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Synthesis 2022; 54(15): 3328-3340
DOI: 10.1055/a-1816-3334
short review

Catalyst Engineering through Heterobidentate (N–X-Type) Ligand Design for Iridium-Catalyzed Borylation

Md Emdadul Hoque
,
Mirja Md Mahamudul Hassan
,
Chabush Haldar
,
Sayan Dey
,
Saikat Guria
,
Jagriti Chaturvedi
,
Buddhadeb Chattopadhyay  ∗

This work was supported by grants from the Science and Engineering Research Board – Core Research Grant (SERB-CRG; CRG/2018/000133), Science and Engineering Research Board – Scientific and Useful Profound Research Advancement (SERB-SUPRA; SPR/2019/000158), and Science and Engineering Research Board – Science and Technology Award for Research (SERB-STAR; STR/2019/000045). M.E.H. thanks SERB-SUPRA for an RA fellowship, M.M.M.H. thanks the University Grants Commission (UGC) for an SRF, C.H. thanks Council of Scientific and Industrial Research (CSIR) for an SRF, S.D. and S.G. thanks the CSIR for a JRF fellowship, J.C. thanks UGC for an SRF. B.C. thanks SERB-STAR for an award.
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Abstract

Iridium-catalyzed C–H activation and borylation reactions operate under mild conditions that enable easy and atom-economical installation of the versatile boronate ester group in (het)arenes and alkanes. The standard catalytic system for iridium-catalyzed borylation uses [Ir(cod)(OMe)]2 as a precatalyst, a bipyridine type ligand, and B2pin2 or HBpin as the borylating agent. Initially, a bipyridine-ligated trisboryl–iridium complex is generated that enables the borylation reaction and the regioselectivity is mainly governed by the sterics of substituents present on the ring. As a result, monosubstituted and 1,2-disubstituted arenes give mixtures of isomers. Significant efforts by several research groups have overcome the selectivity issue for directed proximal C–H borylation by introducing a directing group and newly developed ligands. This short review aims to summarize recent elegant discoveries in directed C(sp2)–H and C(sp3)–H borylation by using heterobidentate ligand (P/N–Si, N–B, and N–C) coordinated iridium catalysts.

1 Introduction

2 Iridium-Catalyzed Directed C–H Borylation of C(sp2)–H Bonds

3 Iridium-Catalyzed Directed C–H Borylation of C(sp3)–H Bonds

4 Conclusions


#

Key words

C–H bond activation - ligand development - directing groups - heterobidentate ligand - iridium catalyst
1

Introduction

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Buddhadeb Chattopadhyaywas born and raised in Insura-Hooghly, West Bengal. He obtained his B.Sc. (2001) in chemistry from the Burdwan University and M.Sc. (2003) in chemistry from Visva-Bharati University. He completed his Ph.D. in 2019 with Professor K. C. Majumdar. Buddhadeb spent around six years as a postdoctoral research associate in the USA at the University of Illinois at Chicago, with Professor Vladimir Gevorgyan and Michigan State University, Michigan, with Professor Milton R. Smith. In August 2014, he moved to the Centre of Biomedical Research (CBMR) Lucknow, India as an Assistant Professor (Ramanujan Fellow) and he was promoted to Associate Professor in November 2019. His research interest includes metal-catalyzed C–H borylation chemistry (catalyst/ligand engineering) via noncovalent interaction and radical activation chemistry via denitrogenative annulation to obtain high value N-heterocycles. He is the recipient of Thieme Chemistry Journal Award (2017) and SERB-STAR Award (2019) for Science and Technology Research.

Transition-metal-catalyzed direct C–H activation and functionalization of highly similar C–H bonds in (het)arenes and alkanes has emerged as one of the most promising methods in modern synthetic chemistry.[1] Because the substrates generally require no pre-activation, just use of this direct C–H activation protocol provides an atom-economical approach to access value-added products and intermediates that do not require the formation of halogenated or otherwise pre-functionalized starting materials. Although the use of homogeneous catalysis in C–H activation and functionalization reactions employing transition metal complexes began earlier,[2] the development was hastened by the pioneering report by Murai and co-workers in 1993.[1f] In this report, it was demonstrated that a transition-metal catalyst could be employed to selectively functionalize the arene ortho-position in a parallel manner to DoM.[3] Subsequently, a variety of transition-metal-catalyzed methods have been developed owing to their milder reaction conditions and higher selectivity.[1] In this context, among the various metal-catalyzed C–H bond functionalization reactions developed so far, the recent development of iridium-catalyzed C–H bond activation and borylation[4] is important because of the versatility of the C–B bond in many synthetically useful transformations.[1c]

(Het)arene–boron complexes are versatile (het)aryl transfer agents in Pd-catalyzed Suzuki–Miyaura coupling because their environmentally benign and user-friendly characteristics make them superior alternatives to other toxic or sensitive organometallic reagents.[5] [6] [7] Moreover, since 2000 organoboron compounds have served as important synthons as they can be transformed into a range of functional groups via halogenation, arylation, amination, oxygenation, thiolation, and many more.[1c,8] Furthermore, boronic acids and several of their ester derivatives (being Lewis acidic in nature[9]) exhibit excellent potential for catalyst engineering and development for organic reactions including asymmetric transformations.[10] In the pharmaceutical industry, (het)arene–boron complexes are key building blocks in the manufacture of certain drug molecules, as well as important reagents for use in parallel synthesis in drug discovery.[11]

Thus, considering the uniqueness of organoboron compounds, many practical and convenient methods have been developed for the introduction of the boron functionality into (het)arenes by many pioneering research groups over the last two decades. There are two general methods for the synthesis of organoboron compounds from organic halides. The first involves the reaction between an aromatic halide and a strong organometallic reagent[4] [12] (organolithium or Grignard reagent) to generate an organometallic intermediate that subsequently reacts with an alkyl borate to give an arylboronic acid or ester. Generally, this method is unsuccessful for substrates containing base-sensitive, electrophilic, or protic functional groups (Scheme [1a]). The second approach to form arylboronic acids is by the Miyaura borylation reaction. In this reaction, an aryl halide or pseudohalide (OTf, OTs) is reacted with bis(pinacolato)diboron to form the desired borylated arene with higher functional group tolerance (Scheme [1b]).[13] The main drawback of these two strategies is the need for functionalized arene starting materials (that must be synthesized from their hydrocarbon analogues). A transition-metal-catalyzed direct C–H activation and borylation can overcome all these limitations. C–H Bonds are the most abundant in organic molecules and methods for their direct, selective, catalytic functionalization are attractive as well as efficient strategies to access more complex molecular entities, hence new synthetic strategies for the direct synthesis of organoboron compounds by virtue of strong C–H bond cleavage are highly desirable and have been pioneered by many research groups.

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Scheme 1 Two general methods for the synthesis of boryl compounds

In this context, the Smith group, in 1999, introduced[14] a catalytic system for the C–H borylation of benzene using HBpin as the boron reagent at 150 °C in the presence of Cp*Ir(PMe3)(H)(Bpin) as the catalyst. While this report was a seminal contribution to borylation reactions, the yield of the borylated product was 53% and TON was only 3. Sub­sequently, they[4a] improved the efficiency of the borylation reaction by introducing a new type of catalyst employing a combination of [(Ind)Ir(cod)] and various phosphine ligands­, such as PMe3, 1,2-bis(diphenylphosphino)ethane (dppe), and 1,2-bis(dimethylphosphino)ethane (dmpe). At the same time, Ishiyama, Miyaura, Hartwig, and co-workers discovered[4b] a new series of C–H borylation Ir catalysts using­ a combination of several nitrogen-containing bidentate ligand frameworks, such as bipyridine and 4,4′-di-tert-butylbipyridine, and concluded that iridium-containing bipyridine derivatives are a more reactive catalytic system than the phosphine-ligated iridium catalysts. In these cases, the selectivity of the borylation reactions was mainly dominated by the sterics of the substituents present in arene, and borylation occurred preferentially at the less sterically hindered site. For example, while monosubstituted or 1,2-disubstituted benzenes afforded a mixture of meta- and para-substituted products, the 1,3-disubstituted arenes yielded meta-arylboronates exclusively. Notably, since the discovery of these borylation catalysts, various pre-catalysts, ligand frameworks, and boron reagents have been reported in the literature.

Mechanistically, while the scope of the C–H borylation reactions had been examined extensively using various catalytic systems, the detailed reaction mechanism had not been studied. To elucidate the mechanism of the iridium-catalyzed C–H borylation reaction, several important experiments were performed. For example, in Smith and Maleczka’s report,[4a] two iridium complexes Ir(Bpin)(PMe3)4 and Ir(Bpin)3(PMe3)2 were prepared and these reacted smoothly with benzene to afford PhBpin. But, of these two iridium complexes, only the iridium(trisboryl) complex reacted with iodobenzene to give meta- and para-C6H4I(Bpin) in the same isomeric ratio indicating that the iridium(trisboryl) complex is the catalytic intermediate.

In 2005, the Hartwig group thoroughly investigated[15] the reaction mechanism of arene C–H borylation with the diboron reagent B2pin2 catalyzed by the combination of 4,4′-di-tert-butyl-2,2′-bipyridine (dtbpy) and [Ir(cod)OMe]2. The [Ir(dtbpy)(η2-COE)(Bpin)3] complex was synthesized and characterized by X-ray crystallography and subsequent studies confirmed that this species is the chemically and kinetically active catalytic intermediate in the catalytic cycle for aromatic C–H borylation. Based on the numerous experimental and kinetic data, they proposed a mechanism for the reaction which is illustrated in Scheme [2]. Labile cyclooctene reversibly dissociates from the 18-electron iridium(trisboryl) complex to generate an empty coordination site for the incoming arene and formed a 16-electron catalytic intermediate Int-I. Next, the 16-electron intermediate approaches the π-system of the arene and oxidative insertion of the iridium into the arene C–H bond gives the Ir(V) intermediate Int-II; this is believed to be the rate-limiting step. Next reductive elimination of the borylated arene produces Ir(III) intermediate Int-III, which undergoes oxidative addition of B2pin2 followed by the reductive elimination of HBpin to regenerate the iridium(trisboryl) complex and complete the catalytic cycle.

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Scheme 2 Mechanisms of the bipyridine ligated Ir-catalyzed borylation reaction

Since the establishment of the reaction mechanism for iridium-catalyzed aromatic C–H borylation, numerous powerful methods have been developed either by the modification of a substrate or by the design of a new ligand framework to achieve the desired ortho-selective borylation.[16] The first example of ortho-borylation by a homogeneous iridium catalyst was developed[17] by the Hartwig group in 2008 and the strategy was based on the use of hydrosilanes as a traceless directing group. They then developed a series of methods for ortho-selective borylation by employing hydrosilanes as directing groups.[18] On the other hand, Ishiyama, Miyaura, and co-workers developed[19] a new catalytic system using [Ir(cod)OMe]2 and a monodentate electron-deficient tris[3,5-bis(trifluoromethyl)phenyl]phosphine ligand in the presence of B2pin2 as the borylating reagent, which successfully directs the incoming boryl group to the ortho-position of the ester functional group. In contrast to Hartwig’s homogeneous iridium catalyst for directed ortho-borylation reactions, the Ir-catalyzed borylations using silica-supported phosphine ligands,[20] pioneered by Sawamura and co-workers demonstrated a broad scope for directed ortho-borylations of arenes bearing a large number of functional groups. This is the first report of directed ortho-borylation using a heterogeneous iridium catalytic system. Fernández and Lassaletta subsequently introduced[21] a series of powerful methods for designing a new type of ligand frameworks that acts as a hemilabile ligand for directed ortho-borylation reactions. Meanwhile, the Clark group[22] also reported an elegant concept for the ortho-borylation of N,N-dimethylbenzylamine using a hemilabile ligand. Since these pioneering discoveries, many research groups have reported new methods by developing new types of catalyst systems to achieve the directed ortho-borylation of (het)arenes.

On the other hand, remote meta- or para-borylation was explored mainly after 2015 by various research groups such as Kanai and Kuninobu,[23] Itami,[24] Chattopadhyay,[25] Phipps,[26] Smith and Maleczka,[27] Nakao,[28] Sawamura,[29] and others. In this short review, we intend to discuss recent developments in directed borylation by employing heterobidentate ligand (P/N–Si, N–B, and N–C) coordinated iridium catalysts with a particular focus on catalyst development for the site-selective borylation of diverse substrates unattainable using the standard catalytic system (refers to Ir-dtbpy catalyst system).[15] We will discuss borylation reactions with heterobidentate ligands from their inception to 2021 in this short review article.


# 2

Iridium-Catalyzed Directed C–H Borylation of C(sp2)–H Bonds

Inspired by Sawamura’s surface-supported phosphine system[20] and Shimada’s work[30] on the use of pincer PSiP ligands in iridium-catalyzed borylation, Krska, Maleczka, Smith, and co-workers hypothesized that bidentate Si–P ligand L1 [31] might also be suitable for the borylation of arenes. They anticipated that the bidentate Si–P ligand L1 forms an active complex AC (Scheme [3]), where the silyl ligand substitutes a spectating boryl ligand attached to the iridium. Silane metathesis with a boryl ligand would steer the phosphine to the iridium metal center to form the active catalytic intermediate AC with accessible coordination sites. Moreover, L1 acts as a bidentate ligand and the active catalyst formed is electron-rich and may show better reactivity in comparison to the previously used electron-deficient ligated iridium catalyst.

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Scheme 3 Heterobidentate P/N–Si coordinated Ir-catalyzed borylation of arenes

Based on this hypothesis, they prepared P–Si ligand L1 and used it for the borylation of methyl benzoate. A comparative study of their catalytic system with the previously reported P(3,5-bis(trifluoromethyl)phenyl)3 (PArF3)[19a] and triphenylarsine[19b] ligand systems, which are known for directed borylation in iridium-catalyzed borylation reactions, showed that their catalytic system gave better results (Scheme [3]), however a comparison with the silica-SMAP ligated Ir-catalyst system showed it to be more active (Scheme [3]). Next to show the utility of this catalytic system, the scope of the borylation was examined by performing directed ortho-borylation of various substituted esters and this gave the products with excellent ortho-selectivity. In addition to esters, this catalytic system was compatible with other substituted arenes, such as, amides and ethers and 2-phenylpyridines. Notably, in contrast substrates bearing ketone and carbamate functionalities were less compatible under these conditions. As the ketone functionality is reduced under these conditions and the carbamate reacts slowly, they developed a new type of N–X ligand framework (Si–N), which was excellent for substrates containing ketone and carbamate functionalities. They envisioned that an Ir catalyst with a nitrogen donor ligand would be more reactive than the P-donor ligand and developed N–Si ligand L2 that showed better reactivity with ketones and carbamate substrates. Comparison of Sawamura’s silica-SMAP ligand[20] with L2 ligand showed that L2 gave better selectivity, as no para-borylated product was detected with carbamate substrates but it was detectable with silica-SMAP systems. This modified N–Si ligand L2 was better compared to the arsine ligand[19b] system for the ortho-borylation of ketones.

Krska, Maleczka, Smith, and co-workers isolated the active­ catalyst by reaction of Si–P ligand L1 with Ir(OMe)(cod)]2 catalyst and confirmed the structure by X-ray crystallography; this active catalyst was superior to the combination of Ir precatalyst and ligand in their boryl­ation reaction by shortening the reaction time.

In 2009, the groups of Yamashita and Nozaki[32] and Mirkin[33] independently introduced the XBX (X = P, Se, S) pincer-type tridentate ligands and their transition metal complexes. Since then, pincer boryl ligands and their transition metal complexes have been applied in various catalytic reactions,[34] but the bidentate boryl ligands were not explored in transition-metal-catalyzed reactions even though they can form a more flexible coordination sphere. Mechanistically, the active catalyst in Ir-catalyzed borylations is a bipyridine-coordinated Ir(III)–trisboryl complex bearing three boryl ligands and only one of which is introduced into the product. In this context, the Li group[35] discovered an elegant catalytic system by introducing a new type of N,B-bidentate ligands for borylation reactions (Scheme [4]). They envisioned that two boryl ligands in the active catalyst can be pre-installed and this can change the electronic and steric properties of the iridium center. They proposed an active catalyst for the borylation by reconstructing the bipyridine ligand and two boryl ligands with a double N,B-bidentate ligand (Scheme [4]) and considered that the 1,3,2-diazaborole unit of the ligand would enhance the electron-donating propensity of the boryl as well as pyridine ligand. With this proposed hypothesis, they synthesized an N,B-bidentate boryl ligand L3 and reacted it with [Ir(cod)Cl]2 to obtain a complex with two N,B-bidentate boryl ligands and a cod ligand that underwent a metathetic reaction with a diboron reagent to give the proposed catalytic intermediate. Interestingly, the pyridine ligands and boryl ligand are found to be cis to each other, which resembles of the Ir-dtbpy tris-boryl complex. Therefore proposed catalytic intermediate can readily be accessed from N,B-bidentate ligand L3, paving the pathway for catalyst generation. Next, they tested the efficiency of the developed preligand L3 under iridium-catalyzed borylation conditions in the borylation of the electron-rich substrate 1,3-dimethoxybenzene[36] in CPME solvent at 100 °C for 16 h resulting in almost quantitative conversion into the meta-borylated product in 95% isolated yield (Scheme [4]). Performing the same reaction, for comparison, but replacing L3 by TMPHEN gave a lower isolated yield with some unidentified products. Using the more electron-rich N 1,N 1,N 3,N 3-tetramethylbenzene-1,3-diamine as the substrate with L3 ligand gave meta-borylated product in 93% yield, while the same reaction using TMPHEN ligand afforded only 50% isolated yield of the borylated product (Scheme [4]). Various electron-rich and electron-poor arenes were also reacted successfully under the developed reaction conditions.

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Scheme 4 Double N,B-bidentate ligand meditate nondirected borylation

In 2017, the Li group introduced[37] another powerful preligand for the directed ortho-borylation of a wide range of arenes. They designed a new type of single N,B-bidentate ligand containing a silylborane that reacts with the Iridium metal catalysts via Si–B oxidative addition and applied it to the directed borylation of arenes. Based on the work of Sawamura’s heterogeneous catalysis[20] and Smith’s[31] P–Si electron-rich anionic ligand L1, it was envisioned that this single N,B-bidentate ligand would be suitable for directed ortho-borylation. It was hypothesized that silylborane ligand L4 is a suitable precursor for the introduction of single N,B-ligands with a metal center for the following important reasons: (i) the Si–B bond undergoes oxidative addition with a low-valent transition metal, (ii) the undesired silyl group may be specifically removed by either reductive elimination or ligand exchange, and (iii) the sterically congested silyl group may inhibit the introduction of a second N,B-ligand on the metal, which is common for hydroboranes or diboranes.

Following these considerations, silylborane preligands and their corresponding iridium precatalysts were synthesized (Scheme [5]). The structure of the iridium complex was confirmed by X-ray crystallography and it was shown that the iridium(III) atom is associated with an N,B-bidentate boryl ligand, a silyl group, a chloride, and a cycloocta-1,5-diene (cod) ligand. This iridium complex on further treatment with B2pin2 generates the bis(boryl)Ir complex instead of the standard tris(boryl)Ir complex with two vacant coordination sites for chelation-directed borylation. The newly developed N,B-bidentate boryl ligand in combination with [Ir(cod)Cl]2 precatalyst and B2pin2 is a practical catalyst system that is highly effective for the directed ortho-selective­ borylation of differently substituted aromatic esters­, acetates, carbamates, N,N-methylamide, hydrazones, ketones, and nitrogen-based directing groups containing arenes. The main advantage of these preligands is that the structures can be modified for better selectivity.

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Scheme 5 Mono-N,B-bidentate ligated Ir-catalyzed directed borylation

In 2019, the Xu group[38] reported the first chelate-directed iridium-catalyzed regioselective asymmetric C(sp2)–H borylation of aromatic C–H bonds of diarylmethylamines directed by amine groups (Scheme [6]). Using this method, they also reported the desymmetrization and kinetic resolution for asymmetric borylation using various chiral bidentate boryl ligands.

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Scheme 6 Amine-directed enantioselective borylationby using chiral N,B-bidentate ligated Ir catalyst

Pioneering work by the Yu group[39] had demonstrated that usually in the active catalytic species a second vacant or weakly coordinating site is necessary to perform chelate-directed enantioselective C–H functionalization. The Smith and Li groups have also previously reported iridium-catalyzed ortho-borylation using silyl phosphorus and nitrogen donor ligands[31] and N,B-bidentate boryl ligands,[37] respectively. Inspired by these works, the Xu group[38] investigated suitable chiral ligands for asymmetric C–H borylation and found that in presence of [Ir(cod)Cl]2 and B2pin2, the chiral N,B-ligands are efficient for the enantioselective C–H borylation of prochiral diarylmethylamines (Scheme [6]). They also observed that the aryl group of the ligand has a significant role in the ee of the desired product and ligand L5 bearing the aryl group 3,5-Me2C6H3 is optimal.

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Scheme 7 ortho-Borylation using air stable S–Si ligand
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Scheme 8 Catalyst development for the directed borylation

Most N,N-dimethyldiarylmethylamines reacted smoothly under the developed reaction conditions affording the corresponding borylated products in high yields and good to excellent enantioselectivity. Moreover, employing their developed reaction conditions, the kinetic resolution of various racemic diarylmethylamines was also explored; it can differentiate two enantiomers from the racemic mixture. A model substrate containing two different arene rings (Ph and 3,5-di-CF3-C6H3) with ligand L5 afforded the product with 89% ee and 35% conversion, while modified L6 ligand, containing a bulky tert-butyl group, gave 94% ee and 30% conversion (Scheme [6]). Computational studies showed that the mechanism involves an IrV/IrIII reductive elimination pathway.

In 2021, the Li group reported[40] an Ir-catalyzed ortho-C–H borylation of substrates containing various functional groups using their newly designed air-stable Si,S-chelating ligand L7 (Scheme [7]). In 2017, the Li group had reported that cyclic dithioacetals are effective directing groups for iridium-catalyzed ortho-C–H borylation.[41] Moreover, the Hartwig[17] and Smith groups[31] showed that the chelation of the silyl group can generate an electron-rich metal center with better nucleophilicity. Thus based on these findings, the Li group proposed that L7 might be an effective option for C–H borylation. The prepared L7 ligand, in the presence of [Ir(cod)OMe]2 pre-catalyst and B2pin2 as borylating agent, displayed excellent ortho-selectivity for various directing groups in arenes and heteroarenes (Scheme [7]). (Het)arene esters and amides and N,N-disubstituted benzylamines were compatible with the reaction conditions and afforded the corresponding ortho-borylated products in high yields.

A plausible catalytic cycle was proposed based on various controlled experiments (Scheme [7]). First, the Si–H bond of the ligand undergoes formal σ-bond metathesis generating a Si–Ir species along with S–Ir chelation leading to the formation of the bis(boryl)Ir intermediate I with two vacant coordination sites. Subsequently, the carbonyl group of the substrate coordinates with one of the vacant coordination sites to generate intermediate II as an electron-rich framework. Intermediate II then facilitates ortho-C–H bond activation of the substrate to generate an Ir(V) species III. Next, intermediate III undergoes reductive elimination to form intermediate IV delivering the product and regenerating the catalytic cycle.

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Scheme 9 Ir-catalyzed C–H borylations using PYT ligand

In 2021, our group reported[42] a series of C–H borylation catalysts via ligand engineering (Scheme [8]). The new catalysts/ligands exhibited remarkable reactivity and selectivity for the ortho-borylation of a range of substrates containing several functional groups. Moreover, the developed catalysts/ligand is compatible with the borylation of aliphatic substrates (see Section 3). The 2-pyridylthiophene ligand L8 [43] undergoes bidentate coordination to iridium via C-anionic (thienyl) coordination. The developed catalysts CB1 and CB2 derived from L8 showed excellent reactivity for C–H borylation and CB2 catalyst, which is dimeric, is air-stable with the ability to perform the C–H borylation under atmospheric conditions. CB1 was synthesized from the reaction of L8 ligand and [Ir(cod)OMe]2 by the loss of MeOH, whereas CB2 was synthesized from [Ir(cod)Cl]2 and the dimeric structure gives it its air stability.

Using the optimized 2-pyridylthiophene (N–X-type) ligand L8, we studied the C–H borylation of a series of aromatic amides containing different substituents on the arene and N-substitution. This method tolerated heterocycle amides as well as a variety of substrates containing different functional groups. The optimized reaction conditions gave a broad spectrum of C–H borylation of more than 35 different substrates irrespective of the electronic properties of the functional groups (Scheme [9]). Moreover, this method can be employed for the borylation of heterocycles as well as for the late-stage C–H borylation of drug-like molecules. Interestingly, the catalyst CB2 exhibited excellent reactivity and selectivity for C–H borylation under atmospheric conditions, which makes the method more general (Scheme [10]).

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Scheme 10 Borylation under atmospheric conditions using CB2 catalyst

To identify the mechanism, we performed several control experiments including ligand titration and investigations of the stability of the developed catalyst and the bidentate nature of the ligand. These control experiments indicated an interesting mechanism, where reaction goes through the formation of an Ir-bis(boryl) complex, which is supported by spectroscopic data (Scheme [11]). The simplified mechanism for the ortho-borylation is shown in Scheme [11]. Initially, the CB1 catalyst undergoes oxidative addition of B2pin2 to generate the cod-ligated bis(boryl)(Ir)complex complex-A, which undergoes reversible cod dissociation to afford the Ir(bis)boryl complex Int-1. The arene substrate subsequently enters into the catalytic cycle by coordination of its functional group with Int-1 and C–H bond activation in Int-2 occurs giving Int-3. Finally, reductive elimination of the borylated product from Int-3 gives Int-4 that reacts with B2pin2 to complete the catalytic cycle.

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Scheme 11 Plausible mechanism of borylation using CB2 catalyst

In 2021, the Li group developed a chiral pyridine containing N,B-bidentate ligand L9 and utilized it in the enantioselective C–H borylation of diaryl(2-pyridyl)methanes (Scheme [12]).[44]

They hypothesized that the compact framework of the ligand with annulated polycyclic rings would be beneficial in asymmetric catalysis and that the annulated cyclopentane and cyclopropane rings would minimize local steric hindrance and allow structural tunability of their ligand framework. A tunable chiral pyridine unit was designed and attached to their previously developed boryl ligand partner of N,B-ligand for the iridium-catalyzed asymmetric C–H borylation.[37] Electronic and steric tuning of their ligand using a model system of diphenyl(2-pyridyl)methane led to ligand L9 that gave 2-hydroxyphenyl(phenyl)(2-pyridyl)methane in 93% yield with excellent enantioselectivity (94% ee) using a solvent mixture of n-hexane and 2-MeTHF. The scope of the borylation was very wide for various meta- and para-substituted substrates, but the reaction failed to give product in the ortho-substituted cases. For ease of isolation, the borylated products were converted directly into the alcohol or chloride. Based on several computational and experimental results, the authors propose that the catalyst makes a reaction pocket where the ketal motif in the cyclohexane chair forms oriented in an outward fashion (Scheme [12]). Both outward and inward bent of the ketal motif forms two types of transition state and from the energy calculation the s-selective transition state is favorable where the ketal motif bends in an outward way. The enantioselectivity is governed by the suitable chiral reaction pocket in the transition state and weak noncovalent interaction (H bonding and C–H/π-interactions) between the chiral ligand and the substrate.

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Scheme 12 Enantioselective Ir-catalyzed C–H borylation

# 3

Iridium-Catalyzed Directed C–H Borylation of C(sp3)–H Bonds

In 2019, the Clark group reported an amide-directed alkane C–H borylation (Scheme [13]).[45] In 2012, the Sawamura group had previously reported an amide-directed rhodium-catalyzed C–H borylation of the C–H bond adjacent to the amide nitrogen atom using a solid-supported phosphine ligand.[46] On this basis, the Clark group investigated an iridium-catalyzed amide-directed C(sp3)–H borylation. Initially they used various commercially available common catalyst/ligand systems, but none of the combinations gave a satisfactory outcome. Using various other catalytic systems, they found that, in presence of [Ir(cod)OMe]2 and B2pin2, a silane-substituted quinolone ligand L2 was effective for the selective C(sp3)–H borylation of the C–H bond adjacent to the nitrogen atom of the amide functionality. The bidentate anionic ligand L2 maintains the rigidity at the iridium center like bidentate diamine ligands. In the active catalyst, two vacant coordination sites accommodate the substrates followed by C–H activation to afford the directed aliphatic borylation. Cyclic and acyclic amides reacted smoothly with better conversion compared to Sawamura’s solid-supported phosphine ligand.[46] However, some substrates exhibited poor reactivity under the developed reaction conditions.

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Scheme 13 Ir-catalyzed amide directed alkane borylation using N–Si ligand

In 2019, Xu and co-workers reported an amide-directed enantioselective Ir-catalyzed C(sp3)–H borylation of cyclopropanes using their modified chiral bidentate boryl ligand (CBL) L10 (Scheme [14]).[47] During ligand screening, it was observed that the sterically hindered substituents in the ligand framework played an important role in achieving higher stereoselectivity. By introducing bulky tert-butyl and isopropyl groups in the ligand framework, the enantioselectivity increased to 92%, and lowering the reaction temperature using ligand L10 further increased the enantio­selectivity to 94% after 36 h in THF solvent.

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Scheme 14 Ir-catalyzed enantioselective C(sp3)–H borylation of cyclopropanecarboxamides using chiral bidentate boryl ligand

The developed method demonstrated excellent reactivity and selectivity for a wide range of functional groups like diethylamide-, pyrrolidine-, piperidine-, and piperazine-derived cyclopropanecarboxamides with α-quaternary carbon centers and provided β-borylated products in moderate to good yields and good to excellent enantioselectivities. The synthetic utility of the borylated product was shown by stereospecifically transforming the C–B bond into various C(sp3)–C(sp3) coupling products, including the synthesis of a bioactive compound levomilnacipran.

A reaction mechanism is proposed by the formation of a 14-electron trisboryl-Ir(III) complex containing two vacant coordination sites (Scheme [14]). One of the vacant sites is docked by a directing group and the other site engages in agostic interaction between Ir(III) and one of the β-C–H bonds of the cyclopropanecarboxamide. To explain the origin of the enantioselectivity, two intermediates are proposed, in one the untouched CH2 unit of the cyclopropane is presented away from the pyridine ring and the phenyl group of the ligand experiences less steric repulsion resulting in the major enantiomer.

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Scheme 15 Enantioselective α-C(sp3)–H borylation of various azacycles by chiral N,B-boryl ligated Ir catalyst

The application of the chiral boryl ligands (CBLs) was extended by the Xu group to the enantioselective methylene α-C(sp3)–H borylation of a wide range of azacycles using iridium catalysis (Scheme [15]).[48] They previously demonstrated that the origin of the chiral induction was because of the desymmetrization of two enantiotropic carbons[47] whereas this method successfully differentiated enantiotropic methylene C–H bonds of a single carbon center. They selected tetrahydroisoquinoline (THIQ) with the directing group diethylcarbamoyl as the pilot substrate to modify the ligand framework L11/L12 in such a way as to suppress C(sp2)–H borylated byproducts and maximize the enantioselectivity for the α-C(sp3)–H borylation of the azacycle.

The arene borylation was reduced by the introduction of the substituents at the pyridine ring of the chiral boryl ligand. The optimized reaction conditions are capable of borylating the C1 position of THIQs and tolerating various directing groups. Using this method, a wide range of functional groups was tolerated and the corresponding products obtained in good yields and good to excellent enantioselectivities. The reaction scope was further extended using saturated azacycles, such as pyrrolidine, piperidine, azepane, morpholine, and piperazine; in all cases the reaction smoothly afforded enantioenriched α-borylated products in good yields. Moreover, this protocol also showed promising applicability for the late-stage functionalization of azacycle-related bioactive compounds.

In 2020, the Xu group reported a method for the enantioselective β-C–H borylation of acyclic amides using their designed chiral bidentate boryl ligand L13 under Ir catalysis (Scheme [16]).[49] The ligand scaffold with a bulky substituent was superior in obtaining high enantioselectivity.

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Scheme 16 Ir-catalyzed enantioselective β-C(sp3)–H borylation acyclic amides

To highlight the differences in reactivity between L14 and L15, two models A and B were proposed (Scheme [16]). A bulky substituent at the C5 position of pyridine prevents deactivation of the catalyst by minimizing the approach of other substrate molecules, see model B. This allows C(sp3)–H bond activation by the vacant site, which is not possible in model A where both are occupied by substrates that result in catalyst deactivation. The method appeared to be general for the borylation of a variety of N,N-diisopropyl-5-arylpentanamides and gave the corresponding products in good to excellent ees. The method also tolerated various alkyl chains, and heteroatom substituents on the alkyl chain even at 60 °C, affording the products with high enantioselectivities (90–98%). Moreover, simple butanamide and pentanamide and γ- and δ-branched amides provided enantioenriched β-borylated products exclusively.

In 2021, the Xu group reported another elegant method for the enantioselective C(sp3)–H borylation of unbiased methylene centers (Scheme [17]).[50] This method used modified chiral boryl ligand L16 and [Ir(cod)OMe]2 for the reaction of N-alkylpyrazoles, in which pyrazole is a directing group and mainly responsible for the high enantio- and regioselectivity. The optimized chiral boryl ligand L16 contained a phenyl ring substituted with three cyclohexyl groups and this gave good yields and enantioselectivities of up to 98% ee, however attempts to fine-tune the pyridine ring resulted in lower yields and ees. 3,5-Dimethyl-1-propyl-1H-pyrazole was selected as a test substrate for the optimization process and the protocol that was developed selectively borylate it at the β-position with respect to the nitrogen center of the pyrazole. All the borylated compounds were isolated after in situ oxidation to the hydroxyl compounds in good yields and excellent enantioselectivities. The method tolerated a wide range of functional groups such as Me, NO2, Br, and CO2Et at C4 of the pyrazole (R′) along with branched and linear alkyl chains ranging from four to eighteen carbon atoms. The reaction of 1-(4-arylbutyl)- and 1-(3-arylpropyl)-3,5-dimethyl-1H-pyrazoles selectively gave the corresponding 4-aryl-2-hydroxybutyl and 3-aryl-2-hydroxypropyl products, reaction at the β-position and not at the benzylic position, with high ee (89–94%) while 1-phenethyl-3,5-dimethyl-1H-pyrazole gave the 1-(2-hydroxy-2-phenylethyl product, in which the β-position is also the benzylic position, with low enantioselectivity (33%). The utility of the reaction was shown by various stereospecific transformations of both the C–B bond and pyrazole group of the borylated products.

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Scheme 17 Ir-catalyzed enantioselective C(sp3)–H bonds borylation using pyrazole-based directing group

In 2021, our group developed a general method for the C–H borylation of substrates containing more than 35 different types of functional groups (Section 2, Scheme [8]).[42] The catalytic system developed was also effective for pyridine-directed aliphatic C–H borylations. Reaction of 2-pyrrolidino-, 2-piperidino-, and 2-(azepan-1-yl)pyridines and -pyrimidines gave the products of aliphatic C–H borylation while 2-[benzyl(methyl)amino]pyridines reacted at the primary methyl group and not at the more reactive benzylic position (Scheme [18]). The reaction of 2-pentylpyridine gave the 2-Bpin-pentyl product in 59% yield. This type of pyridyl substrates also gave aliphatic borylation with a silica-SMAP ligand[46] [51] and an enantioselective version with a phosphine ligand.[29] [52]

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Scheme 18 Ir-catalyzed C(sp3)–H borylation using pyridyl-thiophene ligand

# 4

Conclusions

In this short review, we have focused on recent advances in directed C(sp2)–H and C(sp3)–H borylations implemented by heterobidentate ligand (P/N–Si, N–B, and N–C) coordinated iridium catalysts and their application to address the site-selective borylation of diverse classes of arenes and enantioselectivity issue of aliphatic substrates. The regioselectivity is achieved by the coordination of the functional group of the substrate with an active iridium catalyst which contains two vacant coordination sites, one for functional group coordination and the other for the C–H activation. Whereas enantioselectivity is achieved mainly by the use of the chiral N,B-bidentate boryl ligated iridium active catalyst, which generates the chiral environment around the catalyst to differentiate one enantiomer over the other. These developed strategies offer an illustration of similarly extensive use of the design of attractive heterobidentate ligands to control the positional selectivity of the iridium-metal catalyzed C–H borylation. We hope that the methodologies described in this review for the directed C–H borylation of the C(sp2)–H and C(sp3)–H borylation will encourage the future design of the new catalytic system for iridium-catalyzed borylation.


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Conflict of Interest

The authors declare no conflict of interest.


Corresponding Author

Buddhadeb Chattopadhyay
Center of Biomedical Research, Division of Molecular Synthesis & Drug Discovery
SGPGIMS Campus, Raebareli Road, Lucknow 226014, Uttar Pradesh
India   

Publication History

Received: 07 March 2022

Accepted after revision: 04 April 2022

Accepted Manuscript online:
04 April 2022

Article published online:
16 May 2022

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Buddhadeb Chattopadhyaywas born and raised in Insura-Hooghly, West Bengal. He obtained his B.Sc. (2001) in chemistry from the Burdwan University and M.Sc. (2003) in chemistry from Visva-Bharati University. He completed his Ph.D. in 2019 with Professor K. C. Majumdar. Buddhadeb spent around six years as a postdoctoral research associate in the USA at the University of Illinois at Chicago, with Professor Vladimir Gevorgyan and Michigan State University, Michigan, with Professor Milton R. Smith. In August 2014, he moved to the Centre of Biomedical Research (CBMR) Lucknow, India as an Assistant Professor (Ramanujan Fellow) and he was promoted to Associate Professor in November 2019. His research interest includes metal-catalyzed C–H borylation chemistry (catalyst/ligand engineering) via noncovalent interaction and radical activation chemistry via denitrogenative annulation to obtain high value N-heterocycles. He is the recipient of Thieme Chemistry Journal Award (2017) and SERB-STAR Award (2019) for Science and Technology Research.
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Scheme 1 Two general methods for the synthesis of boryl compounds
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Scheme 2 Mechanisms of the bipyridine ligated Ir-catalyzed borylation reaction
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Scheme 3 Heterobidentate P/N–Si coordinated Ir-catalyzed borylation of arenes
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Scheme 4 Double N,B-bidentate ligand meditate nondirected borylation
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Scheme 5 Mono-N,B-bidentate ligated Ir-catalyzed directed borylation
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Scheme 6 Amine-directed enantioselective borylationby using chiral N,B-bidentate ligated Ir catalyst
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Scheme 7 ortho-Borylation using air stable S–Si ligand
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Scheme 8 Catalyst development for the directed borylation
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Scheme 9 Ir-catalyzed C–H borylations using PYT ligand
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Scheme 10 Borylation under atmospheric conditions using CB2 catalyst
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Scheme 11 Plausible mechanism of borylation using CB2 catalyst
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Scheme 12 Enantioselective Ir-catalyzed C–H borylation
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Scheme 13 Ir-catalyzed amide directed alkane borylation using N–Si ligand
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Scheme 14 Ir-catalyzed enantioselective C(sp3)–H borylation of cyclopropanecarboxamides using chiral bidentate boryl ligand
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Scheme 15 Enantioselective α-C(sp3)–H borylation of various azacycles by chiral N,B-boryl ligated Ir catalyst
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Scheme 16 Ir-catalyzed enantioselective β-C(sp3)–H borylation acyclic amides
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Scheme 17 Ir-catalyzed enantioselective C(sp3)–H bonds borylation using pyrazole-based directing group
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Scheme 18 Ir-catalyzed C(sp3)–H borylation using pyridyl-thiophene ligand