Easily available click ligands enable iridium-catalysed aromatic C–H borylation with proximal selectivity: the critical role of solvent and B₂pin₂ in catalyst modification under operando conditions

Abstract

Transition metal-catalyzed C–H functionalization provides a powerful platform for the efficient synthesis of complex molecules, with iridium-catalyzed C–H borylation representing a cornerstone of this field. Fine-tuning N,N-chelating ligands effectively controls remote selectivity in aromatic substrates, whereas achieving proximal (ortho) selectivity typically requires preformed iridium complexes or highly sophisticated, air-sensitive ligands. Herein, we report a convenient and modular synthesis of sustainable ligands via cost-effective copper-catalyzed click chemistry. Although the resulting pyridyl–triazolyl ligands are in principle designed for neutral N,N-chelation, they preferentially adopt an anionic N,C-chelating mode under catalytically relevant conditions. This behavior arises from triazolyl proton abstraction promoted by excess bis(pinacolato)diboron (B₂pin₂) and the use of polar, coordinating solvents. Control experiments, spectroscopic analysis, and kinetic studies support this mechanistic scenario. As a consequence, sterically demanding substrates, including phthalimides and related carbonyl-containing aromatics, undergo efficient proximal C–H borylation. Overall, this work underscores the importance of catalyst structural evolution under reaction conditions and highlights a general design principle that may apply to other transition metal-catalyzed atom-economical processes.

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Introduction

Transition metal-catalysed C–H functionalization has expanded rapidly, enabling efficient access to complex molecules from minimally functionalized substrates.^1–6 As a result, atom- and step-economical strategies continue to enrich the synthetic toolbox.^7–12 Further expansion of chemical space requires a detailed understanding of catalyst behaviour to anticipate and control reactivity, particularly to modify established selectivity patterns and to improve catalyst activity and stability.

In this context, iridium-catalysed C–H borylations have been widely studied and applied in the pharmaceutical industry and academia since the pioneering discoveries from Ishiyama, Hartwig and Miyaura.^13–17 They demonstrated the suitability of N,N-chelating ligands to form catalytically active iridium-tris-boryl species to achieve C–H borylations at the most sterically accessible site of the molecule of interest, similarly to P,P-chelating ligands.¹⁸ The last few decades have witnessed the boost of the field with the rational design of different classes of ligands in order to achieve highly efficient regio-, enantio- or stereo-controlled iridium-catalysed C–H borylations^19–22 due to the versatile post-functionalization of boron-containing groups.^23–25

In the case of aromatic C–H borylations, remote attractive interactions between substrates and catalysts have been mastered for controlling the meta/para selectivity with modified versions of bipyridine ligands being of choice.^26–36 On the other hand, achieving ortho selectivity in iridium-catalysed aromatic C–H borylations is not trivial because it is sterically less accessible and requires, initially, the use of monodentate ligands derived from arsenic or fluorinated phosphines as shown by Miyaura (Fig. 1, top).^36,37 Further research led to the use of highly sophisticated and air-sensitive P-, Si- and B-containing heteroditopic ligands L1–L4 developed, independently, by Maleczka & Smith,^38–40 Li,⁴¹ and Xu^42–46 (Fig. 1, top), which are accessible via energetically demanding cryogenic chemistry (i.e. organolithium reagents) and are postulated to behave as anionic ligands upon coordination to iridium (Ir-1, Fig. 1, top). Equally efficient is the strategy relying on the beforehand preparation of well-defined iridium complexes such as Ir-PTY, which consists of a S-containing N,C-chelating ligand (PTY) that is prepared via costly palladium-catalysed cross-coupling chemistry by Chattopadhyay's group⁴⁷ or the bis-cyclometallated iridium catalysts Ir-BCM developed by Wencel-Delord and Smejkal (Fig. 1, top).^48,49 Alternatively, and beyond Sawamura's heterogeneous system,⁵⁰ Mascarenas (L5, Fig. 1, top),⁵¹ Reek,⁵² and others,^53,54 independently, reported iridium-catalysed ortho-C–H borylation with attractive remote interactions between the substrate and the catalyst claimed to explain the selectivity.

Fig. 1 State-of-the-art of the iridium-catalysed ortho-C–H bond borylation in aromatics (top) and the current strategy based on click ligands including mechanistic considerations and applicability (bottom). FG = functional group amenable to transient coordination with the iridium centre, Ar = aryl, B = (boron)pinacolato, Ar¹ = p-^tBu-C₆H₄, Ar² = p-NR₂-C₆H₄ (R = Et and Pr), COD = 1,5-cyclooctadiene, X = CO or H, and Y = NR₂, R, or OR.

It appears obvious that a major issue for the broad implementation of iridium-catalysed C–H borylations is the affordability of ligands that form highly powerful iridium catalysts. Consequently, aiming at diversifying the structural nature of the ligand frameworks while simultaneously broadening the accessibility for ligands enabling challenging ortho-selective C–H borylations under iridium catalysis, we anticipated that click ligands L* (Fig. 1, bottom) formed via copper-catalysed azide–alkyne cycloadditions (CuAAC), also known as click chemistry, may represent a unique entry.^55–57 These click ligands are straightforward to access using catalysts based on more abundant and affordable copper while increasing molecular diversity and upgrading chemical stability.^58–61 In addition, based on the fact that the triazolyl core features a relatively acidic C–H bond^62,63 comparable to that found in thiophenes^64,65 such as in ligand PTY,⁴⁷ we anticipated that in situ proton abstraction may lead to anionic L,X-type ligands prone to chelate iridium.^66,67 In this respect, we herein demonstrate, for the very first time, that bis(pinacolato)diboron (B₂pin₂) behaves as both a borylating agent and mediator in proton abstraction at the click ligand in the presence of iridium, thereby forming the active iridium(III)-bis-boryl species Ir-L* (Fig. 1, bottom) under operando conditions according to in-depth mechanistic investigations. Such a unique event, which takes place under conditions relevant to catalysis, is further strongly facilitated by the nature of the solvent, being polar coordinating ones such as THF, 1,4-dioxane or bio-sourced 2-MeTHF of choice.

Moreover, we herein tackle the proximal C–H borylation of phthalimides,⁶⁸ useful difunctionalized aromatics that are key intermediates for the further elaboration of biologically-relevant scaffolds as well as promising dyes, porous solids, and polymers.^69–72 Such a class of substrates, which are based on a benzene core 1,2-doubly fused with a small five-membered imide ring, are extremely challenging to activate at the proximal C–H site because the postulated key C–H-activated iridacycle intermediate will have to overcome a highly strained 130° angle between the carbonyl directing group, the iridium centre and the proximal C–H site (Fig. 1, top). In this respect, Xu and co-workers reported the sole example of proximal, enantioselective C–H borylation of prochiral N-arylphthalimides comprising bulky substituents in the ortho position of the aryl units using the highly elaborated ligand L6 (Fig. 1, top).⁷³ In a complementary manner, the herein reported click ligands compare well in terms of activity and selectivity for phthalimides beyond N-aryl-substituted patterns (Fig. 1, bottom). The applicability of the herein developed click ligands in iridium-catalysed proximal C–H borylation is further demonstrated to other synthetically useful carbonyl-containing aromatic substrates operating under relatively short reaction times compared to current state-of-the-art catalytic systems (Fig. 1, bottom). This work gives a glimpse that structural ligand modification during catalysis, promoted by both reagents and solvents, is beneficial and does not lead to undesired catalyst deactivation pathways, thereby underlining the importance and challenge of identifying the truly active species under operando conditions in metal-catalysed C–H bond functionalization.^74,75

Results and discussion

Preparation of a library of click ligands and activation mode at iridium

In order to develop a library of click ligands with different steric and electronic properties around a sigma donor 2-pyridyl motif, ligands A–F were accessed by reacting the corresponding alkynes (phenylacetylene or 2-pyridylacetylene) with 2-azido-pyridyl derivatives using copper catalysts, namely Cu(PPh₃)₃Br and Cu(OTf)₂ (Scheme 1, left).^76–78 This methodology also made possible to obtain ligand G in which the triazolyl core is flanked by two phenyl groups. An alternative two-step strategy was more convenient to prepare ligands H–N (Scheme 1, right), which is based on the formation of key 1-tosyl-1H-1,2,3-triazolyl derivatives under copper catalysis followed by a nucleophilic addition to bench stable pyridine-N-oxide reagents.^79–83 As such, a convenient library of 14 click ligands was straightforward prepared by means of a cheap and sustainable key copper-catalysed azide–alkyne cycloaddition (CuAAC).

Scheme 1 Stepwise build-up of a library of click ligands (A–N) under CuAAC catalysis (for details, see the SI) including SCXRD of A (CCDC 2480983, left) and K (CCDC 2480984, right) and the N-oxide precursor of N (CCDC 2480985, middle – ORTEP drawings with thermal ellipsoids at 50% probability; selected hydrogen atoms are omitted for the sake of clarity). Ts = p-toluene sulfonyl.

Furthermore, we obtained single crystals suitable for X-ray diffraction (SCXRD) studies for two of these ligands (A and K, Scheme 1), which revealed an almost perfect co-planarity between the (hetero)aromatic rings and the triazolyl core with relatively small dihedral angles of 4.5° and 13.2° in A and 11.5° and 14.6° in K. In addition, the nitrogen atom from the 2-pyridyl ring faces the hydrogen atom from the triazolyl core with N⋯H–C short distances of 2.66 Å for click ligand A and 2.71 Å for click ligand K (Scheme 1). Solution NMR studies performed by means of ¹H–¹H NOESY experiments with ligand K in THF-d₈ solvent revealed a strong correlation between the hydrogen atom from the triazolyl C–H bond and the ortho-hydrogen atoms of the phenyl fragment (Scheme 1, right), thereby strongly supporting that the thermodynamically stable conformation observed in the solid state persists in solution as well.⁸⁴ This observation is likely the consequence of a destabilization effect for the opposite scenario in which the pyridyl ring rotates and its nitrogen lone pair faces the lone pair from the central nitrogen atom of the triazolyl core. It is worthy to note that the nitrogen lone pair from the pyridyl ring and the carbon lone pair that could result from the C–H abstraction at the triazolyl core are well pre-organized within these click ligands to undergo potential L,X-chelation towards an iridium metal centre.

Next, we evaluated the coordinating ability of the click ligands to iridium under operando conditions, namely conditions relevant for C–H bond borylation. For that, click ligand A was reacted with [Ir(COD)OMe]₂ (COD = 1,5-cyclooctadiene), which is the archetypical pre-catalyst employed in iridium-catalyzed C–H borylations, using undistilled THF-d₈ as the solvent (Fig. 2). In contrast to Chattopadhyay's ligand PTY that does readily undergo iridacycle formation at room temperature in THF solvent in the absence of B₂pin₂ (Ir-PTY, Fig. 1, top),⁴⁷ no reactivity was observed with click ligand A (Fig. 2, top), thereby indicating the less acidic character of the triazolyl C–H bond in A with respect to the α-thiophenyl C–H bond in PTY. On the other hand, upon addition of 10 equivalents of B₂pin₂ and heating at 65 °C, which are conditions that are employed in iridium-catalyzed C–H borylations, the proton signal from the C–H triazolyl core at δ = 9.5 ppm vanished (Fig. 2, bottom) with concomitant formation of signals ascribed to the iridium-coordinated COD ligand (δ = 5.6 ppm) and the borylated side-products, namely (HO)Bpin (δ_H = 6.7 ppm and δ_B = 22.4 ppm) and O(Bpin)₂ (δ_B = 21.3 ppm), according to ¹H and ¹¹B{¹H} NMR spectroscopy studies (Fig. S1–S7 in the SI), resulting from HBpin degradation due to the presence of water traces in the solvent.

Fig. 2 Formation of Ir-A species under operando conditions inferred by ¹H NMR spectroscopy and HR-MS studies.

In addition, HR-MS studies on this mixture revealed the formation of Ir-A species (m/z = 777.3329) involving the presence of two Bpin units and a deprotonated, anionic click ligand A engaged in N,C-chelation to iridium also bound to a COD ligand (Fig. S2 in the SI). The presence of [(OH)(MeO)(Bpin)₂] species was also evidenced by HR-MS studies (Fig. S2 in the SI). We noted that click ligand A did not react with B₂pin₂ (10 equiv.) unless [Ir(COD)OMe]₂ was later added to the reaction mixture (Fig. S1 in the SI). These findings strikingly contrasts to the fact that click ligand A does readily undergo N,N-chelation at iridium in toluene solvent as reported by us previously.^34,35,54 As such, the nature the solvent, here THF, strongly influences the coordination of click ligand A to iridium under operando conditions.

In order to study whether this behaviour is general to other click ligands, HR-MS studies were performed by combining click ligand I, the iridium precursor [Ir(COD)OMe]₂ and B₂pin₂ in THF-d₈ solvent at 65 °C (Scheme 2). Besides some signals resulting from mono-, bis- and tris-borylation of the click ligand, two major signals belonging to iridium species were identified (Fig. S8 in the SI). The first one, namely Ir-I, at m/z = 841.3636 corresponded to [(I)Ir(Bpin)₂(COD)] (m/z = 841.3649) that could exist as a 16 and/or 18 electron complex depending on whether the COD ligand is engaged in η²- or η⁴-coordination to iridium (Scheme 2). The second iridium species at m/z = 966.4527 was consistent with Ir-I species being borylated at the click ligand or at the COD ligand. In addition, ¹H NMR studies also supported the formation of COD-ligated species (δ = 4.9–5.6 ppm) although multiple species were present most likely due to formation of conformers and/or the variable hapticity of the COD ligand when coordinating to iridium (Fig. S3–S8 in the SI).

Scheme 2 Formation of Ir-I species under operando conditions inferred by ¹H NMR spectroscopy and HR-MS studies.

The role of click ligands in tuning the regio-selectivity of iridium-catalysed C–H borylation of carbonyl-containing aromatic substrates

With a library of click ligands with diverse steric and electronic features in hand, and after effectively disclosing their unique coordinating ability to iridium as L,X-ligands under operando conditions, we screened their potential in the iridium-catalysed proximal C–H borylation of phthalimides that feature completely different substitution patterns compared to Xu's contribution with ligand L6 (Fig. 1, top and Table S5 in the SI).⁷³ We first focused on the iridium-catalysed C–H borylation of N-methylphthalimide (1a) as a benchmark model, which can lead to proximal or distal borylated products 2a and 3a, respectively (Scheme 3). It is relevant to note that proximally-borylated 2a constitutes a key intermediate for the elaboration of biologically-relevant aristolactam alkaloids.⁸⁵

Scheme 3 Evaluation of ligands in the iridium-catalysed C–H borylation of N-methylphthalimide (conversion of 1a in percentage and the ratio of 2a : 3a are displayed in brackets after being determined by GC analysis using dodecane as an internal standard).

The reaction conditions applied consisted of 4 mol% of the ligand, 2 mol% of the [Ir(COD)OMe]₂ precursor and two equivalents of B₂pin₂ in freshly distilled THF at reflux for 48 hours (Scheme 3). As expected, using 4,4-di-tert-butyl-2,2′-bipyridine (dtbpy) or phenanthroline (phen) as the ligands, independently, exclusively led to the distal C–H borylated product 3a in quantitative yield in agreement with a highly favourable C–H activation event taking place at the most sterically accessible site in the substrate with a preference for the aromatic site over the N-methyl site, further corroborating the ease of reactivity under non-directed conditions.^86,87 Unexpectedly, using benzo[h]quinoline (bzq), which is structurally related to phen but with a nitrogen atom swapped by a CH group, increased the ratio of proximal borylated product 2a to a promising 20% although with a low conversion of 51%. Similar results were observed with 2-phenylpyridine (ϕ-py) and to a less extent with 2-ethylpyridine (Et-py). For comparison purposes, Chattopadhyay's PTY ligand was utilized and it afforded 63% conversion and a percentage ratio of proximal versus distal of 26 : 74. Interestingly, using click ligands such as A gave rise to superior amounts of proximal borylated product 2a up to 35% yield with a decent 79% conversion of 1a. Remarkably, click ligand B that contains a 2-methyl substituent in the pyridyl ring completely reversed the regioselectivity, leading to proximal 2a as the major product (60%), thus indicating that the substitution pattern in the pyridyl ring profoundly impacts the regioselectivity outcome in the iridium-catalysed C–H bond borylation. However, introducing different steric and electronic patterns in position 4 of the pyridyl ring (click ligands C–E) eroded the regioselectivity in favour of the distally-borylated product 3a (91–96%). Click ligand F, which contains two 2-pyridyl substituents around the triazolyl core afforded only the distally-borylated product 3a. These findings suggest that click ligands C–F can also behave as N,N-chelators or mono-dentate ligands, leading to L,L-type iridium tris-boryl species (Scheme 11, top), which are more reactive than the L,X-type iridium species when exposed to a substrate such as 1a that requires to reach a highly-demanding iridacycle intermediate with a 130° between the functional group, the iridium centre and the CH site for enabling proximal selectivity (Fig. 1, top).

Surprisingly, click ligand G, which contains no pyridyl unit, outperformed click ligand A, leading to 43% of proximal borylated product 2a although with a modest conversion of 1a (61%). Click ligand H, in which the triazolyl core is linked to a quinoline unit, slightly outperformed click ligand B in terms of conversion (67%) and the formation of proximal borylated product 2a (65%). Following this trend, click ligands I–M (Scheme 3, framed), which feature a bulky 8-methylquinoline unit linked to the triazolyl motif, revealed, gratifyingly, the highest conversions (up to 87%) with the proximal borylated product 2a formed in up to 76% yield with minimal influence of the substitution pattern at the quaternary carbon atom from the triazolyl core. Click ligand N that bears a 7,8-benzoquinoline motif did not surpass the activity or selectivity of click ligands I–M. Modification of reaction conditions (temperature, solvent, concentration, and variation of the stoichiometry of reagents) when using the most active and selective click ligands I–M (Scheme 3, framed) did not afford higher conversions nor improved proximal selectivity (Tables S1–S4 in the SI). We also noted that the reaction did not take place in the absence of the iridium precursor nor in the absence of the ligand. Other borylating reagents instead of B₂pin₂ such as HBpin, bis(neopentyl glycolato)diboron or bis(catecholato)diboron were tested but led to very low conversions not exceeding 30%.

The reactivity of diversely-functionalized phthalimide substrates was further evaluated using click ligand I, which gave a good balance of conversion/selectivity under iridium-catalysed C–H borylation conditions, leading to proximally-borylated products 2 while being only based on C, H, and N atoms (Scheme 4). The number of equivalents of B₂pin₂ was adjusted to 1.2 after slight fine-tuning of the reaction conditions in order to reduce undesired bis-borylated side-products (Tables S1–S4 in the SI). Due to the experimental difficulty of isolating some of the Bpin-containing products 2 derived from phthalimides, we also provided the isolated yields for the boronic acid post-functionalized products in Scheme 4.

Scheme 4 Substrate scope evaluation of click ligand I-controlled iridium-catalysed C–H borylation for proximal selectivity with phthalimides. ^a Conversion of 1 and product selectivity in brackets for 2 (2 : others) were determined by GC analysis using dodecane as an internal standard. ^b Isolated yield as the corresponding boronic acid derivative after purification by silica column chromatography.

The catalysis was tolerant to alkyl groups as shown in the reactivity of N-methylphthalimide that afforded the proximally borylated product 2a in 70% selectivity and it was isolated as the corresponding boronic acid in 47% yield. Similar observations were encountered for the reactivity of N-(p-tolyl)phthalimide 1b, in which no C–H borylation took place in the p-tolyl unit. 1-Naphthylphthalimide 1c was borylated in the proximal position in an excellent 92% selectivity and 67% isolated yield with no detectable C–H borylation at the naphthalene core besides the presence of seven additional aromatic C–H bonds. Phthalimides containing synthetically useful handles such as ester and ether groups were tolerated and reacted with conversions in the range of 76–84% as shown in the formation of 2d and 2e in 68% and 73% selectivity, respectively. Remarkably, the N-unprotected phthalimide 1f was converted in 71% yield with a selectivity of 80% for the borylated product 2f in the proximal position, thereby evidencing no catalyst inhibition effect by the unprotected NH imide group. The reaction was compatible with fluorinated groups as shown in the high conversion (85%) of 1g, leading to the proximal borylated product 2g in 60% selectivity. Probing the reactivity of N-methylisoindolinone and phthalic anhydride resulted in a mixture of unidentified products as it was observed with iodine- and alkyne-containing substrates (Scheme 4 and Chart S1 in the SI). Overall, click ligand I appears complementary to Xu's ligand L6 (Fig. 1) in order to perform iridium-catalysed proximal C–H borylation of phthalimides beyond N-aryl substitution patterns. Note that proximal iridium-catalysed C–H borylation with larger perylene diimides or 1,2-doubly-fused six-membered rings are known.^88–90

Moreover, the regio-selectivity of the click ligand I-controlled iridium-catalysed C–H borylation of phthalimides was unambiguously confirmed by SCXRD performed with the hydroxylated derivatives 4a and 4f obtained from oxidative post-functionalizations of 2a and 2f, independently, upon treatment with oxone, respectively (Scheme 5).

Scheme 5 Sequential iridium-catalysed C–H borylation and oxidative post-functionalization of phthalimides 1a and 1f (top) and SCXRD of proximal hydroxylated derivatives 4a (CCDC 2480986) and 4f (CCDC 2480987), respectively (ORTEP drawings with thermal ellipsoids at 50% probability, bottom).

Furthermore, the click ligand-controlled proximal C–H borylation under iridium catalysis was compatible with other useful carbonyl-containing aromatic substrates. Importantly, it was possible to replace click ligand I by click ligand A, whose synthesis implies a single step, with equal efficiency in terms of activity and selectivity for the proximal iridium-catalysed C–H borylation of these substrates (Scheme 6). Applying the optimal, iridium-catalysed borylating reaction conditions with click ligand A to acetophenone (1h), methylbenzoate (1i) and N,N-dimethylbenzamide (1j) as substrates, respectively, led to virtually quantitative conversions and exclusive proximal, ortho-selectivity with the corresponding borylated products 2h, 2i and 2j isolated in 87–94% yields in short reaction times of 3–4 hours. The click ligand-controlled iridium-catalysed C–H borylation was also tolerant to benzyl ether groups (2k), thus indicating that the carbonyl group from the amide is a better directing group than the oxygen from the ether group as further corroborated by the lack of reactivity found for anisole when used as the substrate (Chart S1 in the SI) and without any detectable borylation in the aromatic benzylic site. Moreover, useful halogen functional groups such as fluoride, chloride and bromide were compatible with the catalysis as demonstrated in the quantitative formation of ortho-borylated products 2l, 2m and 2n in 77–96% isolated yields. For the case of the meta-substituted starting materials 1m and 1n, we noted that the reaction did not occur in the C–H bond flanked by the amide and the halide group, but in the most sterically accessible ortho-C–H site. The stability of these compounds made possible to isolate them as the corresponding Bpin-containing products.

Scheme 6 Substrate scope evaluation of the click ligand A-controlled iridium-catalyzed C–H borylation for proximal ortho-selectivity with carbonyl-containing aromatics. ^a Conversion of 1 and product selectivity in brackets for 2 (2 : others) were determined by GC analysis using dodecane as an internal standard. ^b Isolated yield after purification by silica column chromatography. ^c 3 hours of reaction time.

For comparison purposes, we performed the catalysis for substrates 1h–1j, respectively, by replacing click ligand A for Chattopadhyay's PTY ligand. In this case, although exclusive ortho-selectivity was achieved, the conversions dropped to <60% after 4 hours of the reaction time (see the SI). Overall, the iridium-catalysed C–H borylation of carbonyl-containing substrates using click ligands outperforms the current state-of-the-art ligands (Tables S6–S8 in the SI). We also found that the catalysis was not compatible with unfunctionalized, primary benzamide nor aniline (Scheme 6), whilst a mixture of unidentified products was observed when employing methyl phenyl sulfone as the substrate (Chart S1 in the SI). Chlorobenzene, N,N-dimethylaniline and (L)-phenylalanine, respectively, did not react under these reaction conditions (Chart S1 in the SI). Note that statistical mixtures of meta- and para-borylated products are known to form with iridium catalysts based on classical N,N-chelating ligands such as bpy, dtbpy and phen.^{26–28,50–54} To further demonstrate the applicability of the click ligand-controlled iridium-catalysed C–H borylation, a scale-up experiment was carried out with more than 2 mmol of methylbenzoate 1i (Scheme 7). This time, the catalyst loading was reduced to only 1 mol% of [Ir(COD)OMe]₂ and 4 mol% of click ligand A at 80 °C using 2-MeTHF as the green solvent.⁹¹ After 6 hours, full conversion was observed with exclusive ortho-selectivity and the borylated product 2i was isolated in 85% yield, which corresponds to more than 500 mg.

Scheme 7 Scale-up experiment for the click ligand A-controlled iridium-catalysed C–H borylation of 1j using 2-MeTHF as the green solvent.

Postulated nature of the catalytically-active iridium species: role of the solvent and influence of the substrate

In the case of acyclic carbonyl-containing substrates such as acetophenone (1h), methylbenzoate (1i) and N,N-dimethylbenzamide (1j) (Fig. 3, top), the use of relatively polar and potentially metal-coordinating solvents (THF, 1,4-dioxane or 2-MeTHF) strongly favours the formation of the ortho-C–H borylated products 2h–2j regardless of the nature of click ligand A or I (Fig. 3, top). These findings together with the above-described coordination chemistry studies with click ligands (vide supra) strongly support the formation of N,C-chelating bis(boryl)iridium species Ir-L* under operando conditions, namely excess of B₂pin₂, when using THF as the solvent (Scheme 8). Indeed, N,C-chelating bis(boryl)iridium Ir-L* species, with a vacant site at iridium, should allow the transient coordination of the carbonyl group of the substrate to the iridium prior C–H activation (Fig. 3, top). On the other hand, an apolar non-coordinating solvent such as p-xylene afforded, besides the main formation of the ortho-borylated product 2h (95%), non-negligible trace amount of the distally borylated product 3h at the expenses of a poor conversion below 40% with the click ligands (Fig. 3, top). This is rationalized by the fact that N,C-chelating bis(boryl)iridium Ir-L* species are formed under operando conditions but in little amounts, thanks to the presence of additional, small quantities of the coordinating COD ligand that may play a similar role as the THF solvent in transiently stabilizing catalytically productive iridium intermediates. In this case, with an apolar solvent, N,N-chelating tris(boryl)iridium species Ir′-L* (Scheme 8), responsible for the non-directed C–H borylation leading to the products 3h–3j, are also formed but to a much less extent or either they are less reactive than the N,C-chelated species Ir-L*. Due to the fact that the carbonyl-containing substrates feature a standard 120° angle between the carbonyl group and the ortho-C–H bond (Fig. 3, top), it is reasonable to postulate that the reaction intermediates responsible for ortho-selectivity that are also involved in the coordination of the carbonyl group of the substrate to the iridium are rather accessible (Ir-1*, Fig. 3, bottom), which makes these reactions relatively fast (3–4 hours with 2 mol% of the iridium dimer pre-catalyst, Scheme 6).

Fig. 3 Comparative study of the iridium-catalysed C–H borylation of acyclic carbonyl-containing aromatics (top) and bicyclic phthalimide (middle) with different click ligands (A and I) and solvents of different natures: polar, coordinating versus apolar, non-coordinating, and plausible transition state intermediates for the iridium-mediated C–H activation step depending on the nature of the carbonyl-containing aromatic substrate (bottom). B = (boron)pinacolato.

Scheme 8 Postulated mechanism for both solvent- and B₂pin₂-mediated click ligand C–H abstraction under operando conditions towards the formation of N,C-chelating bis(boryl)iridium species Ir-L*. B = (boron)pinacolato and S = THF or COD.

Alternatively, when considering phthalimides, which display a larger ca. 130° angle between the carbonyl group and the proximal C–H bond (Fig. 3, middle), the difference of reactivity is remarkable when comparing click ligands A and I in the presence of polar, metal-coordinating solvents (Fig. 3, middle). Although both click ligands are expected to form N,C-chelated bis(boryl)iridium species Ir-L* (vide supra), ligand I appears to be more suitable than A to further accommodate the reaction intermediates responsible for carbonyl-directed proximal C–H borylation with 2a, forming in >70% yield. The expected highly strained intermediates associated with the proximal C–H borylation of phthalimides (Ir-1**, Fig. 3, bottom) have also to compete with the likely presence of small amounts of N,N-chelating tris(boryl)iridium species Ir′-L* (Scheme 8) responsible for distal selectivity (3a). This is further indirectly corroborated by the fact that click ligands A and I exclusively lead to non-directed distal C–H borylation when using an apolar, non-coordinating solvent such as p-xylene yet with low conversion below 30% (Fig. 3, middle). Consequently, click ligands can be considered as ambiphiles as they can switch from neutral N,N-chelators to anionic N,C-chelators to iridium depending on the nature of the solvent and the reaction conditions.

In short, all these observations are compelling with the fact that THF or COD are at the origin for enabling eventual decoordination at Ir′-L* species of the triazolyl nitrogen atom from the click ligand followed by roll-over at iridium.^92,93 Then, C–H abstraction at the triazolyl core takes place either via sigma-bond metathesis or via oxidative addition at iridium; in both cases, HBpin is released with additional stabilization by THF or COD ligands. In this manner, the N,C-chelated bis(boryl)iridium species Ir-L* might form with click ligands under operando conditions (Scheme 8), being them responsible for the observed proximal C–H bond borylation selectivity. Furthermore, and supported by the substrate scope evaluation (vide supra), the anionic click ligands formed under operando conditions led to very active iridium species for substrate-directed ortho-C–H borylation and underscores the challenge to perform proximal C–H borylation with more sterically-demanding phthalimides compared to acyclic carbonyl-containing substrates.

Mechanistic considerations of the iridium-catalysed C–H borylation with click ligands

As control experiments, we noted that N-phenylisoindoline and carbonyl-free aromatics such as ethylbenzene did not undergo iridium-catalysed C–H borylation using click ligands A or I (Scheme 9). These findings strongly suggest that substrate coordination to the iridium via the carbonyl group is a key event for enabling the highly efficient, ortho-C–H borylation in carbonyl-containing aromatic substrates, which is also in line with the observations encountered during the scope evaluation (vide supra).^94,95

Scheme 9 Control experiments of the unsuccessful iridium-catalysed C–H borylation of carbonyl-free substrates using click ligands.

To assess whether the C–H bond activation step is the rate-determining one, kinetic isotope effect (KIE) experiments were performed using the benzamide starting material (1j) and the penta-deuterated one (1j-d₅), respectively (Scheme 10).⁹⁶ From the two parallel experiments, a relatively high KIE of 2.13 was found in the initial hour of the catalysis (Fig. S9–S12 in the SI). The intermolecular competition experiment was less conclusive to analyze because of signals overlapping in the ¹H NMR spectrum yet an estimated KIE value in the range 1.6–2.4 was established (Fig. S13 and S14 in the SI).

Scheme 10 Kinetic isotope effect (KIE) determined from parallel reactions of substrates 1j and 1j-d₅.

In order to further study the reaction mechanism operating, in-depth kinetic studies were performed by performing both Blackmond's reaction progress kinetic analysis (RPKA) and Bures’ visual kinetic analysis (VKA) to the iridium-catalysed C–H borylation of N-methylphthalimide (1a) in the presence of click ligand I.^97,98 Although the reaction was not trivial to monitor due to the presence of non-negligible amounts of the distal borylated product 3a and bis-borylated side-products after 8 hours, acceptable curve fittings were obtained in the initial moments of the catalysis (Fig. S15–S29 in the SI). As a result, the reaction was found first order in iridium and in the substrate. The fact that the reaction order in B₂pin₂ was also one likely indicates that isomerization at the C–H activated iridium(V) complex Ir-b (Scheme 11) might be turnover-limiting.^99,100 These observations together with the KIE studies (vide supra) indicate that both C–H activation (Ir-a → Ir-b, Scheme 11) and isomerization at the C–H-activated iridium(V) complex Ir-b (Scheme 11) may have similar energetic barriers for their respective transition states, being not possible to differentiate at this stage which one is turnover-limiting. Further kinetic studies indicated that product inhibition instead of catalyst deactivation was taking place, which might account for the formation of bis-borylated side-products.

Scheme 11 Postulated reaction mechanism for proximal iridium-catalysed C–H borylation of carbonyl-containing aromatics using click ligands A and I and summary of kinetic studies with N-methylphthalimide 1a (framed). X = H or CO; Y = NR₂, R, or OR; S = THF or COD.

Considering all the above-stated findings and previous reports from the literature,^38–49 a plausible reaction mechanism is proposed in Scheme 11 for the iridium-catalysed C–H borylation using click ligands L*. Besides the fact that solvent plays a major role (vide supra), it is relevant to note that some click ligands such as C–F may give rise to tris(boryl)iridium species responsible for distal C–H borylation either via N,N-chelation or via two-fold monodentate coordination (Scheme 11, top). The other click ligands, and in particular A and I, undergo iridacycle formation upon abstraction of the triazolyl C–H bond and oxidative addition in the presence of excess of B₂pin₂, resulting in the formation of Ir-L* species that can be further stabilized by transient coordination of THF or COD to iridium as evidenced by NMR and HR-MS studies (vide supra, Scheme 11). Upon decoordination of the COD ligand or ligand exchange with the THF solvent, the substrate (1) coordinates to the iridium via the carbonyl group (Ir-a) and brings the proximal C–H bond at close proximity. Next, iridium-mediated C–H activation takes place, leading to iridium(V) species (Ir-b). Finally, reductive elimination at iridium allows C–B bond formation (Ir-c), leading to the ortho-borylated product (2), while B₂pin₂ regenerates the catalytically active iridium species. Note that we attempted the iridium-catalysed C–H borylation of N-methylphthalimide 1a with the preformed Ir-A species, leading to a similar regioselectivity as obtained with the ex situ approach yet with a low conversion likely due to the low stability of the Ir-A species (Scheme S1 in the SI).

Conclusions

In summary, we have reported the original action mode of click ligands L*, which are straightforward to prepare via sustainable copper-catalysed CuAAC click chemistry, in ortho-selective iridium-catalysed C–H bond borylation of synthetically useful carbonyl-containing substrates including phthalimides with high functional group tolerance. In contrast to previously reported ligands that contain heavy heteroatoms such as As, B, P, Si, F or S,^36–54 the click ligands herein developed rely on C, H, and N atoms, are air-stable and are easy to fine tune at different positions while leading to a unique co-planarity between the triazolyl core and the aromatic substituents. Such pre-organization together with the slight acidity of the triazolyl C–H bond enables the click ligands to behave as anionic ones, enabling L,X-chelation to iridium exclusively under operando conditions, namely an excess of the borylating agent with respect to the ligand/iridium loading with a polar-coordinating solvent (i.e. THF, 1,4-dioxane or bio-sourced 2-MeTHF), as supported by a number of experimental studies (NMR, HR-MS, and kinetics). This contribution highlights that ligands that contain C–H bonds close to 2-pyridyl motifs, which are omnipresent in iridium-catalysed C–H bond borylations, can potentially undergo C–H abstraction switching from neutral to anionic under catalytically relevant conditions, thereby raising questions about previously postulated reaction mechanisms for ortho-selectivity in iridium-catalysed C–H borylations.^51–53

Importantly, the overlooked additional role of both solvent and B₂pin₂ in enabling ligand modification under operando conditions is demonstrated, and such an action mode might be considered in the future design of more active and selective iridium catalysts for C–H bond borylations. Beyond solvent-controlled selective catalysis,^101–105 understanding the real nature of the active species under operando conditions and the precise chemical structure of the ligand should allow the rational design of a more powerful, future generation of catalysts for selective C–H borylation. Furthermore, structural ligand modification during metal-catalysed C–H bond functionalization beyond iridium catalysts could represent an interesting opportunity for the advancement of more atom-economical and efficient chemical processes.

Author contributions

Conceptualization: M. A. and R. G.-D.; data curation: V. D. and R. G.-D.; formal analysis: V. D., T. R., M. A. and R. G.-D.; supervision: S. D., M. A. and R. G.-D.; funding acquisition: S. D., M. A. and R. G.-D.; validation, visualization and investigation: V. D. and R. G.-D.; methodology: V. D. and T. R.; writing – original draft: V. D. and R. G.-D.; project administration: S. D., M. A. and R. G.-D.; writing – review and editing: V. D. and R. G.-D.

Conflicts of interest

There are no conflicts to declare.

Data availability

The dataset supporting this article has been uploaded as part of the supplementary information (SI). Supplementary information: experimental details for the preparation and characterization of click ligands, details of operando coordination chemistry to iridium (NMR and HR-MS), catalysis, kinetics, and details on isolation and characterization of the reaction products. See DOI: https://doi.org/10.1039/d6qi00270f.

CCDC 2480983 (A), 2480984 (K), 2480985 (precursor of N), 2480986 (4a) and 2480987 (4f) contain the supplementary crystallographic data for this paper.^106a–e

Acknowledgements

The CNRS, the University of Rennes and Ministère de l'Enseignement supérieur et de la Recherche (PhD grant to VD) are acknowledged for financial support. Jonathan Trouvé is acknowledged for the initial experimentation, and Elisa Travers and Kamil Kupietz are acknowledged for the synthesis of one starting material and for obtaining a single crystal suitable for X-ray diffraction studies, respectively.

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