6579. [CrossRef][PubMed] 348. Nowak, A.E.; Wojaczyńska,E.; Skarewski, J. Enantiopure trans-1-amino-2-(arylsulfanyl)cyclohexanes: Novel chiral motifs for ligands and organocatalysts. Tetrahedron: Asymmetry 2011, 22, 1687–1691. [CrossRef] 349. Krasnovskaya, O.O.; Malinnikov, V.M.; Dashkova, N.S.; Gerasimov, V.M.; Grishina, I.V.; Kireev, I.I.; Lavrushkina, S.V.; Panchenko, P.A.; Zakharko, M.A.; Ignatov, P.A. Thiourea modified doxorubicin: A perspective pH-sensitive prodrug. Bioconjug. Chem. 2019, 30, 741–750. [CrossRef][PubMed] 350. Ma, Z.-W.; Liu, Y.-X.; Zhang, W.; Tao, Y.; Zhu, Y.; Tao, J.-C.; Tang, M.-S. Highly enantioselective Michael additions of isobutyraldehyde to nitroalkenes promoted by amphiphilic bifunctional primary amine-thioureas in organic or aqueous medium. Eur. J. Org. Chem. 2011, 6747–6754. [CrossRef] 351. Ma, Z.-W.; Liu, Y.-X.; Huo, L.-J.; Gao, X.; Tao, J.-C. Doubly stereocontrolled asymmetric Michael addition of acetylacetone to nitroolefins promoted by an isosteviol-derived bifunctional thiourea. Tetrahedron: Asymmetry 2012, 23, 443–448. [CrossRef] 352. Song, Z.-T.; Zhang, T.; Du, H.-L.; Ma, Z.-W.; Zhang, C.-H.; Tao, J.-C. Highly enantioselective Michael addition promoted by a new diterpene-derived bifunctional thiourea catalyst: A doubly stereocontrolled approach to chiral succinimide derivatives. Chirality 2014, 26, 121–127. [CrossRef] 353. Grošelj, U.; Golobiˇc,A.; Stare, K.; Svete, J.; Stanovnik, B. Synthesis and structural elucidation of novel camphor-derived thioureas. Chirality 2012, 24, 307–317. [CrossRef] 354. Khan, S.A.; Singh, N.; Saleem, K. Synthesis, characterization and in vitro antibacterial activity of thiourea and urea derivatives of steroids. Eur. J. Med. Chem. 2008, 43, 2272–2277. [CrossRef][PubMed] 355. Ramadas, K.; Suresh, G.; Janarthanan, N.; Masilamani, S. Antifungal activity of 1,3-disubstituted symmetrical and unsymmetrical thioureas. Pestic. Sci. 1998, 52, 145–151. [CrossRef] 356. Cunha, S.; Macedo, F.C.; Costa, G.A.N.; Rodrigues, M.T.; Verde, R.B.V.; de Souza Neta, L.C.; Vencato, I.; Lariucci, C.; Sá, F.P. Antimicrobial activity and structural study of disubstituted thiourea derivatives. Monatsh. Chem. 2007, 138, 511–516. [CrossRef] 357. Omar, A.-M.M.E.; Farghaly, A.M.; Hazzai, A.A.B.; Eshba, N.H.; Sharabi, F.M.; Daabees, T.T. Thiourea and thiosemicarbazide derivatives structurally related to hexestrol: Synthesis and anticancer and other pharmacological properties. J. Pharm. Sci. 1981, 70, 1075–1079. [CrossRef][PubMed] 358. Kafarski, P.; Lejczak, B. Biological activity of aminophosphonic acids. Phosphorus. Sulfur. Silicon Relat. Elem. 1991, 63, 193–215. [CrossRef] 359. Yang, X.; Song, B.; Jin, L.; Wei, X.; Bhadury, S.P.; Li, X.; Yang, S.; Hu, D. Synthesis and antiviral bioactivities of novel chiral bis-thiourea-type derivatives containing α-aminophosphonate moiety. Sci. China Chem. 2011, 54, 103–109. [CrossRef] 360. Liu, J.; Yang, S.; Li, X.; Fan, H.; Bhadury, P.; Xu, W.; Wu, J.; Wang, Z. Synthesis and antiviral bioactivity of chiral thioureas containing leucine and phosphonate moieties. Molecules 2010, 15, 5112–5123. [CrossRef] 361. Yan, Z.; Cai, X.; Yang, X.; Song, B.; Chen, Z.; Bhadury, S.P.; Hu, D.; Jin, L.; Xue, W.; Lu, P. Synthesis and antiviral activities of chiral thiourea derivatives. Chin. J. Chem. 2009, 27, 593–601. [CrossRef] 362. Lewi, P.; Heeres, J.; Ariën, K.; Venkatraj, M.; Joossens, J.; Van der Veken, P.; Augustyns, K.; Vanham, G. Reverse transcriptase inhibitors as microbicides. Curr. HIV Res. 2012, 10, 27–35. [CrossRef] 363. Jones, T.R.; Lee, S.-W.; Johann, S.V.; Razinkov, V.; Visalli, R.J.; Feld, B.; Bloom, J.D.; O’Connell, J. Specific inhibition of human cytomegalovirus glycoprotein B-mediated fusion by a novel thiourea small molecule. J. Virol. 2004, 78, 1289–1300. [CrossRef] 364. Struga, M.; Kossakowski, J.; Koziol, A.E.; Kedzierska, E.; Fidecka, S.; La Colla, P.; Ibba, C.; Collu, G.; Sanna, G.; Secci, B.; et al. Synthesis, pharmacological and antiviral activity of 1,3-thiazepine derivatives. Eur. J. Med. Chem. 2009, 44, 4960–4969. [CrossRef][PubMed] Molecules 2020, 25, 401 55 of 56

365. De Clercq, E. Perspectives of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. Farmaco 1999, 54, 26–45. [CrossRef] 366. Robl, J.A.; Sun, C.-Q.; Stevenson, J.; Ryono, D.E.; Simpkins, L.M.; Cimarusti, M.P.; Dejneka, T.; Slusarchyk, W.A.; Chao, S.; Stratton, L.; et al. Dual metalloprotease inhibitors: Mercaptoacetyl-based fused heterocyclic dipeptide mimetics as inhibitors of angiotensin-converting enzyme and neutral endopeptidase. J. Med. Chem. 1997, 40, 1570–1577. [CrossRef][PubMed] 367. Saha, D.; Jain, G.; Sharma, A. Benzothiazepines: Chemistry of a privileged scaffold. RSC Adv. 2015, 5, 70619–70639. [CrossRef] 368. Venkatachalam, T.K.; Sudbeck, E.A.; Mao, C.; Uckun, F.M. Stereochemistry of halopyridyl and thiazolyl thiourea compounds is a major determinant of their potency as nonnucleoside inhibitors of HIV-1 reverse transcriptase. Bioorg. Med. Chem. Lett. 2000, 10, 2071–2074. [CrossRef] 369. Venkatachalam, T.K.; Mao, C.; Uckun, F.M. Stereochemistry as a major determinant of the anti-HIV activity of chiral naphthyl thiourea compounds. Antivir. Chem. Chemother. 2001, 12, 213–221. [CrossRef][PubMed] 370. Bell, F.W.; Cantrell, A.S.; Hoegberg, M.; Jaskunas, S.R.; Johansson, N.G.; Jordan, C.L.; Kinnick, M.D.; Lind, P.; Morin, J.M. Phenethylthiazolethiourea (PETT) compounds, a new class of HIV-1 reverse transcriptase inhibitors. 1. Synthesis and basic structure-activity relationship studies of PETT analogs. J. Med. Chem. 1995, 38, 4929–4936. [CrossRef][PubMed] 371. Cantrell, A.S.; Engelhardt, P.; Högberg, M.; Jaskunas, S.R.; Johansson, N.G.; Jordan, C.L.; Kangasmetsä, J.; Kinnick, M.D.; Lind, P.; Morin, J.M.; et al. Phenethylthiazolylthiourea (PETT) compounds as a new class of HIV-1 reverse transcriptase inhibitors. 2. Synthesis and further structure activity relationship studies of − PETT analogs. J. Med. Chem. 1996, 39, 4261–4274. [CrossRef][PubMed] 372. Venkatachalam, T.K.; Mao, C.; Uckun, F.M. Effect of stereochemistry on the anti-HIV activity of chiral thiourea compounds. Bioorg. Med. Chem. 2004, 12, 4275–4284. [CrossRef][PubMed] 373. Pingaew, R.; Sinthupoom, N.; Mandi, P.; Prachayasittikul, V.V.; Cherdtrakulkiat, R.; Prachayasittikul, S.; Ruchirawat, S.; Prachayasittikul, V.V. Synthesis, biological evaluation and in silico study of bis-thiourea derivatives as anticancer, antimalarial and antimicrobial agents. Med. Chem. Res. 2017, 26, 3136–3148. [CrossRef] 374. Rohde, J.M.; Brimacombe, K.R.; Liu, L.; Pacold, M.E.; Yasgar, A.; Cheff, D.M.; Lee, T.D.; Rai, G.; Baljinnyam, B.; Li, Z.; et al. Discovery and optimization of piperazine-1-thiourea-based human phosphoglycerate dehydrogenase inhibitors. Bioorg. Med. Chem. 2018, 26, 1727–1739. [CrossRef][PubMed] 375. Manjula, S.N.; Noolvi, N.M.; Vipan Parihar, K.; Reddy, S.A.M.; Ramani, V.; Gadad, A.K.; Singh, G.; Kutty, N.G.; Rao, C.M. Synthesis and antitumor activity of optically active thiourea and their 2-aminobenzothiazole derivatives: A novel class of anticancer agents. Eur. J. Med. Chem. 2009, 44, 2923–2929. [CrossRef][PubMed] 376. Dinakaran, V.S.; Jacob, D.; Mathew, J.E.; Seekarajapuram, V.; Divya, D.; Jessy, J.; Mathew, E. Synthesis and biological evaluation of novel pyrimidine-2(1H)-ones/thiones as potent anti-inflammatory and anticancer agents. Med. Chem. Res. 2012, 21, 3598–3606. [CrossRef] 377. Liu, J.-Z.; Song, B.-A.; Fan, H.-T.; Bhadury, P.S.; Wan, W.-T.; Yang, S.; Xu, W.; Wu, J.; Jin, L.-H.; Wei, X.; et al. Synthesis and in vitro study of pseudo-peptide thioureas containing α-aminophosphonate moiety as potential antitumor agents. Eur. J. Med. Chem. 2010, 45, 5108–5112. [CrossRef] 378. Liu, J.; Liao, P.; Hu, J.; Zhu, H.; Wang, Y.; Li, Y.; Li, Y.; He, B. Synthesis and Antitumor Activities of Chiral Dipeptide Thioureas Containing an Alpha-Aminophosphonate Moiety. Molecules 2017, 22, 238–248. [CrossRef] 379. Huang, X.-C.; Wang, M.; Pan, Y.-M.; Yao, G.-Y.; Wang, H.-S.; Tian, X.-Y.; Qin, J.-K.; Zhang, Y. Synthesis and antitumor activities of novel thiourea α-aminophosphonates from dehydroabietic acid. Eur. J. Med. Chem. 2013, 69, 508–520. [CrossRef] 380. Rao, X.; Song, Z.; He, L.; Jia, W. Synthesis, structure analysis and cytotoxicity studies of novel unsymmetrically

N,N0-substituted ureas from dehydroabietic acid. Chem. Pharm. Bull. 2008, 56, 1575–1578. [CrossRef] 381. Venkatachalam, T.K.; Vassilev, A.O.; Benyunov, A.; Grigoriants, O.O.; Tibbles, H.E.; Uckun, F.M. Stereochemistry as a determinant of the anti-leukemic potency of halopyridyl and thiazolyl thiourea compounds. Lett. Drug Des. Discov. 2007, 4, 318–326. [CrossRef] 382. Venkatachalam, T.K.; Qazi, S.; Samuel, P.; Uckun, F.M. Substituted heterocyclic thiourea compounds as a new class of anti-allergic agents inhibiting IgE/FcεRI receptor mediated mast cell leukotriene release. Bioorg. Med. Chem. 2003, 11, 1095–1105. [CrossRef] Molecules 2020, 25, 401 56 of 56

383. Wasserman, S.I. Mast cell biology. J. Allergy Clin. Immunol. 1990, 86, 590–593. [CrossRef] 384. Bildirici, I.; Cetin, A.; Menges, N.; Alan, Y. Synthesis and SAR studies of pyrazole-3-carboxamides and -3-carbonyl thioureides including chiral moiety: Novel candidates as antibacterial agents. J. Serb. Chem. Soc. 2018, 83, 795–807. [CrossRef] 385. O’Dwyer, P.J.; King, S.A.; Plowman, J.; Grieshaber, C.K.; Hoth, D.F.; Leyland-Jones, B. Pyrazole: Preclinical reassessment. Invest. New Drugs 1988, 6, 305–310. [CrossRef][PubMed] 386. Saeed, S.; Rashid, N.; Jones, P.G.; Ali, M.; Hussain, R. Synthesis, characterization and biological evaluation of some thiourea derivatives bearing benzothiazole moiety as potential antimicrobial and anticancer agents. Eur. J. Med. Chem. 2010, 45, 1323–1331. [CrossRef][PubMed] 387. Singh, L.P.; Tiwari, O.P. Brijog Synthesis and antimicrobial activity of some methyl 4-(1H-benzo[d] imidazol-2-yl) phenyl carbamodithioate amine derivatives. Int. J. Pharm. Sci. Res. 2018, 9, 1194–1200. [CrossRef] 388. Madabhushi, S.; Mallu, K.K.R.; Vangipuram, V.S.; Kurva, S.; Poornachandra, Y.; Kumar, C.G. Synthesis of novel benzimidazole functionalized chiral thioureas and evaluation of their antibacterial and anticancer activities. Bioorg. Med. Chem. Lett. 2014, 24, 4822–4825. [CrossRef][PubMed]

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).