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

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.


Introduction
Azoles are important heterocyclic scaffolds because of their wide application in pharmaceuticals, natural products, and functional materials [1][2][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 regio-selectivity, 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][8][9][10][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 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 t BuOLi for alkenylation of less-acidic 1,3-diazoles to furnish the desired monofluorinated products [23]. Recently, nanoparticles have emerged as a robust catalytic system for many organic transformations [24][25][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. 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 azoles such as oxazoles and benzoxazoles with substituents at the C5 position (methyl, methoxy, and 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 as compared with previous reports. However, benzothiazoles did not react with styryl pivalates and carbamates under the optimized reaction conditions. Later in 2015, the same group improved the efficiency of this reaction by employing a Ni(II)/dcypt catalytic system to deliver the alkenyled imidazoles in high yields (Scheme 7b) [30].  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 azoles such as oxazoles and benzoxazoles with substituents at the C5 position (methyl, methoxy, and 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 as compared with previous reports. However, benzothiazoles did not react with styryl pivalates and carbamates under the optimized reaction conditions. Later in 2015, the same group improved the efficiency of this reaction by employing a Ni(II)/dcypt catalytic system to deliver the alkenyled 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 (Scheme 8).
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).
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 azoles such as oxazoles and benzoxazoles with substituents at the C5 position (methyl, methoxy, and 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 as compared with previous reports. However, benzothiazoles did not react with styryl pivalates and carbamates under the optimized reaction conditions. Later in 2015, the same group improved the efficiency of this reaction by employing a Ni(II)/dcypt catalytic system to deliver the alkenyled 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 (Scheme 8). 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). Scheme 8. Direct C2-alkenylation of oxazoles with alkenyl tosylates.
Molecules 2020, 25, x FOR PEER REVIEW 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 out a gram-scale synthesis without altering the reaction conditions, affording the desired product in 85% yield (Scheme 8). 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). 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 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 10) [33]. These modified reaction conditions presented a moderate scope for C2-alkenylation. However, a higher reaction temperature was needed for sterically hindered bromoalkenes.
Molecules 2020, 25, x FOR PEER REVIEW 6 of 33 10) [33]. These modified reaction conditions presented a moderate scope for C2-alkenylation. However, a higher reaction temperature was needed for sterically hindered bromoalkenes.

C-H/C-H Cross-Coupling
From the viewpoint of sustainable and atom-economic development, C-H/C-H cross-coupling 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 direct C-C bond formation via C-H bond cleavage is also known as the Fujiwara-Moritani reaction. In 2010, Miura and coworkers reported direct alkenylation of 2-substituted azoles using Pd(OAc)2 as catalyst and AgOAc as oxidant to deliver the corresponding 5-alkenylated azoles in moderate to good yields (Scheme 11) [34]. Internal or aliphatic alkenes were not suitable under the optimized reaction conditions and gave lower yields. They exemplified the utility of the process by synthesis of πconjugated 2,5-dialkenylated thiazoles, which showed interesting solid-state fluorescence properties. Scheme 11. Pd-catalyzed direct oxidative alkenylation of azoles.
In 2011, Antilla and coworkers replaced Ag with a cheaper Cu oxidant for C4-olefination of oxazoles catalyzed by Pd(II) acetate via C-H bond activation under mild reaction conditions (Scheme 12) [35]. They applied their optimized reaction conditions to a wide substrate scope including various olefins such as electron-deficient alkyl acrylates, N,N-ethylphenylacrylamide and substituted styrenes, with good functional group tolerance. Interestingly, more-challenging substrates such as vinyl trimethylsilane and 1-phenyl-1,3-diene also afforded the desired products in moderate to good yields.
Gem-difluoromethylene exhibits extraordinary biological activities with potential pharmaceutical applications [36]. Owing to its importance, Wu and coworkers reported synthesis of pyrazole derivatives containing a gem-difluoromethylene moiety through a Pd-catalyzed direct oolefination of CF3-substituted pyrazoles (Scheme 13) [37].

C-H/C-H Cross-Coupling
From the viewpoint of sustainable and atom-economic development, C-H/C-H cross-coupling 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 direct C-C bond formation via C-H bond cleavage is also known as the Fujiwara-Moritani reaction. In 2010, Miura and coworkers reported direct alkenylation of 2-substituted azoles using Pd(OAc) 2 as catalyst and AgOAc as oxidant to deliver the corresponding 5-alkenylated azoles in moderate to good yields (Scheme 11) [34]. Internal or aliphatic alkenes were not suitable under the optimized reaction conditions and gave lower yields. They exemplified the utility of the process by synthesis of π-conjugated 2,5-dialkenylated thiazoles, which showed interesting solid-state fluorescence properties.
Molecules 2020, 25, x FOR PEER REVIEW 6 of 33 10) [33]. These modified reaction conditions presented a moderate scope for C2-alkenylation. However, a higher reaction temperature was needed for sterically hindered bromoalkenes.

C-H/C-H Cross-Coupling
From the viewpoint of sustainable and atom-economic development, C-H/C-H cross-coupling 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 direct C-C bond formation via C-H bond cleavage is also known as the Fujiwara-Moritani reaction. In 2010, Miura and coworkers reported direct alkenylation of 2-substituted azoles using Pd(OAc)2 as catalyst and AgOAc as oxidant to deliver the corresponding 5-alkenylated azoles in moderate to good yields (Scheme 11) [34]. Internal or aliphatic alkenes were not suitable under the optimized reaction conditions and gave lower yields. They exemplified the utility of the process by synthesis of πconjugated 2,5-dialkenylated thiazoles, which showed interesting solid-state fluorescence properties. Scheme 11. Pd-catalyzed direct oxidative alkenylation of azoles.
In 2011, Antilla and coworkers replaced Ag with a cheaper Cu oxidant for C4-olefination of oxazoles catalyzed by Pd(II) acetate via C-H bond activation under mild reaction conditions (Scheme 12) [35]. They applied their optimized reaction conditions to a wide substrate scope including various olefins such as electron-deficient alkyl acrylates, N,N-ethylphenylacrylamide and substituted styrenes, with good functional group tolerance. Interestingly, more-challenging substrates such as vinyl trimethylsilane and 1-phenyl-1,3-diene also afforded the desired products in moderate to good yields.
In 2011, Antilla and coworkers replaced Ag with a cheaper Cu oxidant for C4-olefination of oxazoles catalyzed by Pd(II) acetate via C-H bond activation under mild reaction conditions (Scheme 12) [35]. They applied their optimized reaction conditions to a wide substrate scope including various olefins such as electron-deficient alkyl acrylates, N,N-ethylphenylacrylamide and substituted styrenes, with good functional group tolerance. Interestingly, more-challenging substrates such as vinyl trimethylsilane and 1-phenyl-1,3-diene also afforded the desired products in moderate to good yields.
Molecules 2020, 25, x FOR PEER REVIEW 6 of 33 10) [33]. These modified reaction conditions presented a moderate scope for C2-alkenylation. However, a higher reaction temperature was needed for sterically hindered bromoalkenes.

C-H/C-H Cross-Coupling
From the viewpoint of sustainable and atom-economic development, C-H/C-H cross-coupling 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 direct C-C bond formation via C-H bond cleavage is also known as the Fujiwara-Moritani reaction. In 2010, Miura and coworkers reported direct alkenylation of 2-substituted azoles using Pd(OAc)2 as catalyst and AgOAc as oxidant to deliver the corresponding 5-alkenylated azoles in moderate to good yields (Scheme 11) [34]. Internal or aliphatic alkenes were not suitable under the optimized reaction conditions and gave lower yields. They exemplified the utility of the process by synthesis of πconjugated 2,5-dialkenylated thiazoles, which showed interesting solid-state fluorescence properties. Scheme 11. Pd-catalyzed direct oxidative alkenylation of azoles.
In 2011, Antilla and coworkers replaced Ag with a cheaper Cu oxidant for C4-olefination of oxazoles catalyzed by Pd(II) acetate via C-H bond activation under mild reaction conditions (Scheme 12) [35]. They applied their optimized reaction conditions to a wide substrate scope including various olefins such as electron-deficient alkyl acrylates, N,N-ethylphenylacrylamide and substituted styrenes, with good functional group tolerance. Interestingly, more-challenging substrates such as vinyl trimethylsilane and 1-phenyl-1,3-diene also afforded the desired products in moderate to good yields.
Yao and coworkers reported a Pd(II)-catalyzed oxidative Heck coupling of thiazole-4carboxylates 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. 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. Inspired by You's work, in 2014 Ong and coworkers employed a Pd(TFA)2 and 1,10phenanthroline 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 step. Moreover, they achieved direct and efficient synthesis of naturally occurring Annuloline and Siphonazole, showing a promising opportunity in natural product synthesis [40]. Scheme 16. Pd-catalyzed dehydrogenative alkenylation of azole motifs.
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. Yao and coworkers reported a Pd(II)-catalyzed oxidative Heck coupling of thiazole-4carboxylates 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. 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. Inspired by You's work, in 2014 Ong and coworkers employed a Pd(TFA)2 and 1,10phenanthroline 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 step. Moreover, they achieved direct and efficient synthesis of naturally occurring Annuloline and Siphonazole, showing a promising opportunity in natural product synthesis [40].  In 2012, You and coworkers reported an efficient trimetallic catalytic system using Pd(OAc) 2 /CuCl/Cu(OAc) 2 ·H 2 O 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. Yao and coworkers reported a Pd(II)-catalyzed oxidative Heck coupling of thiazole-4carboxylates 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. 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. Inspired by You's work, in 2014 Ong and coworkers employed a Pd(TFA)2 and 1,10phenanthroline 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 step. Moreover, they achieved direct and efficient synthesis of naturally occurring Annuloline and Siphonazole, showing a promising opportunity in natural product synthesis [40].  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 step. Moreover, they achieved direct and efficient synthesis of naturally occurring Annuloline and Siphonazole, showing a promising opportunity in natural product synthesis [40].
Inspired by You's work, in 2014 Ong and coworkers employed a Pd(TFA)2 and 1,10phenanthroline 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 step. Moreover, they achieved direct and efficient synthesis of naturally occurring Annuloline and Siphonazole, showing a promising opportunity in natural product synthesis [40]. Kuang and coworkers performed an extensive experimental study for C2-selective alkenylation of thiazoles. The overall selectivity of this process relies on the neutral reaction conditions and the ligand choice (1,10-phenanthroline). The authors presented a broad substrate scope with good functional group tolerance (Scheme 17) [41]. Kuang and coworkers performed an extensive experimental study for C2-selective alkenylation of thiazoles. The overall selectivity of this process relies on the neutral reaction conditions and the ligand choice (1,10-phenanthroline). The authors presented a broad substrate scope with good functional group tolerance (Scheme 17) [41]. Thiazolo[3,2-b]-1,2,4-triazole moieties are valuable molecules that exhibit a wide range of biological activities [42]. In 2014, Wang and coworkers reported an atom-economical approach to obtain alkenylation of thiazolo[3,2-b]-1,2,4-triazoles via a palladium-catalyzed, two-fold C-H functionalization [43]. Interestingly, the synergetic effect of a metal oxidant, Cu(OAc)2, with oxygen plays an important role in the C-H activation step, affording the desired products in high yields (Scheme 18). In 2015, Shi and coworkers employed a semi-continuous approach to overcome the longstanding homocoupling problem in direct oxidative cross-coupling to functionalize thiazole derivatives (Scheme 19) [44]. Interestingly, t AmylOH and DMSO played an important role in increasing the yield of the desired products. The authors showed a broad substrate scope with good to moderate yields.  Thiazolo[3,2-b]-1,2,4-triazole moieties are valuable molecules that exhibit a wide range of biological activities [42]. In 2014, Wang and coworkers reported an atom-economical approach to obtain alkenylation of thiazolo[3,2-b]-1,2,4-triazoles via a palladium-catalyzed, two-fold C-H functionalization [43]. Interestingly, the synergetic effect of a metal oxidant, Cu(OAc) 2 , with oxygen plays an important role in the C-H activation step, affording the desired products in high yields (Scheme 18). Kuang and coworkers performed an extensive experimental study for C2-selective alkenylation of thiazoles. The overall selectivity of this process relies on the neutral reaction conditions and the ligand choice (1,10-phenanthroline). The authors presented a broad substrate scope with good functional group tolerance (Scheme 17) [41]. Thiazolo[3,2-b]-1,2,4-triazole moieties are valuable molecules that exhibit a wide range of biological activities [42]. In 2014, Wang and coworkers reported an atom-economical approach to obtain alkenylation of thiazolo[3,2-b]-1,2,4-triazoles via a palladium-catalyzed, two-fold C-H functionalization [43]. Interestingly, the synergetic effect of a metal oxidant, Cu(OAc)2, with oxygen plays an important role in the C-H activation step, affording the desired products in high yields (Scheme 18). In 2015, Shi and coworkers employed a semi-continuous approach to overcome the longstanding homocoupling problem in direct oxidative cross-coupling to functionalize thiazole derivatives (Scheme 19) [44]. Interestingly, t AmylOH and DMSO played an important role in increasing the yield of the desired products. The authors showed a broad substrate scope with good to moderate yields.  In 2015, Shi and coworkers employed a semi-continuous approach to overcome the long-standing homocoupling problem in direct oxidative cross-coupling to functionalize thiazole derivatives (Scheme 19) [44]. Interestingly, t AmylOH and DMSO played an important role in increasing the yield of the desired products. The authors showed a broad substrate scope with good to moderate yields. Kuang and coworkers performed an extensive experimental study for C2-selective alkenylation of thiazoles. The overall selectivity of this process relies on the neutral reaction conditions and the ligand choice (1,10-phenanthroline). The authors presented a broad substrate scope with good functional group tolerance (Scheme 17) [41]. Thiazolo[3,2-b]-1,2,4-triazole moieties are valuable molecules that exhibit a wide range of biological activities [42]. In 2014, Wang and coworkers reported an atom-economical approach to obtain alkenylation of thiazolo[3,2-b]-1,2,4-triazoles via a palladium-catalyzed, two-fold C-H functionalization [43]. Interestingly, the synergetic effect of a metal oxidant, Cu(OAc)2, with oxygen plays an important role in the C-H activation step, affording the desired products in high yields (Scheme 18). In 2015, Shi and coworkers employed a semi-continuous approach to overcome the longstanding homocoupling problem in direct oxidative cross-coupling to functionalize thiazole derivatives (Scheme 19) [44]. Interestingly, t AmylOH and DMSO played an important role in increasing the yield of the desired products. The authors showed a broad substrate scope with good to moderate yields.  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. In 2017, for the first time, Ackermann and coworkers introduced a Ni-catalyzed regioselective hydroarylation of allenes with purines and imidazoles [46]. The authors successfully applied this catalytic system for dienylation through C-H functionalization and concurrent C-O cleavage (Scheme 21). The employed base plays a key role in the isomerization step to deliver the desired products. The practical utility of this protocol was shown by the late stage-diversification of diphophodiesterase inhibitors. In 2018, Xu and coworkers employed cationic rhodium(III) for the direct olefination of imidazoles with high regio-and stereo-selectivity [47]. Unlike the other reported methods, this catalytic system requires a directing group for the selective C-2 alkenylation. A broad range of benzimidazoles and activated olefins successfully delivered the desired products in good yields. In the proposed mechanism, the reaction starts with the Rh(III)-mediated C-H bond activation to form the cyclorhodium intermediate B, followed by coordination with olefin 2 to give intermediate C. In 2017, for the first time, Ackermann and coworkers introduced a Ni-catalyzed regioselective hydroarylation of allenes with purines and imidazoles [46]. The authors successfully applied this catalytic system for dienylation through C-H functionalization and concurrent C-O cleavage (Scheme 21). The employed base plays a key role in the isomerization step to deliver the desired products. The practical utility of this protocol was shown by the late stage-diversification of diphophodiesterase inhibitors. In 2017, for the first time, Ackermann and coworkers introduced a Ni-catalyzed regioselective hydroarylation of allenes with purines and imidazoles [46]. The authors successfully applied this catalytic system for dienylation through C-H functionalization and concurrent C-O cleavage (Scheme 21). The employed base plays a key role in the isomerization step to deliver the desired products. The practical utility of this protocol was shown by the late stage-diversification of diphophodiesterase inhibitors.
In 2018, Xu and coworkers employed cationic rhodium(III) for the direct olefination of imidazoles with high regio-and stereo-selectivity [47]. Unlike the other reported methods, this catalytic system requires a directing group for the selective C-2 alkenylation. A broad range of benzimidazoles and activated olefins successfully delivered the desired products in good yields. In the proposed mechanism, the reaction starts with the Rh(III)-mediated C-H bond activation to form the cyclorhodium intermediate B, followed by coordination with olefin 2 to give intermediate C. In 2018, Xu and coworkers employed cationic rhodium(III) for the direct olefination of imidazoles with high regio-and stereo-selectivity [47]. Unlike the other reported methods, this catalytic system requires a directing group for the selective C-2 alkenylation. A broad range of benzimidazoles and activated olefins successfully delivered the desired products in good yields. In the proposed mechanism, the reaction starts with the Rh(III)-mediated C-H bond activation to form the cyclorhodium 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 1,3-azoles, i.e., thiazoles and oxazoles. Furthermore, the installed 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. Recently, Kumar and Kapur developed an interesting catalyst-driven selective C-H 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 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. Recently, Kumar and Kapur developed an interesting catalyst-driven selective C-H 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 Recently, Kumar and Kapur developed an interesting catalyst-driven selective C-H 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 activation step. The synthetic utility of this position-selective C-H olefination approach was demonstrated by the synthesis of densely substituted pyrroles by employing a Ru-and Cu-mediated cooperative catalysis. The regioselective alkenylation of 2,5-unsubstituted thiazole derivatives has been a challenging issue among synthetic chemists. Maiti and coworkers overcame this challenge by using a tricoordinating directing group (T) bearing a cyanide template for the selective metalation of thiazole at the C-5 position followed by reductive elimination to deliver the desired products [50]. The authors presented a wide range of substrate scope with good functional group tolerance (Scheme 25).

C-H Addition of Azoles to Alkynes
Alkynes are potentially good substrates for alkenylation because of their wide availability and low cost. The transition metal-catalyzed direct cleavage of the C-H bond of azoles followed by insertion of alkynes appears an ideal and atom economical method for the alkenylation of azoles. This straightforward synthetic strategy was early reported by Miura [51]. Later, in 2009, Miura and coworkers reported a Ni-catalyzed C-H alkenylation of 1,3,4-oxadiazoles [52]. At the same time, Hiyama and coworkers also reported a similar approach for the alkenylation of imidazoles [53]. In 2010, Ding and Yoshikai reported a Cobased catalytic system for the addition of benzoxazoles to unactivated internal alkynes (Scheme 26) [54]. The optimized reaction conditions showed good regioand chemo-selectivity possibly originating during the alkyne insertion step. Unfortunately, the optimized conditions were not suitable for the alkenylation of benzoxazoles with terminal alkynes.

Scheme 26.
Co-catalyzed addition of benzoxazoles to alkynes. The regioselective alkenylation of 2,5-unsubstituted thiazole derivatives has been a challenging issue among synthetic chemists. Maiti and coworkers overcame this challenge by using a tricoordinating directing group (T) bearing a cyanide template for the selective metalation of thiazole at the C5 position followed by reductive elimination to deliver the desired products [50]. The authors presented a wide range of substrate scope with good functional group tolerance (Scheme 25).
Molecules 2020, 25, x FOR PEER REVIEW 11 of 33 activation step. The synthetic utility of this position-selective C-H olefination approach was demonstrated by the synthesis of densely substituted pyrroles by employing a Ru-and Cu-mediated cooperative catalysis. The regioselective alkenylation of 2,5-unsubstituted thiazole derivatives has been a challenging issue among synthetic chemists. Maiti and coworkers overcame this challenge by using a tricoordinating directing group (T) bearing a cyanide template for the selective metalation of thiazole at the C-5 position followed by reductive elimination to deliver the desired products [50]. The authors presented a wide range of substrate scope with good functional group tolerance (Scheme 25).

C-H Addition of Azoles to Alkynes
Alkynes are potentially good substrates for alkenylation because of their wide availability and low cost. The transition metal-catalyzed direct cleavage of the C-H bond of azoles followed by insertion of alkynes appears an ideal and atom economical method for the alkenylation of azoles. This straightforward synthetic strategy was early reported by Miura [51]. Later, in 2009, Miura and coworkers reported a Ni-catalyzed C-H alkenylation of 1,3,4-oxadiazoles [52]. At the same time, Hiyama and coworkers also reported a similar approach for the alkenylation of imidazoles [53]. In 2010, Ding and Yoshikai reported a Cobased catalytic system for the addition of benzoxazoles to unactivated internal alkynes (Scheme 26) [54]. The optimized reaction conditions showed good regioand chemo-selectivity possibly originating during the alkyne insertion step. Unfortunately, the optimized conditions were not suitable for the alkenylation of benzoxazoles with terminal alkynes.

C-H Addition of Azoles to Alkynes
Alkynes are potentially good substrates for alkenylation because of their wide availability and low cost. The transition metal-catalyzed direct cleavage of the C-H bond of azoles followed by insertion of alkynes appears an ideal and atom economical method for the alkenylation of azoles. This straightforward synthetic strategy was early reported by Miura [51]. Later, in 2009, Miura and coworkers reported a Ni-catalyzed C-H alkenylation of 1,3,4-oxadiazoles [52]. At the same time, Hiyama and coworkers also reported a similar approach for the alkenylation of imidazoles [53]. In 2010, Ding and Yoshikai reported a Cobased catalytic system for the addition of benzoxazoles to unactivated internal alkynes (Scheme 26) [54]. The optimized reaction conditions showed good regio-and chemo-selectivity possibly originating during the alkyne insertion step. Unfortunately, the optimized conditions were not suitable for the alkenylation of benzoxazoles with terminal alkynes. The regioselective alkenylation of 2,5-unsubstituted thiazole derivatives has been a challenging issue among synthetic chemists. Maiti and coworkers overcame this challenge by using a tricoordinating directing group (T) bearing a cyanide template for the selective metalation of thiazole at the C-5 position followed by reductive elimination to deliver the desired products [50]. The authors presented a wide range of substrate scope with good functional group tolerance (Scheme 25).

C-H Addition of Azoles to Alkynes
Alkynes are potentially good substrates for alkenylation because of their wide availability and low cost. The transition metal-catalyzed direct cleavage of the C-H bond of azoles followed by insertion of alkynes appears an ideal and atom economical method for the alkenylation of azoles. This straightforward synthetic strategy was early reported by Miura [51]. Later, in 2009, Miura and coworkers reported a Ni-catalyzed C-H alkenylation of 1,3,4-oxadiazoles [52]. At the same time, Hiyama and coworkers also reported a similar approach for the alkenylation of imidazoles [53]. In 2010, Ding and Yoshikai reported a Cobased catalytic system for the addition of benzoxazoles to unactivated internal alkynes (Scheme 26) [54]. The optimized reaction conditions showed good regioand chemo-selectivity possibly originating during the alkyne insertion step. Unfortunately, the optimized conditions were not suitable for the alkenylation of benzoxazoles with terminal 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 provide the reason for the observed selectivity, but their work opens the door for further investigations (Scheme 27) [55].
Molecules 2020, 25, x FOR PEER REVIEW 12 of 33 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 provide the reason for the observed selectivity, but their work opens the door for further investigations (Scheme 27) [55]. Scheme 27. Co-catalyzed alkenylation of thiazoles with alkynes.
The selective alkenylation of triazolopyridines using a Ni-catalytic system was reported by Driver and coworkers. In this pioneering work, the authors highlighted the steering role of a Lewis acid (AlMe3) interaction for the selective oxidative addition of the C7-H bond to generate intermediate B, followed by alkyne insertion to obtain the desired products (Scheme 28) [56]. The alkyne insertion step was mainly curbed by the substituent steric factor on the alkyne bond, favouring the new C-C bond between the smaller alkynyl substituent and the C7 of the triazolopyridine. Similar to this report, Ong and coworkers employed the same Ni/Al bimetallic catalytic system for the remote C-H functionalization of imidazo[1,5-a]pyridines. Interestingly, the authors were able to switch the regioselectivity of alkenylation from C5 to C3 by excluding AlMe3 from the catalytic system (Scheme 29) [57]. A wide scope was presented with good functional group tolerance. The selective alkenylation of triazolopyridines using a Ni-catalytic system was reported by Driver and coworkers. In this pioneering work, the authors highlighted the steering role of a Lewis acid (AlMe 3 ) interaction for the selective oxidative addition of the C7-H bond to generate intermediate B, followed by alkyne insertion to obtain the desired products (Scheme 28) [56]. The alkyne insertion step was mainly curbed by the substituent steric factor on the alkyne bond, favouring the new C-C bond between the smaller alkynyl substituent and the C7 of the triazolopyridine. 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 provide the reason for the observed selectivity, but their work opens the door for further investigations (Scheme 27) [55]. Scheme 27. Co-catalyzed alkenylation of thiazoles with alkynes.
The selective alkenylation of triazolopyridines using a Ni-catalytic system was reported by Driver and coworkers. In this pioneering work, the authors highlighted the steering role of a Lewis acid (AlMe3) interaction for the selective oxidative addition of the C7-H bond to generate intermediate B, followed by alkyne insertion to obtain the desired products (Scheme 28) [56]. The alkyne insertion step was mainly curbed by the substituent steric factor on the alkyne bond, favouring the new C-C bond between the smaller alkynyl substituent and the C7 of the triazolopyridine. Similar to this report, Ong and coworkers employed the same Ni/Al bimetallic catalytic system for the remote C-H functionalization of imidazo[1,5-a]pyridines. Interestingly, the authors were able to switch the regioselectivity of alkenylation from C5 to C3 by excluding AlMe3 from the catalytic system (Scheme 29) [57]. A wide scope was presented with good functional group tolerance. Similar to this report, Ong and coworkers employed the same Ni/Al bimetallic catalytic system for the remote C-H functionalization of imidazo[1,5-a]pyridines. Interestingly, the authors were able to switch the regioselectivity of alkenylation from C5 to C3 by excluding AlMe 3 from the catalytic system (Scheme 29) [57]. A wide scope was presented with good functional group tolerance. 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 provide the reason for the observed selectivity, but their work opens the door for further investigations (Scheme 27) [55]. Scheme 27. Co-catalyzed alkenylation of thiazoles with alkynes.
The selective alkenylation of triazolopyridines using a Ni-catalytic system was reported by Driver and coworkers. In this pioneering work, the authors highlighted the steering role of a Lewis acid (AlMe3) interaction for the selective oxidative addition of the C7-H bond to generate intermediate B, followed by alkyne insertion to obtain the desired products (Scheme 28) [56]. The alkyne insertion step was mainly curbed by the substituent steric factor on the alkyne bond, favouring the new C-C bond between the smaller alkynyl substituent and the C7 of the triazolopyridine. Similar to this report, Ong and coworkers employed the same Ni/Al bimetallic catalytic system for the remote C-H functionalization of imidazo[1,5-a]pyridines. Interestingly, the authors were able to switch the regioselectivity of alkenylation from C5 to C3 by excluding AlMe3 from the catalytic system (Scheme 29) [57]. A wide scope was presented with good functional group tolerance. In 2015, Huang and coworkers exploited an oxime as directing group in the selective alkenylation of thiazoles employing a Rh-catalyst. This was followed by a tandem cyclization to deliver azole fused pyridines (Scheme 30) [58]. Despite having lower reactivity at the C-4 position, various thiazoles underwent smooth alkenylation with alkynes. In general, electron-rich alkynes gave better yields than electron deficient alkynes. Notably, this catalytic system also successfully delivered the desired products with unsymmetrical alkynes.
Molecules 2020, 25, x FOR PEER REVIEW 13 of 33 In 2015, Huang and coworkers exploited an oxime as directing group in the selective alkenylation of thiazoles employing a Rh-catalyst. This was followed by a tandem cyclization to deliver azole fused pyridines (Scheme 30) [58]. Despite having lower reactivity at the C-4 position, various thiazoles underwent smooth alkenylation with alkynes. In general, electron-rich alkynes gave better yields than electron deficient alkynes. Notably, this catalytic system also successfully delivered the desired products with unsymmetrical alkynes. In 2017, You and coworkers exploited a Rh/Cu-catalytic system for the alkenylation of azoles via a C-H addition/oxidation sequence to generate tetra(hetero)arylethylenes (Scheme 31). Interestingly, control experiments and DFT calculations revealed that the C-H bond cleavage of azoles could be facilitated by either Rh or Cu. The authors also supported the necessity of Cu(OAc)2 to obtain the desired product by computational studies. Tetra-arylethylene (TAE) derivatives have widely been used in OLED applications. This makes the protocol highly alluring for future developments in the area of functional materials [59]. Employing this catalytic system, a broad range of alkenylated azoles could be readily generated in good yields from alkynes. Another interesting approach for the alkenylation of the C5-position of thiazoles using a Pd/PCy3/RCO2H-catalytic system was disclosed by Joo and coworkers in 2019 [60]. The key intermediate of this catalytic cycle is the alkenyl Pd(II)-carboxylate complex, which enables the concerted metalation deprotonation of substituted azoles, followed by reductive elimination to deliver the corresponding products. The reaction conditions were not only compatible with In 2017, You and coworkers exploited a Rh/Cu-catalytic system for the alkenylation of azoles via a C-H addition/oxidation sequence to generate tetra(hetero)arylethylenes (Scheme 31). Interestingly, control experiments and DFT calculations revealed that the C-H bond cleavage of azoles could be facilitated by either Rh or Cu. The authors also supported the necessity of Cu(OAc) 2 to obtain the desired product by computational studies. Tetra-arylethylene (TAE) derivatives have widely been used in OLED applications. This makes the protocol highly alluring for future developments in the area of functional materials [59]. Employing this catalytic system, a broad range of alkenylated azoles could be readily generated in good yields from alkynes. In 2015, Huang and coworkers exploited an oxime as directing group in the selective alkenylation of thiazoles employing a Rh-catalyst. This was followed by a tandem cyclization to deliver azole fused pyridines (Scheme 30) [58]. Despite having lower reactivity at the C-4 position, various thiazoles underwent smooth alkenylation with alkynes. In general, electron-rich alkynes gave better yields than electron deficient alkynes. Notably, this catalytic system also successfully delivered the desired products with unsymmetrical alkynes. In 2017, You and coworkers exploited a Rh/Cu-catalytic system for the alkenylation of azoles via a C-H addition/oxidation sequence to generate tetra(hetero)arylethylenes (Scheme 31). Interestingly, control experiments and DFT calculations revealed that the C-H bond cleavage of azoles could be facilitated by either Rh or Cu. The authors also supported the necessity of Cu(OAc)2 to obtain the desired product by computational studies. Tetra-arylethylene (TAE) derivatives have widely been used in OLED applications. This makes the protocol highly alluring for future developments in the area of functional materials [59]. Employing this catalytic system, a broad range of alkenylated azoles could be readily generated in good yields from alkynes. Another interesting approach for the alkenylation of the C5-position of thiazoles using a Pd/PCy3/RCO2H-catalytic system was disclosed by Joo and coworkers in 2019 [60]. The key intermediate of this catalytic cycle is the alkenyl Pd(II)-carboxylate complex, which enables the concerted metalation deprotonation of substituted azoles, followed by reductive elimination to deliver the corresponding products. The reaction conditions were not only compatible with Another interesting approach for the alkenylation of the C5-position of thiazoles using a Pd/PCy 3 /RCO 2 H-catalytic system was disclosed by Joo and coworkers in 2019 [60]. The key intermediate of this catalytic cycle is the alkenyl Pd(II)-carboxylate complex, which enables the concerted metalation deprotonation of substituted azoles, followed by reductive elimination to deliver the corresponding 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 position if the C5 position was not available. In 2019, Breit and coworkers introduced an interesting cascade sequence to achieve the trisallyation of benzoxazoles catalyzed by Pd(OAc)2 using Ruphos as ligand [61]. In the proposed mechanism, the reaction starts with the generation of a Pd-hydride species through oxidative addition of the Pd-catalyst with HOPiv. Then, the Pd-hydride species facilitates the isomerization of the alkyne to allene and affords the π-allylpalladium intermediate. Subsequently, intermediate A reacts with azoles by C-H activation to produce mono-allylated product B, followed by isomerization and sequential two-fold C(sp3)-H allylation with π-allylpalladium intermediate A to furnish the desired product D (Scheme 33).

Decarbonylative C-H Alkenylation
In recent years, decarboxylative C-H bond functionalization has drawn growing attention, since carboxylic acids are commercially available and are structurally diverse. Obviously, the use of 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 coupling methodologies for the direct decarboxylative olefination have been In 2019, Breit and coworkers introduced an interesting cascade sequence to achieve the trisallyation of benzoxazoles catalyzed by Pd(OAc) 2 using Ruphos as ligand [61]. In the proposed mechanism, the reaction starts with the generation of a Pd-hydride species through oxidative addition of the Pd-catalyst with HOPiv. Then, the Pd-hydride species facilitates the isomerization of the alkyne to allene and affords the π-allylpalladium intermediate. Subsequently, intermediate A reacts with azoles by C-H activation to produce mono-allylated product B, followed by isomerization and sequential two-fold C(sp3)-H allylation with π-allylpalladium intermediate A to furnish the desired product D (Scheme 33). In 2019, Breit and coworkers introduced an interesting cascade sequence to achieve the trisallyation of benzoxazoles catalyzed by Pd(OAc)2 using Ruphos as ligand [61]. In the proposed mechanism, the reaction starts with the generation of a Pd-hydride species through oxidative addition of the Pd-catalyst with HOPiv. Then, the Pd-hydride species facilitates the isomerization of the alkyne to allene and affords the π-allylpalladium intermediate. Subsequently, intermediate A reacts with azoles by C-H activation to produce mono-allylated product B, followed by isomerization and sequential two-fold C(sp3)-H allylation with π-allylpalladium intermediate A to furnish the desired product D (Scheme 33).

Decarbonylative C-H Alkenylation
In recent years, decarboxylative C-H bond functionalization has drawn growing attention, since carboxylic acids are commercially available and are structurally diverse. Obviously, the use of 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 coupling methodologies for the direct decarboxylative olefination have been Scheme 33. Pd-catalyzed trisallylation of benzoxazoles with an alkyne.

Decarbonylative C-H Alkenylation
In recent years, decarboxylative C-H bond functionalization has drawn growing attention, since carboxylic acids are commercially available and are structurally diverse. Obviously, the use of 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 coupling methodologies for the direct decarboxylative olefination have been reported [62,63]. Decarbonylative cross-couplings for the alkenylation of azoles have remained elusive for some time. In 2013, Itami and coworkers reported an inimitable method for the alkenylation of azoles with a Ni/dcype catalytic system, using enol derivatives and α,β-unsaturated esters [29]. Moreover, this catalytic system can also efficiently enable decarbonylative alkenylation with enol derivatives of styryl pivalate, styryl carbamate and phenyl cinnamate (Scheme 34). In general, the coupling product of various azoles with carbamates delivered the corresponding products with higher yields as compared to styryl pivalates. reported [62,63]. Decarbonylative cross-couplings for the alkenylation of azoles have remained elusive for some time. In 2013, Itami and coworkers reported an inimitable method for the alkenylation of azoles with a Ni/dcype catalytic system, using enol derivatives and ɑ,β-unsaturated esters [29]. Moreover, this catalytic system can also efficiently enable decarbonylative alkenylation with enol derivatives of styryl pivalate, styryl carbamate and phenyl cinnamate (Scheme 34). In general, the coupling product of various azoles with carbamates delivered the corresponding products with higher yields as compared to styryl pivalates. Fluorinated heterocycles have always been attractive scaffolds for pharmaceuticals and organic materials. In 2014, Hoarau and coworkers reported an efficient method for the direct C-H/C-CO2H cross-coupling between azoles and α-fluoroacrylic acids via a decarboxylative process, using a Pd/Cu-catalytic system [64]. The reaction mechanism is believed to start with a Cu-promoted decarboxylation step generating an alkenylcopper intermediate. This is followed by a transmetalation step with the Pd-azole intermediate. Finally, reductive elimination generates the desired product. The various (Z/E)-α-fluroacrylic acids successfully delivered the Z/E-isomeric products in good to moderate yields with good functional group tolerance (Scheme 35).

Scheme 35. Decarboxylative/direct C-H monofluoroalkenylation with fluoroacrylic acids.
Later in 2017, the same group developed a decarboxylative C-H alkenylation of various azoles with α-alkoxylated acrylic acids [65]. This decarboxylative coupling proceeded smoothly employing [Pd(acac)2] as catalyst along with CuCO3.Cu(OH)2. This transformation displays good E/Z stereochemistry and α/β regiochemistry. For less acidic benzothiazoles, CuI played a key role in increasing the acidity at the C2-H of the heteroarene, forming a [Cu]-heterocycle. Therefore, depending on the acidity and the nucleophilicity of the azole, there could be two possible pathways to activate the azoles and afford intermediate (I): (i) direct Pd-catalyzed heteroarenes (azoles) via a base-assisted concerted or nonconcerted (carbanionic-type) process, or (ii) heteroarylcopper(III) through a transmetalation step with Pd(OAc)2 (Scheme 36). Using these optimized conditions, the authors successfully reported a convenient approach to generate α,β-enolizable α-ketoazoles and biologically active C2−C4′ linked azoles. Fluorinated heterocycles have always been attractive scaffolds for pharmaceuticals and organic materials. In 2014, Hoarau and coworkers reported an efficient method for the direct C-H/C-CO 2 H cross-coupling between azoles and α-fluoroacrylic acids via a decarboxylative process, using a Pd/Cu-catalytic system [64]. The reaction mechanism is believed to start with a Cu-promoted decarboxylation step generating an alkenylcopper intermediate. This is followed by a transmetalation step with the Pd-azole intermediate. Finally, reductive elimination generates the desired product. The various (Z/E)-α-fluroacrylic acids successfully delivered the Z/E-isomeric products in good to moderate yields with good functional group tolerance (Scheme 35). reported [62,63]. Decarbonylative cross-couplings for the alkenylation of azoles have remained elusive for some time. In 2013, Itami and coworkers reported an inimitable method for the alkenylation of azoles with a Ni/dcype catalytic system, using enol derivatives and ɑ,β-unsaturated esters [29]. Moreover, this catalytic system can also efficiently enable decarbonylative alkenylation with enol derivatives of styryl pivalate, styryl carbamate and phenyl cinnamate (Scheme 34). In general, the coupling product of various azoles with carbamates delivered the corresponding products with higher yields as compared to styryl pivalates.

Scheme 34. Ni-catalyzed decarbonylative C-H alkenylation of various azoles.
Fluorinated heterocycles have always been attractive scaffolds for pharmaceuticals and organic materials. In 2014, Hoarau and coworkers reported an efficient method for the direct C-H/C-CO2H cross-coupling between azoles and α-fluoroacrylic acids via a decarboxylative process, using a Pd/Cu-catalytic system [64]. The reaction mechanism is believed to start with a Cu-promoted decarboxylation step generating an alkenylcopper intermediate. This is followed by a transmetalation step with the Pd-azole intermediate. Finally, reductive elimination generates the desired product. The various (Z/E)-α-fluroacrylic acids successfully delivered the Z/E-isomeric products in good to moderate yields with good functional group tolerance (Scheme 35). Later in 2017, the same group developed a decarboxylative C-H alkenylation of various azoles with α-alkoxylated acrylic acids [65]. This decarboxylative coupling proceeded smoothly employing [Pd(acac)2] as catalyst along with CuCO3.Cu(OH)2. This transformation displays good E/Z stereochemistry and α/β regiochemistry. For less acidic benzothiazoles, CuI played a key role in increasing the acidity at the C2-H of the heteroarene, forming a [Cu]-heterocycle. Therefore, depending on the acidity and the nucleophilicity of the azole, there could be two possible pathways to activate the azoles and afford intermediate (I): (i) direct Pd-catalyzed heteroarenes (azoles) via a base-assisted concerted or nonconcerted (carbanionic-type) process, or (ii) heteroarylcopper(III) through a transmetalation step with Pd(OAc)2 (Scheme 36). Using these optimized conditions, the authors successfully reported a convenient approach to generate α,β-enolizable α-ketoazoles and biologically active C2−C4′ linked azoles. Later in 2017, the same group developed a decarboxylative C-H alkenylation of various azoles with α-alkoxylated acrylic acids [65]. This decarboxylative coupling proceeded smoothly employing [Pd(acac) 2 ] as catalyst along with CuCO 3 .Cu(OH) 2 . This transformation displays good E/Z stereochemistry and α/β regiochemistry. For less acidic benzothiazoles, CuI played a key role in increasing the acidity at the C2-H of the heteroarene, forming a [Cu]-heterocycle. Therefore, depending on the acidity and the nucleophilicity of the azole, there could be two possible pathways to activate the azoles and afford intermediate (I): (i) direct Pd-catalyzed heteroarenes (azoles) via a base-assisted concerted or nonconcerted (carbanionic-type) process, or (ii) heteroarylcopper(III) through a transmetalation step with Pd(OAc) 2 (Scheme 36). Using these optimized conditions, the authors successfully reported a convenient approach to generate α,β-enolizable α-ketoazoles and biologically active C2−C4 linked azoles.

Alkylation of Azoles
Friedel-Craft alkylation has been used as the first-line technique for the alkylation of azoles before direct C-H functionalization came on the scene [6]. However, Friedel-Crafts alkylation mostly encounters several difficulties such as low chemo-and/or regioselectivity, being limited to electronrich substrates, and harsh reaction conditions [12]. C-H activation is providing an efficient tool for the direct alkylation of azoles with almost surgical precision. Great contributions by Fagnou, Miura and Ackermann in the field of azole alkylation via C-H activation have made this field wide open for further developments [66][67][68].

Primary C-H alkylation of Azoles
Among different C-H alkylations of azoles, primary alkylation has been widely investigated using halides, pseudohalides and alkenes as coupling partners. Among the various metals used, it is no surprise that Pd adopts a key role, though other metals like Rh, Ni and Cu are catching up, and 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 Scheme 36. Pd-catalyzed α-carboxyenol ether formation with various azoles via direct decarboxylative cross-coupling and proposed mechanism.

Alkylation of Azoles
Friedel-Craft alkylation has been used as the first-line technique for the alkylation of azoles before direct C-H functionalization came on the scene [6]. However, Friedel-Crafts alkylation mostly encounters several difficulties such as low chemo-and/or regioselectivity, being limited to electron-rich substrates, and harsh reaction conditions [12]. C-H activation is providing an efficient tool for the direct alkylation of azoles with almost surgical precision. Great contributions by Fagnou, Miura and Ackermann in the field of azole alkylation via C-H activation have made this field wide open for further developments [66][67][68].

Primary C-H alkylation of Azoles
Among different C-H alkylations of azoles, primary alkylation has been widely investigated using halides, pseudohalides and alkenes as coupling partners. Among the various metals used, it is no surprise that Pd adopts a key role, though other metals like Rh, Ni and Cu are catching up, and 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 a cocatalyst (Scheme 37) [69]. A wide range of functional groups branching at the β-position of the halides showed good reactivity, and high chemo-and regioselectivity.
Molecules 2020, 25, x FOR PEER REVIEW 17 of 33 a cocatalyst (Scheme 37) [69]. A wide range of functional groups branching at the β-position of the halides showed good reactivity, and high chemo-and regioselectivity.

Scheme 37. The Ni/Cu-catalyzed direct alkylation of heterocyclic C-H bonds.
Concurrently, Miura and coworkers reported a Pd-catalyzed direct alkylation of oxazoles with nonactivated alkyl halides [70]. A variety of alkyl bromides possessing a benzyl ether, a silyl ether or a pivaloyl ester functional group, transformed into the desired products in moderate to good yields (Scheme 38). Moreover, unactivated alkyl chlorides were also well tolerated employing this catalytic system. Unfortunately, 1-iodohexane gave a much lower yield (20%) while bromocyclohexane could not provide the product due to the rapid decomposition and steric hindrance, respectively.

Scheme 38. Pd-catalyzed direct C-H alkylation of benzoxazoles with various alkyl halides.
In 2011, Ackermann and coworkers reported the alkylation of oxazoles with benzyl chlorides and benzyl phosphate applying a Pd(II) complex [71]. The authors found that phosphinous acid Pd(II) complex significantly improved the yield in comparison with other palladium catalysts. In the presence of a prefunctionalized Pd(II) complex, a wide range of differently substituted benzyl chlorides reacted efficiently with (benz)oxazoles, providing the corresponding products in moderate to high yields (Scheme 39).

Scheme 39.
Benzylations on oxazol(in)es with a Pd-catalyst of a secondary phosphine oxide.
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 with cesium acetate, (ii) base-promoted deprotonation and metalation to generate the Rh/heteroaryl species II, (iii) olefin insertion, (iv) β-hydride elimination and re-insertion affording Concurrently, Miura and coworkers reported a Pd-catalyzed direct alkylation of oxazoles with nonactivated alkyl halides [70]. A variety of alkyl bromides possessing a benzyl ether, a silyl ether or a pivaloyl ester functional group, transformed into the desired products in moderate to good yields (Scheme 38). Moreover, unactivated alkyl chlorides were also well tolerated employing this catalytic system. Unfortunately, 1-iodohexane gave a much lower yield (20%) while bromocyclohexane could not provide the product due to the rapid decomposition and steric hindrance, respectively. Concurrently, Miura and coworkers reported a Pd-catalyzed direct alkylation of oxazoles with nonactivated alkyl halides [70]. A variety of alkyl bromides possessing a benzyl ether, a silyl ether or a pivaloyl ester functional group, transformed into the desired products in moderate to good yields (Scheme 38). Moreover, unactivated alkyl chlorides were also well tolerated employing this catalytic system. Unfortunately, 1-iodohexane gave a much lower yield (20%) while bromocyclohexane could not provide the product due to the rapid decomposition and steric hindrance, respectively. In 2011, Ackermann and coworkers reported the alkylation of oxazoles with benzyl chlorides and benzyl phosphate applying a Pd(II) complex [71]. The authors found that phosphinous acid Pd(II) complex significantly improved the yield in comparison with other palladium catalysts. In the presence of a prefunctionalized Pd(II) complex, a wide range of differently substituted benzyl chlorides reacted efficiently with (benz)oxazoles, providing the corresponding products in moderate to high yields (Scheme 39).

Scheme 39.
Benzylations on oxazol(in)es with a Pd-catalyst of a secondary phosphine oxide.
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 with cesium acetate, (ii) base-promoted deprotonation and metalation to generate the Rh/heteroaryl species II, (iii) olefin insertion, (iv) β-hydride elimination and re-insertion affording Scheme 38. Pd-catalyzed direct C-H alkylation of benzoxazoles with various alkyl halides.
In 2011, Ackermann and coworkers reported the alkylation of oxazoles with benzyl chlorides and benzyl phosphate applying a Pd(II) complex [71]. The authors found that phosphinous acid Pd(II) complex significantly improved the yield in comparison with other palladium catalysts. In the presence of a prefunctionalized Pd(II) complex, a wide range of differently substituted benzyl chlorides reacted efficiently with (benz)oxazoles, providing the corresponding products in moderate to high yields (Scheme 39). Concurrently, Miura and coworkers reported a Pd-catalyzed direct alkylation of oxazoles with nonactivated alkyl halides [70]. A variety of alkyl bromides possessing a benzyl ether, a silyl ether or a pivaloyl ester functional group, transformed into the desired products in moderate to good yields (Scheme 38). Moreover, unactivated alkyl chlorides were also well tolerated employing this catalytic system. Unfortunately, 1-iodohexane gave a much lower yield (20%) while bromocyclohexane could not provide the product due to the rapid decomposition and steric hindrance, respectively. In 2011, Ackermann and coworkers reported the alkylation of oxazoles with benzyl chlorides and benzyl phosphate applying a Pd(II) complex [71]. The authors found that phosphinous acid Pd(II) complex significantly improved the yield in comparison with other palladium catalysts. In the presence of a prefunctionalized Pd(II) complex, a wide range of differently substituted benzyl chlorides reacted efficiently with (benz)oxazoles, providing the corresponding products in moderate to high yields (Scheme 39). 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 with cesium acetate, (ii) base-promoted deprotonation and metalation to generate the Rh/heteroaryl species II, (iii) olefin insertion, (iv) β-hydride elimination and re-insertion affording intermediated IV and V respectively, and final protonation to deliver products VI with regeneration of the Rh(I) species. Styrene can act as an efficient alkylating reagent. In 2012, the Ong group reported a Ni-Al bimetallic catalyzed alkylation of benzimidazoles with styrenes to deliver linear products [73]. The reaction was successfully performed by using Ni(COD)2/AlMe3 cooperative catalysis along with amino-NHC (L) as ligand (Scheme 41). Like in the previous reports, the binding of the Lewis acid (AlCl3) to the benzimidazole favors the linear chain product due to steric hindrance. In 2015, Filloux and Rovis for the first time introduced the enantioselective alkylation of benzoxazoles with α-substituted acrylates using a Rh(I)/chiralphosphine catalytic system to afford 2substitued benzoxazoles in moderate to excellent yields with good enantioselectivities [74]. Mechanistically, Rh(I)-acetate first activates the C-H bond of the benzoxazole and migratory insertion 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 attenuating coordination-promoted product epimerization (Scheme 42). Styrene can act as an efficient alkylating reagent. In 2012, the Ong group reported a Ni-Al bimetallic catalyzed alkylation of benzimidazoles with styrenes to deliver linear products [73]. The reaction was successfully performed by using Ni(COD) 2 /AlMe 3 cooperative catalysis along with amino-NHC (L) as ligand (Scheme 41). Like in the previous reports, the binding of the Lewis acid (AlCl 3 ) to the benzimidazole favors the linear chain product due to steric hindrance. Styrene can act as an efficient alkylating reagent. In 2012, the Ong group reported a Ni-Al bimetallic catalyzed alkylation of benzimidazoles with styrenes to deliver linear products [73]. The reaction was successfully performed by using Ni(COD)2/AlMe3 cooperative catalysis along with amino-NHC (L) as ligand (Scheme 41). Like in the previous reports, the binding of the Lewis acid (AlCl3) to the benzimidazole favors the linear chain product due to steric hindrance. In 2015, Filloux and Rovis for the first time introduced the enantioselective alkylation of benzoxazoles with α-substituted acrylates using a Rh(I)/chiralphosphine catalytic system to afford 2substitued benzoxazoles in moderate to excellent yields with good enantioselectivities [74]. Mechanistically, Rh(I)-acetate first activates the C-H bond of the benzoxazole and migratory insertion 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 attenuating coordination-promoted product epimerization (Scheme 42). In 2015, Filloux and Rovis for the first time introduced the enantioselective alkylation of benzoxazoles with α-substituted acrylates using a Rh(I)/chiralphosphine catalytic system to afford 2-substitued benzoxazoles in moderate to excellent yields with good enantioselectivities [74]. Mechanistically, Rh(I)-acetate first activates the C-H bond of the benzoxazole and migratory insertion 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 attenuating coordination-promoted product epimerization (Scheme 42). 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 broad substrate scope with good functional group tolerance (Scheme 44). Scheme 44. NHC-Pd(II) complex-catalyzed benzylation of (benz)oxazoles with benzyl chlorides. 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]. 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]. 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 broad substrate scope with good functional group tolerance (Scheme 44). Scheme 44. NHC-Pd(II) complex-catalyzed benzylation of (benz)oxazoles with benzyl chlorides. 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 broad substrate scope with good functional group tolerance (Scheme 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/K 3 PO 4 -catalytic system [78]. 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 broad substrate scope with good functional group tolerance (Scheme 44). Scheme 44. NHC-Pd(II) complex-catalyzed benzylation of (benz)oxazoles with benzyl chlorides. Scheme 44. NHC-Pd(II) complex-catalyzed benzylation of (benz)oxazoles with benzyl chlorides. 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/K 3 PO 4 -catalytic system [78]. Mechanistically, in situ generated Pd(0) undergoes oxidative addition with ArCH 2 NMe 3 + OTfto form the intermediate B.
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 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/K 3 PO 4 -catalytic system [78]. Mechanistically, in situ generated Pd (0)   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).
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).

Secondary C-H Alkylation of Azoles
Although significant progress has been made for primary alkylation, the introduction of a secondary alkyl group is a much more difficult task. In 2010, Nakao et al. reported a Ni(0) catalyzed hydroheteroarylation of vinylarenes to give 1,1-diarylalkanes through oxidative addition of C-H bonds to heteroaryl groups [80]. [Ni(cod)2] and carbene ligand 1,3-dimesitylimidazol-2-ylidene (IMes) were employed as catalytic system in the nonpolar solvent hexane. A variety of vinylarenes that contain a phenyl group bearing both electron-rich and electron-poor substituents, reacted successfully. Several kinds of azoles including benzimidazole, benzoxazole, oxazole, and benzothiazole were also well tolerated, affording 1,1-diarylalkanes with modest to good yields (Scheme 48). In a pioneering work of Wang and coworkers, N-tosylhydrazones have been exploited as a secondary alkyl source for the direct alkylation of azoles with a Cu-catalyst, offering a general method to introduce a secondary alkyl group on an azole framework [81]. Under basic conditions, the authors proposed that a heterocycle-copper species was the intermediate, and a migratory insertion of the Cu carbene species was the key step in this Cu-catalyzed C-H functionalization reaction as shown in Scheme 49.

Secondary C-H Alkylation of Azoles
Although significant progress has been made for primary alkylation, the introduction of a secondary alkyl group is a much more difficult task. In 2010, Nakao et al. reported a Ni(0) catalyzed hydroheteroarylation of vinylarenes to give 1,1-diarylalkanes through oxidative addition of C-H bonds to heteroaryl groups [80]. [Ni(cod) 2 ] and carbene ligand 1,3-dimesitylimidazol-2-ylidene (IMes) were employed as catalytic system in the nonpolar solvent hexane. A variety of vinylarenes that contain a phenyl group bearing both electron-rich and electron-poor substituents, reacted successfully. Several kinds of azoles including benzimidazole, benzoxazole, oxazole, and benzothiazole were also well tolerated, affording 1,1-diarylalkanes with modest to good yields (Scheme 48).

Secondary C-H Alkylation of Azoles
Although significant progress has been made for primary alkylation, the introduction of a secondary alkyl group is a much more difficult task. In 2010, Nakao et al. reported a Ni(0) catalyzed hydroheteroarylation of vinylarenes to give 1,1-diarylalkanes through oxidative addition of C-H bonds to heteroaryl groups [80]. [Ni(cod)2] and carbene ligand 1,3-dimesitylimidazol-2-ylidene (IMes) were employed as catalytic system in the nonpolar solvent hexane. A variety of vinylarenes that contain a phenyl group bearing both electron-rich and electron-poor substituents, reacted successfully. Several kinds of azoles including benzimidazole, benzoxazole, oxazole, and benzothiazole were also well tolerated, affording 1,1-diarylalkanes with modest to good yields (Scheme 48). In a pioneering work of Wang and coworkers, N-tosylhydrazones have been exploited as a secondary alkyl source for the direct alkylation of azoles with a Cu-catalyst, offering a general method to introduce a secondary alkyl group on an azole framework [81]. Under basic conditions, the authors proposed that a heterocycle-copper species was the intermediate, and a migratory insertion of the Cu carbene species was the key step in this Cu-catalyzed C-H functionalization reaction as shown in Scheme 49. In a pioneering work of Wang and coworkers, N-tosylhydrazones have been exploited as a secondary alkyl source for the direct alkylation of azoles with a Cu-catalyst, offering a general method to introduce a secondary alkyl group on an azole framework [81]. Under basic conditions, the authors proposed that a heterocycle-copper species was the intermediate, and a migratory insertion of the Cu carbene species was the key step in this Cu-catalyzed C-H functionalization reaction as shown in Scheme 49. In 2012, Sawamura and coworkers extended this concept for the allylic alkylation of electrondeficient heteroarenes with internal secondary allylic phosphates resulting in excellent γregioselectivity and E-stereoselectivity (Scheme 50) [82]. In this reaction, steric factors played an important role in determining the regioselectivity of the product. Miura and coworkers also utilized N-tosylhydrazones as a radical source in a Ni-catalyzed alkylation of azoles [83]. The authors employed two different catalytic systems depending on the azole, i.e., a nickel catalyst for benzoxazoles and a Co(II) catalyst for 5-aryloxazoles and benzothiazoles (Scheme 51). Interestingly, the authors ruled out a carbene insertion pathway for this catalytic system. In 2013, Van der Eycken and coworkers discovered a novel heteroarene-amine-ketone coupling (HAK-coupling) for the direct secondary alkylation of azoles [84]. This unprecedented Cu-catalyzed HAK coupling was operationally simple and allowed the facile installation of nitrogen-containing alkyl or alkaloid side chains on the azole moiety, using readily available starting materials. The HAK coupling reaction plausibly proceeded through the initial condensation of the aldehyde/ketone with the amine, leading to the corresponding iminium ion which was attacked by the azole-Cu to afford the final product (Scheme 52). In 2012, Sawamura and coworkers extended this concept for the allylic alkylation of electron-deficient heteroarenes with internal secondary allylic phosphates resulting in excellent γ-regioselectivity and E-stereoselectivity (Scheme 50) [82]. In this reaction, steric factors played an important role in determining the regioselectivity of the product. In 2012, Sawamura and coworkers extended this concept for the allylic alkylation of electrondeficient heteroarenes with internal secondary allylic phosphates resulting in excellent γregioselectivity and E-stereoselectivity (Scheme 50) [82]. In this reaction, steric factors played an important role in determining the regioselectivity of the product. Miura and coworkers also utilized N-tosylhydrazones as a radical source in a Ni-catalyzed alkylation of azoles [83]. The authors employed two different catalytic systems depending on the azole, i.e., a nickel catalyst for benzoxazoles and a Co(II) catalyst for 5-aryloxazoles and benzothiazoles (Scheme 51). Interestingly, the authors ruled out a carbene insertion pathway for this catalytic system. In 2013, Van der Eycken and coworkers discovered a novel heteroarene-amine-ketone coupling (HAK-coupling) for the direct secondary alkylation of azoles [84]. This unprecedented Cu-catalyzed HAK coupling was operationally simple and allowed the facile installation of nitrogen-containing alkyl or alkaloid side chains on the azole moiety, using readily available starting materials. The HAK coupling reaction plausibly proceeded through the initial condensation of the aldehyde/ketone with the amine, leading to the corresponding iminium ion which was attacked by the azole-Cu to afford the final product (Scheme 52). Miura and coworkers also utilized N-tosylhydrazones as a radical source in a Ni-catalyzed alkylation of azoles [83]. The authors employed two different catalytic systems depending on the azole, i.e., a nickel catalyst for benzoxazoles and a Co(II) catalyst for 5-aryloxazoles and benzothiazoles (Scheme 51). Interestingly, the authors ruled out a carbene insertion pathway for this catalytic system. In 2012, Sawamura and coworkers extended this concept for the allylic alkylation of electrondeficient heteroarenes with internal secondary allylic phosphates resulting in excellent γregioselectivity and E-stereoselectivity (Scheme 50) [82]. In this reaction, steric factors played an important role in determining the regioselectivity of the product. Miura and coworkers also utilized N-tosylhydrazones as a radical source in a Ni-catalyzed alkylation of azoles [83]. The authors employed two different catalytic systems depending on the azole, i.e., a nickel catalyst for benzoxazoles and a Co(II) catalyst for 5-aryloxazoles and benzothiazoles (Scheme 51). Interestingly, the authors ruled out a carbene insertion pathway for this catalytic system. In 2013, Van der Eycken and coworkers discovered a novel heteroarene-amine-ketone coupling (HAK-coupling) for the direct secondary alkylation of azoles [84]. This unprecedented Cu-catalyzed HAK coupling was operationally simple and allowed the facile installation of nitrogen-containing alkyl or alkaloid side chains on the azole moiety, using readily available starting materials. The HAK coupling reaction plausibly proceeded through the initial condensation of the aldehyde/ketone with the amine, leading to the corresponding iminium ion which was attacked by the azole-Cu to afford the final product (Scheme 52). In 2013, Van der Eycken and coworkers discovered a novel heteroarene-amine-ketone coupling (HAK-coupling) for the direct secondary alkylation of azoles [84]. This unprecedented Cu-catalyzed HAK coupling was operationally simple and allowed the facile installation of nitrogen-containing alkyl or alkaloid side chains on the azole moiety, using readily available starting materials. The HAK coupling reaction plausibly proceeded through the initial condensation of the aldehyde/ketone with the amine, leading to the corresponding iminium ion which was attacked by the azole-Cu to afford the final product (Scheme 52). Similar to Wang's group report, in 2013, Das and coworkers also employed N-tosylhydrazones for the direct benzylation of aryl substituted 1,3,4-oxadiazoles in the presence of a Cu-catalyst [85]. A wide range of substituted oxadiazoles were prepared in high yields (Scheme 53). In 2014, Miura and coworkers employed diarylmethyl carbonates or pivalates as coupling partners for the alkylation of oxazoles with a PdCl2(MeCN)2/PPhCy2 catalytic system [86]. This gives the access to challenging heteroarene-containing triarylmethanes (Scheme 54). In the same year, Chen and coworkers further evolved the direct C-H bond alkylation of azoles with ferrocenyl ketone-derived N-tosylhydrazones using an inexpensive CuBr catalyst [87]. Without using CuBr, the product was obtained in low yield, whereas replacement of CuBr with other transition metal salts slowed down the reaction. This catalyst system displayed good tolerance towards a range of functional groups on the ferrocenyl ketone derived N-tosylhydrazones (Scheme 55). Similar to Wang's group report, in 2013, Das and coworkers also employed N-tosylhydrazones for the direct benzylation of aryl substituted 1,3,4-oxadiazoles in the presence of a Cu-catalyst [85]. A wide range of substituted oxadiazoles were prepared in high yields (Scheme 53). Similar to Wang's group report, in 2013, Das and coworkers also employed N-tosylhydrazones for the direct benzylation of aryl substituted 1,3,4-oxadiazoles in the presence of a Cu-catalyst [85]. A wide range of substituted oxadiazoles were prepared in high yields (Scheme 53). In 2014, Miura and coworkers employed diarylmethyl carbonates or pivalates as coupling partners for the alkylation of oxazoles with a PdCl2(MeCN)2/PPhCy2 catalytic system [86]. This gives the access to challenging heteroarene-containing triarylmethanes (Scheme 54). In the same year, Chen and coworkers further evolved the direct C-H bond alkylation of azoles with ferrocenyl ketone-derived N-tosylhydrazones using an inexpensive CuBr catalyst [87]. Without using CuBr, the product was obtained in low yield, whereas replacement of CuBr with other transition metal salts slowed down the reaction. This catalyst system displayed good tolerance towards a range of functional groups on the ferrocenyl ketone derived N-tosylhydrazones (Scheme 55). In 2014, Miura and coworkers employed diarylmethyl carbonates or pivalates as coupling partners for the alkylation of oxazoles with a PdCl 2 (MeCN) 2 /PPhCy 2 catalytic system [86]. This gives the access to challenging heteroarene-containing triarylmethanes (Scheme 54). Similar to Wang's group report, in 2013, Das and coworkers also employed N-tosylhydrazones for the direct benzylation of aryl substituted 1,3,4-oxadiazoles in the presence of a Cu-catalyst [85]. A wide range of substituted oxadiazoles were prepared in high yields (Scheme 53). In 2014, Miura and coworkers employed diarylmethyl carbonates or pivalates as coupling partners for the alkylation of oxazoles with a PdCl2(MeCN)2/PPhCy2 catalytic system [86]. This gives the access to challenging heteroarene-containing triarylmethanes (Scheme 54). In the same year, Chen and coworkers further evolved the direct C-H bond alkylation of azoles with ferrocenyl ketone-derived N-tosylhydrazones using an inexpensive CuBr catalyst [87]. Without using CuBr, the product was obtained in low yield, whereas replacement of CuBr with other transition metal salts slowed down the reaction. This catalyst system displayed good tolerance towards a range of functional groups on the ferrocenyl ketone derived N-tosylhydrazones (Scheme 55). In the same year, Chen and coworkers further evolved the direct C-H bond alkylation of azoles with ferrocenyl ketone-derived N-tosylhydrazones using an inexpensive CuBr catalyst [87]. Without using CuBr, the product was obtained in low yield, whereas replacement of CuBr with other transition metal salts slowed down the reaction. This catalyst system displayed good tolerance towards a range of functional groups on the ferrocenyl ketone derived N-tosylhydrazones (Scheme 55). In 2015, Zhou and coworkers reported a challenging cyclopropylation of benzoxazoles using stereoretentive cyclopropyl halides and a Pd(0) catalystic system [88]. The reaction started with the oxidative addition to the cyclopropyl C-X bond followed by transmetalation of an anionic heterocycle. Finally, reductive elimination delivered the desired coupling product (Scheme 56). Scheme 56. Pd catalyzed cyclopropylation of benzoxazoles with cyclopropyl halides.
The first rhodium-catalyzed selective alkylation of benzimidazoles with N,N-dimethyl acrylamide was successfully developed by Ellman and coworkers in 2017 [89]. The combination of the electron-poor ligand dAr F pe with a Rh(I) catalyst in the presence of K3PO4 selectively delivered the alkylation product in high yields (Scheme 57). In the same year, a Pd-catalyzed desulfonative deprotonative cross-coupling reaction of benzylic sulfone derivatives with 1,3-oxazoles was reported by Crudden and coworkers [90]. The presented methodology showed a high functional group tolerance and afforded excellent yields (Scheme 58).
In 2015, Zhou and coworkers reported a challenging cyclopropylation of benzoxazoles using stereoretentive cyclopropyl halides and a Pd(0) catalystic system [88]. The reaction started with the oxidative addition to the cyclopropyl C-X bond followed by transmetalation of an anionic heterocycle. Finally, reductive elimination delivered the desired coupling product (Scheme 56). In 2015, Zhou and coworkers reported a challenging cyclopropylation of benzoxazoles using stereoretentive cyclopropyl halides and a Pd(0) catalystic system [88]. The reaction started with the oxidative addition to the cyclopropyl C-X bond followed by transmetalation of an anionic heterocycle. Finally, reductive elimination delivered the desired coupling product (Scheme 56). Scheme 56. Pd catalyzed cyclopropylation of benzoxazoles with cyclopropyl halides.
The first rhodium-catalyzed selective alkylation of benzimidazoles with N,N-dimethyl acrylamide was successfully developed by Ellman and coworkers in 2017 [89]. The combination of the electron-poor ligand dAr F pe with a Rh(I) catalyst in the presence of K3PO4 selectively delivered the alkylation product in high yields (Scheme 57). In the same year, a Pd-catalyzed desulfonative deprotonative cross-coupling reaction of benzylic sulfone derivatives with 1,3-oxazoles was reported by Crudden and coworkers [90]. The presented methodology showed a high functional group tolerance and afforded excellent yields (Scheme 58). Scheme 56. Pd catalyzed cyclopropylation of benzoxazoles with cyclopropyl halides.
The first rhodium-catalyzed selective alkylation of benzimidazoles with N,N-dimethyl acrylamide was successfully developed by Ellman and coworkers in 2017 [89]. The combination of the electron-poor ligand dAr F pe with a Rh(I) catalyst in the presence of K 3 PO 4 selectively delivered the alkylation product in high yields (Scheme 57). In 2015, Zhou and coworkers reported a challenging cyclopropylation of benzoxazoles using stereoretentive cyclopropyl halides and a Pd(0) catalystic system [88]. The reaction started with the oxidative addition to the cyclopropyl C-X bond followed by transmetalation of an anionic heterocycle. Finally, reductive elimination delivered the desired coupling product (Scheme 56). Scheme 56. Pd catalyzed cyclopropylation of benzoxazoles with cyclopropyl halides.
The first rhodium-catalyzed selective alkylation of benzimidazoles with N,N-dimethyl acrylamide was successfully developed by Ellman and coworkers in 2017 [89]. The combination of the electron-poor ligand dAr F pe with a Rh(I) catalyst in the presence of K3PO4 selectively delivered the alkylation product in high yields (Scheme 57). In the same year, a Pd-catalyzed desulfonative deprotonative cross-coupling reaction of benzylic sulfone derivatives with 1,3-oxazoles was reported by Crudden and coworkers [90]. The presented methodology showed a high functional group tolerance and afforded excellent yields (Scheme 58). In the same year, a Pd-catalyzed desulfonative deprotonative cross-coupling reaction of benzylic sulfone derivatives with 1,3-oxazoles was reported by Crudden and coworkers [90]. The presented methodology showed a high functional group tolerance and afforded excellent yields (Scheme 58). In 2017, Mandal and coworkers developed a Ni(COD)2 catalyzed regioselective hydroheteroarylation of vinylarenes with benzoxazoles, providing an exclusively wide range of 1,1diarylethane products [91]. The authors were able to isolate and characterize the active catalyst by single-crystal X-ray crystallography (Scheme 59). Similarly, Sun and coworkers also employed a NHCs-based nickel catalytic system for the regioselective hydroarylation of vinylarenes with benzothiazoles, affording the desired product in high yield [92]. In this reaction, the regioselectivity is controlled by the sterically demanding Ni(IMes)[P(OEt)3]Br2 catalyst (Scheme 60). In 2019, Wang and coworkers exploited an economical Cu(I)-catalyst to achieve the crosscoupling of bis(trimethylsilyl)diazomethane and benzoxazoles/oxazoles, affording a series of 1,1bis(trimethylsilyl)-methylated heteroaromatic compounds in moderate to good yields, through a carbene migratory insertion process [93]. Mechanistic studies indicated that the main step is the formation of a Cu(I) carbene species, followed by migratory insertion and protonation to produce the final products, as shown in Scheme 61. Scheme 58. Pd-catalyzed desulfonative cross-coupling reaction of benzylic sulfone derivatives with 1,3-oxazoles.
In 2017, Mandal and coworkers developed a Ni(COD) 2 catalyzed regioselective hydroheteroarylation of vinylarenes with benzoxazoles, providing an exclusively wide range of 1,1-diarylethane products [91]. The authors were able to isolate and characterize the active catalyst by single-crystal X-ray crystallography (Scheme 59). In 2017, Mandal and coworkers developed a Ni(COD)2 catalyzed regioselective hydroheteroarylation of vinylarenes with benzoxazoles, providing an exclusively wide range of 1,1diarylethane products [91]. The authors were able to isolate and characterize the active catalyst by single-crystal X-ray crystallography (Scheme 59). Similarly, Sun and coworkers also employed a NHCs-based nickel catalytic system for the regioselective hydroarylation of vinylarenes with benzothiazoles, affording the desired product in high yield [92]. In this reaction, the regioselectivity is controlled by the sterically demanding Ni(IMes)[P(OEt)3]Br2 catalyst (Scheme 60). In 2019, Wang and coworkers exploited an economical Cu(I)-catalyst to achieve the crosscoupling of bis(trimethylsilyl)diazomethane and benzoxazoles/oxazoles, affording a series of 1,1bis(trimethylsilyl)-methylated heteroaromatic compounds in moderate to good yields, through a carbene migratory insertion process [93]. Mechanistic studies indicated that the main step is the formation of a Cu(I) carbene species, followed by migratory insertion and protonation to produce the final products, as shown in Scheme 61. Similarly, Sun and coworkers also employed a NHCs-based nickel catalytic system for the regioselective hydroarylation of vinylarenes with benzothiazoles, affording the desired product in high yield [92]. In this reaction, the regioselectivity is controlled by the sterically demanding Ni(IMes)[P(OEt) 3 ]Br 2 catalyst (Scheme 60). In 2017, Mandal and coworkers developed a Ni(COD)2 catalyzed regioselective hydroheteroarylation of vinylarenes with benzoxazoles, providing an exclusively wide range of 1,1diarylethane products [91]. The authors were able to isolate and characterize the active catalyst by single-crystal X-ray crystallography (Scheme 59). Similarly, Sun and coworkers also employed a NHCs-based nickel catalytic system for the regioselective hydroarylation of vinylarenes with benzothiazoles, affording the desired product in high yield [92]. In this reaction, the regioselectivity is controlled by the sterically demanding Ni(IMes)[P(OEt)3]Br2 catalyst (Scheme 60). In 2019, Wang and coworkers exploited an economical Cu(I)-catalyst to achieve the crosscoupling of bis(trimethylsilyl)diazomethane and benzoxazoles/oxazoles, affording a series of 1,1bis(trimethylsilyl)-methylated heteroaromatic compounds in moderate to good yields, through a carbene migratory insertion process [93]. Mechanistic studies indicated that the main step is the formation of a Cu(I) carbene species, followed by migratory insertion and protonation to produce the final products, as shown in Scheme 61. In 2019, Wang and coworkers exploited an economical Cu(I)-catalyst to achieve the cross-coupling of bis(trimethylsilyl)diazomethane and benzoxazoles/oxazoles, affording a series of 1,1-bis(trimethylsilyl)-methylated heteroaromatic compounds in moderate to good yields, through a carbene migratory insertion process [93]. Mechanistic studies indicated that the main step is the formation of a Cu(I) carbene species, followed by migratory insertion and protonation to produce the final products, as shown in Scheme 61.

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 Na 2 CO 3 as base to synthesize the tribenzylated products via nucleophilic substitution with benzyl chloride (Scheme 62).

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 Pdcatalyzed 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).
Ni and a base, undergoes transmetalation with the heteroaryllithium. 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 nickelcatalyzed 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). 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). 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 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 nickelcatalyzed 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). 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). 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 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). 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 nickelcatalyzed 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). 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). 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 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 many advantages over other approaches, such as better functional group tolerance, mild reaction conditions, and the possibility of forming complex scaffolds (Scheme 66).
Molecules 2020, 25, x FOR PEER REVIEW 28 of 33 many advantages over other approaches, such as better functional group tolerance, mild reaction conditions, and the possibility of forming complex scaffolds (Scheme 66). In 2015, Mannepalli and coworkers developed an air-and moisture-stable Pd(II) carbene complex for the alkynylation of azoles with terminal alkynes and aryl propiolic acids by crossdehydrogenative or decarboxylative coupling, respectively [100]. A wide range of azoles including benzoxazoles, benzothiazoles, imidazoles, and benzimizoles afforded the desired alkynylation products in moderate to high yields (Scheme 67). Molecules 2020, 25, x FOR PEER REVIEW 29 of 33 Scheme 69.Ni (II)-catalyzed C-H bond alkynylation of benzothiazoles and related azoles.

Conclusions and Perspectives
In this review, we summarized recent developments in the transition metal-catalyzed direct C−H functionalization of azoles. These functionalizations are some of the most efficient methods to introduce various substituted olefins, alkanes, and alkynes to azoles. In addition to the importance of Pd in this field, researchers have widely explored several other transition metals such as Cu, Rh, Co, Ni, and Ru. The major advantage of transition metal-catalyzed direct C-H activation is that it requires no prefunctionalization of the starting azoles, resulting in, e.g., a wide scope, modularity, and high yields. Despite considerable advances, many challenges remain, e.g., overcoming the need for strong and harsh bases such as LiO and t Bu anions, and the unavoidable use of activated derivatives such as halo groups (Cl, Br, and I), carbonyl groups, and metal acetylides. Thus, compared with C−X/C−M coupling reactions, organic chemists should prefer catalytic activation of inert C-H bonds for new C-C bond formation reactions, starting from inexpensive and structurally diverse alkanes, alkenes, or alkynes. Furthermore, another challenge is to develop recyclable and highly efficient transition metal catalyst systems with low catalyst loading. Finally, researchers have partially solved the chemoselectivity and regioselectivity issues in these reactions by means of incorporating a directing group or using the sterics/electronics of the substrates. However, it is feasible to develop a suitable catalyst or fine-tune reaction conditions to change/control the regioselectivity.
Funding: This research received no external funding.