Advances in Enantioselective C–H Activation/Mizoroki-Heck Reaction and Suzuki Reaction

: Traditional cross-coupling reactions, like Mizoroki-Heck Reaction and Suzuki Reaction, have revolutionized organic chemistry and are widely applied in modern organic synthesis. With the rapid development of C–H activation and asymmetric catalysis in recent years, enantioselective C–H activation/cross-coupling reactions have drawn much attention from researchers. This review summarizes recent advances in enantioselective C–H activation/Mizoroki-Heck Reaction and Suzuki Reaction, with emphasis on the structures and functions of chiral ligands utilized in different reactions.


Introduction
Over the past few decades, C-H bond activation was established as a credible and viable strategy in organic synthesis [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18]. On the basis of previous work, C-H activation/functionalization is employed as a dynamic strategy for the synthesis of a great deal of highly valuable natural products and other classes of compounds for pharmaceutics or research interests [19][20][21][22]. Chemists have long been captivated by such synthetic techniques, owing to the obvious merits. From a philosophical point of view, chemists regard C-H bonds as dormant equivalents of various pre-functionalized groups. Moreover, the direct modification of ubiquitously-existing C-H bonds successfully live up to the criteria of one perfect catalytic reaction that ought to be atom-economic and environmental-friendly [23]. Thus, it provides new synthetic disconnections in retrosynthetic analysis [24][25][26][27][28].
It is widely acknowledged that carbon-carbon (C-C) bond formation is fundamental and essential in organic chemistry. Numerous methods have been well developed to enable such C-C bond formation to proceed smoothly. Among these reactions, transition-metals (Pd, Rh, Ru, Cu, Zn, Sn, Mg, etc.) catalyzed cross-coupling reactions are efficient techniques to realize C-C bond formation, which can be well exemplified by Suzuki [29], Mizoroki-Heck [30], Sonogashira [31], Negishi [32], Stille [33], Kumada [34] coupling reaction, etc. These coupling reactions are renowned for their extraordinary utility, practicality, and reliability, and have been broadly utilized in many syntheses, involving pharmaceuticals, fine chemicals, agrochemicals, etc. Consequently, Richard Mizoroki-Heck, Ei-ichi Negishi, and Akira Suzuki jointly won the Nobel Prize in Chemistry 2010 for their excellent work of "palladium-catalyzed cross-coupling reactions in organic synthesis", which furnished a novel way to achieve C-C bond formation that substantially accelerated the development of pharmaceutics and electronics industries [35]. Although lots of outstanding achievements in this field have been made, from an atom-economic and environmental-harmoniously perspective, there are still shortcomings Scheme 1. Traditional Suzuki coupling reaction.
In recent years, the direct asymmetric C-H activation/Suzuki cross-coupling reactions have substantially attracted the attention of synthetic chemists. Herein, we review the recent progresses on enantioselective C-H activation/Suzuki cross-coupling reactions of prochiral substrates.
In 2008, Li et al., developed the asymmetric C(sp 3 )-H arylation reactions of tetrahydroisoquinolines with aryl boronic acids [58]. The reaction proceeded smoothly with CuBr as the catalyst and T-HYDRO as the oxidant in DME. Interestingly, when chiral PhPyBox was added as the ligand, the desired product was obtained with 30% ee (Scheme 2). The addition of CuOTf instead of CuBr further increased the enantioselectivity to 44%. Scheme 1. Traditional Suzuki coupling reaction.
In recent years, the direct asymmetric C-H activation/Suzuki cross-coupling reactions have substantially attracted the attention of synthetic chemists. Herein, we review the recent progresses on enantioselective C-H activation/Suzuki cross-coupling reactions of prochiral substrates.
In 2008, Li et al., developed the asymmetric C(sp 3 )-H arylation reactions of tetrahydroisoquinolines with aryl boronic acids [58]. The reaction proceeded smoothly with CuBr as the catalyst and T-HYDRO as the oxidant in DME. Interestingly, when chiral PhPyBox was added as the ligand, the desired product was obtained with 30% ee (Scheme 2). The addition of CuOTf instead of CuBr further increased the enantioselectivity to 44%. After investigating various conditions, impressively, the asymmetric induction truly occurred (Scheme 5). When the n-PrOH solution of 4a and 5a was exposed to Pd(OAc)2/L2 and TEMPO at 70 °C for 12 h under air, the product (S)-6aa was obtained with 41% ee and 63% yield. When a more sterically encumbered arylboronic acid 5e was used, the enantiometric excess of the corresponding product was improved to 72%, albeit with a lower yield. The absolute stereo-configuration of the asymmetric products was determined by X-ray crystallography.
In 2013, the same group revealed another version of this reaction [61]. In this paper, they utilized a Pd II -sulfoxide-oxazoline/iron-phthalocyanine (FePc) dual catalyst system for the syntheses of sterically hindered heterobiaryls with air as the oxidant instead of using TEMPO as the stoichiometric co-oxidant (Scheme 6). It was proposed that the ligands (e.g., L4) took effect in the form of a Pd-sox complex, which exhibited higher reactivity in coupling hindered partners. Scheme 6. Enantioselective C-H activation/C-C coupling between heteroarenes and arylboronic acids [61].
In 2008, a huge advance was made by Yu and coworkers [62]. They developed the Pd II /chiral mono-N-protected amino acid (MPAA) system and applied it in the desymmetrization reaction of prochiral substrates (Scheme 7). After investigating various conditions, impressively, the asymmetric induction truly occurred (Scheme 5). When the n-PrOH solution of 4a and 5a was exposed to Pd(OAc) 2 /L2 and TEMPO at 70 • C for 12 h under air, the product (S)-6aa was obtained with 41% ee and 63% yield. When a more sterically encumbered arylboronic acid 5e was used, the enantiometric excess of the corresponding product was improved to 72%, albeit with a lower yield. The absolute stereo-configuration of the asymmetric products was determined by X-ray crystallography.
In 2013, the same group revealed another version of this reaction [61]. In this paper, they utilized a Pd II -sulfoxide-oxazoline/iron-phthalocyanine (FePc) dual catalyst system for the syntheses of sterically hindered heterobiaryls with air as the oxidant instead of using TEMPO as the stoichiometric co-oxidant (Scheme 6). It was proposed that the ligands (e.g., L4) took effect in the form of a Pd-sox complex, which exhibited higher reactivity in coupling hindered partners. As the ligands delivering excellent performance (L2 and L3) are chiral, the enantioselective synthesis of axially chiral heterobiaryls was predicted to be possible. To have a better understanding of the axial chirality of the substituted heterobiaryls, the rotation energy of 3-methyl-4-(2-methylnaphthalen-1-yl)-thiophene (6ba) between two conformations was investigated by DFT calculations (Figure 1). It was found that the rotation energy was high enough for the two atropisomers to exist stably at room temperature. After investigating various conditions, impressively, the asymmetric induction truly occurred (Scheme 5). When the n-PrOH solution of 4a and 5a was exposed to Pd(OAc)2/L2 and TEMPO at 70 °C for 12 h under air, the product (S)-6aa was obtained with 41% ee and 63% yield. When a more sterically encumbered arylboronic acid 5e was used, the enantiometric excess of the corresponding product was improved to 72%, albeit with a lower yield. The absolute stereo-configuration of the asymmetric products was determined by X-ray crystallography.
In 2013, the same group revealed another version of this reaction [61]. In this paper, they utilized a Pd II -sulfoxide-oxazoline/iron-phthalocyanine (FePc) dual catalyst system for the syntheses of sterically hindered heterobiaryls with air as the oxidant instead of using TEMPO as the stoichiometric co-oxidant (Scheme 6). It was proposed that the ligands (e.g., L4) took effect in the form of a Pd-sox complex, which exhibited higher reactivity in coupling hindered partners. Scheme 6. Enantioselective C-H activation/C-C coupling between heteroarenes and arylboronic acids [61].
In 2008, a huge advance was made by Yu and coworkers [62]. They developed the Pd II /chiral mono-N-protected amino acid (MPAA) system and applied it in the desymmetrization reaction of prochiral substrates (Scheme 7). Scheme 6. Enantioselective C-H activation/C-C coupling between heteroarenes and arylboronic acids [61].
In 2008, a huge advance was made by Yu and coworkers [62]. They developed the Pd II /chiral mono-N-protected amino acid (MPAA) system and applied it in the desymmetrization reaction of prochiral substrates (Scheme 7). Detailed mechanism studies by Yu and coworkers suggested that using conformationally rigid chiral carboxylic acids as ligands as well as Pd II catalyst might induce the enantioselective C-H activation process. Indeed, when Boc-protected chiral amino acids were used, the asymmetric induction took place. With compound 7 and butylboronic acid as model substrates, Boc-L-leucine afforded the corresponding product with 63% yield and 90% ee (Scheme 8). Intriguingly, when the Boc protecting group was removed or substituted by methyl group, the reactions failed to occur, which indicates that an electron-withdrawing group on the nitrogen atom is essential in maintaining the electrophilicity of Pd II towards the C-H bond. Moreover, the esterification of the amino acid or the decrease of the nitrogen protecting group size resulted in significant declines of enantioselectivities. Thus, the bulkier menthoxycarbonyl protecting groups were introduced and ligand L13 was found to give the best results.  Detailed mechanism studies by Yu and coworkers suggested that using conformationally rigid chiral carboxylic acids as ligands as well as Pd II catalyst might induce the enantioselective C-H activation process. Indeed, when Boc-protected chiral amino acids were used, the asymmetric induction took place. With compound 7 and butylboronic acid as model substrates, Boc-L-leucine afforded the corresponding product with 63% yield and 90% ee (Scheme 8). Intriguingly, when the Boc protecting group was removed or substituted by methyl group, the reactions failed to occur, which indicates that an electron-withdrawing group on the nitrogen atom is essential in maintaining the electrophilicity of Pd II towards the C-H bond. Moreover, the esterification of the amino acid or the decrease of the nitrogen protecting group size resulted in significant declines of enantioselectivities. Thus, the bulkier menthoxycarbonyl protecting groups were introduced and ligand L13 was found to give the best results. Detailed mechanism studies by Yu and coworkers suggested that using conformationally rigid chiral carboxylic acids as ligands as well as Pd II catalyst might induce the enantioselective C-H activation process. Indeed, when Boc-protected chiral amino acids were used, the asymmetric induction took place. With compound 7 and butylboronic acid as model substrates, Boc-L-leucine afforded the corresponding product with 63% yield and 90% ee (Scheme 8). Intriguingly, when the Boc protecting group was removed or substituted by methyl group, the reactions failed to occur, which indicates that an electron-withdrawing group on the nitrogen atom is essential in maintaining the electrophilicity of Pd II towards the C-H bond. Moreover, the esterification of the amino acid or the decrease of the nitrogen protecting group size resulted in significant declines of enantioselectivities. Thus, the bulkier menthoxycarbonyl protecting groups were introduced and ligand L13 was found to give the best results.  With the optimized condition in hand, different substrates and boronic acids were investigated and the products were obtained in good yields and moderate to excellent ee (Table 1). Furthermore, enantioselective alkylation of C(sp 3 )-H bonds, such as substrate 9, was also executed and the desired product was obtained with 38% yield and 37% ee (Scheme 9). With the optimized condition in hand, different substrates and boronic acids were investigated and the products were obtained in good yields and moderate to excellent ee (Table 1). Furthermore, enantioselective alkylation of C(sp 3 )-H bonds, such as substrate 9, was also executed and the desired product was obtained with 38% yield and 37% ee (Scheme 9). In the proposed transition state, both the nitrogen atom and the carboxylate group of the amino acid ligand coordinate with the Pd II center in a bidentate way, providing a chiral environment. Transition state 11a rather than 11b is preferred, in that the steric repulsion between the substituent on the newly generated chiral center (o-Tol) and the Boc group on the nitrogen center is minimized ( Figure 2).   With the optimized condition in hand, different substrates and boronic acids were investigated and the products were obtained in good yields and moderate to excellent ee (Table 1). Furthermore, enantioselective alkylation of C(sp 3 )-H bonds, such as substrate 9, was also executed and the desired product was obtained with 38% yield and 37% ee (Scheme 9). In the proposed transition state, both the nitrogen atom and the carboxylate group of the amino acid ligand coordinate with the Pd II center in a bidentate way, providing a chiral environment. Transition state 11a rather than 11b is preferred, in that the steric repulsion between the substituent on the newly generated chiral center (o-Tol) and the Boc group on the nitrogen center is minimized ( Figure 2).  In the proposed transition state, both the nitrogen atom and the carboxylate group of the amino acid ligand coordinate with the Pd II center in a bidentate way, providing a chiral environment. Transition state 11a rather than 11b is preferred, in that the steric repulsion between the substituent on the newly generated chiral center (o-Tol) and the Boc group on the nitrogen center is minimized ( Figure 2). With the optimized condition in hand, different substrates and boronic acids were investigated and the products were obtained in good yields and moderate to excellent ee (Table 1). Furthermore, enantioselective alkylation of C(sp 3 )-H bonds, such as substrate 9, was also executed and the desired product was obtained with 38% yield and 37% ee (Scheme 9). In the proposed transition state, both the nitrogen atom and the carboxylate group of the amino acid ligand coordinate with the Pd II center in a bidentate way, providing a chiral environment. Transition state 11a rather than 11b is preferred, in that the steric repulsion between the substituent on the newly generated chiral center (o-Tol) and the Boc group on the nitrogen center is minimized ( Figure 2).  In 2011, Yu and coworkers reported the enantioselective C(sp 3 )-H activation of cyclopropanes catalyzed by Pd II /MPAA (Scheme 10) [44].
In this reaction, the amide derivative of 1-methylcyclopropanecarboxylic acid was utilized as the substrate and the electron-deficient arylamide group plays as a directing group. In the process of screening the chiral MPAA ligands, it was discovered that both the protecting group of the amine and the backbone of the amino acid were crucial for the enantioseectivities (Scheme 11). When the protecting group Boc was changed into TcBoc, the enantioselectivity increased dramatically to 78% from 31%, indicating that CCl3 might serve as a bulkier group and an electron-withdrawing group (EWG) simultaneously. Further screening revealed that phenylalanine derivative L23 was the best ligand, and up to 93% ee was achieved.
In this reaction, the amide derivative of 1-methylcyclopropanecarboxylic acid was utilized as the substrate and the electron-deficient arylamide group plays as a directing group. In the process of screening the chiral MPAA ligands, it was discovered that both the protecting group of the amine and the backbone of the amino acid were crucial for the enantioseectivities (Scheme 11). When the protecting group Boc was changed into TcBoc, the enantioselectivity increased dramatically to 78% from 31%, indicating that CCl 3 might serve as a bulkier group and an electron-withdrawing group (EWG) simultaneously. Further screening revealed that phenylalanine derivative L23 was the best ligand, and up to 93% ee was achieved. Scheme 10. Asymmetric C-H activation/C-C coupling reaction of cyclopropane [44].
In this reaction, the amide derivative of 1-methylcyclopropanecarboxylic acid was utilized as the substrate and the electron-deficient arylamide group plays as a directing group. In the process of screening the chiral MPAA ligands, it was discovered that both the protecting group of the amine and the backbone of the amino acid were crucial for the enantioseectivities (Scheme 11). When the protecting group Boc was changed into TcBoc, the enantioselectivity increased dramatically to 78% from 31%, indicating that CCl3 might serve as a bulkier group and an electron-withdrawing group (EWG) simultaneously. Further screening revealed that phenylalanine derivative L23 was the best ligand, and up to 93% ee was achieved.

Scheme 11.
Screening of chiral mono-protected amino acid ligands [44]. With the optimized conditions, different cyclopropanes and organoboronic compounds were investigated and the products were obtained in good yields and good to excellent ee ( Figure 3). With the optimized conditions, different cyclopropanes and organoboronic compounds were investigated and the products were obtained in good yields and good to excellent ee ( Figure 3).
In 2014, the same group reported a further research for the arylation of methylene β-C(sp 3 )-H bonds of cyclobutanecarboxylic acid derivatives with arylboron reagents using palladium(II) catalyst with chiral mono-N-protected α-amino-O-methylhydroxamic acid (MPAHA) as the ligand (Scheme 12) [63]. This method provided a complementary protocol for the syntheses of enantioenriched cyclobutanes containing chiral quaternary stereocenters [64,65]. [63]. In 2014, the same group reported a further research for the arylation of methylene β-C(sp 3 )-H bonds of cyclobutanecarboxylic acid derivatives with arylboron reagents using palladium(II) catalyst with chiral mono-N-protected α-amino-O-methylhydroxamic acid (MPAHA) as the ligand (Scheme 12) [63]. This method provided a complementary protocol for the syntheses of enantioenriched cyclobutanes containing chiral quaternary stereocenters [64,65]. With the optimized conditions, different cyclopropanes and organoboronic compounds were investigated and the products were obtained in good yields and good to excellent ee ( Figure 3). In 2014, the same group reported a further research for the arylation of methylene β-C(sp 3 )-H bonds of cyclobutanecarboxylic acid derivatives with arylboron reagents using palladium(II) catalyst with chiral mono-N-protected α-amino-O-methylhydroxamic acid (MPAHA) as the ligand (Scheme 12) [63]. This method provided a complementary protocol for the syntheses of enantioenriched cyclobutanes containing chiral quaternary stereocenters [64,65]. Similar to the precedent studies, MPAHA can generate a chiral complex with Pd II catalyst and is the key to obtain appreciable yield and enantioselectivity. When O-methylhydroxamic acids were used as ligands instead of the previously used mono-protected amino acids, a significant boost of enantioselectivity was observed, which might derive from the stronger coordination between the ligand and the Pd II center. Further evaluation revealed that the Boc protecting group and an aromatic side chain within the ligand were prone to elevate the enantioselectivities. Of the various ligands that were tested, L32 gave the best results (Scheme 13). Further optimization of the solvents, bases and catalysts eventually led to the desired product with 75% yield and 92% ee. Similar to the precedent studies, MPAHA can generate a chiral complex with Pd II catalyst and is the key to obtain appreciable yield and enantioselectivity. When O-methylhydroxamic acids were used as ligands instead of the previously used mono-protected amino acids, a significant boost of enantioselectivity was observed, which might derive from the stronger coordination between the ligand and the Pd II center. Further evaluation revealed that the Boc protecting group and an aromatic side chain within the ligand were prone to elevate the enantioselectivities. Of the various ligands that were tested, L32 gave the best results (Scheme 13). Further optimization of the solvents, bases and catalysts eventually led to the desired product with 75% yield and 92% ee. Scheme 13. Designs of chiral ligands [63].

Scheme 12. Enantioselective C(sp 3 )-H activation of cyclobutanes
Under the optimized condition, the reaction was found to work well between a variety of arylboronic acid pinacol esters and various 1-substituted 1-cyclobutanecarboxylic acid derivatives (Scheme 14). Scheme 13. Designs of chiral ligands [63].
Under the optimized condition, the reaction was found to work well between a variety of arylboronic acid pinacol esters and various 1-substituted 1-cyclobutanecarboxylic acid derivatives (Scheme 14). Substrates scope for C(sp 3 )-H activation of cyclobutanes [63].
It is well known that planar chiral ferrocenes are frequently applied as highly efficient catalysts or ligands in asymmetric synthesis [66][67][68][69][70][71]. Inspired by previous studies from Yu group [44,62] In this work, dimethylaminomethylferrocene 22a and phenylboronic acid 23a were chosen as model substrates. The reaction proceeded smoothly in the presence of 10 mol % Pd(OAc) 2 , 20 mol % Boc-L-Val-OH, and 1 equiv of K 2 CO 3 in DMA (Dimethylacetamide) at 80 • C under air, providing the desired product with 58% yield and 97% ee. The yield was further improved to 79% with 25 mol % TBAB as the additive when the reaction was performed at 60 • C.
With the optimized condition, various aminomethylferrocene derivatives and boronic acids were examined. Substituted arylboronic acids bearing either an electron-donating group or an electronwithdrawing group were well-tolerated and afforded the corresponding products in good yields and excellent enantioselectivities. Moreover, the reaction was also general for aminomethylferrocenes with different alkyl groups on the nitrogen atom (Scheme 16). In addition, a large scale reaction was executed smoothly, which further confirmed the practicality of this method. In this work, dimethylaminomethylferrocene 22a and phenylboronic acid 23a were chosen as model substrates. The reaction proceeded smoothly in the presence of 10 mol % Pd(OAc)2, 20 mol % Boc-L-Val-OH, and 1 equiv of K2CO3 in DMA (Dimethylacetamide) at 80 °C under air, providing the desired product with 58% yield and 97% ee. The yield was further improved to 79% with 25 mol % TBAB as the additive when the reaction was performed at 60 °C.
With the optimized condition, various aminomethylferrocene derivatives and boronic acids were examined. Substituted arylboronic acids bearing either an electron-donating group or an electron-withdrawing group were well-tolerated and afforded the corresponding products in good yields and excellent enantioselectivities. Moreover, the reaction was also general for aminomethylferrocenes with different alkyl groups on the nitrogen atom (Scheme 16). In addition, a large scale reaction was executed smoothly, which further confirmed the practicality of this method.  [72].
At last, the planar-chiral P,N-ligand L34 prepared from compound 24 was successfully utilized in the palladium-catalyzed allylic alkylation reaction (Scheme 17), which fully demonstrated the potential application of this novel protocol.
At last, the planar-chiral P,N-ligand L34 prepared from compound 24 was successfully utilized in the palladium-catalyzed allylic alkylation reaction (Scheme 17), which fully demonstrated the potential application of this novel protocol. In this work, dimethylaminomethylferrocene 22a and phenylboronic acid 23a were chosen as model substrates. The reaction proceeded smoothly in the presence of 10 mol % Pd(OAc)2, 20 mol % Boc-L-Val-OH, and 1 equiv of K2CO3 in DMA (Dimethylacetamide) at 80 °C under air, providing the desired product with 58% yield and 97% ee. The yield was further improved to 79% with 25 mol % TBAB as the additive when the reaction was performed at 60 °C.
With the optimized condition, various aminomethylferrocene derivatives and boronic acids were examined. Substituted arylboronic acids bearing either an electron-donating group or an electron-withdrawing group were well-tolerated and afforded the corresponding products in good yields and excellent enantioselectivities. Moreover, the reaction was also general for aminomethylferrocenes with different alkyl groups on the nitrogen atom (Scheme 16). In addition, a large scale reaction was executed smoothly, which further confirmed the practicality of this method. At last, the planar-chiral P,N-ligand L34 prepared from compound 24 was successfully utilized in the palladium-catalyzed allylic alkylation reaction (Scheme 17), which fully demonstrated the potential application of this novel protocol.
Similarly, chiral mono-N-protected amino acids (MPAA) were used as ligands in this reaction. The presence of the carbamate moiety employed as the N-protecting group and the carboxylic acid group within the ligand were essential to deliver the desired products with good enantioselectivities. Of the various chiral ligands tested, ligand L35 was found to be the optimal ligand, affording 68% yield and 96% ee (Scheme 18). The best reaction condition was found to be 10 mol % Pd(OAc)2, 20 mol % L35, 0.5 equiv of BQ, 1.5 equiv of Ag2CO3, 3.0 equiv of Li2CO3, and 40.0 equiv of H2O in anhydrous DMF at 40 °C under air. In addition, an array of substrates, including arylboronic esters decorated with different groups and different diarylphosphinamides, were subjected to this protocol and most of the reactions occurred efficiently (Scheme 19). Practically, this novel approach could be carried out in the gram scale with consistent efficiency.
Similarly, chiral mono-N-protected amino acids (MPAA) were used as ligands in this reaction. The presence of the carbamate moiety employed as the N-protecting group and the carboxylic acid group within the ligand were essential to deliver the desired products with good enantioselectivities.
Of the various chiral ligands tested, ligand L35 was found to be the optimal ligand, affording 68% yield and 96% ee (Scheme 18). The best reaction condition was found to be 10 mol % Pd(OAc) 2 , 20 mol % L35, 0.5 equiv of BQ, 1.5 equiv of Ag 2 CO 3 , 3.0 equiv of Li 2 CO 3 , and 40.0 equiv of H 2 O in anhydrous DMF at 40 • C under air. In addition, an array of substrates, including arylboronic esters decorated with different groups and different diarylphosphinamides, were subjected to this protocol and most of the reactions occurred efficiently (Scheme 19). Practically, this novel approach could be carried out in the gram scale with consistent efficiency. It is well known that chiral phosphorus compounds play important roles as ligands or organocatalysts in asymmetric synthesis [73][74][75][76]. In 2015, Han group reported the asymmetric syntheses of traditionally inaccessible P-stereogenic phosphinamides via Pd-catalyzed enantioselective C(sp 2 )-H functionalization (Scheme 18) [77].
Similarly, chiral mono-N-protected amino acids (MPAA) were used as ligands in this reaction. The presence of the carbamate moiety employed as the N-protecting group and the carboxylic acid group within the ligand were essential to deliver the desired products with good enantioselectivities. Of the various chiral ligands tested, ligand L35 was found to be the optimal ligand, affording 68% yield and 96% ee (Scheme 18). The best reaction condition was found to be 10 mol % Pd(OAc)2, 20 mol % L35, 0.5 equiv of BQ, 1.5 equiv of Ag2CO3, 3.0 equiv of Li2CO3, and 40.0 equiv of H2O in anhydrous DMF at 40 °C under air. In addition, an array of substrates, including arylboronic esters decorated with different groups and different diarylphosphinamides, were subjected to this protocol and most of the reactions occurred efficiently (Scheme 19). Practically, this novel approach could be carried out in the gram scale with consistent efficiency.
Herein, chiral mono-N-protected amino acids (MPAA) were adopted as chiral ligands at first. Further screening revealed that carbamate-protected, N-methoxyamide-substituted aliphatic amino acids were the best choice. When Fmoc-L-Leu-NHOMe was used, the desired product could be obtained in 90% yield and 96% ee. This method was further applied to a variety of different diarymethylamines with arylboronic acid pinacol esters as coupling partners. Under the optimized condition, most of the reactions proceeded smoothly with good yields and excellent enantioselectivities (Schemes 21 and 22).
Herein, chiral mono-N-protected amino acids (MPAA) were adopted as chiral ligands at first. Further screening revealed that carbamate-protected, N-methoxyamide-substituted aliphatic amino acids were the best choice. When Fmoc-L-Leu-NHOMe was used, the desired product could be obtained in 90% yield and 96% ee. This method was further applied to a variety of different diarymethylamines with arylboronic acid pinacol esters as coupling partners. Under the optimized condition, most of the reactions proceeded smoothly with good yields and excellent enantioselectivities (Schemes 21 and 22). Recently, the enantioselective ortho-C(sp 2 )-H coupling between para-nitrobenzenesulfonyl (nosyl) protected diarylmethylamines and arylboronic acid pinacol esters was established by Yu and coworkers (Scheme 20) [78].
Herein, chiral mono-N-protected amino acids (MPAA) were adopted as chiral ligands at first. Further screening revealed that carbamate-protected, N-methoxyamide-substituted aliphatic amino acids were the best choice. When Fmoc-L-Leu-NHOMe was used, the desired product could be obtained in 90% yield and 96% ee. This method was further applied to a variety of different diarymethylamines with arylboronic acid pinacol esters as coupling partners. Under the optimized condition, most of the reactions proceeded smoothly with good yields and excellent enantioselectivities (Schemes 21 and 22).
A stereochemical model was proposed (Figure 4). It was assumed that the coordination between the imine moiety of the deprotonated anionic sulfonamide and Pd II center promoted the stereoselective C-H activation followed by arylation.

Enantioselective C-H Activation/Mizoroki-Heck Type Reaction
Another important type of cross coupling reaction is the Mizoroki-Heck reaction (Scheme 23), which exhibits extraordinary performance with high efficiency in assembling C-C bonds [79,80]. Herein, we will highlight the recent progresses in the field of enantioselective C-H activation concerning Mizoroki-Heck type reaction.
A stereochemical model was proposed (Figure 4). It was assumed that the coordination between the imine moiety of the deprotonated anionic sulfonamide and Pd II center promoted the stereoselective C-H activation followed by arylation. Reactions with different diarymethylamines [78].
A stereochemical model was proposed (Figure 4). It was assumed that the coordination between the imine moiety of the deprotonated anionic sulfonamide and Pd II center promoted the stereoselective C-H activation followed by arylation.

Enantioselective C-H Activation/Mizoroki-Heck Type Reaction
Another important type of cross coupling reaction is the Mizoroki-Heck reaction (Scheme 23), which exhibits extraordinary performance with high efficiency in assembling C-C bonds [79,80]. Herein, we will highlight the recent progresses in the field of enantioselective C-H activation concerning Mizoroki-Heck type reaction.

Enantioselective C-H Activation/Mizoroki-Heck Type Reaction
Another important type of cross coupling reaction is the Mizoroki-Heck reaction (Scheme 23), which exhibits extraordinary performance with high efficiency in assembling C-C bonds [79,80]. Herein, we will highlight the recent progresses in the field of enantioselective C-H activation concerning Mizoroki-Heck type reaction.

Scheme 23. Mizoroki-Heck reaction.
Inspired by the excellent performances of monoprotected amino acids (MPAA) as ligands for enantioselective C-H activation [62], Yu and coworkers developed an enantioselective C-H olefination reaction of diphenylacetic acids using MPAA as chiral ligands [81].
Among the various chiral monoprotected α-amino acids examined, Boc-Ile-OH proved to be the best one. The yield could be improved to 73% (97% ee) with the preformed sodium salt of the starting material and KHCO3 as the base (Scheme 24).

Scheme 24. Enantioselective C-H olefination of diphenylacetic acids [81].
A broad range of styrenes with different substituents were inspected and it was found that styrenes with para and meta alkyl substituents gave higher enantioselectivities (92-97% ee). In addition, acrylate coupling partners were also tolerant to such condition, affording 99% ee. However, a mixture of the desired olefination product and the corresponding conjugated addition product was isolated (Scheme 25).
Different carboxylic acids were also treated with this strategy and most of them proceeded efficiently except for α-hydrogen containing substrate (58% ee). Besides, substrates containing electron-donating groups and moderately electron-withdrawing groups were well compatible to this procedure, although olefination of the latter gave lower yields (Scheme 26). Inspired by the excellent performances of monoprotected amino acids (MPAA) as ligands for enantioselective C-H activation [62], Yu and coworkers developed an enantioselective C-H olefination reaction of diphenylacetic acids using MPAA as chiral ligands [81].
Among the various chiral monoprotected α-amino acids examined, Boc-Ile-OH proved to be the best one. The yield could be improved to 73% (97% ee) with the preformed sodium salt of the starting material and KHCO 3 as the base (Scheme 24). Inspired by the excellent performances of monoprotected amino acids (MPAA) as ligands for enantioselective C-H activation [62], Yu and coworkers developed an enantioselective C-H olefination reaction of diphenylacetic acids using MPAA as chiral ligands [81].
Among the various chiral monoprotected α-amino acids examined, Boc-Ile-OH proved to be the best one. The yield could be improved to 73% (97% ee) with the preformed sodium salt of the starting material and KHCO3 as the base (Scheme 24).

Scheme 24. Enantioselective C-H olefination of diphenylacetic acids [81].
A broad range of styrenes with different substituents were inspected and it was found that styrenes with para and meta alkyl substituents gave higher enantioselectivities (92-97% ee). In addition, acrylate coupling partners were also tolerant to such condition, affording 99% ee. However, a mixture of the desired olefination product and the corresponding conjugated addition product was isolated (Scheme 25).
Different carboxylic acids were also treated with this strategy and most of them proceeded efficiently except for α-hydrogen containing substrate (58% ee). Besides, substrates containing electron-donating groups and moderately electron-withdrawing groups were well compatible to this procedure, although olefination of the latter gave lower yields (Scheme 26).

Scheme 24. Enantioselective C-H olefination of diphenylacetic acids [81].
A broad range of styrenes with different substituents were inspected and it was found that styrenes with para and meta alkyl substituents gave higher enantioselectivities (92-97% ee). In addition, acrylate coupling partners were also tolerant to such condition, affording 99% ee. However, a mixture of the desired olefination product and the corresponding conjugated addition product was isolated (Scheme 25). Inspired by the excellent performances of monoprotected amino acids (MPAA) as ligands for enantioselective C-H activation [62], Yu and coworkers developed an enantioselective C-H olefination reaction of diphenylacetic acids using MPAA as chiral ligands [81].
Among the various chiral monoprotected α-amino acids examined, Boc-Ile-OH proved to be the best one. The yield could be improved to 73% (97% ee) with the preformed sodium salt of the starting material and KHCO3 as the base (Scheme 24).

Scheme 24. Enantioselective C-H olefination of diphenylacetic acids [81].
A broad range of styrenes with different substituents were inspected and it was found that styrenes with para and meta alkyl substituents gave higher enantioselectivities (92-97% ee). In addition, acrylate coupling partners were also tolerant to such condition, affording 99% ee. However, a mixture of the desired olefination product and the corresponding conjugated addition product was isolated (Scheme 25).
Different carboxylic acids were also treated with this strategy and most of them proceeded efficiently except for α-hydrogen containing substrate (58% ee). Besides, substrates containing electron-donating groups and moderately electron-withdrawing groups were well compatible to this procedure, although olefination of the latter gave lower yields (Scheme 26).
Different carboxylic acids were also treated with this strategy and most of them proceeded efficiently except for α-hydrogen containing substrate (58% ee). Besides, substrates containing electron-donating groups and moderately electron-withdrawing groups were well compatible to this procedure, although olefination of the latter gave lower yields (Scheme 26). Yu also proposed a possible transition state for this enantioselective C-H olefination ( Figure 5). A chiral carbon-Pd intermediate could be formed, followed by olefination to give the corresponding chiral product. Based on the recent development of enantioselective C-H iodination using Pd II /MPAA catalysts for kinetic resolution through C-H hydroxylation and iodination [82,83], Yu and coworkers developed a kinetic resolution method to achieve enantioselective C-H olefinations of α-hydroxy and α-amino phenylacetic acids utilizing Pd II -catalyzed system in 2016 (Scheme 27) [84]. Yu also proposed a possible transition state for this enantioselective C-H olefination ( Figure 5). A chiral carbon-Pd intermediate could be formed, followed by olefination to give the corresponding chiral product. Yu also proposed a possible transition state for this enantioselective C-H olefination ( Figure 5). A chiral carbon-Pd intermediate could be formed, followed by olefination to give the corresponding chiral product. Based on the recent development of enantioselective C-H iodination using Pd II /MPAA catalysts for kinetic resolution through C-H hydroxylation and iodination [82,83], Yu and coworkers developed a kinetic resolution method to achieve enantioselective C-H olefinations of α-hydroxy and α-amino phenylacetic acids utilizing Pd II -catalyzed system in 2016 (Scheme 27) [84]. Based on the recent development of enantioselective C-H iodination using Pd II /MPAA catalysts for kinetic resolution through C-H hydroxylation and iodination [82,83], Yu and coworkers developed a kinetic resolution method to achieve enantioselective C-H olefinations of α-hydroxy and α-amino phenylacetic acids utilizing Pd II -catalyzed system in 2016 (Scheme 27) [84].
In this paper, Yu also employed mono-N-protected amino acid (MPAA) as ligands to enable enantioselective C-H bond olefinations. Of different MPAA ligands screened, Boc-L-Thr(Bz)-OH (L38) gave the best selectivity factor (s) [85] of 54 (90% ee and 45% yield). Notably, the loading of Pd(OAc)2 could be reduced to 5 mol % without a pronounced erosion of the selectivity, and the addition of 0.4 equivalent of olefin increased the enantioselectivity to 93%.
With the optimized reaction condition, a series of olefin coupling partners were subjected to this transformation and a broad range of electron-deficient olefins were well tolerated. Of note, acrylates were a good coupling partner affording s factors ranging from 46 to 54. Vinyl amides and vinyl phosphates also proceeded smoothly. A wide range of different substituted mandelic acid substrates were also successfully olefinated with reasonable s factors (Scheme 28). In this paper, Yu also employed mono-N-protected amino acid (MPAA) as ligands to enable enantioselective C-H bond olefinations. Of different MPAA ligands screened, Boc-L-Thr(Bz)-OH (L38) gave the best selectivity factor (s) [85] of 54 (90% ee and 45% yield). Notably, the loading of Pd(OAc) 2 could be reduced to 5 mol % without a pronounced erosion of the selectivity, and the addition of 0.4 equivalent of olefin increased the enantioselectivity to 93%.
With the optimized reaction condition, a series of olefin coupling partners were subjected to this transformation and a broad range of electron-deficient olefins were well tolerated. Of note, acrylates were a good coupling partner affording s factors ranging from 46 to 54. Vinyl amides and vinyl phosphates also proceeded smoothly. A wide range of different substituted mandelic acid substrates were also successfully olefinated with reasonable s factors (Scheme 28). In this paper, Yu also employed mono-N-protected amino acid (MPAA) as ligands to enable enantioselective C-H bond olefinations. Of different MPAA ligands screened, Boc-L-Thr(Bz)-OH (L38) gave the best selectivity factor (s) [85] of 54 (90% ee and 45% yield). Notably, the loading of Pd(OAc)2 could be reduced to 5 mol % without a pronounced erosion of the selectivity, and the addition of 0.4 equivalent of olefin increased the enantioselectivity to 93%.
With the optimized reaction condition, a series of olefin coupling partners were subjected to this transformation and a broad range of electron-deficient olefins were well tolerated. Of note, acrylates were a good coupling partner affording s factors ranging from 46 to 54. Vinyl amides and vinyl phosphates also proceeded smoothly. A wide range of different substituted mandelic acid substrates were also successfully olefinated with reasonable s factors (Scheme 28).  [84].
Furthermore, for the remaining starting materials 37′ with 87% ee, a following olefination protocol using the opposite configuration ligand could afford the corresponding chiral product with 99% ee (Scheme 30).
In analogy to previously mentioned mechanism, there are two proposed intermediates ( Figure  6), TSS and TSR, respectively, and TSS is the favored configuration due to the less steric repulsion between the Boc group and larger OPiv moiety. This stereomodel can well rationalize the origin of the enantioselectivity. Another interesting finding on enantioselective C-H activation/Heck reaction was provided by Shi and coworkers in 2017 [86]. In this article, atroposelective synthesis of axially chiral biaryls by C-H olefination, utilizing the Pd II /transient chiral auxiliary (TCA) as the catalytic system, was Scheme 29. Enantioselective C-H olefination/kinetic resolution of phenylglycines [84].
Furthermore, for the remaining starting materials 37 with 87% ee, a following olefination protocol using the opposite configuration ligand could afford the corresponding chiral product with 99% ee (Scheme 30).  [84].
Furthermore, for the remaining starting materials 37′ with 87% ee, a following olefination protocol using the opposite configuration ligand could afford the corresponding chiral product with 99% ee (Scheme 30).
In analogy to previously mentioned mechanism, there are two proposed intermediates ( Figure  6), TSS and TSR, respectively, and TSS is the favored configuration due to the less steric repulsion between the Boc group and larger OPiv moiety. This stereomodel can well rationalize the origin of the enantioselectivity. Another interesting finding on enantioselective C-H activation/Heck reaction was provided by Shi and coworkers in 2017 [86]. In this article, atroposelective synthesis of axially chiral biaryls by C-H olefination, utilizing the Pd II /transient chiral auxiliary (TCA) as the catalytic system, was Scheme 30. Enantioselective C-H olefination of the remaining starting material [84].
In analogy to previously mentioned mechanism, there are two proposed intermediates ( Figure 6), TS S and TS R , respectively, and TS S is the favored configuration due to the less steric repulsion between the Boc group and larger OPiv moiety. This stereomodel can well rationalize the origin of the enantioselectivity.  [84].
Furthermore, for the remaining starting materials 37′ with 87% ee, a following olefination protocol using the opposite configuration ligand could afford the corresponding chiral product with 99% ee (Scheme 30).
In analogy to previously mentioned mechanism, there are two proposed intermediates ( Figure  6), TSS and TSR, respectively, and TSS is the favored configuration due to the less steric repulsion between the Boc group and larger OPiv moiety. This stereomodel can well rationalize the origin of the enantioselectivity. Another interesting finding on enantioselective C-H activation/Heck reaction was provided by Shi and coworkers in 2017 [86]. In this article, atroposelective synthesis of axially chiral biaryls by C-H olefination, utilizing the Pd II /transient chiral auxiliary (TCA) as the catalytic system, was Another interesting finding on enantioselective C-H activation/Heck reaction was provided by Shi and coworkers in 2017 [86]. In this article, atroposelective synthesis of axially chiral biaryls by C-H olefination, utilizing the Pd II /transient chiral auxiliary (TCA) as the catalytic system, was achieved. Of note, in this asymmetric C-H olefination reaction, the chiral free amino acid played as a transient chiral auxiliary (TCA), which promoted the C-H activation process instead of only serving as a simple chiral ligand. Of the various TCA examined, the L-tert-leucine (T1) was found to be the optimal. As expected, the other atropisomer was obtained, while the opposite TCA (D-tert-leucine) was employed (Scheme 31). achieved. Of note, in this asymmetric C-H olefination reaction, the chiral free amino acid played as a transient chiral auxiliary (TCA), which promoted the C-H activation process instead of only serving as a simple chiral ligand. Of the various TCA examined, the L-tert-leucine (T1) was found to be the optimal. As expected, the other atropisomer was obtained, while the opposite TCA (D-tert-leucine) was employed (Scheme 31).
With the optimized reaction condition, the substrate generality was inspected. A broad range of biaryls with different substituents were tolerated to this protocol. It ought to be noted that C-H olefination of biaryls with substituents at either 6-or 2′-position or less hindered substituents at both 6-and 2′-position proceeded successfully in a dynamic kinetic resolution (DKR) manner, giving enantioenriched products in good to excellent yields and excellent enantioselectivities (95 to >99% ee) (Scheme 32). Scheme 32. Substrate scope of biaryls concerning C-H olefination/DKR [86].
With the optimized reaction condition, the substrate generality was inspected. A broad range of biaryls with different substituents were tolerated to this protocol. It ought to be noted that C-H olefination of biaryls with substituents at either 6-or 2 -position or less hindered substituents at both 6-and 2 -position proceeded successfully in a dynamic kinetic resolution (DKR) manner, giving enantioenriched products in good to excellent yields and excellent enantioselectivities (95 to >99% ee) (Scheme 32). achieved. Of note, in this asymmetric C-H olefination reaction, the chiral free amino acid played as a transient chiral auxiliary (TCA), which promoted the C-H activation process instead of only serving as a simple chiral ligand. Of the various TCA examined, the L-tert-leucine (T1) was found to be the optimal. As expected, the other atropisomer was obtained, while the opposite TCA (D-tert-leucine) was employed (Scheme 31).
With the optimized reaction condition, the substrate generality was inspected. A broad range of biaryls with different substituents were tolerated to this protocol. It ought to be noted that C-H olefination of biaryls with substituents at either 6-or 2′-position or less hindered substituents at both 6-and 2′-position proceeded successfully in a dynamic kinetic resolution (DKR) manner, giving enantioenriched products in good to excellent yields and excellent enantioselectivities (95 to >99% ee) (Scheme 32). Scheme 32. Substrate scope of biaryls concerning C-H olefination/DKR [86]. Scheme 32. Substrate scope of biaryls concerning C-H olefination/DKR [86].
Nonetheless, for the biaryls bearing sterically more hindered substituents at both 6-and 2 -position, C-H olefination would occur through a kinetic resolution (KR) manner in excellent selectivities (Scheme 33). Moreover, various acrylates and styrenes were investigated and most of them were compatible to this method, except that electronrich styrenes were determined as inert coupling partners (Schemes 32 and 33). Nonetheless, for the biaryls bearing sterically more hindered substituents at both 6-and 2′-position, C-H olefination would occur through a kinetic resolution (KR) manner in excellent selectivities (Scheme 33). Moreover, various acrylates and styrenes were investigated and most of them were compatible to this method, except that electronrich styrenes were determined as inert coupling partners (Schemes 32 and 33). Scheme 33. Substrate scope of biaryls concerning C-H olefination/KR [86].
As far as the mechanism was concerned, it was proposed that the chiral amino acid would react with the racemic substrate to give the imine intermediates A and B reversibly. Then, C-H cleavage of B took place selectively due to the minor steric repulsion, resulting in intermediate C with axially stereoenriched biaryl palladacycle. Then, intermediate C underwent a typical Heck reaction with olefin to afford intermediate D, which would be hydrolyzed to furnish the desired chiral biaryls (Ra)-E. Meanwhile, the Pd 0 was reoxidised into Pd II to close the catalytic cycle (Scheme 34). Scheme 33. Substrate scope of biaryls concerning C-H olefination/KR [86].
As far as the mechanism was concerned, it was proposed that the chiral amino acid would react with the racemic substrate to give the imine intermediates A and B reversibly. Then, C-H cleavage of B took place selectively due to the minor steric repulsion, resulting in intermediate C with axially stereoenriched biaryl palladacycle. Then, intermediate C underwent a typical Heck reaction with olefin to afford intermediate D, which would be hydrolyzed to furnish the desired chiral biaryls (Ra)-E. Meanwhile, the Pd 0 was reoxidised into Pd II to close the catalytic cycle (Scheme 34).
In the proposed mechanism, the cyclopalladated complex A was first generated by palladium species through coordination with the substrate and the ligand. Then, intermediate A underwent a typical Heck reaction to furnish the desired product. It is worth noting that in this catalytic system, the N,N-dimethylaminomethylferrocenium C was generated in situ by air and served as a terminal oxidant to regenerate active Pd II from the reduced Pd 0 species, completing the catalytic cycle. Therefore, no external oxidant was needed (Scheme 36). In the proposed mechanism, the cyclopalladated complex A was first generated by palladium species through coordination with the substrate and the ligand. Then, intermediate A underwent a typical Heck reaction to furnish the desired product. It is worth noting that in this catalytic system, the N,N-dimethylaminomethylferrocenium C was generated in situ by air and served as a terminal oxidant to regenerate active Pd II from the reduced Pd 0 species, completing the catalytic cycle. Therefore, no external oxidant was needed (Scheme 36). Scheme 36. The proposed mechanism for the reaction. Reproduced from Reference [87].
N,N-dimethylaminomethylferrocene and butyl acrylate were chosen as the model substrates. It was found the introduction of mono-N-protected amino acids (MPAA) as ligands to Pd II , not just induced the high enantioselectivities, but also dramatically increased the reaction yields. Both Boc-L-Phe-OH (L39) and Boc-L-Tle-OH (L40) gave excellent yields and enantioselectivities for the model reaction (Scheme 35). Under the optimized condition, various acrylates, styrenes, and even aliphatic olefins were tested (Scheme 37). All of them worked well with excellent enantioselectivities (up to 99%) and yields (up to 98%). Scheme 36. The proposed mechanism for the reaction. Reproduced from Reference [87]. N,N-dimethylaminomethylferrocene and butyl acrylate were chosen as the model substrates. It was found the introduction of mono-N-protected amino acids (MPAA) as ligands to Pd II , not just induced the high enantioselectivities, but also dramatically increased the reaction yields. Both Boc-L-Phe-OH (L39) and Boc-L-Tle-OH (L40) gave excellent yields and enantioselectivities for the model reaction (Scheme 35). Under the optimized condition, various acrylates, styrenes, and even aliphatic olefins were tested (Scheme 37). All of them worked well with excellent enantioselectivities (up to 99%) and yields (up to 98%).
Finally, the product was successfully utilized as ligands in the rhodium-catalyzed conjugate addition of phenylboronic acid to cyclohexenone reaction (Scheme 43), which sufficiently demonstrated the potential of this method. Scheme 42. The investigation of substrate scope [89].
Finally, the product was successfully utilized as ligands in the rhodium-catalyzed conjugate addition of phenylboronic acid to cyclohexenone reaction (Scheme 43), which sufficiently demonstrated the potential of this method. Scheme 43. The application of enantioenriched biaryl products [89].

Summary
Although traditional cross-coupling reactions have revolutionized organic chemistry and are widely applied in modern organic synthesis, the need for prefunctionalized starting materials has prompted chemists to investigate more atom and step economic alternatives. Therefore, C-H activation has emerged as a powerful tool to achieve C-C bond formation, allowing for the transformation of otherwise unreactive C-H bonds, thus maximizing the overall operational efficiency and decreasing the amount of stoichiometric metallic waste. The combinations of C-H activation/C-C cross-coupling reactions provide unlimited possibilities for synthetic chemists to access complex molecules.
This review summarizes the recent development on eantioselective C-H activation/Mizoroki-Heck reaction and Suzuki reaction. Due to the low reactivity of the C-H bonds, and the selectivity problem rooted in the abundance of C-H bonds, these transformations are extremely difficult to achieve. However, thanks to the increased mechanistic studies, chemists continually develop a better understanding of the mechanical aspects ruling these transformations. The Pd II /MPAA systems developed by Yu group have been utilized successfully and represents one of the most important progresses.
It should also be pointed out that the concept of toxic heavy metals and benign lighter metals should not be taken for granted. Recently, studies revealed that some palladium, rhodium compounds, which were often considered heavy and toxic, might be less toxic than lighter metals [90]. This may change our traditional views on the toxic effects of metal salts in favor of Pd-catalyzed C-H activation.
Even though apparent advancements in this area have been made, more general protocols are highly demanded. Much research efforts as far as to design new chiral catalysts and chiral ligands, expand the substrate scope, and improve the efficiency of these transformations are still needed before a more general, atom-economical, and more environmentally friendly process become the method of choice for chemists in industrial or academic settings.