Ir-Catalyzed ortho -C-H Borylation of Aromatic C(sp 2 )-H Bonds of Carbocyclic Compounds Assisted by N -Bearing Directing Groups

: C-H borylation is a powerful strategy for the construction of C-B bonds due to the synthetic versatility of C-B bonds. Various transition metals affect the powerful functionalization of C-H bonds, of which Ir is the most common. Substrate-directed methods have enabled directed Ir-catalyzed C-H borylation at the ortho position. Amongst the powerful directing groups in Ir-catalyzed C-H borylation are N-containing carbocyclic systems. This review covers substrate-directed Ir-catalyzed ortho -C-H borylation of aromatic C(sp2)-H bonds in N-containing carbocyclic compounds, such as anilines, amides, benzyl amines, hydrazones, and triazines.


Introduction
Functionalization of inert C-H bonds has emerged as a powerful strategy for making functional and versatile bonds [1][2][3][4][5][6][7].Transformation of inert non-functional C-H bonds into reactive functional bonds is an attractive chemically powerful strategy.Thus, the functionalization of C-H bonds should provide rapid access to functionalized molecules from simple starting materials.In this process, step and reaction economies can be achieved by shortening the number of steps in multi-step synthesis, simplifying reaction conditions, or minimizing the need for pre-functionalized reagents.C-H Bond functionalization is typically catalyzed by transition metals.Functionalization of C-H bonds by second-row transition metals, such as Pd [8][9][10][11], Rh [12][13][14][15][16], and Ru [17][18][19][20][21], has received widespread attention from the scientific community.Earth-abundant first-row transition metals, ref. [22] such as Ni [23][24][25], Mn [26,27], Fe [28,29], and Co [30][31][32][33][34], have also been used in the field.Given the ubiquitous nature of C-H bonds in molecules, controlling what C-H bonds are functionalized is a challenge.The issue of regioselectivity or site-selectivity in C-H bond functionalization is a constant target.One approach to solve the issue is the use of directing groups, which include two general types, monodentate and bidentate [35].The classification depends on the number of Lewis basic atoms that can participate in the functionalization reaction through chelation assistance.Lewis basic atoms coordinate the Lewis acidic metal used in the reaction, hence directing it in proximity to a C-H bond to be cleaved and subsequently functionalized.The formation of cyclometallated complexes or chelates is controlled by ring size, of which five-membered chelates are thermodynamically more stable and thus favored over other ring sizes [36].Thus, the atom distance between the Lewis basic atom in the directing group and the C-H bond to be functionalized is critical.For the formation of the more common five-membered chelates, the atom distance should be two carbons.Monodentate directing groups possess one Lewis basic atom that allows the formation of a single (typically five-membered) chelate, while bidentate directing groups possess two Lewis basic atoms that facilitate the formation of double or bis-five-membered chelates.In bidentate directing groups, the atom distance between the first Lewis basic atom and the C-H bond to be functionalized is critical, as noted in monodentate directing groups.In addition, the atom distance between the two Lewis basic atoms constituting the bidentate directing group is important as well [37].Many monodentate and bidentate directing groups have been established in the field of C-H bond functionalization [10][11][12].A wide range of functionalization reactions of C-H bonds by "direction" or chelation assistance are possible based on the catalysis of various transition metals.
Conversion of C-H bonds into C-B bonds is a unique type of C-H bond functionalization [38][39][40][41][42][43][44].This is based on the synthetic versatility and utility of alkyl and aryl boronates in organic synthesis.C-B bonds can be transformed into various bonds with a wide range of functional groups, such as amines, alcohols/phenols, aryl halides, and biaryls [45].The synthetic versatility of C-B bonds allows C-H borylation to be used as a unique and powerful C-H functionalization strategy.As noted for C-H bond functionalization as a whole, controlling the pressing issue of regioselectivity or site-selectivity is a constant target.
As noted in C-H bond functionalization, controlling the pressing issue of regioselectivity or site-selectivity is a constant goal.Generally, the Ir-catalyzed C-H borylation reaction of carbocyclic compounds is sterically driven [38][39][40][41][42][43][44].Electronic effects can also play a role in the site-selectivity of C-H borylation of heterocycles.
The regioselectivity or site-selectivity of C-H borylation can be controlled using directing groups via chelation assistance (Scheme 1) [51,52].Directing groups containing Lewis basic atoms (vide supra) in substrate, 1 can direct C-H borylation to take place selectively at the ortho position to give ortho-borylated product 2 (Scheme 1).
eactions 2024, 5, FOR PEER REVIEW 2 while bidentate directing groups possess two Lewis basic atoms that facilitate the formation of double or bis-five-membered chelates.In bidentate directing groups, the atom distance between the first Lewis basic atom and the C-H bond to be functionalized is critical, as noted in monodentate directing groups.In addition, the atom distance between the two Lewis basic atoms constituting the bidentate directing group is important as well [37].Many monodentate and bidentate directing groups have been established in the field of C-H bond functionalization [10][11][12].A wide range of functionalization reactions of C-H bonds by "direction" or chelation assistance are possible based on the catalysis of various transition metals.Conversion of C-H bonds into C-B bonds is a unique type of C-H bond functionalization [38][39][40][41][42][43][44].This is based on the synthetic versatility and utility of alkyl and aryl boronates in organic synthesis.C-B bonds can be transformed into various bonds with a wide range of functional groups, such as amines, alcohols/phenols, aryl halides, and biaryls [45].The synthetic versatility of C-B bonds allows C-H borylation to be used as a unique and powerful C-H functionalization strategy.As noted for C-H bond functionalization as a whole, controlling the pressing issue of regioselectivity or site-selectivity is a constant target.
As noted in C-H bond functionalization, controlling the pressing issue of regioselectivity or site-selectivity is a constant goal.Generally, the Ir-catalyzed C-H borylation reaction of carbocyclic compounds is sterically driven [38][39][40][41][42][43][44].Electronic effects can also play a role in the site-selectivity of C-H borylation of heterocycles.
ctions 2024, 5, FOR PEER REVIEW 2 while bidentate directing groups possess two Lewis basic atoms that facilitate the formation of double or bis-five-membered chelates.In bidentate directing groups, the atom distance between the first Lewis basic atom and the C-H bond to be functionalized is critical, as noted in monodentate directing groups.In addition, the atom distance between the two Lewis basic atoms constituting the bidentate directing group is important as well [37].Many monodentate and bidentate directing groups have been established in the field of C-H bond functionalization [10][11][12].A wide range of functionalization reactions of C-H bonds by "direction" or chelation assistance are possible based on the catalysis of various transition metals.Conversion of C-H bonds into C-B bonds is a unique type of C-H bond functionalization [38][39][40][41][42][43][44].This is based on the synthetic versatility and utility of alkyl and aryl boronates in organic synthesis.C-B bonds can be transformed into various bonds with a wide range of functional groups, such as amines, alcohols/phenols, aryl halides, and biaryls [45].The synthetic versatility of C-B bonds allows C-H borylation to be used as a unique and powerful C-H functionalization strategy.As noted for C-H bond functionalization as a whole, controlling the pressing issue of regioselectivity or site-selectivity is a constant target.
As noted in C-H bond functionalization, controlling the pressing issue of regioselectivity or site-selectivity is a constant goal.Generally, the Ir-catalyzed C-H borylation reaction of carbocyclic compounds is sterically driven [38][39][40][41][42][43][44].Electronic effects can also play a role in the site-selectivity of C-H borylation of heterocycles.
Several Ir precatalysts can be used in Ir-catalyzed C-H borylation.The following Ir catalysts are used: , (Ind)Ir(COD), (η6mesitylene)Ir(Bpin)3, and Ir(acac)(cod).The structures of a few of these catalysts are shown below (Figure 1) [42,59].Various differences are noted between these precatalysts, including their electronic and steric characteristics; their stability, ease of handling and manipulation; and their ability to form active Ir complexes with ligands.In turn, the ligands used can play a pivotal role in forming Ir complexes capable of catalyzing C-H bond borylation.Examples of bipyridine ligands are shown below (Figure 2) [42].Ligands L1-L9 represent common bipyridine ligands used or can be used.Various differences are noted between these precatalysts, including their electronic and steric characteristics; their stability, ease of handling and manipulation; and their ability to form active Ir complexes with ligands.In turn, the ligands used can play a pivotal role in forming Ir complexes capable of catalyzing C-H bond borylation.Examples of bipyridine ligands are shown below (Figure 2) [42].Ligands L1-L9 represent common bipyridine ligands used or can be used.By far, [Ir(OMe)(COD)]2 is the most commonly used catalyst due to its air stability, ease of handling, and most efficient capability of forming Ir trisboryl complexes [Ir(Bpin)3(L2)-alkene] where L is dtbpy or tmphen (Figure 3).COE: cyclooctene, Bpin: 4,4,5,5-tetramethyl-1,3,2-dioxaboro-lanyl [60].The mechanism of Ir-catalyzed C-H borylation has been studied [60,61].Based on these findings, an Ir trisporyl complex A is formed upon treatment of an Ir precatalyst, such as the most commonly used [Ir(OMe)(COD)]2, with a ligand typically dtbpy (Scheme 2) [60][61][62].Subsequent treatment of the Ir trisboryl complex with a carbocyclic compound or hydrocarbon gives intermediate B. A borylated carbocyclic compound is then released with concomitant formation of intermediate C. The addition of B2pin2 or H-BPin forms intermediate D, which subsequently regenerates the starting Ir tisboryl complex A in the catalytic cycle (Scheme 2).By far, [Ir(OMe)(COD)] 2 is the most commonly used catalyst due to its air stability, ease of handling, and most efficient capability of forming Ir trisboryl complexes [Ir(Bpin)3(L2)alkene] where L is dtbpy or tmphen (Figure 3).COE: cyclooctene, Bpin: 4,4,5,5-tetramethyl-1,3,2-dioxaboro-lanyl [60].Various differences are noted between these precatalysts, including their electronic and steric characteristics; their stability, ease of handling and manipulation; and their ability to form active Ir complexes with ligands.In turn, the ligands used can play a pivotal role in forming Ir complexes capable of catalyzing C-H bond borylation.Examples of bipyridine ligands are shown below (Figure 2) [42].Ligands L1-L9 represent common bipyridine ligands used or can be used.
L6 L7: dtbpy L8 L9: tmphen By far, [Ir(OMe)(COD)]2 is the most commonly used catalyst due to its air stability, ease of handling, and most efficient capability of forming Ir trisboryl complexes [Ir(Bpin)3(L2)-alkene] where L is dtbpy or tmphen (Figure 3).COE: cyclooctene, Bpin: 4,4,5,5-tetramethyl-1,3,2-dioxaboro-lanyl [60].The mechanism of Ir-catalyzed C-H borylation has been studied [60,61].Based on these findings, an Ir trisporyl complex A is formed upon treatment of an Ir precatalyst, such as the most commonly used [Ir(OMe)(COD)]2, with a ligand typically dtbpy (Scheme 2) [60][61][62].Subsequent treatment of the Ir trisboryl complex with a carbocyclic compound or hydrocarbon gives intermediate B. A borylated carbocyclic compound is then released with concomitant formation of intermediate C. The addition of B2pin2 or H-BPin forms intermediate D, which subsequently regenerates the starting Ir tisboryl complex A in the catalytic cycle (Scheme 2).The mechanism of Ir-catalyzed C-H borylation has been studied [60,61].Based on these findings, an Ir trisporyl complex A is formed upon treatment of an Ir precatalyst, such as the most commonly used [Ir(OMe)(COD)] 2 , with a ligand typically dtbpy (Scheme 2) [60][61][62].Subsequent treatment of the Ir trisboryl complex with a carbocyclic compound or hydrocarbon gives intermediate B. A borylated carbocyclic compound is then released with concomitant formation of intermediate C. The addition of B 2 pin 2 or H-BPin forms intermediate D, which subsequently regenerates the starting Ir tisboryl complex A in the catalytic cycle (Scheme 2).
Typically, C-H borylation is sterically driven [38][39][40][41][42][43][44].Directing the reaction to regioselectively occur at an ortho position concerning a functional group is not straightforward [51,52].ortho-Directing groups, including monodentate and bidentate directing groups typically used in directed C-H bond functionalization catalyzed by other transition metals may not simply be used to direct Ir-catalyzed C-H borylation reactions.A key challenge in ortho-C-H borylation is directing the reaction to occur regioselectively at the ortho-position.Coordination between the Lewis acidic Ir center and the Lewis basic directing group utilizing a vacant site in the metal center can be problematic.When a directing group coordinates with the Ir center in the 16-electron [Ir] trisboryl species 3, an Ir complex 4 is formed that does not advance the reaction forward to the desired ortho-C-H borylation (Scheme 3) [60,61].Typically, C-H borylation is sterically driven [38][39][40][41][42][43][44].Directing the reaction to regioselectively occur at an ortho position concerning a functional group is not straightforward [51,52].ortho-Directing groups, including monodentate and bidentate directing groups typically used in directed C-H bond functionalization catalyzed by other transition metals may not simply be used to direct Ir-catalyzed C-H borylation reactions.A key challenge in ortho-C-H borylation is directing the reaction to occur regioselectively at the ortho-position.Coordination between the Lewis acidic Ir center and the Lewis basic directing group utilizing a vacant site in the metal center can be problematic.When a directing group coordinates with the Ir center in the 16-electron [Ir] trisboryl species 3, an Ir complex 4 is formed that does not advance the reaction forward to the desired ortho-C-H borylation (Scheme 3) [60][61].Another problem may arise when ligands coordinate with the Ir trisboryl complex rendering the resultant Ir species inactive towards directed ortho-selective C-H borylation.This event could be notable when the ligand is strongly coordinating.

Ir
To overcome these problems, a chelate-directed C-H borylation strategy could be used [51,52].The strategy relies on coordination between the Lewis acidic Ir center and the Lewis basic directing group as well as a judicious choice of the ligand.The latter is critical for the formation of vacant sites in the Ir center [60,61].
Another strategy to circumvent problems of Ir-catalyzed ortho-C-H borylation is to use monodentate or hemi-labile ligands to form a transient vacant coordination site on the Ir center.This strategy specifically circumvents the complications that arise when Lewis basic directing groups coordinate with Ir.The hemi-lability of ligands creates vacant coordination sites on the Ir center setting the stage for subsequent C-H bond cleavage [51].
Another solution for successfully directed C-H borylation is the use of a solid/silicasupported compact monophosphine-Ir system, such as Silica-SMAP-Ir developed by Typically, C-H borylation is sterically driven [38][39][40][41][42][43][44].Directing the reaction to regioselectively occur at an ortho position concerning a functional group is not straightforward [51,52].ortho-Directing groups, including monodentate and bidentate directing groups typically used in directed C-H bond functionalization catalyzed by other transition metals may not simply be used to direct Ir-catalyzed C-H borylation reactions.A key challenge in ortho-C-H borylation is directing the reaction to occur regioselectively at the ortho-position.Coordination between the Lewis acidic Ir center and the Lewis basic directing group utilizing a vacant site in the metal center can be problematic.When a directing group coordinates with the Ir center in the 16-electron [Ir] trisboryl species 3, an Ir complex 4 is formed that does not advance the reaction forward to the desired ortho-C-H borylation (Scheme 3) [60][61].Another problem may arise when ligands coordinate with the Ir trisboryl complex rendering the resultant Ir species inactive towards directed ortho-selective C-H borylation.This event could be notable when the ligand is strongly coordinating.

Ir Bpin
To overcome these problems, a chelate-directed C-H borylation strategy could be used [51,52].The strategy relies on coordination between the Lewis acidic Ir center and the Lewis basic directing group as well as a judicious choice of the ligand.The latter is critical for the formation of vacant sites in the Ir center [60,61].
Another strategy to circumvent problems of Ir-catalyzed ortho-C-H borylation is to use monodentate or hemi-labile ligands to form a transient vacant coordination site on the Ir center.This strategy specifically circumvents the complications that arise when Lewis basic directing groups coordinate with Ir.The hemi-lability of ligands creates vacant coordination sites on the Ir center setting the stage for subsequent C-H bond cleavage [51].
Another solution for successfully directed C-H borylation is the use of a solid/silicasupported compact monophosphine-Ir system, such as Silica-SMAP-Ir developed by Scheme 3. Possible coordination between the Ir trisboryl complex and directing groups.
Another problem may arise when ligands coordinate with the Ir trisboryl complex rendering the resultant Ir species inactive towards directed ortho-selective C-H borylation.This event could be notable when the ligand is strongly coordinating.
To overcome these problems, a chelate-directed C-H borylation strategy could be used [51,52].The strategy relies on coordination between the Lewis acidic Ir center and the Lewis basic directing group as well as a judicious choice of the ligand.The latter is critical for the formation of vacant sites in the Ir center [60,61].
Another strategy to circumvent problems of Ir-catalyzed ortho-C-H borylation is to use monodentate or hemi-labile ligands to form a transient vacant coordination site on the Ir center.This strategy specifically circumvents the complications that arise when Lewis basic directing groups coordinate with Ir.The hemi-lability of ligands creates vacant coordination sites on the Ir center setting the stage for subsequent C-H bond cleavage [51].
Another solution for successfully directed C-H borylation is the use of a solid/silicasupported compact monophosphine-Ir system, such as Silica-SMAP-Ir developed by Sawmaura et al.The strategy has been employed to affect ortho-Ir-catalyzed C-H borylation of various functional groups [63][64][65][66][67][68].
The most common [Ir] precatalyst is the commercially available (1,5-cyclooctadiene)-(methoxy)iridium(I) dimer [Ir(OMe)((COD)] 2 , which upon treatment with ligands and bis(pinacolato)diboron, B 2 pin 2 , can give rise to a 14-electron [Ir] species 5 (Scheme 4).Directing groups (represented by 6) can coordinate with the 14-electron [Ir] species 5 through vacant sites on the metal center.Upon Lewis base-Lewis acid interactions between the directing group and the Lewis acidic metal center, the 16-electron [Ir] species 7 should form.The Lewis base-Lewis acid coordination brings the Ir center in proximity to an ortho C-H in the directing group, thus facilitating C-H bond cleavage and forming the intermediate [Ir] species 8. Subsequently, the ortho position in the directing group is borylated with the Bpin moiety from the Ir center to give rise to ortho-borylated product 9 (Scheme 4) [59][60][61][62].
The most common [Ir] precatalyst is the commercially available (1,5-cyclooctadiene)(methoxy)iridium(I) dimer [Ir(OMe)((COD)]2, which upon treatment with ligands and bis(pinacolato)diboron, B2pin2, can give rise to a 14-electron [Ir] species 5 (Scheme 4).Directing groups (represented by 6) can coordinate with the 14-electron [Ir] species 5 through vacant sites on the metal center.Upon Lewis base-Lewis acid interactions between the directing group and the Lewis acidic metal center, the 16 This review focuses on Ir-catalyzed ortho-C-H borylation of aromatic C(sp 2 )-H bond assisted by N-bearing directing groups.The review covers research findings on the topic from 2012 to 2023.

Anilines
In 2012, the NHBoc group was reported to function as a directing group in Ir-catalyzed ortho-C-H borylation of N-Boc-protected anilines (10, Scheme 5) [69].The directed C-H borylation employed [Ir(OMe)(COD)]2 as a precatalyst and B2pin2 as a boron source and proceeded with ortho selectivity.The reaction proceeded with good functional group tolerance and good yields (Scheme 5).For example, ether and halogens are tolerated as demonstrated by ortho-borylated NH-Boc anilines 11a and 11b, which were obtained with yields of 96% and 79%, respectively.The use of the cyano group as an electron-withdrawing group was tolerated as noted in borylated product 11c, which was obtained with a modest 40% yield.The free hydroxyl group was also tolerated as exemplified by borylated hydroxyl NH-Boc protected aniline 11d, which was obtained with a 78% yield.In addition, carbamates were also tolerated as demonstrated by borylated materials 11e and 11f, This review focuses on Ir-catalyzed ortho-C-H borylation of aromatic C(sp 2 )-H bond assisted by N-bearing directing groups.The review covers research findings on the topic from 2012 to 2023.

Anilines
In 2012, the NHBoc group was reported to function as a directing group in Ir-catalyzed ortho-C-H borylation of N-Boc-protected anilines (10, Scheme 5) [69].The directed C-H borylation employed [Ir(OMe)(COD)] 2 as a precatalyst and B 2 pin 2 as a boron source and proceeded with ortho selectivity.The reaction proceeded with good functional group tolerance and good yields (Scheme 5).For example, ether and halogens are tolerated as demonstrated by ortho-borylated NH-Boc anilines 11a and 11b, which were obtained with yields of 96% and 79%, respectively.The use of the cyano group as an electronwithdrawing group was tolerated as noted in borylated product 11c, which was obtained with a modest 40% yield.The free hydroxyl group was also tolerated as exemplified by borylated hydroxyl NH-Boc protected aniline 11d, which was obtained with a 78% yield.In addition, carbamates were also tolerated as demonstrated by borylated materials 11e and 11f, which were obtained with 44% and 62% yields, respectively (Scheme 3).The reaction reveals good functional group tolerance.
The regioselectivity of the borylation reaction was rationalized by hydrogen bonding between H in N-Bpin aniline and O in the Ir complex 14B in the postulated transition state shown (Figure 4).Principally, this is similar with previous mechanistic findings of the Ir-catalyzed ortho C-H borylation reported earlier (Scheme 5) where hydrogen bonding associates Bpin and NH Boc moieties to produce transition state 14A (Figure 4).It is noteworthy that unsubstituted anilines were not effective under the reaction conditions.Detailed mechanisms of Ir-catalyzed C-H borylation and directed Ir-catalyzed C-H borylation are given and discussed in Schemes 2 and 4 (vide supra).
The regioselectivity of the borylation reaction was rationalized by hydrogen bonding between H in N-Bpin aniline and O in the Ir complex 14B in the postulated transition state shown (Figure 4).Principally, this is similar with previous mechanistic findings of the Ircatalyzed ortho C-H borylation reported earlier (Scheme 5) where hydrogen bonding associates Bpin and NH Boc moieties to produce transition state 14A (Figure 4).It is noteworthy that unsubstituted anilines were not effective under the reaction conditions.Detailed mechanisms of Ir-catalyzed C-H borylation and directed Ir-catalyzed C-H borylation are given and discussed in Schemes 2 and 4 (vide supra).It was observed that the ortho-selectivity of the reaction was greatly reduced when B2Pin2 was used instead of HBpin as a borylating agent.When B2Pin2 is used, aniline is not borylated at N. As a result, this suggests that NHBpin is a better directing group than NH2 in the Ir-catalyzed C-H borylation.Interestingly, when secondary anilines are used instead of anilines, the ortho selectivity is not observed.For example, when N-methyl-3-chloroaniline (15, Scheme 8) is subjected to the reaction conditions, ortho-borylated aniline is not produced.Instead, meta-related product 16 is formed in 86% yield (Scheme 8).monosubstituted anilines were borylated at the ortho position.For instance, electron-rich 4-methoxyaniline gave the corresponding ortho-borylated product 13c in 63% yield.Electron-deficient anilines such as 4-trifluoromethyl and 4-cyanoanilines afforded the corresponding borylation products 13b and 13d in decent yields of 87%, and 60%, respectively (Scheme 6).
The regioselectivity of the borylation reaction was rationalized by hydrogen bonding between H in N-Bpin aniline and O in the Ir complex 14B in the postulated transition state shown (Figure 4).Principally, this is similar with previous mechanistic findings of the Ircatalyzed ortho C-H borylation reported earlier (Scheme 5) where hydrogen bonding associates Bpin and NH Boc moieties to produce transition state 14A (Figure 4).It is noteworthy that unsubstituted anilines were not effective under the reaction conditions.Detailed mechanisms of Ir-catalyzed C-H borylation and directed Ir-catalyzed C-H borylation are given and discussed in Schemes 2 and 4 (vide supra).It was observed that the ortho-selectivity of the reaction was greatly reduced when B2Pin2 was used instead of HBpin as a borylating agent.When B2Pin2 is used, aniline is not borylated at N. As a result, this suggests that NHBpin is a better directing group than NH2 in the Ir-catalyzed C-H borylation.Interestingly, when secondary anilines are used instead of anilines, the ortho selectivity is not observed.For example, when N-methyl-3-chloroaniline (15, Scheme 8) is subjected to the reaction conditions, ortho-borylated aniline is not produced.Instead, meta-related product 16 is formed in 86% yield (Scheme 8).

Scheme 7. Mechanism for Ir-catalyzed C-H borylation of anilines.
It was observed that the ortho-selectivity of the reaction was greatly reduced when B 2 Pin 2 was used instead of HBpin as a borylating agent.When B 2 Pin 2 is used, aniline is not borylated at N. As a result, this suggests that NHBpin is a better directing group than NH 2 in the Ir-catalyzed C-H borylation.Interestingly, when secondary anilines are used instead of anilines, the ortho selectivity is not observed.For example, when N-methyl-3chloroaniline (15, Scheme 8) is subjected to the reaction conditions, ortho-borylated aniline is not produced.Instead, meta-related product 16 is formed in 86% yield (Scheme 8).

Amides
In 2019, the Ir-catalyzed ortho-C-H borylation of secondary aromatic amides was reported (17, Scheme 9) [71].The borylation occurs with high ortho-selectivity and is governed by hydrogen-bonding interactions.The directed Ir-catalyzed C-H borylation employed [Ir(OMe)(COD)]2 as a precatalyst and B2pin2 as a boron source, and a bipyridinebased ligand that has an indole amide (BAIPy) was used (Scheme 7).Investigations of the borylation reaction were performed on various secondary amides using BAIPy ligand and 2,2′-bipyridine (Bpy) itself in control experiments.Exceptionally high ortho-selectivity was Scheme 8. Ir-catalyzed C-H borylation of N-methyl aniline.
It was postulated that the benzamide substrate reorganizes itself to interact with the indole and the amide moieties in the BAIPy ligand by hydrogen bonding to form a hydrogen-bonding-based transition state 19 (Figure 5).This prerequisite hydrogen bonding brings the Ir-metal center in proximity to the ortho-C-H bond, setting the stage for C-H bond cleavage followed by subsequent borylation with Bpin.In 2021, tertiary benzamides have been reported to undergo Ir-catalyzed ortho-C-H borylation that employs [Ir(OMe)(COD)]2 as a precatalyst and B2pin2 as a boron source [72].The borylation reaction features a unique 3-thiophenylpyridine ligand (20, Scheme 10).Bipyridine ligands did not take part in the ortho-selective C-H borylation.However, 2-phenylpyridines were found to be effective in the reaction, which led to the development of the 3-thiophenylpyridine ligand.It was postulated that the reactivity of this ligand was attributed to the higher acidity of the thiophenyl group at C2. Consequently, upon reaction with [Ir(OMe)(COD)]2, the ligand forms a cyclometalated complex with Ir, which sets the stage for C-H borylation.
To investigate the active catalyst system, ligand 20 was treated with two Ir precatalysts: (Ir(Cl)(COD)]2 and [Ir(OMe)(Cod)]2 (Scheme 10).When the 3-thiophenylpyridine ligand was treated with the former, a cyclometallated dimeric iridium(III) complex 21 was formed.This complex was presumably formed by metal-mediated hydride transfer.When the ligand was treated with the latter, the Ir(I)cyclometallated complex 22 was formed (Scheme 10).Both cyclometallated complexes In 2021, tertiary benzamides have been reported to undergo Ir-catalyzed ortho-C-H borylation that employs [Ir(OMe)(COD)] 2 as a precatalyst and B 2 pin 2 as a boron source [72].The borylation reaction features a unique 3-thiophenylpyridine ligand (20, Scheme 10).Bipyridine ligands did not take part in the ortho-selective C-H borylation.However, 2phenylpyridines were found to be effective in the reaction, which led to the development of the 3-thiophenylpyridine ligand.It was postulated that the reactivity of this ligand was attributed to the higher acidity of the thiophenyl group at C2. Consequently, upon reaction with [Ir(OMe)(COD)] 2 , the ligand forms a cyclometalated complex with Ir, which sets the stage for C-H borylation.In 2021, tertiary benzamides have been reported to undergo Ir-catalyzed ortho-C-H borylation that employs [Ir(OMe)(COD)]2 as a precatalyst and B2pin2 as a boron source [72].The borylation reaction features a unique 3-thiophenylpyridine ligand (20, Scheme 10).Bipyridine ligands did not take part in the ortho-selective C-H borylation.However, 2-phenylpyridines were found to be effective in the reaction, which led to the development of the 3-thiophenylpyridine ligand.It was postulated that the reactivity of this ligand was attributed to the higher acidity of the thiophenyl group at C2. Consequently, upon reaction with [Ir(OMe)(COD)]2, the ligand forms a cyclometalated complex with Ir, which sets the stage for C-H borylation.
To investigate the active catalyst system, ligand 20 was treated with two Ir precatalysts: (Ir(Cl)(COD)]2 and [Ir(OMe)(Cod)]2 (Scheme 10).When the 3-thiophenylpyridine ligand was treated with the former, a cyclometallated dimeric iridium(III) complex 21 was formed.This complex was presumably formed by metal-mediated hydride transfer.When the ligand was treated with the latter, the Ir(I)cyclometallated complex 22 was formed (Scheme 10).Both cyclometallated complexes were characterized and confirmed by X-ray [72].
After establishing the active catalytic species in the reaction, the scope of the Ir-cata-Scheme 10.Formation of cyclometallated.
When the 3-thiophenylpyridine ligand was treated with the former, a cyclometallated dimeric iridium(III) complex 21 was formed.This complex was presumably formed by metal-mediated hydride transfer.When the ligand was treated with the latter, the Ir(I)cyclometallated complex 22 was formed (Scheme 10).Both cyclometallated complexes were characterized and confirmed by X-ray [72].
After establishing the active catalytic species in the reaction, the scope of the Ircatalyzed ortho-C-H borylation of tertiary benzamides (23,Scheme 11) was carried out under developed reaction conditions.The effects of substituents on N were studied under the reported optimum conditions (Scheme 11).Thus, various alkyl groups were compatible with the reaction conditions and were able to promote Ir-catalyzed ortho-selective C-H borylation of their benzamides.For example, ortho-borylated N,N-dicyclohexylbenzamide (24a) was obtained in 94% yield.The N,N-dimethyl counterpart (24b) was obtained in 82% yield, and N,N-diethyl (24c) and N,N-dihexyl (24d) benzamides were obtained in 92% yields.Other ortho-borylated benzamides of pyrrolidinyl (24i) and morphine (24j) groups were obtained in yields of 88% and 86%, respectively (Scheme 11).

Benzyl Amines
In 2012, Ir-catalyzed ortho-selective C-H borylation of benzylic amines (31,Scheme 15) was developed [74].The reaction employs [Ir(OMe)(COD)]2 as a precatalyst, B2pin2 as a boron source, and features picolyl amine as a ligand.A key structural feature of picolyamine is that it possesses an N-H bond that could form an H-bond with a benzylamine substrate.Thus, a transition Ir-complex was proposed, where picolyamine binds to the Ir precatalyst, forms hydrogen bonding with the benzylamine substrate, and makes a vacant coordination site on the Ir center available (34, Figure 6).Consequently, ortho-C-H cleavage followed by borylation of the benzylamine subsequently occur.Detailed mechanisms of Ir-catalyzed C-H borylation and directed Ir-catalyzed C-H borylation are given and discussed in Schemes 2 and 4 (vide supra).
A key structural feature of picolyamine is that it possesses an N-H bond that could form an H-bond with a benzylamine substrate.Thus, a transition Ir-complex was proposed, where picolyamine binds to the Ir precatalyst, forms hydrogen bonding with the benzylamine substrate, and makes a vacant coordination site on the Ir center available (34, Figure 6).Consequently, ortho-C-H cleavage followed by borylation of the benzylamine subsequently occur.Detailed mechanisms of Ir-catalyzed C-H borylation and directed Ir-catalyzed C-H borylation are given and discussed in Schemes 2 and 4 (vide supra).A scope of amine directing effect was explored under optimum reaction conditions of the picolylamine-promoted Ir-catalyzed ortho-C-H borylation (Scheme 16).For example, N,N-dimethyl-2-phenylethylamine was borylated at the arene ortho position to give the corresponding ortho-borylated product 35a in a moderate 51% yield.A more sterically hindered benzylamine such as N,N-dimethyl-1-phenylethylamine gave corresponding ortho-borylated product 35b in 86% yield.Imidazolidine-based benzylamine was successfully borylated at the arene ortho position to give the corresponding ortho-borylated product 35c in a moderate 71% yield (Scheme 16) A scope of amine directing effect was explored under optimum reaction conditions of the picolylamine-promoted Ir-catalyzed ortho-C-H borylation (Scheme 16).For example, N,N-dimethyl-2-phenylethylamine was borylated at the arene ortho position to give the corresponding ortho-borylated product 35a in a moderate 51% yield.A more sterically hindered benzylamine such as N,N-dimethyl-1-phenylethylamine gave corresponding ortho-borylated product 35b in 86% yield.Imidazolidine-based benzylamine was successfully borylated at the arene ortho position to give the corresponding ortho-borylated product 35c in a moderate 71% yield (Scheme 16) [74].

Ir
ple, N,N-dimethyl-2-phenylethylamine was borylated at the arene ortho position to give the corresponding ortho-borylated product 35a in a moderate 51% yield.A more sterically hindered benzylamine such as N,N-dimethyl-1-phenylethylamine gave corresponding ortho-borylated product 35b in 86% yield.Imidazolidine-based benzylamine was successfully borylated at the arene ortho position to give the corresponding ortho-borylated product 35c in a moderate 71% yield (Scheme In 2019, an asymmetric enantioselective Ir-catalyzed aromatic ortho-C-H borylation of diaryl N,N-dimethyamines was reported [75].The reaction employs [Ir(Cl)(COD)] 2 as a precatalyst and B 2 pin 2 as a boron source.The key feature of the regioselective asymmetric reaction is the use of chiral (S,S)-DPEN-derived bidentate boryl ligands, and the reaction features picolyl amine as a ligand.
The enantioselectivity in the asymmetric Ir-catalyzed C-H borylation relied on the use of chiral boryl silyl ligand (36, Scheme 17) that is based on commercially available (S,S)-DPEN.It was proposed that upon treatment of such chiral ligands with [Ir]-B 2 pin 2 , a vacant coordination site on the Ir center gives the proposed active catalytic Ir species 37 (Scheme 17).
s 2024, 5, FOR PEER REVIEW 15 In 2019, an asymmetric enantioselective Ir-catalyzed aromatic ortho-C-H borylation of diaryl N,N-dimethyamines was reported [75].The reaction employs [Ir(Cl)(COD)]2 as a precatalyst and B2pin2 as a boron source.The key feature of the regioselective asymmetric reaction is the use of chiral (S,S)-DPEN-derived bidentate boryl ligands, and the reaction features picolyl amine as a ligand.

Conclusions
Directed Ir-catalyzed C-H borylation is a significant type of C-H bond functionalization.The directed borylation provides borylated products in a regioselective manner.Specifically, ortho-regioselective Ir-catalyzed C-H borylation of arenes directed by N-containing directing groups is of unique importance.Various N-bearing directing groups have been proven to be effective in steering Ir-catalyzed C-H borylation to occur at ortho positions in a regioselective manner.The directed C-H borylation was demonstrated by various Nbearing directing groups, including anilines, amides, benzyl amines, hydrazones, and triazines.The directing ability of such directing groups lies in their coordination power with vacant sites on intermediate Ir-catalytic species, thus setting the stage for interactions between the Ir center and an ortho C-H bond and facilitating C-H borylation through C-H bond cleavage.

Scheme 3 .
Scheme 3. Possible coordination between the Ir trisboryl complex and directing groups.

Scheme 3 .
Scheme 3. Possible coordination between the Ir trisboryl complex and directing groups.

Figure 5 .
Figure 5. Hydrogen-bonding transition state for the directed C-HJ borylation.

Figure 6 .
Figure 6.Proposed transition state for the Ir-catalyzed C-H borylation of benzylamines.

Figure 6 .
Figure 6.Proposed transition state for the Ir-catalyzed C-H borylation of benzylamines.

Scheme 17 .
Scheme 17. Use of chiral DPEN-derived boryl ligand and the proposed active Ir catalyst.

Scheme 17 .
Scheme 17. Use of chiral DPEN-derived boryl ligand and the proposed active Ir catalyst.
-electron [Ir] species 7 should form.The Lewis base-Lewis acid coordination brings the Ir center in proximity to an ortho C-H in the directing group, thus facilitating C-H bond cleavage and forming the intermediate [Ir] species 8. Subsequently, the ortho position in the directing group is borylated with the Bpin moiety from the Ir center to give rise to ortho-borylated product 9 (Scheme 4) [59-62].Scheme 4. Envisaged directing role in the substrate-directed Ir-catalyzed C-H ortho-borylation of carbocycles.