Recent Developments in Transition-Metal Catalyzed Direct C–H Alkenylation, Alkylation, and Alkynylation of Azoles

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Review Recent Developments in Transition-Metal Catalyzed Direct C–H Alkenylation, Alkylation, and Alkynylation of Azoles

Su Chen 1, Prabhat Ranjan 1, Leonid G. Voskressensky 2, Erik V. Van der Eycken 1,2,* and Upendra K. Sharma 1,*

1 Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), Department of Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001 Leuven, Belgium; [email protected] (S.C.); [email protected] (P.R.) 2 Organic Chemistry Department, Science Faculty, Peoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya street 6, RU-117198 Moscow, Russia; [email protected] * Correspondence: [email protected] (E.V.V.d.E.); [email protected] (U.K.S.)

Academic Editor: Patricia Garcia-Garcia Received: 14 October 2020; Accepted: 24 October 2020; Published: 27 October 2020

Abstract: The transition metal-catalyzed C–H bond functionalization of azoles has emerged as one of the most important strategies to decorate these biologically important scaffolds. Despite significant progress in the C–H functionalization of various heteroarenes, the regioselective alkylation and alkenylation of azoles are still arduous transformations in many cases. This review covers recent advances in the direct C–H alkenylation, alkylation and alkynylation of azoles utilizing transition metal-catalysis. Moreover, the limitations of different strategies, chemoselectivity and regioselectivity issues will be discussed in this review.

Keywords: azoles; C–H functionalization; transition metal-catalysis; C–H activation; alkenylation; alkylation; alkynylation

1. Introduction Azoles are important heterocyclic scaffolds because of their wide application in pharmaceuticals, natural products, and functional materials [1–3]. After the first report of the antifungal activity of azoles in 1944 by Woolley, their functionalization and synthesis started attracting the attention of researchers [4]. The functionalization of azoles has been well elaborated for decades by classical metalation with strong bases such as n-BuLi [5]. However, these classical methods suffer from general limitations, such as low chemo- and/or regioselectivity, low atom economy, sophisticated reaction conditions, and more importantly, poor reactivity in the case of electron-deficient azoles [6]. Moreover, the cost of waste disposal and the need to handle reactive bases make these methods unsuitable for industrial scale-up. As a consequence, over the last decade, continuous demand for these scaffolds in the pharmaceutical industry and academia has resulted in several new approaches, mainly based on C–H functionalization. Direct transition-metal catalyzed C–H functionalization is an effective tool for streamlining azole-based biologically important frameworks [7–11]. However, the presence of heteroatoms in an azole framework renders the overall C–H activation more challenging and substrate-specific, owing to their ligation tendency with transition-metal catalysts. Besides the heteroatom issue, the inherent electrophilic nature of azoles favors either a nucleophilic attack via ring opening, or a direct attack in the presence of metal catalysts. Furthermore, the alkylation of azoles with alkyl halides bearing a β-hydrogen is challenging due to the possibility of β-hydride elimination and/or hydrodehalogenation

Molecules 2020, 25, 4970; doi:10.3390/molecules25214970 www.mdpi.com/journal/molecules Molecules 2020, 25, x FOR PEER REVIEW 2 of 33

Moleculeshydrogen2020 is, 25challenging, 4970 due to the possibility of β-hydride elimination and/or hydrodehalogenation2 of 34 in the presence of transition metal catalysts. Similarly, the alkenylation of azoles with alkenyl halides inis problematic the presence due of transition to the tendency metal catalysts. of homocoupling Similarly, of the alkenyl alkenylation halides, of as azoles well as with the alkenyllow stability halides of ismoisture-sensitive problematic due toiodides the tendency and trifla oftes. homocoupling In this context, of alkenylresearchers halides, have as proposed well as the several low stability strategies of moisture-sensitiveto overcome these iodideschallenges, and such triflates. as: (1) In the this use context, of directing researchers groups have to proposedcontrol regioselectivity, several strategies (2) tothe overcome development these of challenges, moisture-sensitive such as: coupling (1) the usepart ofners directing such as groupsphosphates to control and carboxylic regioselectivity, acids, (2)andthe (3) development modulation ofof the moisture-sensitive innate reactivity coupling of azoles partners via electronic such as and phosphates steric modifications. and carboxylic acids, and (3)Nevertheless, modulation this of the field innate needs reactivity close ofinspection azoles via for electronic the development and steric modifications.of stable and reactive electrophilicNevertheless, partners this with field improved needs close catalytic inspection systems. for the Recently, development Evano ofand stable Theunissen and reactive [12] electrophilichighlighted partnersthe importance with improved and challenges catalytic systems.associated Recently, with the Evano alkylation and Theunissen of various [12 heteroarenes.] highlighted theAckermann importance and and coworkers challenges reviewed associated the with alkenylation the alkylation and of alkylation various heteroarenes. of azoles, especially Ackermann via and 3d coworkerstransition metals reviewed [13]. the Many alkenylation reviews and have alkylation been published of azoles, especiallyon C–H viafunctionalization/activation 3d transition metals [13]. Manystrategies reviews [14–16]; have to been the best published of our knowledge, on C–H functionalization none of them /isactivation truly focused strategies on the [14 direct–16]; C–H to the bond best offunctionalization our knowledge, of none azoles. of them The iscontinuously truly focused increasing on the direct demand C–H bondfor new functionalization azole-based antifungal of azoles. Theagents continuously still requires increasing precise demandcontrol of for regioselectivi new azole-basedty and antifungal cost-efficient agents cata stilllytic requires systems. precise Therefore, control ofthroughout regioselectivity this review, and cost-e weffi highlightcient catalytic the role systems. of transition Therefore, metals throughout in the this direct review, C–H we alkylation, highlight thealkenylation, role of transition and alkynylation metals in thechemistry direct C–H of azoles. alkylation, We substantiate alkenylation, theand importance alkynylation of these chemistry processes of azoles.and outline We substantiate common mechanistic the importance patterns, of these focusing processes primarily and outlineon the formation common mechanisticof new C–C patterns,bonds. focusing primarily on the formation of new C–C bonds. 2. Alkenylation 2. AlkenylationThe alkenylation of azoles has attracted much attention due to their widespread use in polymers and materialsThe alkenylation chemistry of [17]. azoles There has attractedare four main much synthetic attention approaches due to their for widespread transition-metal-mediated use in polymers andalkenylation materials of chemistry azoles: (1) [17 ].C–H/C–X There are alkenylation four main synthetic (X = halogen approaches or triflate) for transition-metal-mediated of azoles with alkenyl alkenylationhalides catalyzed of azoles: by palladium (1) C–H/ C–Xor other alkenylation transition (X metals;= halogen (2) C–H/C–H or triflate) alkenylation of azoles with (oxidative alkenyl halidesMizoroki–Heck catalyzed reaction by palladium [18]) of azoles or other with transition simple alkenes metals; (2)catalyzed C–H/C–H by palladium alkenylation and (oxidative rhodium Mizoroki–Heckcatalysts; (3) C–H reaction addition [18 of]) azoles of azoles to alkynes with simple catalyzed alkenes by catalyzedtransition bymetal palladium catalysts and (i.e., rhodium Rh, Pd, catalysts;and Ni); (3)and C–H (4) additiondecarbonylative of azoles C–H to alkynes alkenylation. catalyzed For by clarity, transition we metalwill discuss catalysts all (i.e., the Rh,recent Pd, andpioneering Ni); and developments (4) decarbonylative in C–Heach alkenylation.category with For clarity,some weimportant will discuss mechanisms, all the recent as pioneering well as developmentsshortcomings. in each category with some important mechanisms, as well as shortcomings.

2.1. C–H/C–X C–H/C–X Cross-Coupling Straightforward C–H/C–X C–H/C–X cross-coupling cross-coupling is is a aclas classicalsical and and one one of ofthe the most most studied studied methods methods for forthe thealkenylation alkenylation of azoles, of azoles, due due to the to thewide wide availabi availabilitylity of diverse of diverse coupling coupling partners partners (i.e., (i.e.,halides halides and andtriflates). triﬂates). Moreover, Moreover, the preparation the preparation of an of organometallic an organometallic coupling coupling partner partner can be can avoided be avoided with with this thisapproach. approach. In 2008, In 2008,Doucet Doucet and coworkers and coworkers reported reported an early an example early example of the ofalkenylation the alkenylation of azoles of azoleswith C–H/C–X with C–H cross-coupling/C–X cross-coupling (Schem (Schemee 1) [19].1 )[The19 authors]. The authorsemployed employed α- or ß-substitutedα- or ß-substituted alkenyl alkenylbromides bromides for palladium-catalyzed for palladium-catalyzed coupling coupling of electron-rich of electron-rich benzoxazoles, benzoxazoles, benzothiazoles, benzothiazoles, or 2-n- orpropylthiazoles 2-n-propylthiazoles to afford to the aﬀord desired the desired products products via C–H via bond C–H activation. bond activation. They performed They performed the reaction the reactionat high temperature at high temperature (80 °C (80to 140◦C to°C) 140 and◦C) under and under an inert an inertatmosphere atmosphere (Ar) (Ar)in the in thepresence presence of ofPdCl(C PdCl(C3H53)(dppb)H5)(dppb) as asthe the catalyst. catalyst. They They overcame overcame the the decomposition decomposition of of heterocycles otherwiseotherwise observed atat high high temperatures temperatures by usingby using an excess an excess quantity quantity thereof. thereof. Interestingly, Interestingly, this process this produced process minimalproduced waste; minimal i.e., waste; HX associated i.e., HX withassociated a base, with instead a base, of a instead metallic of salt, a metallic rendering salt, it intriguingrendering init termsintriguing of both in terms atom economyof both atom and economy nontoxic and waste. nontoxic waste.

Scheme 1. Direct Pd-catalyzed alkenylation of azoles with bromoalkenes.

MoleculesMolecules 20202020,, 2525,, 4970x FOR PEER REVIEW 33 ofof 3433 MoleculesMolecules 20202020,, 2525,, xx FORFOR PEERPEER REVIEWREVIEW 33 ofof 3333 Alami and coworkers employed a bimetallic Pd/Cu catalytic system for the direct alkenylation AlamiAlami and and coworkers coworkers employed employed a a bimetallic bimetallic Pd/Cu PdPd/Cu/Cu catalytic catalytic system system for for the the direct direct alkenylationalkenylation of azoles with alkenyl halides to afford the corresponding 2-vinyl-substituted azoles in moderate to ofof azoles azoles with with alkenyl alkenyl halides halides to to afford aaffordﬀord thethe correspondingcorrespcorrespondingonding 2-vinyl-substituted2-vinyl-substituted azoles azoles in in moderate moderate to to good yields [20]. The reaction was not successful in the absence of CuI. Many heterocycles including goodgood yields yields [20]. [[20].20]. TheThe reactionreaction wa waswass not not successful successful in in the the absence absence of of CuI. CuI. Many Many heterocycles heterocycles including including benzimidazole, benzoxazole, benzothiazole, and thiazole derivatives afforded the desired benzimidazole,benzimidazole, benzoxazole,benzoxazole,benzoxazole, benzothiazole, benzothiazole,benzothiazole, and thiazoleanandd thiazolethiazole derivatives derivativesderivatives aﬀorded afforded theafforded desired thethe alkenylated desireddesired alkenylated products with mono-, di-, or trisubstituted alkenyl bromides in good yields (Scheme 2). alkenylatedproductsalkenylated with productsproducts mono-, withwith di-, or mono-,mono-, trisubstituted di-,di-, oror trisubstitutedtrisubstituted alkenyl bromides alkenylalkenyl in bromides goodbromides yields inin (Scheme goodgood yieldsyields2). (Scheme(Scheme 2).2).

Scheme 2. Pd/Cu-catalyzed direct alkenylation of azole heterocycles with alkenyl bromides. SchemeScheme 2. 2. Pd/Cu-catalyzedPd/Cu-catalyzedPd/Cu-catalyzed direct direct alkenylation alkenylation of of azole azole heterocycles heterocycles with with alkenyl alkenyl bromides.bromides. In 2010, Ackermann and coworkers reported Pd-catalyzed alkenylation of benzoxazoles by InIn 2010,2010,2010, Ackermann AckermannAckermann and andand coworkers coworkerscoworkers reported reportedreported Pd-catalyzed Pd-cPd-catalyzedatalyzed alkenylation alkenylationalkenylation of benzoxazoles ofof benzoxazolesbenzoxazoles by using byby using moisture-stable alkenyl phosphates as coupling partners. However, the scope of the reaction usingmoisture-stableusing moisture-stablemoisture-stable alkenyl alkenylalkenyl phosphates phosphatesphosphates as coupling asas couplicoupli partners.ngng partners.partners. However, However,However, the scope thethe scopescope of the ofof reaction thethe reactionreaction was was limited to only five examples (Scheme 3) [21]. waslimitedwas limitedlimited to only toto onlyonly ﬁve examplesfivefive examplesexamples (Scheme (Scheme(Scheme3)[21 3)].3) [21].[21].

SchemeScheme 3.3. Direct alkenylation ofof azolesazoles withwith phosphates.phosphates. SchemeScheme 3.3. DirectDirect alkenylationalkenylation ofof azolesazoles withwith phosphates.phosphates.

The microwave-assisted synthesis utilizing H 2O as solvent is a cost-eﬃcient and green approach The microwave-assisted synthesis utilizing H22O as solvent is a cost-efficient and green approach TheThe microwave-assistedmicrowave-assisted synthesissynthesis utilizingutilizing HH2OO asas solventsolvent isis aa cost-efficientcost-efficient andand greengreen approachapproach inin organicorganic synthesis.synthesis. In 2012,2012, WillisWillis andand coworkerscoworkers employedemployed suchsuch anan approachapproach forfor thethe couplingcoupling ofof inin organicorganic synthesis.synthesis. InIn 2012,2012, WillisWillis andand coworkerscoworkers employedemployed suchsuch anan approachapproach forfor thethe couplingcoupling ofof various alkenyl iodides with benzoxazoles using [Pd(dppf)Cl .CH2 2Cl 2], PPh 3, and Ag 2CO 3 as the various alkenyl iodides with benzoxazoles using [Pd(dppf)Cl2 2.CH22Cl22], PPh33, and Ag22CO33 as the variousvarious alkenylalkenyl iodidesiodides withwith bebenzoxazolesnzoxazoles usingusing [Pd(dppf)Cl[Pd(dppf)Cl2.CH.CH2ClCl2],], PPhPPh3,, andand AgAg2COCO3 asas thethe catalyticcatalytic systemsystem [[22]22] (Scheme(Scheme4 4).). TheyThey coupledcoupled aa widewide rangerange ofof alkenylalkenyl iodidesiodides toto aaffordﬀord thethe desireddesired catalyticcatalytic systemsystem [22][22] (Scheme(Scheme 4).4). TheyThey coupledcoupled aa wiwidede rangerange ofof alkenylalkenyl iodidesiodides toto affordafford thethe desireddesired productsproducts withwith goodgood regioselectivity.regioselectivity. productsproducts withwith goodgood regioselectivity.regioselectivity.

SchemeScheme 4.4. Pd-catalyzed direct functionalization ofof benzoxazolesbenzoxazoles withwith alkenylalkenyl iodides.iodides. SchemeScheme 4.4. Pd-catalyzedPd-catalyzed directdirect functionalizationfunctionalization ofof benzoxazolesbenzoxazoles withwith alkenylalkenyl iodides.iodides. Owing to the importance of monoﬂuorinated alkenes in several areas, Hoarau and coworkers Owing to the0 importance1 of monofluorinated alkenes in several areas, Hoarau and coworkers developedOwing ato Pdthe0 / Cuimportance1 bimetallic of monofluorinated catalytic system alkenes for stereospeciﬁc in several areas, direct Hoarau C–H alkenylationand coworkers of developed a Pd0/Cu1 bimetallic catalytic system for stereospecific direct C–H alkenylation of various developeddeveloped aa PdPd0/Cu/Cu1 bimetallicbimetallic catalyticcatalytic systemsystem forfor stereospecstereospecificific directdirect C–HC–H alkenylationalkenylation ofof variousvarious 1,3-diazoles utilizing gem-bromofluoroalkenes as electrophiles (Scheme 5). A range of electron- 1,3-diazoles1,3-diazoles utilizingutilizing gemgem-bromofluoroalkenes-bromofluoroalkenes asas electrophileelectrophiless (Scheme(Scheme 5).5). AA rangerange ofof electron-electron-

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Molecules 2020,, 25,, xx FORFOR PEERPEER REVIEWREVIEW 4 of 33 various 1,3-diazoles utilizing gem-bromofluoroalkenes as electrophiles (Scheme5). A range of electron-withdrawingwithdrawing and donating and donating groups on groups gem-bromofluoroalkenes on gem-bromofluoroalkenes successfully successfully afforded a thefforded desired the desiredproducts products in good in yields good without yields without producing producing the undesired the undesired alkynylated alkynylated product. product. The authors The authors used t t usedstrong strong bases bases such such as Cs as2CO Cs23CO andand3 and tBuOLiBuOLi for foralkenylation alkenylation of ofless-acidic less-acidic 1,3-diazoles 1,3-diazoles to to furnish furnish the desireddesired monofluorinatedmonofluorinated productsproducts [[23].23].

Scheme 5. Direct C–H fluoroalkenylation ﬂuoroalkenylation ofof 2-phenyl-1,3,4-oxadiazole.2-phenyl-1,3,4-oxadiazole.

Recently,Recently, nanoparticles have emerged as a robustrobust catalyticcatalytic systemsystem forfor manymany organicorganic transformationstransformations [[24–26],24–26], providingproviding anan alternativealternative toto conventionalconventional homogenoushomogenous catalysis.catalysis. In In 2014, WangWang andand coworkerscoworkers employedemployed CuOCuO (6.5(6.5 nm)nm) nanoparticlesnanoparticles forfor alkenylationalkenylation of benzoxazoles, benzothiazoles,benzothiazoles, and 1-methylbenzimidazoles1-methylbenzimidazoles with alkenyl bromides (Scheme(Scheme6 6)6))[ [27].[27].27]. TheThe authorsauthorsauthors proposedproposed aa mechanismmechanism similarsimilar toto thethe homogeneous catalyticcatalytic system reported byby Miura [[28],28], inin whichwhich PPhPPh33 stabilizedstabilized thethe surfacesurface ofof the the nanoparticles nanoparticles and and acted acted as as a ligand.ligand. Moreover,Moreover, the catalystcatalyst cancan bebe usedused severalseveral timestimes withoutwithout losinglosing itsits catalyticcatalytic activity.activity.

Scheme 6.6. Nano CuO-catalyzed C–H functionalization of azoles with bromoalkenes.bromoalkenes.

In 2013, Yamaguchi and Itami disclosed an efficient nickel-catalyzed C–H/C–O coupling of In 2013, Yamaguchi and Itami disclosed an efficient nickel-catalyzed C–H/C–O coupling of heteroarenes and enol derivatives [29]. A 1,2-bis(dicyclohexylphosphino)ethane (dcype) ligand was heteroarenes and enol derivatives [29]. A 1,2-bis(dicyclohexylphosphino)ethane (dcype) ligand was necessary for this Ni(0) catalytic system (similar ligands displayed an extremely low or no promoting necessary for this Ni(0) catalytic system (similar ligands displayed an extremely low or no promoting effect; Scheme7a). They employed styryl pivalate and carbamate as coupling partners with various effect; Scheme 7a). They employed styryl pivalate and carbamate as coupling partners with various azoles such as oxazoles and benzoxazoles with substituents at the C5 position (methyl, methoxy, azoles such as oxazoles and benzoxazoles with substituents at the C5 position (methyl, methoxy, and and t-butyl) to afford the corresponding styrylated products in moderate to good yields. Moreover, t-butyl) to afford the corresponding styrylated products in moderate to good yields. Moreover, the the authors showed the utility of this new method by synthesizing Siphonazole B in a convergent authors showed the utility of this new method by synthesizing Siphonazole B in a convergent manner manner as compared with previous reports. However, benzothiazoles did not react with styryl pivalates as compared with previous reports. However, benzothiazoles did not react with styryl pivalates and and carbamates under the optimized reaction conditions. Later in 2015, the same group improved carbamates under the optimized reaction conditions. Later in 2015, the same group improved the the efficiency of this reaction by employing a Ni(II)/dcypt catalytic system to deliver the alkenyled efficiency of this reaction by employing a Ni(II)/dcypt catalytic system to deliver the alkenyled imidazoles in high yields (Scheme7b) [30]. imidazoles in high yields (Scheme 7b) [30]. In 2016, Kwong and coworkers disclosed a Pd/PhMezole-Phos-catalyst system for alkenylation of oxazoles by employing readily available and stable alkenyl tosylates as coupling partners [31]. They reduced the catalyst loading to 250 ppm, providing an opportunity to minimize the residual Pd-content in pharmaceutical products. Moreover, they synthesized a new class of Ir(III) complexes by using C2-alkenyloxazoles, useful for applications such as cell imaging. In addition, they carried out a gram-scale synthesis without altering the reaction conditions, affording the desired product in 85% yield (Scheme8). A year later, Chen and coworkers described an efficient method for C2-alkenylation of benzoxazoles by using an economical Cu-atalytic system and allyl halides as coupling partners under ligand-free conditions [32]. Interestingly, slightly modified reaction conditions produced a more conjugated

Scheme 7. Ni-catalyzed alkenylation of azoles with (a) enol derivatives and (b) carbamate.

Molecules 2020, 25, x FOR PEER REVIEW 4 of 33 withdrawing and donating groups on gem-bromofluoroalkenes successfully afforded the desired products in good yields without producing the undesired alkynylated product. The authors used strong bases such as Cs2CO3 and tBuOLi for alkenylation of less-acidic 1,3-diazoles to furnish the desired monofluorinated products [23].

Scheme 5. Direct C–H fluoroalkenylation of 2-phenyl-1,3,4-oxadiazole.

Recently, nanoparticles have emerged as a robust catalytic system for many organic transformations [24–26], providing an alternative to conventional homogenous catalysis. In 2014, Wang and coworkers employed CuO (6.5 nm) nanoparticles for alkenylation of benzoxazoles, benzothiazoles, and 1-methylbenzimidazoles with alkenyl bromides (Scheme 6) [27]. The authors proposed a mechanism similar to the homogeneous catalytic system reported by Miura [28], in which PPh3 stabilized the surface of the nanoparticles and acted as a ligand. Moreover, the catalyst can be used several times without losing its catalytic activity.

Scheme 6. Nano CuO-catalyzed C–H functionalization of azoles with bromoalkenes.

In 2013, Yamaguchi and Itami disclosed an efficient nickel-catalyzed C–H/C–O coupling of heteroarenes and enol derivatives [29]. A 1,2-bis(dicyclohexylphosphino)ethane (dcype) ligand was necessary for this Ni(0) catalytic system (similar ligands displayed an extremely low or no promoting effect; Scheme 7a). They employed styryl pivalate and carbamate as coupling partners with various azolesMolecules such2020 ,as25 ,oxazoles 4970 and benzoxazoles with substituents at the C5 position (methyl, methoxy,5 and of 34 t-butyl) to afford the corresponding styrylated products in moderate to good yields. Moreover, the authors showed the utility of this new method by synthesizing Siphonazole B in a convergent manner as2-(buta-1,3-dienyl)benzo[ compared with previousd]oxazole reports. product However, in 75%benzothiazoles yield from 1,4-dibromobut-2-enedid not react with styryl and pivalates benzoxazole. and carbamatesThe reaction under starts withthe optimized deprotonation reaction of the conditio benzoxazolens. Later followed in 2015, by metalation the same to group form intermediateimproved theB. efficiencyThe in situ intermediateof this reaction then by undergoes employing oxidative a Ni(II) insertion/dcypt withcatalytic the allyl system halide to to deliver generate the intermediate alkenyled imidazolesC, whichMolecules further in 2020 high, 25 undergoes, xyields FOR PEER (Scheme REVIEW reductive 7b) elimination[30]. to aﬀord the desired product (Scheme9). 5 of 33

In 2016, Kwong and coworkers disclosed a Pd/PhMezole-Phos-catalyst system for alkenylation of oxazoles by employing readily available and stable alkenyl tosylates as coupling partners [31]. They reduced the catalyst loading to 250 ppm, providing an opportunity to minimize the residual Pd-content in pharmaceutical products. Moreover, they synthesized a new class of Ir(III) complexes by using C2-alkenyloxazoles, useful for applications such as cell imaging. In addition, they carried Moleculesout 2020 a gram-scale, 25, x FOR synthesisPEER REVIEW without altering the reaction conditions, affording the desired product in5 of 33 85% yield (Scheme 8). In 2016, Kwong and coworkers disclosed a Pd/PhMezole-Phos-catalyst system for alkenylation of oxazoles by employing readily available and stable alkenyl tosylates as coupling partners [31]. They reduced the catalyst loading to 250 ppm, providing an opportunity to minimize the residual Pd-content in pharmaceutical products. Moreover, they synthesized a new class of Ir(III) complexes by using C2-alkenyloxazoles, useful for applications such as cell imaging. In addition, they carried out a gram-scaleScheme 7. synthesis Ni-catalyzedNi-catalyzed without alkenylation alkenylation altering of of the azoles azoles reac with tion ( conditions,aa)) enol enol derivatives derivatives affording and and ( theb) carbamate. desired product in 85% yield (Scheme 8). Scheme 8. Direct C2-alkenylation of oxazoles with alkenyl tosylates.

A year later, Chen and coworkers described an efficient method for C2-alkenylation of benzoxazoles by using an economical Cu-atalytic system and allyl halides as coupling partners under ligand-free conditions [32]. Interestingly, slightly modified reaction conditions produced a more conjugated 2-(buta-1,3-dienyl)benzo[d]oxazole product in 75% yield from 1,4-dibromobut-2-ene and benzoxazole. The reaction starts with deprotonation of the benzoxazole followed by metalation to form intermediate B. The in situ intermediate then undergoes oxidative insertion with the allyl halide to generate intermediateScheme 8.8. C Direct, which C2-alkenylation further undergoes of oxazoles reductive with elimination alkenylalkenyl tosylates.tosylates. to afford the desired product (Scheme 9). A year later, Chen and coworkers described an efficient method for C2-alkenylation of benzoxazoles by using an economical Cu-atalytic system and allyl halides as coupling partners under ligand-free conditions [32]. Interestingly, slightly modified reaction conditions produced a more conjugated 2-(buta-1,3-dienyl)benzo[d]oxazole product in 75% yield from 1,4-dibromobut-2-ene and benzoxazole. The reaction starts with deprotonation of the benzoxazole followed by metalation to form intermediate B. The in situ intermediate then undergoes oxidative insertion with the allyl halide to generate intermediate C, which further undergoes reductive elimination to afford the desired product (Scheme 9).

SchemeScheme 9. CuCl-catalyzed 9. CuCl-catalyzed direct direct C–H C–H alkenylationalkenylation of of benzoxazoles benzoxazoles with with allyl allyl halides. halides.

In 2019, Liang and coworkers followed Doucet’s Pd-catalytic approach for C2-alkenylation of a variety of azole-based heterocycles by using a more efficient Ni–xantphos catalytic system (Scheme

Scheme 9. CuCl-catalyzed direct C–H alkenylation of benzoxazoles with allyl halides.

In 2019, Liang and coworkers followed Doucet’s Pd-catalytic approach for C2-alkenylation of a variety of azole-based heterocycles by using a more efficient Ni–xantphos catalytic system (Scheme

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Molecules 2020, 25, x FOR PEER REVIEW 6 of 33 MoleculesIn 2019,2020, 25 Liang, x FOR PEER and coworkersREVIEW followed Doucet’s Pd-catalytic approach for C2-alkenylation6 of 33 10)Molecules [33]. 2020 These, 25, x FORmodified PEER REVIEW reaction conditions presented a moderate scope for C2-alkenylation.6 of 33 of a variety of azole-based heterocycles by using a more eﬃcient Ni–xantphos catalytic system However,10) [33]. These a higher modified reaction reaction temperature conditions was needed presented for sterically a moderate hindered scope bromoalkenes. for C2-alkenylation. (Scheme10) [33]. 10 These)[33]. modified These modiﬁed reaction reaction conditions conditions presented presented a moderate a moderate scope scope for for C2-alkenylation. C2-alkenylation. However, a higher reaction temperature was needed for sterically hindered bromoalkenes. However,However, aa higherhigher reactionreaction temperaturetemperature waswas neededneeded forfor sterically sterically hindered hindered bromoalkenes. bromoalkenes.

Scheme 10. Ni-catalyzed direct alkenylation of azole derivatives with alkenyl bromides.

Scheme 10. Ni-catalyzed direct alkenylation of azole derivatives with alkenyl bromides. 2.2. C–H/C–HSchemeScheme Cross-Coupling 10.10. Ni-catalyzed direct alkenylation ofof azoleazole derivativesderivatives withwith alkenylalkenyl bromides.bromides. 2.2. C–H/C–H C–H/C–H Cross-Coupling 2.2. C–H/C–HFrom the Cross-Couplingviewpoint of sustainable and atom-economic development, C–H/C–H cross-coupling offersFrom the most the viewpoint straightforward of sustainablesustainable approach andand in atom-economicatom-ealkenylationconomic of development,azoles. Also, substrate C–HC–H/C–H/C–H pre-activation cross-coupling is From the viewpoint of sustainable and atom-economic development, C–H/C–H cross-coupling onotoffersffers required. thethe mostmost straightforwardstraightforward approachapproach inin alkenylationalkenylation ofof azoles.azoles. Also, substrate pre-activation is offers the most straightforward approach in alkenylation of azoles. Also, substrate pre-activation is not required.Transition-metal-catalyzed oxidative olefination (typically from acrylates) of heteroarenes for not required. directTransition-metal-catalyzed C–C bond formation via C–H oxidative bond cleavageolefination olefination is also (typically known from as the acrylates) Fujiwara–Moritani of heteroarenes reaction. for Transition-metal-catalyzed oxidative olefination (typically from acrylates) of heteroarenes for directIn 2010, C–C Miura bond and formation coworkers via reported C–H bond direct cleavage alkenylation is also known of 2-substituted as the Fujiwara–Moritani azoles using Pd(OAc) reaction. reaction.2 as direct C–C bond formation via C–H bond cleavage is also known as the Fujiwara–Moritani reaction. Incatalyst 2010, andMiura Miura AgOAc and and coworkers coworkersas oxidant reported to reported deliver direct directthe corresp alke alkenylationnylationonding of 5-alkenylated of 2-substituted 2-substituted azoles azoles azoles in using moderate using Pd(OAc) Pd(OAc) to good2 as2 In 2010, Miura and coworkers reported direct alkenylation of 2-substituted azoles using Pd(OAc)2 as asyieldscatalyst catalyst (Scheme and and AgOAc AgOAc11) [34]. as oxidant asInternal oxidant to or deliver to aliphatic deliver the correspalkenes the correspondingonding were not 5-alkenylated suitable 5-alkenylated under azoles the azoles in optimized moderate in moderate reaction to good to catalyst and AgOAc as oxidant to deliver the corresponding 5-alkenylated azoles in moderate to good goodconditionsyields yields(Scheme and (Scheme 11)gave [34]. lower11 )[Internal34 yields.]. Internal or aliphaticThey or exemplif aliphatic alkenesied alkeneswere the notutility were suitable of not the suitableunder process the under optimizedby synthesis the optimized reaction of π- yields (Scheme 11) [34]. Internal or aliphatic alkenes were not suitable under the optimized reaction reactionconjugatedconditions conditions and2,5-dialkenylated gave and lower gave yields. lowerthiazoles, yields.They which exemplif They showed exemplifiedied interestingthe utility the utility solid-stateof the of process the fluorescence process by synthesis by synthesis properties. of π of- conditions and gave lower yields. They exemplified the utility of the process by synthesis of π- πconjugated-conjugated 2,5-dialkenylated 2,5-dialkenylated thiazoles, thiazoles, which which showed showed interesting interesting solid-state solid-state fluorescence fluorescence properties. properties. conjugated 2,5-dialkenylated thiazoles, which showed interesting solid-state fluorescence properties.

Scheme 11. Pd-catalyzed direct oxidative alkenylation of azoles.

Scheme 11. Pd-catalyzed direct oxidativeoxidative alkenylation of azoles. In 2011, Antilla andScheme coworkers 11. Pd-catalyzed replaced direct Ag oxidativwith a echeaper alkenylation Cu oxidantof azoles. for C4-olefination of oxazolesIn 2011, catalyzed Antilla Antilla by and Pd(II) and coworkers coworkers acetate via replaced replaced C–H bond Ag Ag acwithtivation with a acheaper cheaperunder mildCu Cu oxidant reaction oxidant for conditions for C4-olefination C4-olefination (Scheme of In 2011, Antilla and coworkers replaced Ag with a cheaper Cu oxidant for C4-olefination of of12)oxazolesoxazoles [35]. They catalyzed catalyzed applied by theirPd(II) by Pd(II) optimized acetate acetate via reaction C–H via bond C–H conditions ac bondtivation activationto a under wide substratemild under reaction mild scope reactionconditions including conditions (Scheme various oxazoles catalyzed by Pd(II) acetate via C–H bond activation under mild reaction conditions (Scheme (Schemeolefins12) [35]. suchThey12)[ 35 appliedas]. Theyelectron-deficient their applied optimized their optimizedalkyl reaction acrylates, reactionconditions N conditions,N to-ethylphenylacrylamide a wide to substrate a wide substrate scope includingand scope substituted including various 12) [35]. They applied their optimized reaction conditions to a wide substrate scope including various variousstyrenes,olefins olefinssuch with asgood such electron-deficient asfunctional electron-deficient group alkyl tolerance. alkyl acrylates, acrylates, Interestingly, N,NN,-ethylphenylacrylamideN-ethylphenylacrylamide more-challenging substrates and and substituted such as olefins such as electron-deficient alkyl acrylates, N,N-ethylphenylacrylamide and substituted styrenes,vinyl trimethylsilane withwith good good functional functionaland 1-phenyl-1,3-diene group group tolerance. tolerance. also Interestingly, Inaffordedterestingly, the more-challenging desired more-challenging products substrates in substrates moderate such to assuch good vinyl as styrenes, with good functional group tolerance. Interestingly, more-challenging substrates such as trimethylsilaneyields.vinyl trimethylsilane and 1-phenyl-1,3-diene and 1-phenyl-1,3-diene also aff alsoorded afforded the desired the desired products products in moderate in moderate to good to yields. good vinyl trimethylsilane and 1-phenyl-1,3-diene also afforded the desired products in moderate to good yields. yields.

Scheme 12. Pd-catalyzed C4-olefination C4-oleﬁnation of oxazoles.

Scheme 12. Pd-catalyzed C4-olefination of oxazoles. Gem-diﬂuoromethylene-difluoromethyleneScheme exhibitsexhibits 12. extraordinary Pd-catalyzed extraordinar C4-olefination biologicaly biological activities of oxazoles. withactivities potential with pharmaceutical potential applications [36]. Owing to its importance, Wu and coworkers reported synthesis of pyrazole pharmaceuticalGem-difluoromethylene applications [36].exhibits Owing toextraordinar its importance,y biologicalWu and coworkers activities reported with synthesispotential of Gem-difluoromethylene exhibits extraordinary biological activities with potential pyrazolepharmaceutical derivatives applications containing [36]. a Owing gem-difluoromethylene to its importance, moietyWu and through coworkers a Pd-catalyzed reported synthesis direct ofo- pharmaceutical applications [36]. Owing to its importance, Wu and coworkers reported synthesis of olefinationpyrazole derivatives of CF3-substituted containing pyrazoles a gem-difluoromethylene (Scheme 13) [37]. moiety through a Pd-catalyzed direct o- pyrazole derivatives containing a gem-difluoromethylene moiety through a Pd-catalyzed direct o- olefination of CF3-substituted pyrazoles (Scheme 13) [37]. olefination of CF3-substituted pyrazoles (Scheme 13) [37].

Molecules 2020, 25, 4970 7 of 34 derivatives containing a gem-diﬂuoromethylene moiety through a Pd-catalyzed direct o-oleﬁnation of Molecules 2020, 25, x FOR PEER REVIEW 7 of 33 CFMolecules3-substituted 2020,, 25,, xx pyrazolesFORFOR PEERPEER REVIEWREVIEW (Scheme 13)[37]. 7 of 33

Scheme 13. Pd-catalyzed reaction of 1,3,5-trisubstituted pyrazoles with gem-difluoromethylenated Scheme 13. 13.Pd-catalyzedPd-catalyzed reaction of 1,3,5- reactiontrisubstituted of pyrazoles 1,3,5-trisubstituted with gem-difluoromethylenated pyrazoles with acetonide. gemacetonide.-diﬂuoromethylenated acetonide.

YaoYao and andand coworkers coworkerscoworkers reported reportedreported a Pd(II)-catalyzed aa Pd(II)-catalyzedPd(II)-catalyzed oxidative oxidativeoxidative Heck coupling HeckHeck ofcouplingcoupling thiazole-4-carboxylates ofof thiazole-4-thiazole-4- tocarboxylatescarboxylates deliver the toto deliverdeliver desired thethe alkenylation desireddesired alkenylationalkenylation products prodprod inuctsucts moderate inin moderatemoderate to good toto goodgood yields yieldsyieldsyields (Scheme (Scheme(Scheme(Scheme 14 14)14)14))[ [38].[38].[38].38]. ThisThis C–HC–H functionalizationfunctionalization uses uses neither neither ligands ligands nor nor acidic acidic additives additives to to accelerate accelerate the the reaction. reaction. ThiazolesThiazoles containingcontainingcontaining 2-alkyl2-alkyl2-alkyl andandand 2-carbonyl2-carbonyl2-carbonyl substituentssubstituentssubstituents mainlymainlymainly gavegavegave homocouplinghomocouplinghomocoupling byproductsbyproducts withwith nn-butyl-butyl-butyl acrylates.acrylates.acrylates.

SchemeScheme 14.14. Pd(II)-catalyzed oxidative HeckHeck couplingcoupling ofof thiazole-4-carboxylates.thiazole-4-carboxylates. Scheme 14. Pd(II)-catalyzed oxidative Heck coupling of thiazole-4-carboxylates. In 2012, You and coworkers reported an efficient trimetallic catalytic system using InIn 2012,2012, YouYou andand coworkerscoworkers reportedreported anan efefficientficient trimetallictrimetallic catalyticcatalytic systemsystem usingusing Pd(OAc)Pd(OAc)222//CuCl/Cu(OAc)/CuCl/Cu(OAc)CuCl/Cu(OAc)222·H·HH222O forfor aa dehydrogenativedehydrogenative Heck Heck coupling, coupling, achieving achieving direct direct alkenylation alkenylation of Pd(OAc)2/CuCl/Cu(OAc)2··H2O for a dehydrogenative Heck coupling, achieving direct alkenylation various biologically relevant N-heteroarenes with alkenes [39]. They applied their reaction conditions ofof variousvarious biologicallybiologically relevantrelevant NN-heteroarenes-heteroarenes withwith alkenesalkenes [39].[39]. TheyThey appliedapplied theirtheir reactionreaction to caffeine and xanthine derivatives, and afforded the desired products in good to moderate yields conditionsconditions toto caffeinecaffeine andand xanthixanthinene derivatives,derivatives, andand affordedafforded thethe desireddesired productsproducts inin goodgood toto (Scheme 15). The authors highlighted the importance of this protocol by showing the fluorescence moderatemoderate yieldsyields (Scheme(Scheme 15).15). TheThe authorsauthors highlighhighlightedted thethe importanceimportance ofof thisthis protocolprotocol byby showingshowing emission ability of these new scaffolds. thethe fluorescencefluorescence emissionemission abilabilityity ofof thesethese newnew scaffolds.scaffolds.

Scheme 15.15. PdPd/Cu-catalyzed/Cu-catalyzed dehydrogenative alkenylationalkenylation ofof cacaffeineﬀeine derivatives.derivatives. Scheme 15. Pd/Cu-catalyzed dehydrogenative alkenylation of caffeine derivatives. Inspired by You’s work, in 2014 Ong and coworkers employed a Pd(TFA) and 1,10-phenanthroline InspiredInspired byby You’sYou’s work,work, inin 20142014 OngOng andand coworkerscoworkers employedemployed2 aa Pd(TFA)Pd(TFA)22 andand 1,10-1,10- Inspired by You’s work, in 2014 Ong and coworkers employed a Pd(TFA)2 and 1,10- catalytic system with Ag as oxidant for C-2 alkenylation of azoles (Scheme 16). The authors revealed phenanthrolinephenanthroline catalyticcatalytic systemsystem wiwithth AgAg asas oxidantoxidant forfor C-2C-2 alkenylaalkenylationtion ofof azolesazoles (Scheme(Scheme 16).16). TheThe the considerable role of C–H bond cleavage of the alkene in the rate-determining step. Moreover, authorsauthors revealedrevealed thethe considerableconsiderable rolerole ofof C–HC–H bondbond cleavagecleavagecleavage ofofof thethethe alkenealkenealkene ininin thethethe rate-determiningrate-determiningrate-determining they achieved direct and eﬃcient synthesis of naturally occurring Annuloline and Siphonazole, step.step. Moreover,Moreover, theythey achievedachieved directdirect andand efficienefficientt synthesissynthesis ofof naturallynaturally occurringoccurring AnnulolineAnnuloline andand showing a promising opportunity in natural product synthesis [40]. Siphonazole,Siphonazole, showingshowing aa promisingpromising opportunityopportunity inin naturalnatural productproduct synthesissynthesis [40].[40].

Scheme 16. Pd-catalyzed dehydrogenative alkenylation of azole motifs. Scheme 16. Pd-catalyzed dehydrogenative alkenylation of azole motifs.

Molecules 2020, 25, x FOR PEER REVIEW 7 of 33

Scheme 13. Pd-catalyzed reaction of 1,3,5-trisubstituted pyrazoles with gem-difluoromethylenated acetonide.

Yao and coworkers reported a Pd(II)-catalyzed oxidative Heck coupling of thiazole-4- carboxylates to deliver the desired alkenylation products in moderate to good yields (Scheme 14) [38]. This C–H functionalization uses neither ligands nor acidic additives to accelerate the reaction. Thiazoles containing 2-alkyl and 2-carbonyl substituents mainly gave homocoupling byproducts with n-butyl acrylates.

Scheme 14. Pd(II)-catalyzed oxidative Heck coupling of thiazole-4-carboxylates.

In 2012, You and coworkers reported an efficient trimetallic catalytic system using Pd(OAc)2/CuCl/Cu(OAc)2·H2O for a dehydrogenative Heck coupling, achieving direct alkenylation of various biologically relevant N-heteroarenes with alkenes [39]. They applied their reaction conditions to caffeine and xanthine derivatives, and afforded the desired products in good to moderate yields (Scheme 15). The authors highlighted the importance of this protocol by showing the fluorescence emission ability of these new scaffolds.

Scheme 15. Pd/Cu-catalyzed dehydrogenative alkenylation of caffeine derivatives.

Inspired by You’s work, in 2014 Ong and coworkers employed a Pd(TFA)2 and 1,10- phenanthroline catalytic system with Ag as oxidant for C-2 alkenylation of azoles (Scheme 16). The authors revealed the considerable role of C–H bond cleavage of the alkene in the rate-determining Moleculesstep. Moreover,2020, 25, 4970 they achieved direct and efficient synthesis of naturally occurring Annuloline8 ofand 34 Siphonazole, showing a promising opportunity in natural product synthesis [40].

Molecules 2020, 25, x FOR PEER REVIEW 8 of 33 Molecules 2020, 25, x FOR PEER REVIEW 8 of 33 MoleculesKuang 2020, and25, x FORcoworkersScheme PEER 16.REVIEW performed Pd-catalyzed an dehydrogenative extensive expe rimental alkenylationalkenylation study of azole for C2-selective motifs. alkenylation8 of 33 of thiazoles.Kuang and The coworkers overall selectivity performed of anthis extensive process expereliesrimental on the neutralstudy for reaction C2-selective conditions alkenylation and the ofligand thiazoles.KuangKuang choice and andThe (1,10-phenanthroline). coworkerscoworkers overall selectivity performed performed of an thisThean extensive extensive processauthors experimental reliesexpepresentedrimental on the a studyneutral studybroad for forreactionsubstrate C2-selective C2-selective conditions scope alkenylation alkenylation with and good the of thiazoles.ligandoffunctional thiazoles. choice The group The overall(1,10-phenanthroline). overalltolerance selectivity selectivity (Scheme of this of17) The processthis [41]. authorsprocess relies reliespresented on the on neutral the a neutralbroad reaction substratereaction conditions conditionsscope and with the and ligandgood the choicefunctionalligand (1,10-phenanthroline).choice group (1,10-phenanthroline). tolerance (Scheme The authors 17) The [41]. presentedauthors presented a broad substratea broad scopesubstrate with scope good with functional good groupfunctional tolerance group (Scheme tolerance 17 (Scheme)[41]. 17) [41].

Scheme 17. Pd-catalyzed C2-selective olefination of thiazoles.

Scheme 17. Pd-catalyzed C2-selective olefination of thiazoles. Thiazolo[3,2-b]-1,2,4-triazoleScheme 17.17. Pd-catalyzed moieties are C2-selective valuable olefinationolefination molecules ofof thiazoles.thiazoles.that exhibit a wide range of biologicalThiazolo[3,2-b]-1,2,4-triazole activities [42]. In 2014, moietiesWang moieties and are are coworkers valuable reportedmolecules an that atom-economical exhibit a wide approach range ofto Thiazolo[3,2-b]-1,2,4-triazole moieties are valuable molecules that exhibit a wide range of biologicalobtain alkenylation activities [42]. [42of]. Inthiazolo[3,2-b]-1,2,4-triazoles In 2014, 2014, Wang Wang and and coworkers coworkers via reported reporteda palladium-catalyzed, an an atom-economical atom-economical two-fold approach approach C–H to biological activities [42]. In 2014, Wang and coworkers reported an atom-economical approach to toobtainfunctionalization obtain alkenylation alkenylation [43]. of Interestingly, ofthiazolo[3,2-b]-1,2,4-triazoles thiazolo[3,2-b]-1,2,4-triazoles the synergetic effect via viaof a a metalpalladium-catalyzed, palladium-catalyzed, oxidant, Cu(OAc) two-fold two-fold2, with oxygen C–H obtain alkenylation of thiazolo[3,2-b]-1,2,4-triazoles via a palladium-catalyzed, two-fold C–H functionalizationplays an important [43]. role Interestingly, in the C–H the activation synergetic step effect, affording of a metal the oxidant,desired productsCu(OAc) 2in, with high oxygen yields functionalization [43]. Interestingly, the synergetic effect of a metal oxidant, Cu(OAc)2, with oxygen functionalization [43]. Interestingly, the synergetic effect of a metal oxidant, Cu(OAc)2, with oxygen plays(Scheme an an 18).important important role role in inthe the C–H C–H activation activation step step,, affording affording the desired the desired products products in high in yields high plays an important role in the C–H activation step, affording the desired products in high yields yields(Scheme (Scheme 18). 18). (Scheme 18).

Scheme 18. Pd-catalyzed direct alkenylation of thiazolo[3,2-b]-1,2,4-triazoles.

Scheme 18. Pd-catalyzed direct alkenylation of thiazolo[3,2-b]-1,2,4-triazoles. In 2015, ShiScheme and 18.coworkers Pd-catalyzed employed direct alkenylation a semi-continuous of thiazolo[3,2-b]-1,2,4-triazoles. approach to overcome the long- standingIn 2015,2015, homocoupling Shi Shi and and coworkers coworkers problem employed employed in direct a semi-continuous a oxidatsemi-continuousive cross-coupling approach approach to overcome to tofunctionalize overcome the long-standing the thiazole long- homocouplingstandingderivativesIn 2015, homocoupling (Scheme Shi problem and 19) coworkers inproblem[44]. direct Interestingly, employed oxidativein direct cross-couplingatAmylOHoxidat semi-continuousive andcross-coupling toDMSO functionalizeapproach played to to functionalizean thiazoleovercome important derivatives thethiazole role long- in standing homocoupling problemt in direct oxidative cross-coupling to functionalize thiazole (Schemederivativesincreasing 19 )[ the(Scheme44 yield]. Interestingly, of 19) the [44]. desired AmylOHInterestingly, products. and The DMSOtAmylOH authors played andshowed an DMSO important a broad played rolesubstrate an in increasingimportant scope with the role yieldgood in t ofincreasingderivativesto themoderate desired the (Scheme yields. products.yield of 19) the The [44].desired authors Interestingly, products. showed The aAmylOH broad authors substrate showedand DMSO scope a broad withplayed substrate good an to important moderate scope with yields.role good in toincreasing moderate the yields. yield of the desired products. The authors showed a broad substrate scope with good to moderate yields.

SchemeScheme 19.19. SynthesisSynthesis ofof multifunctionalizedmultifunctionalized thiazolethiazole derivativesderivatives viavia regioselectiveregioselective andand programmedprogrammed

C–HSchemeC–H activation.activation. 19. Synthesis of multifunctionalized thiazole derivatives via regioselective and programmed C–HScheme activation. 19. Synthesis of multifunctionalized thiazole derivatives via regioselective and programmed C–HIn 2016, activation. Huang and coworkers utilized a well-established Pd-catalyzed direct C–H bond functionalizationIn 2016, Huang strategy and forcoworkers dehydrogenative utilized a alkenylationwell-established of imidazo[2,1-b]thiazole Pd-catalyzed direct C–Hderivatives bond functionalization(SchemeIn 2016, 20) [45]. Huang Thestrategy reactionand forcoworkers conditionsdehydrogenative utilized were compatible aalkenylation well-established with of a wideimidazo[2,1-b]thiazole Pd-catalyzed range of alkenes direct and derivativesC–H thiazoles. bond (Schemefunctionalization 20) [45]. The strategy reaction for conditions dehydrogenative were compatible alkenylation with ofa wide imidazo[2,1-b]thiazole range of alkenes and derivatives thiazoles. (Scheme 20) [45]. The reaction conditions were compatible with a wide range of alkenes and thiazoles.

Molecules 2020, 25, 4970 9 of 34

In 2016, Huang and coworkers utilized a well-established Pd-catalyzed direct C–H bond functionalization strategy for dehydrogenative alkenylation of imidazo[2,1-b]thiazole derivatives (Scheme 20)[45]. The reaction conditions were compatible with a wide range of alkenes and thiazoles. Molecules 2020, 25, x FOR PEER REVIEW 9 of 33

Scheme 20.20. Pd-catalyzed site-selective C–HC–H alkenylation of imidazo[2,1-b]thiazoles.imidazo[2,1-b]thiazoles.

In 2017,2017, forfor thethe ﬁrstfirst time,time, AckermannAckermann andand coworkerscoworkers introducedintroduced aa Ni-catalyzedNi-catalyzed regioselectiveregioselective hydroarylation of of allenes allenes with with purines purines and and imidazoles imidazoles [46]. [46 ].The The authors authors successfully successfully applied applied this thiscatalytic catalytic system system for dienylation for dienylation through through C-H functionalization C–H functionalization and concurrent and concurrent C-O cleavage C–O cleavage(Scheme (Scheme21). The employed 21). The employedbase plays basea key plays role in a the key isom roleerization in the isomerization step to deliver step the todesired deliver products. the desired The products.practical utility The of practical this protocol utility was of thisshown protocol by the was late shownstage-diversification by the late stage-diversiﬁcation of diphophodiesterase of diphophodiesteraseinhibitors. inhibitors.

Scheme 21. Ni-catalyzed functionalization of imidazoles with allenes.

In 2018,2018, Xu Xu and and coworkers coworkers employed employed cationic cationic rhodium(III) rhodium(III) for the directfor the olefination direct olefination of imidazoles of withimidazoles high regio- with andhigh stereo- regio- selectivity and stereo- [47 ].selectivity Unlike the [47]. other Unlike reported the methods,other reported this catalytic methods, system this requirescatalytic asystem directing requires group a fordirecting the selective group C-2for the alkenylation. selective C-2 A broadalkenylation. range ofA benzimidazolesbroad range of andbenzimidazoles activated olefins and activated successfully olefins delivered successfully the desired delivered products the desired in good products yields. in In good the proposedyields. In mechanism,the proposed the mechanism, reaction starts thewith reaction the Rh(III)-mediated starts with the Rh(III)-mediated C–H bond activation C-H to bo formnd activation the cyclorhodium to form intermediatethe cyclorhodiumB, followed intermediate by coordination B, followed with by coordination olefin 2 to give with intermediate olefin 2 to giveC. Thenintermediate a regioselective C. Then migratorya regioselective insertion migratory of the olefin insertion delivers of the the complexolefin deliversD. The theβ-H complex elimination D. furnishesThe β-H elimination the desired productfurnishes3 theand desired Rh(I). The product Rh(I)-species 3 and Rh(I). is further The Rh(I)-species oxidized by Ois2 ,further regenerating oxidized Rh(III) by O to2, completeregenerating the catalyticRh(III) to cycle complete (Scheme the cata22). lytic cycle (Scheme 22). Later on, Joo and coworkers reported a systematic access to functionalized (benz)imidazoles via direct C–H functionalization [48]. Molecular oxygen as an oxidant was found essential for the selective C5-alkenylation of imidazoles. In this study, the authors highlighted the distinctive role of imidazole as ligand for Pd(II) to regioselectively install alkenyl groups at the more nucleophilic C5 position of the imidazoles (Scheme 23a,b). Notably, the reaction conditions were not compatible with related

Molecules 2020, 25, x FOR PEER REVIEW 10 of 33

Molecules 2020, 25, 4970 10 of 34

1,3-azoles, i.e., thiazoles and oxazoles. Furthermore, the installed C5-alkenylated imidazoles could be subjectedMolecules 2020 to, additional25, x FOR PEER alkenylation, REVIEW aﬀording unsymmetrically substituted benzimidazoles. 10 of 33

Scheme 22. Rh (III)-catalyzed selective direct olefination of imidazoles.

Later on, Joo and coworkers reported a systematic access to functionalized (benz)imidazoles via direct C–H functionalization [48]. Molecular oxygen as an oxidant was found essential for the selective C-5 alkenylation of imidazoles. In this study, the authors highlighted the distinctive role of imidazole as ligand for Pd(II) to regioselectively install alkenyl groups at the more nucleophilic C5 position of the imidazoles (Scheme 23a,b). Notably, the reaction conditions were not compatible with related 1,3-azoles, SchemeSchemei.e., thiazoles 22.22. Rh and (III)-catalyzed oxazoles. selective Furthermore, direct oleﬁnationolefination the installed ofof imidazoles.imidazoles. C5-alkenylated imidazoles could be subjected to additional alkenylation, affording unsymmetrically substituted benzimidazoles. Later on, Joo and coworkers reported a systematic access to functionalized (benz)imidazoles via direct C–H functionalization [48]. Molecular oxygen as an oxidant was found essential for the selective C-5 alkenylation of imidazoles. In this study, the authors highlighted the distinctive role of imidazole as ligand for Pd(II) to regioselectively install alkenyl groups at the more nucleophilic C5 position of the imidazoles (Scheme 23a,b). Notably, the reaction conditions were not compatible with related 1,3-azoles, i.e., thiazoles and oxazoles. Furthermore, the installed C5-alkenylated imidazoles could be subjected to additional alkenylation, affording unsymmetrically substituted benzimidazoles.

SchemeScheme 23. 23.Regioselective Regioselective C–H C–H alkenylation alkenylation for for (a) C2-unsubstituted andand ( bC2-substituted) C2-substituted imidazoles. imidazoles.

Recently, Kumar and Kapur developeddeveloped anan interestinginteresting catalyst-drivencatalyst-driven selectiveselective C–HC-H functionalization of of isoxazoles at at the the distal distal an andd the proximal position as as shown shown in in Scheme Scheme 2424 [[49].49]. The mode of activation in the case of cationic Rh involves the strong coordination with the isoxazole nitrogen, favoringfavoring the the proximal proximal C–H C-H activation activation of theof arenethe arene ring. ring. On the On contrary, the contrary, the Pd-catalyst the Pd-catalyst prefers toprefers undergo to undergo the electrophilic the electrophilic metalation metalation at the C(4)-H at the of C(4)-H the isoxazole of the toisoxazole furnish theto furnish desired the distal desired C–H activation. Furthermore, the kinetic isotope studies elucidated the possibility of carbometallation or distal SchemeC-H activation. 23. Regioselective Furthermore, C–H alkenylation the kinetic for C2-unsubstituted isotope studies and elucidatedC2-substituted the imidazoles. possibility of thecarbometallationβ-hydride elimination or the toβ-hydride be the rate-limiting elimination step, to insteadbe the ofrate-limiting the C–H activation step, instead step. The of syntheticthe C-H utility of this position-selective C–H oleﬁnation approach was demonstrated by the synthesis of densely Recently, Kumar and Kapur developed an interesting catalyst-driven selective C-H substituted pyrroles by employing a Ru- and Cu-mediated cooperative catalysis. functionalization of isoxazoles at the distal and the proximal position as shown in Scheme 24 [49]. The mode of activation in the case of cationic Rh involves the strong coordination with the isoxazole nitrogen, favoring the proximal C-H activation of the arene ring. On the contrary, the Pd-catalyst prefers to undergo the electrophilic metalation at the C(4)-H of the isoxazole to furnish the desired distal C-H activation. Furthermore, the kinetic isotope studies elucidated the possibility of carbometallation or the β-hydride elimination to be the rate-limiting step, instead of the C-H

MoleculesMolecules 20202020 2020,, 25,25 25,, x,x x FORFOR FOR PEERPEER PEER REVIEWREVIEW REVIEW 111111 ofof of 3333 33 activationactivation step.step. TheThe syntheticsynthetic utilityutility ofof thisthis position-selectiveposition-selective C-HC-H olefinationolefination approachapproach waswas Moleculesdemonstrateddemonstrated2020, 25 ,by 4970by the the synthesis synthesis of of denselydensely densely substitutedsubstituted substituted pyrroles pyrroles by by employing employing a a Ru- Ru- and and Cu-mediated Cu-mediated11 of 34 cooperativecooperative catalysis. catalysis.

SchemeSchemeScheme 24.24. 24. Catalyst Catalyst control control inin in positional-selectivepositional-selective positional-selective C–HC-H C-H alkenylation alkenylation of of isoxazoles. isoxazoles.

TheTheThe regioselectiveregioselective regioselective alkenylationalkenylation alkenylation ofof of 2,5-unsubstituted2,5-unsubstitu 2,5-unsubstitutedtedted thiazolethiazole thiazole derivativesderivatives derivatives hashas has beenbeen been aa a challengingchallenging challenging issueissueissue among amongamongamong synthetic syntheticsyntheticsynthetic chemists. chemists.chemists.chemists. Maiti MaitiMaiti andMaiti coworkers andandand coworkerscoworkerscoworkers overcame overcameovercameovercame this challenge thisthisthis by challengechallengechallenge using a tricoordinating bybyby usingusingusing aaa directingtricoordinatingtricoordinatingtricoordinating group (T)directingdirecting directing bearing groupgroup group a cyanide (T)(T) (T) bearingbearing bearing template aa a cyanidecyanide forcyanide the selective templatetemplate template metalation forfor for thethe the selectiveselective selective of thiazole metalationmetalation metalation at the C5 ofof of positionthiazolethiazole thiazole followedatat the the C-5 C-5 by position position reductive followed followed elimination by by reductive reductive to deliver eliminatio eliminatio the desirednn to to deliver productsdeliver the the [ desired50 desired]. The pr authorsproductsoducts presented[50]. [50]. The The authors aauthors wide rangepresentedpresented of substrate a a wide wide range scoperange of withof substrate substrate good functional scope scope with with group good good tolerance functional functional (Scheme group group tolerance 25tolerance). (Scheme (Scheme 25). 25).

SchemeScheme 25. 25. Pd-catalyzed Pd-catalyzed template-directed template-directed C-5 C-5 selective selective oleﬁnationolefination olefination ofof of thiazoles.thiazoles. thiazoles.

2.3.2.3.2.3. C-H C–H C-H Addition AdditionAddition of ofof AzolesAzoles AzolesAzoles toto toto AlkynesAlkynes AlkynesAlkynes AlkynesAlkynesAlkynes are are potentiallypotentially potentially goodgood good substratessubstrates substrates forfor for alkenylationalkenylation alkenylation becausebecause because ofof of theirtheir their widewide wide availabilityavailability availability andand and lowlowlow cost.cost. cost.cost. The The TheThe transition transition transitiontransition metal-catalyzed metal-catalyzed metal-catalyzedmetal-catalyzed direct direct directdirect cl cl cleavagecleavageeavage of ofof the thethe C–H C–HC–H bondbond ofof azoles azoles followedfollowed byby insertioninsertioninsertion of of of alkynesalkynes alkynes appears appears appears an anan ideal ideal ideal and and and atom atom atom economical economical economical method methodmethod forfor for the thethe alkenylation alkenylationalkenylation ofof of azoles.azoles. azoles. ThisThisThis straightforwardstraightforward straightforward syntheticsynthetic synthetic strategy strategy was was early early reportedre reportedported by by MiuraMiura Miura [[51]. 51[51].]. Later, Later, inin in 2009,2009, 2009, MiuraMiura Miura andand and coworkerscoworkerscoworkers reportedreportedreported aaa Ni-catalyzedNi-catalyzed Ni-catalyzed C–HC-H C-H alkenylation alkenylation of of 1,3,4-oxadiazoles1,3,4-oxadiazoles1,3,4-oxadiazoles [52]. [52[52].]. At AtAt the thethe same samesame time, time, HiyamaHiyamaHiyama and andand coworkers coworkerscoworkers also alsoalso reported reported a a similar similar similar approa approa approachchch for for for the the the alkenylation alkenylation alkenylation of of ofimidazoles imidazoles imidazoles [53]. [53]. [53 In In]. In2010,2010, 2010, Ding Ding Ding and and and Yoshikai Yoshikai Yoshikai reported reported reported a a Cobased aCobased Cobased catalytic catalytic catalytic system system system for for for the the the addition addition addition of of ofbenzoxazoles benzoxazoles benzoxazoles to to tounactivatedunactivated unactivated internal internal internal alkynes alkynes alkynes (Scheme (Scheme (Scheme 26) 26) [54].26 [54].)[ The54 The]. optimized Theoptimized optimized reaction reaction reaction conditions conditions conditions showed showed showed good good regio- goodregio- regio-andand chemo-chemo- and chemoselectivity selectivity selectivity possiblypossibly possibly originatingoriginating originating during during during thethethe alkynealkyne thealkyne alkyne insertioninsertioninsertion insertion step. step.step. step. Unfortunately,Unfortunately,Unfortunately, Unfortunately, thethethe theoptimizedoptimized optimized conditions conditions conditions were were were not not not suitable suitable suitable for for for the thethe alke alke alkenylationnylationnylation of of ofbenzoxazoles benzoxazoles benzoxazoles with with with terminal terminal terminal alkynes. alkynes. alkynes.

SchemeSchemeScheme 26.26. 26. Co-catalyzed Co-catalyzed addition addition of of benzoxazoles benzoxazoles to to alkynes. alkynes.

Later, Ding and Yoshikai observed the chemoselective alkenylation of (benzo)thiazoles in the presence of (benz)oxazoles by changing the ligand from DPEphos to Xantphos. The authors could not MoleculesMolecules 20202020,, 2525,, xx FORFOR PEERPEER REVIEWREVIEW 1212 ofof 3333 Molecules 2020, 25, 4970 12 of 34 Later,Later, DingDing andand YoshikaiYoshikai observedobserved thethe chemoselchemoselectiveective alkenylationalkenylation ofof (benzo)thiazoles(benzo)thiazoles inin thethe presencepresence ofof (benz)oxazoles(benz)oxazoles byby changingchanging thethe ligaligandnd fromfrom DPEphosDPEphos toto Xantphos.Xantphos. TheThe authorsauthors couldcould providenotnot provideprovide the reason thethe reasonreason for the forfor observed thethe observedobserved selectivity, selectivselectiv but theirity,ity, workbutbut theirtheir opens workwork the door opensopens for the furtherthe doordoor investigations forfor furtherfurther (Schemeinvestigationsinvestigations 27)[55 (Scheme(Scheme]. 27)27) [55].[55].

SchemeScheme 27.27. Co-catalyzedCo-catalyzed alkenylation alkenylation ofof thiazolesthiazoles withwith alkynes.alkynes. The selective alkenylation of triazolopyridines using a Ni-catalytic system was reported by Driver TheThe selectiveselective alkenylationalkenylation ofof triazolopyridinestriazolopyridines usingusing aa Ni-catalyticNi-catalytic systemsystem waswas reportedreported byby and coworkers. In this pioneering work, the authors highlighted the steering role of a Lewis acid DriverDriver andand coworkers.coworkers. InIn thisthis pioneeringpioneering work,work, thethe authorsauthors highlightedhighlighted thethe steeringsteering rolerole ofof aa LewisLewis (AlMe3) interaction for the selective oxidative addition of the C7-H bond to generate intermediate B, acidacid (AlMe(AlMe33)) interactioninteraction forfor thethe selectiveselective oxidativeoxidative additionaddition ofof thethe C7-HC7-H bondbond toto generategenerate followed by alkyne insertion to obtain the desired products (Scheme 28)[56]. The alkyne insertion step intermediateintermediate BB,, followedfollowed byby alkynealkyne insertioninsertion toto obtainobtain thethe desireddesired productsproducts (Scheme(Scheme 28)28) [56].[56]. TheThe was mainly curbed by the substituent steric factor on the alkyne bond, favouring the new C–C bond alkynealkyne insertion insertion stepstep waswas mainly mainly curbedcurbed byby thethe subssubstituenttituent stericsteric factor factor onon thethe alkyne alkyne bond,bond, favouring favouring between the smaller alkynyl substituent and the C7 of the triazolopyridine. thethe newnew C-CC-C bondbond betweenbetween thethe smallersmaller alkynylalkynyl susubstituentbstituent andand thethe C7C7 ofof thethe triazolopyridine.triazolopyridine.

SchemeScheme 28.28. Ni-catalyzedNi-catalyzed alkenylation alkenylation of of triazolopyridines.triazolopyridines.

SimilarSimilar tototo thisthisthis report, report,report, Ong OngOng and andand coworkers coworkerscoworkers employed employemployeded the thethe same samesame Ni Ni/Al/Ni/AlAl bimetallic bimetallicbimetallic catalytic catalyticcatalytic system systemsystem for forthefor the remotethe remoteremote C–H C-HC-H functionalization functionalizationfunctionalization of imidazo[1,5-a]pyridines.ofof imidazo[1,5-imidazo[1,5-a]pyridines.a]pyridines. Interestingly, Interestingly,Interestingly, the thethe authors authorsauthors were werewere able ableable to toswitchto switchswitch the thethe regioselectivity regioselectivityregioselectivity of alkenylation ofof alkenyalkenylationlation from fromfrom C5 to C5C5 C3 toto by C3C3 excluding byby excludingexcluding AlMe3 AlMeAlMefrom3 the3 fromfrom catalytic thethe catalyticcatalytic system (Schemesystemsystem (Scheme(Scheme 29)[57]. 29)29) A wide[57].[57]. AA scope widewide was scopescope presented waswas presentedpresented with good withwith functional goodgood functionalfunctional group tolerance. groupgroup tolerance.tolerance.

SchemeScheme 29.29. C-HC–HC-H alkenylation alkenylation of of imidazo[1,5-a]pyridine imidazo[1,5-a]pyridine with with alkynes. alkynes.

Molecules 2020, 25, 4970 13 of 34 MoleculesMolecules 20202020,, 2525,, xx FORFOR PEERPEER REVIEWREVIEW 1313 ofof 3333

InIn 2015,2015,2015, Huang HuangHuang and andand coworkers coworkerscoworkers exploited exploitedexploited an oxime anan asoximeoxime directing asas directingdirecting group in thegroupgroup selective inin thethe alkenylation selectiveselective ofalkenylationalkenylation thiazoles employing ofof thiazolesthiazoles a Rh-catalyst.employingemploying aa This Rh-catalyst.Rh-catalyst. was followed ThisThis waswas by afollowedfollowed tandem cyclizationbyby aa tandemtandem to cyclizationcyclization deliver azole toto fuseddeliverdeliver pyridines azoleazole fusedfused (Scheme pyridinespyridines 30)[58 (Scheme(Scheme]. Despite 30)30) having [58].[58]. DespDesp loweriteite reactivity havinghaving lower atlower the C-4reactivityreactivity position, atat the variousthe C-4C-4 thiazolesposition,position, underwentvariousvarious thiazolesthiazoles smooth underwentunderwent alkenylation smoothsmooth with alkenylation alkynes.alkenylation In general, wiwithth alkynes.alkynes. electron-rich InIn general,general, alkynes electron-richelectron-rich gave better alkynesalkynes yields thangavegave electronbetterbetter yieldsyields deﬁcient thanthan alkynes. electronelectron Notably, deficientdeficient this alkynes.alkynes. catalytic Notably,Notably, system alsothisthis successfullycatalyticcatalytic systemsystem delivered alsoalso successfullysuccessfully the desired productsdelivereddelivered with thethe desireddesired unsymmetrical productsproducts alkynes. withwith unsymmetricalunsymmetrical alkynes.alkynes.

SchemeScheme 30.30. Rh(III)-catalyzedRh(III)-catalyzed cyclization cyclization reactionreaction ofof azolesazoles withwith alkynes.alkynes.

InIn 2017,2017, YouYouYou and andand coworkers coworkerscoworkers exploited exploitedexploited a aa Rh Rh/Cu-catalyRh/Cu-cataly/Cu-catalytictictic system systemsystem for forfor the thethe alkenylation alkenyalkenylationlation of ofof azoles azolesazoles via viavia a C–Haa C-HC-H addition addition/oxidationaddition/oxidation/oxidation sequence sequencesequence to toto generate generategenerate tetra(hetero)arylethylenes tetrtetra(hetero)arylethylenesa(hetero)arylethylenes (Scheme(Scheme(Scheme 3131).31).). Interestingly,Interestingly, controlcontrol experimentsexperiments andand DFTDFT calculationscalculationscalculations revealedrevealed thatthat thethethe C–HC-HC-H bond bond cleavagecleavage ofof azolesazoles couldcould bebe facilitated by either Rh or Cu. The authors also supported the necessity of Cu(OAc) to obtain the facilitatedfacilitated byby eithereither RhRh oror Cu.Cu. TheThe authorauthorss alsoalso supportedsupported thethe necessitynecessity ofof Cu(OAc)Cu(OAc)222 toto obtainobtain thethe desireddesired productproduct bybyby computationalcomputationalcomputational studies.studies.studies. Tetra-arylethylene Tetra-arylethylene (TAE) (TAE) derivativesderivatives havehave widelywidely beenbeen usedused inin OLEDOLEDOLED applications.applications.applications. This This makes makes the the protocolprotocol highlyhighly alluringalluring forfor futurefuture developmentsdevelopments inin thethe areaarea ofof functionalfunctional materialsmaterials [[59].[59].59]. Employing Employing thisthis catalytic catalytic system,system, aa broad broad range range of of alkenylated alkenylated azolesazoles couldcould bebe readilyreadily generatedgeneratedgenerated ininin goodgoodgood yieldsyieldsyields fromfromfrom alkynes. alkynes.alkynes.

SchemeScheme 31.31. Rh/Cu-catalyzedRhRh/Cu-catalyzed/Cu-catalyzed highly highly trans-selective trans-selective 1,2-diheteroarylation1,2-1,2-diheteroarylationdiheteroarylation ofof alkynesalkynes withwith azoles.azoles.

AnotherAnother interestinginteresting approachapproach forfor thethe alkenylationalkenylatialkenylationon ofof thethe C5-positionC5-position ofof thiazolesthiazoles usingusing aa PdPd/PCyPd/PCy/PCy333//RCO/RCORCO222H-catalyticH-catalytic system systemsystem was waswas disclosed discloseddisclosed by Joo byby and JooJoo coworkers andand coworkerscoworkers in 2019 [ 60 inin]. The20192019 key [60].[60]. intermediate TheThe keykey ofintermediateintermediate this catalytic ofof cycle thisthis is catalyticcatalytic the alkenyl cyclecycle Pd(II)-carboxylate isis thethe alkenylalkenyl Pd(II)-carboxylate complex,Pd(II)-carboxylate which enables complex,complex, the concerted whichwhich enablesenables metalation thethe deprotonationconcertedconcerted metalationmetalation of substituted deprotonationdeprotonation azoles, followed ofof substitutedsubstituted by reductive azoles,azoles, elimination followedfollowed by toby deliver reductivereductive the correspondingeliminationelimination toto deliverdeliver thethe correspondingcorresponding products.products. TheThe reactionreaction conditionsconditions werewere notnot onlyonly compatiblecompatible withwith

Molecules 2020, 25, 4970 14 of 34

Molecules 2020,, 25,, xx FORFOR PEERPEER REVIEWREVIEW 14 of 33 products. The reaction conditions were not only compatible with substituted thiazoles but also with oxazoles, benzoxazoles, and pyrazoles (Scheme 32). The hydroarylation of azoles occured at the C2 substituted thiazoles but also with oxazoles, benzoxazoles, and pyrazoles (Scheme 32). The position if the C5 position was not available. hydroarylation of azoles occured at the C2 position if the C5 position was not available.

SchemeScheme 32. 32. Pd-catalyzedPd-catalyzed synsyn-hydroarylation-hydroarylation-hydroarylation reactionreaction reaction ofof diaryldiaryl alkynesalkynes withwith azoles.azoles.

InIn 2019,2019,2019, Breit BreitBreit and andand coworkers coworkerscoworkers introduced introducedintroduced an interesting anan interestinginteresting cascade cascade sequencecascade sequencesequence to achieve toto the achieveachieve trisallyation thethe trisallyationtrisallyationof benzoxazoles ofof benzoxazolesbenzoxazoles catalyzed by catalyzedcatalyzed Pd(OAc) 2bybyusing Pd(OAc)Pd(OAc) Ruphos22 usingusing as ligand RuphosRuphos [61 asas]. ligand Inligand the proposed[61].[61]. InIn thethe mechanism, proposedproposed mechanism,the reaction startsthe reaction with the starts generation with the of agenera Pd-hydridetiontion ofof speciesaa Pd-hydridePd-hydride through speciesspecies oxidative throughthrough addition oxidativeoxidative of the additionPd-catalyst of the with Pd-catalyst HOPiv. Then, with theHOPiv. Pd-hydride Then, the species Pd-hydride facilitates species the isomerizationfacilitates the isomerization of the alkyne of to thetheallene alkynealkyne and atotoﬀords alleneallene the andandπ-allylpalladium affordsaffords thethe π-allylpalladium intermediate.-allylpalladium Subsequently, intermediate.intermediate. intermediate Subsequently,Subsequently,A reacts intermediateintermediate with azoles A reactsby C–H with activation azoles by to C-H produce activation mono-allylated toto produceproduce product mono-allylatedmono-allylatedB, followed productproduct by isomerization B, followedfollowed byby and isomerizationisomerization sequential andtwo-fold sequential C(sp3)–H two-fold allylation C(sp3)–H with π allylation-allylpalladium with π intermediate-allylpalladium-allylpalladiumA to intermediateintermediate furnish the desired A toto furnishfurnish product thetheD desired(Scheme product 33). D (Scheme(Scheme 33).33).

SchemeScheme 33. Pd-catalyzedPd-catalyzed trisallylation trisallylation of of benzoxazolesbenzoxazoles withwith anan alkyne.alkyne.

2.4.2.4. Decarbonylativ Decarbonylativee C-H C–H Alkenylation Alkenylation InIn recentrecent years,years, decarboxylativedecarboxylative C-H C–HC-H bondbond bond funcfunc functionalizationtionalizationtionalization hashas has drawndrawn drawn growinggrowing growing attention,attention, attention, sincesince carboxyliccarboxylic acids acids are commercially available and areare structurallystructurally diverse.diverse. Obviously, Obviously, the the use use of transition-metaltransition-metal catalyzedcatalyzed vinylvinyl carboxyliccarboxylic acidsacids asas olefinolefin sourcessources withwith heterocyclesheterocycles viavia directdirect activation of C–H bonds is an attractive and atom-economic synthetic methodology. Several transition-metaltransition-metal couplingcoupling methodmethodologies for the direct decarboxylative olefination have been

Molecules 2020, 25, 4970 15 of 34 transition-metal catalyzed vinyl carboxylic acids as olefin sources with heterocycles via direct activation of C–H bonds is an attractive and atom-economic synthetic methodology. Several transition-metal Molecules 2020, 25, x FOR PEER REVIEW 15 of 33 couplingMolecules 2020 methodologies, 25, x FOR PEER REVIEW for the direct decarboxylative olefination have been reported [6215 ,of63 33]. Decarbonylativereported [62,63]. cross-couplingsDecarbonylative for cross-couplings the alkenylation for ofthe azoles alkenylation have remained of azoles elusive have forremained some reported [62,63]. Decarbonylative cross-couplings for the alkenylation of azoles have remained time.elusive In for 2013, some Itami time. and In coworkers 2013, Itami reported and ancoworkers inimitable reported method an for inimitable the alkenylation method of for azoles the elusive for some time. In 2013, Itami and coworkers reported an inimitable method for the withalkenylation a Ni/dcype of azoles catalytic with system, a Ni/dcype using catalytic enol derivatives system, andusingα ,enolβ-unsaturated derivatives esters and [ɑ29,β-unsaturated]. Moreover, alkenylation of azoles with a Ni/dcype catalytic system, using enol derivatives and ɑ,β-unsaturated thisesters catalytic [29]. Moreover, system can this also catalytic efficiently system enable can decarbonylativealso efficiently enable alkenylation decarbonylative with enol alkenylation derivatives esters [29]. Moreover, this catalytic system can also efficiently enable decarbonylative alkenylation ofwith styryl enol pivalate, derivatives styryl of carbamatestyryl pivalate, and phenylstyryl carbamate cinnamate and (Scheme phenyl 34 ).cinnamate In general, (Scheme the coupling 34). In with enol derivatives of styryl pivalate, styryl carbamate and phenyl cinnamate (Scheme 34). In productgeneral, of the various coupling azoles product with carbamates of various delivered azoles thewith corresponding carbamates productsdelivered with thehigher corresponding yields as general, the coupling product of various azoles with carbamates delivered the corresponding comparedproducts with to styryl higher pivalates. yields as compared to styryl pivalates. products with higher yields as compared to styryl pivalates.

SchemeScheme 34.34.Ni-catalyzed Ni-catalyzed decarbonylativedecarbonylative C–HC-H alkenylationalkenylation ofof variousvarious azoles.azoles. Scheme 34. Ni-catalyzed decarbonylative C-H alkenylation of various azoles. FluorinatedFluorinated heterocyclesheterocycles havehave alwaysalways beenbeen attractiveattractive scascaffoldsffolds forfor pharmaceuticalspharmaceuticals andand organicorganic Fluorinated heterocycles have always been attractive scaffolds for pharmaceuticals and organic materials.materials. InIn 2014,2014, HoarauHoarau andand coworkerscoworkers reportedreported anan e efficientfficient method method for for the the direct direct C–H C-H/C-CO/C–CO22HH materials. In 2014, Hoarau and coworkers reported an efficient method for the direct C-H/C-CO2H cross-couplingcross-coupling betweenbetween azolesazoles andand αα-fluoroacrylic-fluoroacrylic acidsacids viavia aa decarboxylativedecarboxylative process,process, usingusing aa cross-coupling between azoles and α-fluoroacrylic acids via a decarboxylative process, using a PdPd/Cu-catalytic/Cu-catalytic systemsystem [[64].64]. The The reaction mech mechanismanism is believed to startstart withwith aa Cu-promotedCu-promoted Pd/Cu-catalytic system [64]. The reaction mechanism is believed to start with a Cu-promoted decarboxylationdecarboxylation step step generatinggenerating an an alkenylcopperalkenylcopper intermediate. intermediate. ThisThis isis followedfollowed byby aa transmetalationtransmetalation decarboxylation step generating an alkenylcopper intermediate. This is followed by a transmetalation stepstep withwith thethe Pd-azolePd-azole intermediate.intermediate. Finally, reductivereductive eliminationelimination generates the desired product. step with the Pd-azole intermediate. Finally, reductive elimination generates the desired product. TheThe variousvarious ((ZZ/E/E)-)-αα-fluroacrylic-fluroacrylic acidsacids successfullysuccessfully delivereddelivered thethe ZZ/E/E-isomeric-isomeric productsproducts inin goodgood toto The various (Z/E)-α-fluroacrylic acids successfully delivered the Z/E-isomeric products in good to moderatemoderate yieldsyields withwith goodgood functionalfunctional groupgroup tolerancetolerance (Scheme(Scheme 35 35).). moderate yields with good functional group tolerance (Scheme 35).

Scheme 35. Decarboxylative/direct C-H monofluoroalkenylation with fluoroacrylic acids. SchemeScheme 35.35. DecarboxylativeDecarboxylative/direct/direct C–HC-H monofluoroalkenylationmonofluoroalkenylation withwith fluoroacrylicfluoroacrylic acids.acids. Later in 2017, the same group developed a decarboxylative C-H alkenylation of various azoles LaterLater in 2017, 2017, the the same same group group developed developed a decarb a decarboxylativeoxylative C-H C–Halkenylati alkenylationon of various of various azoles with α-alkoxylated acrylic acids [65]. This decarboxylative coupling proceeded smoothly employing azoleswith α-alkoxylated with α-alkoxylated acrylic acids acrylic [65]. acids This [65 decarboxylative]. This decarboxylative coupling proceeded coupling proceededsmoothly employing smoothly [Pd(acac)2] as catalyst along with CuCO3.Cu(OH)2. This transformation displays good E/Z employing[Pd(acac)2] [Pd(acac)as catalyst2] as along catalyst with along CuCO with3 CuCO.Cu(OH)3.Cu(OH)2. This 2.transformation This transformation displays displays good good E/Z stereochemistry and α/β regiochemistry. For less acidic benzothiazoles, CuI played a key role in Estereochemistry/Z stereochemistry and andα/β αregiochemistry./β regiochemistry. For Forless less acidic acidic benzothiazoles, benzothiazoles, CuI CuI played played a key a key role role in increasing the acidity at the C2-H of the heteroarene, forming a [Cu]-heterocycle. Therefore, inincreasing increasing the the acidity acidity at at the the C2-H C2-H of of the heteroarene,heteroarene, formingforming aa [Cu]-heterocycle.[Cu]-heterocycle. Therefore,Therefore, depending on the acidity and the nucleophilicity of the azole, there could be two possible pathways dependingdepending onon thethe acidityacidity andand thethe nucleophilicitynucleophilicity ofof thethe azole,azole, therethere couldcould bebe twotwo possiblepossible pathwayspathways to activate the azoles and afford intermediate (I): (i) direct Pd-catalyzed heteroarenes (azoles) via a toto activateactivate thethe azolesazoles and afford afford intermediate ( (II):): (i) (i) direct direct Pd-catalyzed Pd-catalyzed heteroarenes heteroarenes (azoles) (azoles) via via a base-assisted concerted or nonconcerted (carbanionic-type) process, or (ii) heteroarylcopper(III) abase-assisted base-assisted concerted concerted or or nonconcerted nonconcerted (carbani (carbanionic-type)onic-type) process, process, or (ii) heteroarylcopper(heteroarylcopper(IIIIII)) through a transmetalation step with Pd(OAc)2 (Scheme 36). Using these optimized conditions, the throughthrough aa transmetalationtransmetalation step step with with Pd(OAc) Pd(OAc)2 2(Scheme(Scheme 36). 36 ).Using Using these these optimized optimized conditions, conditions, the authors successfully reported a convenient approach to generate α,β-enolizable α-ketoazoles and authors successfully reported a convenient approach to generate α,β-enolizable α-ketoazoles and biologically active C2−C4′ linked azoles. biologically active C2−C4′ linked azoles.

Molecules 2020, 25, 4970 16 of 34 the authors successfully reported a convenient approach to generate α,β-enolizable α-ketoazoles and biologically active C2 C4 linked azoles. Molecules 2020, 25, x FOR PEER− REVIEW0 16 of 33

SchemeScheme 36.36.Pd-catalyzed Pd-catalyzedα-carboxyenol α-carboxyenol ether formation ether formation with various with azoles vari viaous direct azoles decarboxylative via direct decarcross-couplingboxylative and cross proposed-coupling mechanism. and proposed mechanism.

3.3. Alkylation Alkylation of of A Azoleszoles FriedelFriedel-Craft-Craft alkylation alkylation has has been been used used as as the the first first-line-line technique technique for for the the alkylation of of azoles beforebefore direct direct C C–H-H functionalization functionalization came came on on the the scene scene [ [66]].. However, However, Friedel Friedel-Crafts-Crafts alkylation alkylation mostly mostly encountersencounters several didifficultiesfficulties suchsuch as as low low chemo-and chemo-and/or/or regioselectivity, regioselectivity, being being limited limited to electron-richto electron- richsubstrates, substrates, and and harsh harsh reaction reacti conditionson conditions [12]. [12 C–H]. C activation-H activation is providing is providing an eanffi cientefficient tool tool for for the thedirect direct alkylation alkylation of azoles of azoles with with almost almost surgical surgical precision. precision. Great Great contributions contribution bys Fagnou, by Fagnou, Miura Miura and andAckermann Ackermann in the in the field field of azoleof azole alkylation alkylation via via C–H C-H activation activation have have made made thisthis fieldfield wide open for for furtherfurther developments developments [ [66–68].]. 3.1. Primary C–H alkylation of Azoles 3.1. Primary C-H alkylation of Azoles Among different C–H alkylations of azoles, primary alkylation has been widely investigated using Among different C-H alkylations of azoles, primary alkylation has been widely investigated halides, pseudohalides and alkenes as coupling partners. Among the various metals used, it is no using halides, pseudohalides and alkenes as coupling partners. Among the various metals used, it is surprise that Pd adopts a key role, though other metals like Rh, Ni and Cu are catching up, and some no surprise that Pd adopts a key role, though other metals like Rh, Ni and Cu are catching up, and astonishing discoveries have been made in recent years. Alkylation of heteroarenes through the direct some astonishing discoveries have been made in recent years. Alkylation of heteroarenes through the direct cross-coupling with nonactivated alkyl halides containing a β-hydrogen atom, has been a challenging issue. In 2010, Hu and coworkers reported a novel nickel complex for the alkylation of the C-H bond of azoles with nonactivated alkyl halides containing a β-hydrogen atom, using CuI as

Molecules 2020, 25, 4970 17 of 34 cross-coupling with nonactivated alkyl halides containing a β-hydrogen atom, has been a challenging issue. In 2010, Hu and coworkers reported a novel nickel complex for the alkylation of the C–H bond Molecules 2020,, 25,, xx FORFOR PEERPEER REVIEWREVIEW 17 of 33 ofMolecules azoles 2020 with, 25, nonactivatedx FOR PEER REVIEW alkyl halides containing a β-hydrogen atom, using CuI as a cocatalyst17 of 33 (Schemea cocatalyst 37)[ (Scheme69]. A wide 37) range[69]. A of wide functional range groups of functional branching groups at the branchingβ-position at of the the β halides-position showed of the aa cocatalystcocatalyst (Scheme(Scheme 37)37) [69].[69]. AA widewide rangerange ofof functionalfunctional groupsgroups branchingbranching atat thethe ββ--positionposition ofof thethe goodhalides reactivity, showed andgood high reactivity, chemo- and and high regioselectivity. chemo- and regioselectivity. halideshalides showedshowed goodgood reactivity,reactivity, andand highhigh chemo-chemo- andand regioselectivity.regioselectivity.

Scheme 37. The Ni/Cu-catalyzed direct alkylation of heterocyclic C-H bonds. SchemeSchemeScheme 37. 37.37. TheThe NiNi/Cu-catalyzedNi/Cu-catalyzed/Cu-catalyzed direct directdirect alkylation alkylationalkylation of ofof heterocyclic heterocyclicheterocyclic C–H C-HC-H bonds.bonds.

Concurrently,Concurrently, MiuraMiura andand coworkerscoworkers reportedreported aa Pd-catalyzedPd-catalyzed directdirect alkylationalkylation ofof oxazolesoxazoles withwith Concurrently,Concurrently, MiuraMiura andand coworkerscoworkers reportedreported aa Pd-catalyzedPd-catalyzed directdirect alkylationalkylation ofof oxazolesoxazoles withwith nonactivatednonactivated alkylalkyl halideshalides [[70].70]. A variety of alkyl bromidesbromides possessing aa benzyl ether, aa silylsilyl etherether oror nonactivatednonactivated alkylalkyl halideshalides [70].[70]. AA varietyvariety ofof alkylalkyl brbromidesomides possessingpossessing aa benzylbenzyl ether,ether, aa silylsilyl etherether oror aa pivaloylpivaloyl esterester functionalfunctional group,group, transformedtransformed intointo thethe desireddesired productsproducts inin moderatemoderate toto goodgood yieldsyields aa pivaloylpivaloyl esterester functionalfunctional group,group, transformedtransformed intointo thethe desireddesired productsproducts inin momoderatederate toto goodgood yieldsyields (Scheme(Scheme 3838).). Moreover,Moreover, unactivatedunactivated alkylalkyl chlorideschlorides werewere alsoalso wellwell toleratedtolerated employingemploying thisthis catalyticcatalytic (Scheme(Scheme 38).38). Moreover,Moreover, unactivatedunactivated alkylalkyl chlorideschlorides wewerere alsoalso wellwell toleratedtolerated employingemploying thisthis catalyticcatalytic system.system. Unfortunately, 1-iodohexane1-iodohexane gavegave aa muchmuch lowerlower yieldyield (20%)(20%) whilewhile bromocyclohexanebromocyclohexane couldcould system.system. Unfortunately,Unfortunately, 1-iodohexane1-iodohexane gavegave aa muchmuch lowerlower yieldyield (20%)(20%) whilewhile bromocyclohexanebromocyclohexane couldcould notnot provideprovide thethe productproduct duedue toto thethe rapidrapid decompositiondecomposition andand stericsteric hindrance,hindrance, respectively. respectively. notnot provideprovide thethe productproduct duedue toto thethe rapidrapid decompdecompositionosition andand stericsteric hindhindrance,rance, respectively.respectively.

Scheme 38. Pd-catalyzed direct C-H alkylation of benzoxazoles with various alkyl halides. SchemeSchemeScheme 38. 38.38. Pd-catalyzed Pd-catalyzed directdirectdirect C–H C-HC-H alkylationalkylation ofof benzoxazolesbebenzoxazolesnzoxazoles withwith variousvarivariousous alkylalkyl halides.halides.

InIn 2011,2011, AckermannAckermann andand coworkerscoworkers reportedreported thethe alkylationalkylation ofof oxazolesoxazoles withwith benzylbenzyl chlorideschlorides InIn 2011,2011, AckermannAckermann andand coworkerscoworkers reportedreported thethe alkylationalkylation ofof oxazolesoxazoles withwith benzylbenzyl chlorideschlorides andand benzyl phosphate phosphate appl applyingying a aPd(II) Pd(II) complex complex [71]. [71 The]. The authors authors found found that thatphosphinous phosphinous acid Pd(II) acid andand benzylbenzyl phosphatephosphate applapplyingying aa Pd(II)Pd(II) complexcomplex [71].[71]. TheThe authorsauthors foundfound thatthat phosphinousphosphinous acidacid Pd(II)Pd(II) Pd(II)complex complex significantly significantly improved improved the theyield yield in comparison in comparison with with other other palladium palladium catalysts. catalysts. In thethe complexcomplex significantlysignificantly improvedimproved thethe yieldyield inin comparisoncomparison withwith otherother palladiumpalladium catalysts.catalysts. InIn thethe presencepresence of of a prefunctionalizeda prefunctionalized Pd(II) Pd(II) complex, complex, a wide a rangewide ofrange differently of different substitutedly substituted benzyl chlorides benzyl presencepresence ofof aa prefunctionalizedprefunctionalized Pd(II)Pd(II) complex,complex, aa widewide rangerange ofof differentdifferentlyly substitutedsubstituted benzylbenzyl reactedchlorides effi reactedciently efficiently with (benz)oxazoles, with (benz)oxazoles, providing providing the corresponding the corresponding products products in moderate in moderate to high chlorideschlorides reactedreacted efficientlyefficiently withwith (benz)oxazoles,(benz)oxazoles, providingproviding thethe correspondingcorresponding productsproducts inin moderatemoderate yieldsto high (Scheme yields (Scheme 39). 39). toto highhigh yieldsyields (Scheme(Scheme 39).39).

Scheme 39. Benzylations on oxazol(in)es with a Pd- catalyst of a secondary phosphine oxide. SchemeScheme 39.39.39. BenzylationsBenzylations onon oxazol(in)esoxazol(in)es withwith aa Pd-Pd- catalystcacatalysttalyst ofof aaa secondarysecondarysecondary phosphinephosphinephosphine oxide. oxide.oxide.

In 2012, the first example of direct addition between azoles and alkenes via C-H bond activation InIn 2012,2012, thethe firstfirst exampleexample ofof directdirect additionaddition bebetweentween azolesazoles andand alkenesalkenes viavia C-HC-H bondbond activationactivation of heteroarenes was reported by Chang and coworkers using a [{Rh(cod)Cl}2] catalyst (Scheme 40) ofof heteroarenesheteroarenes waswas reportedreported byby ChChangang andand coworkerscoworkers usingusing aa [{Rh(cod)Cl}[{Rh(cod)Cl}22]] catalystcatalyst (Scheme(Scheme 40)40) [72]. A possible reaction pathway follows (i) formation of a mono-rhodium species I via ligand [72].[72]. AA possiblepossible reactionreaction pathwaypathway followsfollows (i)(i) formationformation ofof aa mono-rhodiummono-rhodium speciesspecies II viavia ligandligand exchange with cesium acetate, (ii) base-promoted deprotonation and metalation to generate the exchangeexchange withwith cesiumcesium acetate,acetate, (ii)(ii) base-promotebase-promotedd deprotonationdeprotonation andand metalationmetalation toto generategenerate thethe Rh/heteroaryl species II, (iii) olefin insertion, (iv) β-hydride elimination and re-insertion affording Rh/heteroarylRh/heteroaryl speciesspecies IIII,, (iii)(iii) olefinolefin insertion,insertion, (iv)(iv) ββ-hydride-hydride eliminationelimination andand re-insertionre-insertion affordingaffording

Molecules 2020, 25, 4970 18 of 34

In 2012, the first example of direct addition between azoles and alkenes via C–H bond activation of heteroarenes was reported by Chang and coworkers using a [{Rh(cod)Cl}2] catalyst (Scheme 40)[72]. A possible reaction pathway follows (i) formation of a mono-rhodium species I via ligand exchange MoleculesMolecules 20202020,, 2525,, xx FORFOR PEERPEER REVIEWREVIEW 1818 ofof 3333 with cesium acetate, (ii) base-promoted deprotonation and metalation to generate the Rh/heteroaryl intermediatedspeciesintermediatedII, (iii) olefinIVIV andand insertion, VV respectively,respectively, (iv) β-hydride andand finalfinal elimination protonationprotonation and toto re-insertion deliverdeliver productsproducts affording VIVI withwith intermediated regenerationregenerationIV ofandof thetheV Rh(I)Rh(I)respectively, species.species. and final protonation to deliver products VI with regeneration of the Rh(I) species.

SchemeScheme 40.40. Rh-Rh- catalyzed catalyzed alkylation alkylation by by the the addition addition of of azolesazoles toto alkenes.alkenes.

StyreneStyrene cancancan act actact as asas an an eanﬃ cientefficientefficient alkylating alkylatingalkylating reagent. reagent.reagent. In 2012, InIn the2012,2012, Ong thethe group OngOng reported groupgroup reported areported Ni-Al bimetallic aa Ni-AlNi-Al bimetalliccatalyzedbimetallic alkylation catalyzedcatalyzed ofalkylationalkylation benzimidazoles ofof benzimidazolesbenzimidazoles with styrenes wiwi tothth deliver styrenesstyrenes linear toto deliverdeliver products linearlinear [73 ].productsproducts The reaction [73].[73]. wasTheThe reactionsuccessfullyreaction waswas performed successfullysuccessfully by performed usingperformed Ni(COD) byby using2using/AlMe Ni(COD)Ni(COD)3 cooperative22//AlMeAlMe catalysis33 cooperativecooperative along withcatalysiscatalysis amino-NHC alongalong withwith (L) amino-NHCasamino-NHC ligand (Scheme ((LL)) asas 41ligandligand). Like (Scheme(Scheme in the 41).41). previous LikeLike inin reports, thethe previoprevio theus bindingus reports,reports, of the binding Lewisbinding acid ofof thethe (AlCl LewisLewis3) to acidacid the (AlClbenzimidazole(AlCl33)) to to thethe benzimidazolebenzimidazole favors the linear favorsfavors chain thethe product linearlinear chch dueainain to productproduct steric hindrance. duedue toto stericsteric hindrance.hindrance.

SchemeScheme 41.41. Amino-NHCAmino-NHC mediatedmediated C-HC–HC-H activation activation of of benzimidazole benzimidazole via via Ni-Al Ni-Al synergistic synergistic catalysis. catalysis.

InIn 2015,2015, Filloux Filloux and and Rovis Rovis for for thethe firstfirstfirst timetime introducedintroducedintroduced thethe enantioselectiveenantioselectiveenantioselective alkylationalkylation of of benzoxazolesbenzoxazoles withwith αα-substituted-substituted-substituted acrylatesacrylates acrylates usingusing using aa aRh(I)/chiralphosphineRh(I)/chiralphosphine Rh(I)/chiralphosphine catalyticcatalytic catalytic systemsystem system toto toaffordafford afford 2-2- substitued2-substituedsubstitued benzoxazolesbenzoxazoles benzoxazoles ininin moderatemoderate moderate toto to excellentexcellent excellent yieldsyields yields withwith with goodgood enantioselectivitiesenantioselectivities [74].[74]. [74]. Mechanistically,Mechanistically, Rh(I)-acetate Rh(I)-acetateRh(I)-acetate first firstfirst activates activatesactivates the thethe C–H C-C-HH bondbond ofof the the benzoxazol benzoxazolebenzoxazolee and and migratory migratory insertion insertion follows,follows, providingproviding aa Rh-enolateRh-enolate complex.complex. Then,Then, ββ-H-H eliminationelimination andand hydrorhodationhydrorhodation deliverdeliver thethe heterobenzyl-Rhheterobenzyl-Rh intermediate.intermediate. TheThe authorsauthors proposedproposed ththee crucialcrucial rolerole ofof bulkybulky chiralchiral ligandsligands toto steersteer enantioselectivityenantioselectivity inin thethe desireddesired productsproducts byby discoudiscouragingraging undesiredundesired ligationligation ofof heterocyclesheterocycles oror byby attenuatingattenuating coordination-promotedcoordination-promoted productproduct epimerizationepimerization (Scheme(Scheme 42).42).

Molecules 2020, 25, 4970 19 of 34 follows, providing a Rh-enolate complex. Then, β-H elimination and hydrorhodation deliver the heterobenzyl-Rh intermediate. The authors proposed the crucial role of bulky chiral ligands to steer enantioselectivity in the desired products by discouraging undesired ligation of heterocycles or by attenuatingMolecules 2020,,coordination-promoted 25,, xx FORFOR PEERPEER REVIEWREVIEW product epimerization (Scheme 42). 19 of 33

SchemeScheme 42.42. Rh(I)−bisphosphinebisphosphine catalyzed catalyzed asymmetric, intermolecular hydroheteroarylation ofof − αα-substituted-substituted-substituted acrylateacrylateacrylate derivativesderiderivatives withwith benzoxazoles.benzoxazoles.

InIn thethethe samesamesame year, year,year, Joo JooJoo and andand coworkers coworkerscoworkers explored exploredexplored allylation allylationallylation and andand benzylation benzylationbenzylation reactions reactionsreactions of pyrazolesofof pyrazolespyrazoles by installingby installing an electron-withdrawing an electron-withdrawing group group such assuch a nitro, as aa anitro,nitro, chloro, aa chloro,chloro, or an ester oror anan group esterester at groupgroup the C4 atat position. thethe C4C4 Suchposition. substitution Such substitution decreases thedecreases Lewis basicitythe Lewis of nitrogenbasicity of atom nitrogen and renders atom and the C–Hrenders bond the more C-H acidic, bond thusmore enabling acidic, thus the Pd-catalyzedenabling the Pd-catalyzed regioselective regioselective C–H functionalization C-H functionalization (Scheme 43)[ (Scheme75]. 43) [75].

SchemeScheme 43.43. Pd-catalyzedPd-catalyzed C–HC-H allylation an andd benzylation of pyrazoles.

Concurrently,Concurrently, ShaoShao andand coworkerscoworkers reportedreported aa phosphinephosphine freefree NHC-Pd(II)NHC-Pd(II) complex-catalyzedcomplex-catalyzed directdirect C–HC-H bond benzylation of (benz)oxazoles(benz)oxazoles with benzylbenzyl chlorideschlorides [[76].76]. The authorsauthors presentedpresented aa broadbroad substratesubstrate scopescope withwith goodgood functionalfunctionaltional groupgroupgroup tolerance tolerancetolerance (Scheme (Scheme(Scheme 44 44).44).). In 2017, Li and coworkers described a C5-alkylation of oxazoles with alkylboronic acids using a Pd(OAc)2/AgOAc catalytic system with DDQ as oxidant (Scheme 45)[77]. DDQ facilitates the regeneration of Pd(II) in the catalytic cycle. In 2018, Pan and Wang explored the use of quaternary ammonium triﬂates as a coupling partner for the benzylation of (benz)oxazoles in the presence of a Pd/dcype/K3PO4-catalytic system [78]. + Mechanistically, in situ generated Pd(0) undergoes oxidative addition with ArCH2NMe3 OTf− to form the intermediate B. Subsequent ligand exchange and C–H activation forms the intermediate D via intermediate C. Finally, reductive elimination delivers the desired product (Scheme 46).

Scheme 44. NHC-Pd(II) complex-catalyzed benzylation of (benz)oxazoles with benzyl chlorides.

Molecules 2020, 25, x FOR PEER REVIEW 19 of 33

Scheme 42. Rh(I)−bisphosphine catalyzed asymmetric, intermolecular hydroheteroarylation of α-substituted acrylate derivatives with benzoxazoles.

In the same year, Joo and coworkers explored allylation and benzylation reactions of pyrazoles by installing an electron-withdrawing group such as a nitro, a chloro, or an ester group at the C4 position. Such substitution decreases the Lewis basicity of nitrogen atom and renders the C-H bond more acidic, thus enabling the Pd-catalyzed regioselective C-H functionalization (Scheme 43) [75].

Scheme 43. Pd-catalyzed C-H allylation and benzylation of pyrazoles.

Concurrently, Shao and coworkers reported a phosphine free NHC-Pd(II) complex-catalyzed direct C-H bond benzylation of (benz)oxazoles with benzyl chlorides [76]. The authors presented a Molecules 2020, 25, 4970 20 of 34 broad substrate scope with good functional group tolerance (Scheme 44).

Molecules 2020, 25, x FOR PEER REVIEW 20 of 33

In 2017, Li and coworkers described a C5-alkylation of oxazoles with alkylboronic acids using a Pd(OAc)2/AgOAc catalytic system with DDQ as oxidant (Scheme 45) [77]. DDQ facilitates the Scheme 44. NHC-Pd(II) complex-catalyzed benzylation of (benz)oxazoles with benzyl chlorides.chlorides. regeneration of Pd(II) in the catalytic cycle.

Scheme 45. DDQ-promoted direct C5-alkylation of oxazoles with alkylboronic acids.

In 2018, Pan and Wang explored the use of quaternary ammonium triflates as a coupling partner for the benzylation of (benz)oxazoles in the presence of a Pd/dcype/K3PO4-catalytic system [78]. + - Mechanistically, in situ generated Pd(0) undergoes oxidative addition with ArCH2NMe3 OTf to form the intermediateScheme B. 45. Subsequent DDQ-promoted ligand direct exchange C5-alkylation and C-H of oxazoles activation with forms alkylboronicalkylboronic the intermediate acids.acids. D via intermediate C. Finally, reductive elimination delivers the desired product (Scheme 46). In 2018, Pan and Wang explored the use of quaternary ammonium triflates as a coupling partner for the benzylation of (benz)oxazoles in the presence of a Pd/dcype/K3PO4-catalytic system [78]. + - Mechanistically, in situ generated Pd(0) undergoes oxidative addition with ArCH2NMe3 OTf to form the intermediate B. Subsequent ligand exchange and C-H activation forms the intermediate D via intermediate C. Finally, reductive elimination delivers the desired product (Scheme 46).

SchemeScheme 46.46. Pd-catalyzedPd-catalyzed C–HC-H benzylationbenzylation ofof (benz)oxazoles(benz)oxazoles withwith benzylicbenzylic quaternaryquaternary ammoniumammonium triﬂatestriflates andand aa plausibleplausible mechanism.mechanism.

Recently,Recently, Herbert Herbert and and coworkers coworkers synthesized synthesized Ni(II)-complexes Ni(II)-complexes with phenanthridine-based with phenanthridine-based ligands forligands the alkylationfor the alkylation of azoles of azoles with alkylwith alkyl halides halides [79]. [79]. In this In this work, work, a widea wide range range of of alkyl alkyl halideshalides bearingbearingScheme didifferentﬀerent 46. Pd-catalyzed substituentssubstituents C-H suchsuch benzylation asas carbazole, of (benz)oxazo ester, aryl,aryl,les arylether, with benzylic thioether,thioether, quaternary alkenyl,alkenyl, ammonium andand aliphaticaliphatic groupstriflates show and promising a plausible reactivity mechanism. with benzoxazoles to generate the desired products in low to high yields (Scheme 47). Recently, Herbert and coworkers synthesized Ni(II)-complexes with phenanthridine-based ligands for the alkylation of azoles with alkyl halides [79]. In this work, a wide range of alkyl halides bearing different substituents such as carbazole, ester, aryl, arylether, thioether, alkenyl, and aliphatic groups show promising reactivity with benzoxazoles to generate the desired products in low to high yields (Scheme 47).

Molecules 2020, 25, 4970 21 of 34

groupsMolecules show2020, 25 promising, x FOR PEER reactivity REVIEW with benzoxazoles to generate the desired products in low to21 high of 33 yields (Scheme 47). Molecules 2020, 25, x FOR PEER REVIEW 21 of 33

Scheme 47. [Ni]-catalyzed alkylation of benzannulated azoles with alkylbromides. Scheme 47. [Ni]-catalyzed[Ni]-catalyzed alkylation of ben benzannulatedzannulated azoles with alkylbromides. 3.2. Secondary C-H Alkylation of Azoles 3.2. Secondary C–H Alkylation of Azoles 3.2. SecondaryAlthough C-H significant Alkylation progress of Azoles has been made for primary alkylation, the introduction of a secondaryAlthough alkyl significant significant group is a progress much more has difficult been made task. In for 2010, primary Nakao alkylation, et al. reported the introduction a Ni(0) catalyzed of a secondaryhydroheteroarylation alkyl group of is avinylare much morenes to didifficult givefficult 1,1-diarylalkanes task.task. In 2010, Nakao through et al. oxidativereported a addition Ni(0) catalyzed of C-H hydroheteroarylationbonds to heteroaryl groups[80]. of vinylarenesvinylare [Ni(cod)nes to 2 givegive] and 1,1-diarylalkanes 1,1-diarylalkanescarbene ligand 1,3- throughthrough dimesitylimidazol-2-ylidene oxidativeoxidative additionaddition ofof (IMes) C–HC-H bonds to heteroaryl groups [80]. [Ni(cod) ] and carbene ligand 1,3- dimesitylimidazol-2-ylidene (IMes) bondswere employed to heteroaryl as catalyticgroups[80]. system [Ni(cod) in the2] and nonpol carbenear solvent ligand 1,3-hexane. dimesitylimidazol-2-ylidene A variety of vinylarenes (IMes) that werecontain employedemployed a phenyl as catalyticcatalyticgroup bearing systemsystem ininboth thethe nonpolarnonpolelectronar-rich solventsolvent and hexane.hexane. electron-poor A variety substituents, of vinylarenes reacted that containsuccessfully. aa phenyl phenyl Several group group bearingkinds bearing of both azoles electron-richboth includinelectron andg-rich electron-poorbenzimidazole, and electron-poor substituents, benzoxazole, substituents, reacted oxazole, successfully. reacted and Severalsuccessfully.benzothiazole kinds ofSeveralwere azoles also includingkinds well oftolerated, benzimidazole,azoles affordingincludin benzoxazole,g 1,1-diarylalkanesbenzimidazole, oxazole, withbenzoxazole, and benzothiazolemodest tooxazole, good were yields alsoand wellbenzothiazole(Scheme tolerated, 48). awereffording also 1,1-diarylalkanes well tolerated, affording with modest 1,1-diarylalkanes to good yields (Schemewith modest 48). to good yields (Scheme 48).

Scheme 48. Ni/IMes-catalyzedNi/IMes-catalyzed hydroheteroaryla hydroheteroarylationtion of azoles with styrene.styrene. Scheme 48. Ni/IMes-catalyzed hydroheteroarylation of azoles with styrene. In aa pioneeringpioneering work ofof WangWang andand coworkers,coworkers, N-tosylhydrazonesN-tosylhydrazones have been exploited as a secondaryIn a pioneering alkyl alkyl source source work for for the of the directWang direct alkylation and alkylation coworkers, of az ofoles azolesN-tosylhydrazones with a with Cu-catalyst, a Cu-catalyst, haveoffering been o ﬀa eringgeneral exploited a method general as a methodsecondaryto introduce to alkyl introduce a secondary source a for secondary alkyl the direct group alkyl alkylation on groupan azole of on frameworkaz anoles azole with framework [81]. a Cu-catalyst, Under [ 81basic]. offering Under conditions, a basic general the conditions, methodauthors thetoproposed introduce authors that proposed a secondarya heterocycle-copper that alkyl a heterocycle-copper group species on an azolewas species the framework intermediate, was the [81]. intermediate, Underand a migratory basic and conditions, a migratoryinsertion the of insertion authors the Cu ofproposedcarbene the Cu species that carbene a heterocycle-copperwas species the key was step the in keyspecies this step Cu-catalyzed was in thisthe intermediate, Cu-catalyzed C-H functionalization and C–H a functionalizationmigratory reaction insertion as reaction shownof the Cu asin showncarbeneScheme in 49.species Scheme was 49. the key step in this Cu-catalyzed C-H functionalization reaction as shown in Scheme 49.

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Scheme 49. Cu-catalyzed direct benzylation or allylation of 1,3-azoles with N-tosylhydrazones. SchemeScheme 49.49. Cu-catalyzedCu-catalyzed direct direct benzylation benzylation or or allylationallylation ofof 1,3-azoles1,3-azoles withwith NN-tosylhydrazones.-tosylhydrazones. In 2012, Sawamura and coworkers extended this concept for the allylic alkylation of electron- deficientInIn 2012,2012, 2012, heteroarenes SawamuraSawamura Sawamura andandwith and coworkerscoworkers internal coworkers extendedextendedsecondary extended thisthis allylic conceptconcept this conceptphosphates forfor thethe for allylicallylic resulting the alkylationalkylation allylic in alkylation excellentofof electron-electron- ofγ- electron-deﬁcientdeficientdeficientregioselectivity heteroarenesheteroarenes and heteroarenes E-stereoselectivity withwith internalinternal with internal secondary(Schemesecondary secondary 50) allylicallylic [82]. allylic Inphosphatesphosphates this phosphates reaction, resultingresulting steric resulting factorsinin excellentexcellent in played excellent γγan-- γregioselectivityregioselectivityimportant-regioselectivity role inandand anddetermining EE-stereoselectivity-stereoselectivityE-stereoselectivity the regioselectivity (Scheme(Scheme (Scheme 50)50) of50 )[the[82].[82].82 product.]. InIn In thth thisisis reaction,reaction, reaction, stericsteric steric factorsfactors played played anan importantimportant rolerole ininin determiningdeterminingdetermining thethethe regioselectivityregioselectivityregioselectivity ofofof thethethe product.product.product.

Scheme 50. Cu-catalyzed allylic alkylation of electron-deficient heteroarenes with internal secondary Scheme 50. Cu-catalyzed allylic alkylation of electron-deﬁcient heteroarenes with internal secondary SchemeSchemeallylic phosphates. 50.50. Cu-catalyzedCu-catalyzed allylicallylic alkylationalkylation ofof electron-deficientelectron-deficient heteroarheteroarenesenes withwith internalinternal secondarysecondary allylic phosphates. allylicallylic phosphates.phosphates. Miura and coworkers also utilized N-tosylhydrazones as a radical source in a Ni-catalyzed Miura and coworkers also utilized N-tosylhydrazones as a radical source in a Ni-catalyzed alkylationMiuraMiura ofandand azoles coworkerscoworkers [83]. The alsoalso au utilizedutilizedthors employed N-tosylhydrazonesN-tosylhydrazones two different asas catalyticaa radicalradical systems sourcesource independingin aa Ni-catalyzedNi-catalyzed on the alkylation of azoles [83]. The authors employed two diﬀerent catalytic systems depending on the alkylationalkylationazole, i.e., ofof a azolesazoles nickel [83].[83]. catalyst TheThe auau forthorsthors benzoxazoles employedemployed twotwo and differentdifferent a Co(II) catalyticcatalytic catalyst systemssystems for 5-aryloxazoles dependingdepending onon andthethe azole, i.e., a nickel catalyst for benzoxazoles and a Co(II) catalyst for 5-aryloxazoles and benzothiazoles azole,azole,benzothiazoles i.e.,i.e., aa nickelnickel (Scheme catalystcatalyst 51). Interest forfor benzoxazolesbenzoxazolesingly, the authors andand ruled aa Co(II)Co(II) out a carbenecatalystcatalyst insertionforfor 5-aryloxazoles5-aryloxazoles pathway for and andthis (Scheme 51). Interestingly, the authors ruled out a carbene insertion pathway for this catalytic system. benzothiazolesbenzothiazolescatalytic system. (Scheme(Scheme 51).51). InterestInterestingly,ingly, thethe authorsauthors ruledruled outout aa carbenecarbene insertioninsertion pathwaypathway forfor thisthis catalyticcatalytic system.system.

SchemeScheme 51.51. Ni- and Co-catalyzedCo-catalyzed directdirect alkylationalkylation ofof azolesazoles withwith N-tosylhydrazonesN-tosylhydrazones bearingbearing unactivatedSchemeSchemeunactivated 51.51. secondary secondaryNi-Ni- andand alkylCo-catalyzedCo-catalyzedalkyl groups. groups. (direct(adirecta)) Ni-catalyzed;Ni-catalyzed; alkylationalkylation ( b( bofof)) Co-catalyzed. Co-catalyzed.azolesazoles withwith N-tosylhydrazonesN-tosylhydrazones bearingbearing unactivatedunactivated secondarysecondary alkylalkyl groups.groups. ((aa)) Ni-catalyzed;Ni-catalyzed; ((bb)) Co-catalyzed.Co-catalyzed. InIn 2013,2013, VanVan der der Eycken Eycken and and coworkers coworkers discovered discovered aa novelnovel heteroarene-amine-ketoneheteroarene-amine-ketone couplingcoupling (HAK-coupling)(HAK-coupling)InIn 2013,2013, VanVan for forderder the the EyckenEycken direct direct andand secondary secondary coworkerscoworkers alkylation alkylation discoverdiscover of ofeded azoles azoles aa novelnovel [ 84[84]. ].heteroarene-amine-ketoneheteroarene-amine-ketone ThisThis unprecedentedunprecedented Cu-catalyzedCu-catalyzed couplingcoupling HAK(HAK-coupling)(HAK-coupling)HAK couplingcoupling waswas forfor operationallythetheoperationally directdirect secondarysecondary simplesimple alkylationalkylation andand allowedallowed ofof azolesazoles thethe facilefacile [84].[84]. installation installationThisThis unprecedentedunprecedented ofof nitrogen-containingnitrogen-containing Cu-catalyzedCu-catalyzed alkylHAKHAKalkyl or couplingorcoupling alkaloidalkaloid waswas sideside operationallyoperationally chainschains onon thethe simplesimple azoleazole moiety, moiety, andand allowedallowed using using readily readilythethe facilefacile available available installationinstallation starting starting ofof materials.nitrogen-containing nitrogen-containingmaterials. TheThe HAKHAK couplingalkylalkylcoupling oror alkaloidalkaloid reactionreaction sideside plausiblyplausibly chainschains proceededononproceeded thethe azoleazole throughthrough moiety,moiety, the the usingusing initialinitial readilyreadily condensationcondensation availableavailable of startingstartingof thethe aldehydealdehyde/ketone materials.materials./ketone TheThe HAKHAK withwith thecouplingcouplingthe amine, amine, reactionreaction leading leading plausiblyplausibly to to the the corresponding corresponding proceededproceeded throughthrough iminium iminium thethe ion io inin whichnitialitial which condensationcondensation was was attacked attacked of byof the the by aldehyde/ketonethealdehyde/ketone azole–Cu azole–Cu to a ﬀtoord afford withwith the ﬁnalthethethe amine,amine,final product product leadingleading (Scheme (Scheme toto the the52). correspondingcorresponding 52). iminiumiminium ioionn whichwhich waswas attackedattacked byby thethe azole–Cuazole–Cu toto affordafford thethe finalfinal productproduct (Scheme(Scheme 52).52).

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SchemeScheme 52.52. Cu-catalyzedCu-catalyzed directdirect secondarysecondary C–HC-H alkylationalkylation ofof azoles.azoles. SchemeScheme 52.52. Cu-catalyzedCu-catalyzed directdirect secondarysecondary C-HC-H alkylationalkylation ofof azoles.azoles. SimilarSimilar toto Wang’sWang’s groupgroup report,report, inin 2013,2013,Das Dasand andcoworkers coworkers alsoalso employedemployed N-tosylhydrazonesN-tosylhydrazones SimilarSimilar toto Wang’sWang’s groupgroup reportreport,, inin 2013,2013, DasDas andand coworkerscoworkers alsoalso employedemployed N-tosylhydrazonesN-tosylhydrazones forfor thethe directdirect benzylation of of aryl aryl substituted substituted 1,3,4-oxadiazoles 1,3,4-oxadiazoles in in the the presence presence of of a Cu-catalyst a Cu-catalyst [85]. [85 A]. forfor thethe directdirect benzylationbenzylation ofof arylaryl substitutedsubstituted 1,3,4-oxadiazoles1,3,4-oxadiazoles inin thethe presencepresence ofof aa Cu-catalystCu-catalyst [85].[85]. AA Awide wide range range of of substituted substituted oxadiazoles oxadiazoles were were prepared prepared in in high high yi yieldselds (Scheme (Scheme 53). 53 ). widewide rangerange ofof substitutedsubstituted oxadiazolesoxadiazoles werewere preparedprepared inin highhigh yiyieldselds (Scheme(Scheme 53).53).

CuI (0.05 equiv), N N N N NNHTs CuICuI (0.05 (0.05 equiv), equiv), N N 2 N NN NNHTs Cs2CO3 (2.5 equiv) N N R22 N Cs2CO3 (2.5 equiv) R 1 2 Cs2CO3 (2.5 equiv) 1 R R1 R2 Me o R11 O RR1 O R2 Me toluene, 110 oC, 3h R OO O R Me toluene,toluene, 110 110 oC,C, 3h 3h Me 1 Me R11 = Ar, heteroaromatic; 17 examples R2 = Ar, heteroaromatic; 17 examples R2 = Ar, alkyl 80-89% R2 = Ar, alkyl 80-89%80-89% R = Ar, alkyl Scheme 53. Cu-catalyzed direct cross-coupling of 1,3,4-oxadiazoles with N-tosylhydrazones. SchemeScheme 53.53.53. Cu-catalyzedCu-catalyzed directdirect cross-couplingcross-couplicross-couplingng ofofof 1,3,4-oxadiazoles1,3,4-oxadiazoles1,3,4-oxadiazoles with withwith N NN-tosylhydrazones.-tosylhydrazones.-tosylhydrazones. In 2014, Miura and coworkers employed diarylmethyl carbonates or pivalates as coupling InInIn 2014, 2014,2014, Miura MiuraMiura and andand coworkers coworkerscoworkers employed employedemployed diarylmethyl diaryldiarylmethylmethyl carbonates carbonatescarbonates or pivalates oror pivalatespivalates as coupling asas couplingcoupling partners partners for the alkylation of oxazoles with a PdCl2(MeCN)2/PPhCy2 catalytic system [86]. This gives for the alkylation of oxazoles with a PdCl (MeCN) /2PPhCy catalytic2 system2 [86]. This gives the access partnerspartners forfor thethe alkylationalkylation ofof oxazolesoxazoles withwith2 aa PdClPdCl2 2(MeCN)(MeCN)2 2/PPhCy/PPhCy2 catalyticcatalytic systemsystem [86].[86]. ThisThis givesgives the access to challenging heteroarene-containing triarylmethanes (Scheme 54). tothethe challenging accessaccess toto challengingchallenging heteroarene-containing heteroarene-coheteroarene-co triarylmethanesntainingntaining triarylmettriarylmet (Schemehaneshanes 54 (Scheme).(Scheme 54).54).

Scheme 54. Pd-catalyzed C−H/C−O coupling of oxazoles and diarylmethanol derivatives. SchemeSchemeScheme 54. 54.54. Pd-catalyzed Pd-catalyzedPd-catalyzed C CC−−HH/CH/C/C−−OO coupling coupling of of oxazoles oxazoles and and di diarylmethanoldiarylmethanolarylmethanol derivatives.derivatives. − − In the same year, Chen and coworkers further evolved the direct C–H bond alkylation of azoles InInIn the thethe same samesame year, year,year, Chen ChenChen and andand coworkers coworkerscoworkers further furtherfurther evolved evevolvedolved the the directthe directdirect C–H C–HC–H bond bondbond alkylation alkylationalkylation of azoles ofof azolesazoles with with ferrocenyl ketone-derived N-tosylhydrazones using an inexpensive CuBr catalyst [87]. Without ferrocenylwithwith ferrocenylferrocenyl ketone-derived ketone-derivedketone-derived N-tosylhydrazones N-tosylhydrazonesN-tosylhydrazones using using anusing inexpensive anan inexpensiveinexpensive CuBr catalyst CuBrCuBr catalystcatalyst [87]. Without [87].[87]. WithoutWithout using using CuBr, the product was obtained in low yield, whereas replacement of CuBr with other CuBr,usingusing theCuBr,CuBr, product thethe wasproductproduct obtained waswas inobtainedobtained low yield, inin whereas lowlow yield,yield, replacement whereaswhereas ofreplacementreplacement CuBr with other ofof CuBrCuBr transition withwith metalotherother transition metal salts slowed down the reaction. This catalyst system displayed good tolerance saltstransitiontransition slowed metalmetal down saltssalts the slowedslowed reaction. dodo Thiswnwn the catalystthe reaction.reaction. system ThisThis displayed catalystcatalyst good systemsystem tolerance displayeddisplayed towards goodgood a tolerancetolerance range of towards a range of functional groups on the ferrocenyl ketone derived N-tosylhydrazones (Scheme functionaltowardstowards aa groupsrangerange ofof on functionalfunctional the ferrocenyl groupsgroups ketone onon thethe derived feferrocenylrrocenylN-tosylhydrazones ketoneketone derivedderived (Scheme N-tosylhydrazonesN-tosylhydrazones 55). (Scheme(Scheme 55). 55).55).

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SchemeScheme 55. Cu-catalyzedCu-catalyzed cross-coupling cross-coupling of ferrocenyl of ferrocenyl ketone-derived ketone-derived N-tosylhydrazonesN-tosylhydrazones with SchemeScheme 55.55. Cu-catalyzedCu-catalyzed cross-couplingcross-coupling ofof ferrocenylferrocenyl ketone-derivedketone-derived NN-tosylhydrazones-tosylhydrazones withwith withbenzoxazoles. benzoxazoles. benzoxazoles.benzoxazoles.

InIn 2015,2015, ZhouZhou andand coworkerscoworkers reportedreported aa challengingchallenging cyclopropylationcyclopropylation ofof benzoxazolesbenzoxazoles usingusing InIn 2015,2015, ZhouZhou andand coworkerscoworkers reportedreported aa challengingchallenging cyclopropylationcyclopropylation ofof benzoxazolesbenzoxazoles usingusing stereoretentivestereoretentive cyclopropylcyclopropyl halideshalides andand aa Pd(0)Pd(0) catalysticcatalystic systemsystem [[88].88]. TheThe reactionreaction startedstarted withwith thethe stereoretentivestereoretentive cyclopropylcyclopropyl halideshalides andand aa Pd(0)Pd(0) catalycatalysticstic systemsystem [88].[88]. TheThe reactionreaction startedstarted withwith thethe oxidativeoxidative additionaddition toto thethe cyclopropylcyclopropyl C–XC-X bondbond followedfollowed byby transmetalationtransmetalation ofof anan anionicanionic heterocycle.heterocycle. oxidativeoxidative additionaddition toto thethe cyclopropylcyclopropyl C-XC-X bondbond followedfollowed byby transmetalationtransmetalation ofof anan anionicanionic heterocycle.heterocycle. Finally,Finally, reductivereductive eliminationelimination delivered delivered the the desired desired coupling coupling product product (Scheme (Scheme 56 56).). Finally,Finally, reductivereductive eliminationelimination delivereddelivered thethe desireddesired couplingcoupling productproduct (Scheme(Scheme 56).56).

Scheme 56. Pd catalyzed cyclopropylation of benzoxazoles with cyclopropyl halides. SchemeScheme 56.56. PdPd catalyzedcatalyzed cyclopropylationcyclopropylation ofof benzoxazolesbenzoxazoles withwith cyclopropylcyclopropyl halides.halides.

The first rhodium-catalyzed selective alkylation of benzimidazoles with N,N-dimethyl TheThe ﬁrstfirstfirst rhodium-catalyzed rhodium-catalyzedrhodium-catalyzed selective selectiveselective alkylation alkylationalkylation of benzimidazoles ofof benzimidazolesbenzimidazoles with N,N -dimethylwithwith N,NN,N acrylamide-dimethyl-dimethyl acrylamide was successfully developed by Ellman and coworkers in 2017 [89]. The combination of wasacrylamideacrylamide successfully waswas developedsuccessfullysuccessfully by developeddeveloped Ellman and byby coworkers EllmanEllman and inand 2017 coworkerscoworkers [89]. The inin combination 20172017 [89].[89]. TheThe of the combinationcombination electron-poor ofof the electron-poorF ligand dArFpe with a Rh(I) catalyst in the presence of K3PO4 selectively delivered ligandthethe electron-poorelectron-poor dAr pe with ligandligand a Rh(I) dArdAr catalystFFpepe withwith in aa Rh(I) theRh(I) presence catalystcatalyst ofinin Kthethe3PO presencepresence4 selectively ofof KK33POPO delivered44 selectivelyselectively thealkylation delivereddelivered the alkylation product in high yields (Scheme 57). productthethe alkylationalkylation in high productproduct yields (Scheme inin hihighgh yields yields57). (Scheme(Scheme 57).57).

Scheme 57. Rh(I)-catalyzed branched alkylation of benzimidazoles. SchemeScheme 57.57. Rh(I)-catalyzedRh(I)-catalyzed branchedbranched alkylationalalkylationkylation ofof benzimidazoles.benzimidazoles.

In the same year, a Pd-catalyzed desulfonative deprotonative cross-coupling reaction of benzylic InIn thethe samesame year,year, aa Pd-catalyzedPd-catalyzed desulfonativedesulfonative deprotonativedeprotonative cross-couplingcross-coupling reactionreaction ofof benzylicbenzylic sulfone derivatives with 1,3-oxazoles was reported by Crudden and coworkers [90]. The presented sulfonesulfone derivativesderivatives withwith 1,3-oxazoles1,3-oxaz1,3-oxazolesoles waswas reportedreported byby CruddenCruddenCrudden andandand coworkerscoworkerscoworkers [[90].[90].90]. TheThe presentedpresented methodology showed a high functional group tolerance and afforded excellent yields (Scheme 58). methodologymethodology showedshowed aaa highhighhigh functionalfunctionalfunctional groupgroupgroup tolerance toleratolerancence and andand a affordedaffordedﬀorded excellent excellentexcellent yields yieldsyields (Scheme (Scheme(Scheme 58 58).58).).

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SchemeScheme 58.58. Pd-catalyzedPd-catalyzed desulfonative desulfonative cross-coupling cross-coupling reac reactionreactiontion of of benzylicbenzylic sulfonesulfone derivativesderivatives withwith 1,3-oxazoles.1,3-oxazoles.

2 InIn 2017,2017,2017, Mandal Mandal and and coworkerscoworkers developeddeveloped aaa Ni(COD)Ni(COD)Ni(COD)222 catalyzedcatalyzed regioselectiveregioselective hydroheteroarylationhydroheteroarylation ofof vinylarenevinylarene vinylarenesss withwith with benzoxazoles,benzoxazoles, benzoxazoles, providingproviding providing anan an exclusivelyexclusively exclusively widewide wide rangerange range ofof 1,1-1,1- of 1,1-diarylethanediarylethanediarylethane productsproducts products [91].[91]. [91 TheThe]. The authorsauthors authors werewere were ableable able toto to isolateisolate isolate andand and characterizecharacterize characterize thethe the activeactive active catalystcatalyst by by single-crystalsingle-crystal X-rayX-ray crystallographycrystallography (Scheme(Scheme 5959)59))...

Scheme 59. N-heterocyclic carbene and Ni(COD)2-catalyzed hydroheteroarylation of vinylarenes SchemeScheme 59.59.59. NN-heterocyclic-heterocyclic-heterocyclic carbene carbene andand Ni(COD)Ni(COD)Ni(COD)22-catalyzed-catalyzed-catalyzed hydroheteroarylation hydroheteroarylation of of vinylarenesvinylarenesvinylarenes withwith benzoxazole.benzoxazole.

Similarly,Similarly, SunSun andand coworkerscoworkers alsoalso employedemployed aa NHCs-basedNHCs-based nickelnickel catalyticcatalytic systemsystem for for thethe regioselectiveregioselective hydroarylahydroaryla hydroarylationtiontion ofof of vinylarenesvinylarenes vinylarenes withwith with benzothiazoles,benzothiazoles, benzothiazoles, affordingaffording aﬀording thethe the desireddesired desired productproduct product inin highinhigh high yieldyield yield [92].[92]. [92 ].InIn Inthisthis this reaction,reaction, reaction, thethe the regioselectivityregioselectivity regioselectivity isis is controlledcontrolled controlled byby by the the sterically sterically demandingdemanding 3 2 Ni(IMes)[P(OEt)Ni(IMes)[P(OEt)33]Br]Br]Br22 catalystcatalyst (Scheme(Scheme 60).60).60).

SchemeScheme 60.60. Ni-catalyzedNi-catalyzed hydroarylation hydroarylation of of vinylarenes vinylarenes withwith benzothiazoles.benzothiazoles.

InIn 2019,2019, 2019, WangWang Wang andand and coworkerscoworkers coworkers exploitedexploited exploited anan econ anecon economicalomicalomical Cu(I)-catalystCu(I)-catalyst Cu(I)-catalyst toto achieveachieve to achieve thethe cross-cross- the couplingcross-couplingcoupling ofof bis(trimethylsilyl)diazomethanebis(trimethylsilyl)diazomethane of bis(trimethylsilyl)diazomethane andand bebe andnzoxazoles/oxazoles,nzoxazoles/oxazoles, benzoxazoles/oxazoles, affordingaffording aﬀ ordingaa seriesseries a ofof series 1,1-1,1- bis(trimethylsilyl)-methylatedofbis(trimethylsilyl)-methylated 1,1-bis(trimethylsilyl)-methylated heteroaromaticheteroaromatic heteroaromatic compcomp compoundsoundsounds inin moderatemoderate in moderate toto togoodgood good yields,yields, yields, throughthrough through a a carbenecarbene migratorymigratory insertioninsertion processprocess [[93].[93].93]. MechanistiMechanisti Mechanisticcc studiesstudies indicatedindicated thatthat the the main main step step is is thethe formationformation ofof a a Cu(I) Cu(I) carbene carbene species, species, followed followed by by migratory migratory insertion insertion and and protonation protonation to to produce produce the the finalﬁnalfinal products,products, asas shownshown inin SchemeScheme 6161.61..

3.3. Tertiary C–H Alkylation of Azoles The inclusion of a tertiary alkyl group in the azole scaﬀold is challenging due to the steric eﬀects and possible isomerization. In 2012, Xia and coworkers successfully reported a well-known Pd-catalyzed C–H benzylation of azoles employing benzyl chlorides to generate a quaternary carbon center [94]. Mechanistically, a Pd(0) species undergoes oxidative addition to generate the

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Molecules 2020, 25, 4970 26 of 34 benzylpalladium(II) complex B, followed by a transmetalation step with lithium/azole species A to form intermediate C. Finally, reductive elimination delivers the mono-benzylated product D. The authors used Na2CO3 as base to synthesize the tribenzylated products via nucleophilic substitution with benzyl chlorideMolecules 2020 (Scheme, 25, x FOR 62). PEER REVIEW 26 of 33

Scheme 61. Cu(I)-catalyzed reaction of bis(trimethylsilyl)diazomethane with benzoxazoles and oxazoles.

3.3. Tertiary C-H Alkylation of Azoles The inclusion of a tertiary alkyl group in the azole scaffold is challenging due to the steric effects and possible isomerization. In 2012, Xia and coworkers successfully reported a well-known Pd- catalyzed C-H benzylation of azoles employing benzyl chlorides to generate a quaternary carbon center [94]. Mechanistically, a Pd(0) species undergoes oxidative addition to generate the benzylpalladium(II) complex B, followed by a transmetalation step with lithium/azole species A to form intermediate C. Finally, reductive elimination delivers the mono-benzylated product D. The SchemeScheme 61. Cu(I)-catalyzedCu(I)-catalyzed reaction reaction of ofbis(trimethy bis(trimethylsilyl)diazomethanelsilyl)diazomethane with with benzoxazoles benzoxazoles and authors used Na2CO3 as base to synthesize the tribenzylated products via nucleophilic substitution andoxazoles. oxazoles. with benzyl chloride (Scheme 62). 3.3. Tertiary C-H Alkylation of Azoles The inclusion of a tertiary alkyl group in the azole scaffold is challenging due to the steric effects and possible isomerization. In 2012, Xia and coworkers successfully reported a well-known Pd- catalyzed C-H benzylation of azoles employing benzyl chlorides to generate a quaternary carbon center [94]. Mechanistically, a Pd(0) species undergoes oxidative addition to generate the benzylpalladium(II) complex B, followed by a transmetalation step with lithium/azole species A to form intermediate C. Finally, reductive elimination delivers the mono-benzylated product D. The authors used Na2CO3 as base to synthesize the tribenzylated products via nucleophilic substitution with benzyl chloride (Scheme 62).

Scheme 62. Palladium-catalyzed functionalization of azolesazoles with a quaternary carbon center.

4. Alkynylation The transitiontransition metal-catalyzed metal-catalyzed alkynylation alkynylation of azolesof azoles provides provides a straightforward a straightforward method method to access to diverselyaccess diversely substituted substituted azole acetylenes. azole acetylenes. In 2010, Piguel In 2010, and coworkersPiguel and disclosed coworkers copper-catalyzed disclosed copper- direct alkynylationcatalyzed direct of various alkynylation azoles of with various 1,1-dibromo-1-alkenes azoles with 1,1-dibromo-1-alkenes (Scheme 63, left) [95 (Scheme]. The authors 63, left) proposed [95]. The thatauthors the Cu(III)-intermediateproposed that the Cu(III) readily-intermediate undergoes reductive readily undergoes elimination reductive to deliver elimination the desired productto deliver in moderatethe desired to product good yields in moderate under mild to good reaction yields conditions. under mild Later reaction in 2012, conditions. Zhu and coworkers Later in 2012, reported Zhu alkynylationsand coworkers of oxazolesreported andalkynylations benzothiazoles of oxazoles using apalladium and benzothiazoles catalytic system using employing a palladium inexpensive catalytic gem-dichloroalkenes as user-friendly electrophiles with a broad scope (Scheme 63, right) [96]. system employingScheme 62. inexpensivePalladium-catalyzed gem-dichloroalkenes functionalization as of user-friendly azoles with a electrophilesquaternary carbon with center. a broad scope (SchemeIn 2010, 63, right) Miura [96]. and coworkers reported a pioneering example of the metal-catalyzed direct C–H alkynylation of azoles with terminal alkynes. The reaction proceeded by using a stoichiometric or 4. Alkynylation sub-stoichiometric quantity of copper. Subsequently, the same group further developed nickel-catalyzed directThe alkynylation transition ofmetal-catalyzed azoles [97]. In alkynylation the presence of of azoles a NiBr providesdiglyme a catalyticstraightforward system withmethod O asto 2· 2 oxidant,access diversely they coupled substituted various arylacetylenesazole acetylenes. with In benzoxazoles 2010, Piguel to aandﬀord coworkers the desired disclosed products incopper- low to moderatecatalyzed yields.direct alkynylation In the proposed of various reaction azoles mechanism, with 1,1-dibromo-1-alkenes an (alkynyl)nickel intermediate, (Scheme 63, generated left) [95]. with The authors proposed that the Cu(III)-intermediate readily undergoes reductive elimination to deliver the desired product in moderate to good yields under mild reaction conditions. Later in 2012, Zhu and coworkers reported alkynylations of oxazoles and benzothiazoles using a palladium catalytic system employing inexpensive gem-dichloroalkenes as user-friendly electrophiles with a broad scope (Scheme 63, right) [96].

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Ni and a base, undergoes transmetalation with the heteroaryllithium. The desired product results after reductive elimination (Scheme 64). Molecules 2020, 25, x FOR PEER REVIEW 27 of 33 Scheme 63. Transition metal-catalyzed direct alkynylation of azoles with 1,1-dihalo-1-alkenes.

In 2010, Miura and coworkers reported a pioneering example of the metal-catalyzed direct C–H alkynylation of azoles with terminal alkynes. The reaction proceeded by using a stoichiometric or sub-stoichiometric quantity of copper. Subsequently, the same group further developed nickel- catalyzed direct alkynylation of azoles [97]. In the presence of a NiBr2·diglyme catalytic system with O2 as oxidant, they coupled various arylacetylenes with benzoxazoles to afford the desired products in low to moderate yields. In the proposed reaction mechanism, an (alkynyl)nickel intermediate, generatedSchemeScheme with 63. 63.Ni Transition and a base, metal-catalyzedmetal-catalyzed undergoes directtransmetalationdirect alkynylationalkynylation with ofof azolesazoles the withheteroaryllithium.with 1,1-dihalo-1-alkenes.1,1-dihalo-1-alkenes. The desired product results after reductive elimination (Scheme 64). In 2010, Miura and coworkers reported a pioneering example of the metal-catalyzed direct C–H alkynylation of azoles with terminal alkynes. The reaction proceeded by using a stoichiometric or sub-stoichiometric quantity of copper. Subsequently, the same group further developed nickel- catalyzed direct alkynylation of azoles [97]. In the presence of a NiBr2·diglyme catalytic system with O2 as oxidant, they coupled various arylacetylenes with benzoxazoles to afford the desired products in low to moderate yields. In the proposed reaction mechanism, an (alkynyl)nickel intermediate, generated with Ni and a base, undergoes transmetalation with the heteroaryllithium. The desired product results after reductive elimination (Scheme 64). SchemeScheme 64.64. Ni-catalyzedNi-catalyzed directdirect alkynylationalkynylation ofof azolesazoles withwith terminalterminal alkynes.alkynes.

In 2013, Lee and coworkers exploited the well-known Pd catalytic system for decarboxylative In 2013, Lee and coworkers exploited the well-known Pd catalytic system for decarboxylative C–H alkynylation of benzoxazoles with , -ynoic acids [98]. The authors showed the superior activity C–H alkynylation of benzoxazoles withα α,ββ-ynoic acids [98]. The authors showed the superior activity of 1,3-bis(diphenylphosphanyl)propane (dppp) as ligand for Pd to inhibit dimerization. The proposed of 1,3-bis(diphenylphosphanyl)propane (dppp) as ligand for Pd to inhibit dimerization. The , mechanismproposed mechanism involved (i) silver-oxide-catalyzedinvolved (i) silver-oxide-catalyzedα β-ynoic acid decarboxylation,α,β-ynoic acid (ii)decarboxylation, transmetalation (ii) to B C formtransmetalation intermediate to form, (iii) carbopalladationintermediate B, (iii) with carbopalladation the C–N double bondwith inthe the C–N benzoxazole double bond to aﬀ ordin the, andbenzoxazole (iv) β-hydride to afford elimination C, and (iv) (Scheme β-hydride 65). elimination (Scheme 65). Scheme 64. Ni-catalyzed direct alkynylation of azoles with terminal alkynes.

In 2013, Lee and coworkers exploited the well-known Pd catalytic system for decarboxylative C–H alkynylation of benzoxazoles with α,β-ynoic acids [98]. The authors showed the superior activity of 1,3-bis(diphenylphosphanyl)propane (dppp) as ligand for Pd to inhibit dimerization. The proposed mechanism involved (i) silver-oxide-catalyzed α,β-ynoic acid decarboxylation, (ii) transmetalation to form intermediate B, (iii) carbopalladation with the C–N double bond in the benzoxazole to afford C, and (iv) β-hydride elimination (Scheme 65).

SchemeScheme 65.65. Pd-catalyzedPd-catalyzed decarboxylativedecarboxylative C–HC–H alkynylationalkynylation ofof benzoxazolesbenzoxazoles withwith αα,,ββ-ynoic-ynoic acids.acids.

InIn 2014,2014, Theunissen, Theunissen, Evano Evano and coworkersand coworkers developed developed an alternative an strategyalternative for thestrategy alkynylation for the of azolesalkynylation with copper of azoles acetylides with coppe [99].r The acetylides use of preformed [99]. The use copper of preformed acetylides copper provided acetylides many advantages provided over other approaches, such as better functional group tolerance, mild reaction conditions, and the possibility of forming complex scaﬀolds (Scheme 66).

Scheme 65. Pd-catalyzed decarboxylative C–H alkynylation of benzoxazoles with α,β-ynoic acids.

In 2014, Theunissen, Evano and coworkers developed an alternative strategy for the alkynylation of azoles with copper acetylides [99]. The use of preformed copper acetylides provided

MoleculesMolecules 20202020,, 2525,, xx FORFOR PEERPEER REVIEWREVIEW 2828 ofof 3333 manyMoleculesmany advantagesadvantages2020, 25, 4970 overover otherother approaapproaches,ches, suchsuch asas betterbetter functionalfunctional groupgroup tolerance,tolerance, mildmild reactionreaction28 of 34 conditions,conditions, andand thethe possibilitypossibility ofof formingforming complexcomplex scaffoldsscaffolds (Scheme(Scheme 66).66).

SchemeScheme 66. 66. DirectDirect alkynylationalkynylation of of arenes arenes with with Cu Cu acetylides. acetylides.

InIn 2015,2015,2015, Mannepalli MannepalliMannepalli and andand coworkers coworkerscoworkers developed developeddeveloped an air- ananand air-air- moisture-stable andand moisture-stablemoisture-stable Pd(II) carbene Pd(II)Pd(II) complexcarbenecarbene complexforcomplex the alkynylation forfor thethe alkynylationalkynylation of azoles with ofof azoles terminalazoles withwith alkynes terminalterminal and arylalkynesalkynes propiolic andand acidsarylaryl propiolicpropiolic by cross-dehydrogenative acidsacids byby cross-cross- dehydrogenativeordehydrogenative decarboxylative oror coupling,decarboxylativedecarboxylative respectively coupling,coupling, [100 respecrespec]. A widetivelytively range [100].[100]. ofAA azoleswidewide rangerange including ofof azolesazoles benzoxazoles, includingincluding benzoxazoles,benzothiazoles,benzoxazoles, benzothiazoles,benzothiazoles, imidazoles, and imidazoles, benzimizolesimidazoles, andand aﬀorded benzimizolesbenzimizoles the desired affordedafforded alkynylation thethe desireddesired products alkynylationalkynylation in moderate productstoproducts high yields inin moderatemoderate (Scheme toto 67 highhigh). yieldsyields (Scheme(Scheme 67).67).

SchemeScheme 67. 67. DehydrogenativeDehydrogenative and and decarboxylative decarboxylative C–H C–H alky alkynylationalkynylationnylation ofof heteroarenes, heteroarenes, catalyzed catalyzed by by a a Pd(II)–carbenePd(II)–carbene complex. complex.

SubsequentlySubsequently in in 2018, 2018, Joo Joo and and coworkers coworkers further further extended extended the the substrate substrate scope scope of of the the transition transition metal-catalyzedmetal-catalyzed alkynylationalkynylation alkynylation ofof of azolesazoles azoles withwith with termintermin terminalalal alkynesalkynes alkynes [101].[101]. [101 TheThe]. nitro Thenitro nitrogroupgroup group atat thethe at four-four- the positionfour-positionposition ofof pyrazolespyrazoles of pyrazoles facilitatesfacilitates facilitates C–HC–H cleavagecleavage C–H cleavage toto affordafford to thethe aﬀ desiredorddesired the alkynylalkynyl desired pyrazolespyrazoles alkynyl pyrazolesinin moderatemoderate in yieldsmoderateyields (Scheme(Scheme yields 68).68). (Scheme 68).

SchemeScheme 68. 68. Palladium-catalyzedPalladium-catalyzed cross-couplingcross-coupling ofof nitropyrazoles nitropyrazoles with with terminal terminal alkynes. alkynes.

Recently,Recently, Punji Punji and and coworkers coworkers reported reported a a Ni(II)-catalyzedNi(II)-catalyzed C(2)–H C(2)–H bond bond alkynylation alkynylation of of (benzo)thiazoles,(benzo)thiazoles, (benz)imidazoles,(benz)imidazoles, (benz)imidazoles, andand and oxazolesoxazoles oxazoles wiwi withthth alkynylalkynyl alkynyl bromides,bromides, bromides, withwith with thethe the useuse use ofof of neitherneither neither aa copperacopper copper cocatalystcocatalyst cocatalyst nornor nor phosphinephosphine phosphine ligandsligands ligands [102].[102]. [102]. ThTh Theee reactionsreactions reactions featuredfeatured featured goodgood good functionalfunctional group tolerancetolerance andand widewidewide substrate substratesubstrate scope, scope,scope, despite despitedespite the thethe high hihighgh temperature temperaturetemperature required requiredrequired for forfor the thethe reaction reactionreaction (Scheme (Scheme(Scheme 69). 69).69).

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SchemeScheme 69.69.N Nii (II)-catalyzed (II)-catalyzed C–H bond alkynylation of benzothiazoles and related azoles.

5.5. Conclusions and Perspectives InIn this review, review, we we summarized summarized recent recent developmen developmentsts in the in thetransition transition metal-catalyzed metal-catalyzed direct direct C−H C H functionalization of azoles. These functionalizations are some of the most efficient methods to functionalization− of azoles. These functionalizations are some of the most efficient methods to introduceintroduce variousvarious substitutedsubstituted olefins, olefins, alkanes, alkanes, and and alkynes alkynes to to azoles. azoles. In In addition addition to to the the importance importance of Pdof Pd in thisin this field, field, researchers researchers have have widely widely explored explored several several other transitionother transition metals metals such as such Cu, Rh,as Cu, Co, Rh, Ni, andCo, Ru.Ni, and The majorRu. The advantage major advantage of transition of transition metal-catalyzed metal-catalyzed direct C–H direct activation C–H isactivation that it requires is that no it prefunctionalizationrequires no prefunctionalization of the starting of azoles, the starting resulting azoles, in, e.g., resulting a wide in, scope, e.g., modularity, a wide scope, and modularity, high yields. Despiteand high considerable yields. Despite advances, considerable many advances, challenges ma remain,ny challenges e.g., overcoming remain, e.g., the overcoming need for strong the need and t harshfor strong bases and such harsh as LiO bases and Busuch anions, as LiO and and the unavoidabletBu anions, useand of the activated unavoidable derivatives use suchof activated as halo groups (Cl, Br, and I), carbonyl groups, and metal acetylides. Thus, compared with C X/C M coupling derivatives such as halo groups (Cl, Br, and I), carbonyl groups, and metal acetylides.− Thus,− compared reactions,with C−X/C organic−M coupling chemists reactions, should preferorganic catalytic chemists activation should prefer of inert catalytic C–H bonds activation for new of C–Cinert bond C–H formationbonds for reactions,new C–C startingbond formation from inexpensive reactions, and starting structurally from inexpensive diverse alkanes, and structurally alkenes, or alkynes.diverse Furthermore,alkanes, alkenes, another or alkynes. challenge Furthermore, is to develop another recyclable challenge and highly is to e ffidevelopcient transition recyclable metal and catalyst highly systemsefficient withtransition low catalyst metal loading.catalyst Finally,systems researchers with low have catalyst partially loading. solved Finally, the chemoselectivity researchers have and regioselectivitypartially solved issues the chemoselectivity in these reactions and by regiosel means ofectivity incorporating issues in a these directing reactions group by or usingmeans the of stericsincorporating/electronics a directing of the substrates. group or However, using the it sterics/electronics is feasible to develop of the a suitable substrates. catalyst However, or fine-tune it is reactionfeasible conditionsto develop to a change suitable/control catalyst the regioselectivity.or fine-tune reaction conditions to change/control the Funding:regioselectivity.This research received no external funding. Acknowledgments: The authors wish to thank the FWO Fund for Scientific Research-Flanders (Belgium) and the Funding: This research received no external funding. Research Fund of the University of Leuven (KU Leuven) for the financial support. PR is thankful to Marie–Curie actionAcknowledgments: (Grant No. 721290). The authors We acknowledge wish to thank the supportthe FWO of Fund “RUDN for UniversityScientific Research-Flanders Program 5-100”. (Belgium) and Conflictsthe Research of Interest: Fund of Thethe University authors declare of Leuven no conflict (KU Leuv of interest.en) for the financial support. PR is thankful to Marie– Curie action (Grant No. 721290). We acknowledge the support of “RUDN University Program 5-100”.

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