Iridium-Catalyzed ortho-Selective Borylation of Aromatic Amides Enabled by 5-Trifluoromethylated Bipyridine Ligands

Homogeneous Catalysis Iridium-Catalyzed ortho-Selective Borylation of Aromatic Amides Enabled by 5-Trifluoromethylated Bipyridine Ligands Daniel Marcos-Atanes, Cristian Vidal, Claudio D. Navo, Francesca Peccati, Gonzalo Jiménez-Osés,* and José L. Mascareñas* Abstract: Iridium-catalyzed borylations of aromatic CH bonds are highly attractive transformations because of the diversification possibilities offered by the resulting boronates. These transformations are best carried out using bidentate bipyridine or phenanthroline ligands, and tend to be governed by steric factors, therefore resulting in the competitive functionalization of meta and/or para positions. We have now discovered that a subtle change in the bipyridine ligand, namely, the introduction of a CF3substituent at position 5, enables a complete change of regioselectivity in the borylation of aromatic amides, allowing the synthesis of a wide variety of ortho-borylated derivatives. Importantly, thorough computational studies suggest that the exquisite regioand chemoselectivity stems from unusual outer-sphere interactions between the amide group of the substrate and the CF3-substituted aryl ring of the bipyridine ligand. Introduction The catalytic functionalization of selected CH bonds in complex organic molecules is a formidable challenge.[1] Despite the impressive progress, the field is yet in its infancy.[2] Many of the efforts in this area have been focused on the functionalization of aromatic CH bonds owing to the synthetic relevance of the products, and the challenge of distinguishing very similar C(sp2)H bonds.[3] Among the different type of aromatic CH functionalization reactions, borylations are particularly attractive because of the versatility of the products.[4] A number of rhodium and, particularly, iridium-catalyzed borylation reactions have been studied.[5] These reactions are usually carried out using bidentate 2,2’-bipyridine (bipy) or 1,10phenanthroline ligands, IrIpre-catalysts, and bis(pinacolato)diboron (B2pin2) or pinacolborane (HBpin) as reactants. The accepted mechanism of the process involves a catalytic cycle with IrIII and IrVintermediates like those showed in Figure 1a, and a rate determining oxidative addition of the CH bond to the metal.[6] The regioselectivity is usually controlled by steric effects, which tend to favour the functionalization of meta and/or para positions in benzene derivatives.[7] Ortho-selective borylation of arenes are more challenging, even in precursors featuring a directing group (DG), because coordination of this substituent to complex Aleads to a fully saturated iridium complex (18 electrons) unable to participate in the oxidative addition step. Some groups have overcome this limitation by using monodentate phosphines,[8] or hemilabile bidentate ligands.[9] However, these ligands are usually less efficient than bipyridines and phenanthrolines in promoting the CH activation, and tend to favor the formation of off-cycle species.[10] Alternatively, the reactions can be performed using specifically engineered monoanionic bidentate L,X -type ligands, in which the anionic part (X) replaces one of the boron groups in intermediate A, and therefore coordination of the DG to the iridium atom is now possible.[11] Recently, some elegant strategies for the ortho borylation of electron rich aromatics based on non-covalent interactions between the Ir reagent and the substituent of the arene have been developed (Figure 1b).[12] These include hydrogen bond contacts (Figure 1b, B),[13] or electrostatic interactions between the oxygen of an OBpin group and the bipyridine ligand (C).[14] With some exceptions,[12b] substrates lacking substituents at the para position tend to give mixtures of products, presumably because the weak outersphere interactions do not fully override the intrinsic sterically-driven regiocontrol. Kuninobu and Kanai described the ortho borylation of phenyl thioethers, proposing a Lewis acid-base interaction between the S atom and either a boronate pendant, or the B atom of one of the Bpin groups attached to the iridium (Figure 1b, D,E).[15] [*] D. Marcos-Atanes, Dr. C. Vidal, Prof. Dr. J. L. Mascareñas Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CIQUS), and Departamento de Química Orgánica, Universidade de Santiago de Compostela 15782 Santiago de Compostela, A Coruña (Spain) E-mail: [email protected] Dr. C. D. Navo, Dr. F. Peccati, Dr. G. Jiménez-Osés CIC bioGUNE, Basque Research and Technology Alliance, BRTA Bizkaia Technology Park, 48162 Derio (Spain) E-mail: [email protected] Dr. G. Jiménez-Osés Ikerbasque, Basque Foundation for Science, 48013 Bilbao (Spain) © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is noncommercial and no modifications or adaptations are made. Angewandte Chemie Research Articles www.angewandte.org How to cite: International Edition: doi.org/10.1002/anie.202214510 German Edition: doi.org/10.1002/ange.202214510 Angew. Chem. Int. Ed. 2023, e202214510 (1 of 10) © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202214510 by Consorcio Interuniversitario Do Sistema Universitario De Galicia (Cisug), Wiley Online Library on [23/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License A very attractive type of substrates for CH bond borylation are benzamides, as they form the core of many compounds with valuable properties.[16] However, robust and versatile methods for the direct ortho borylation of different types of benzamides are scarce. Reek and coworkers described a tailored bipyridine derivative that is capable of inducing the ortho borylation of N-methyl and Nbenzyl benzamides (Figure 1c).[17] The strategy relies on an engineered bipyridine–indole ligand, and the scope is restricted to secondary amides. Very recently, Chattopadhyay and co-workers reported the use of monoanionic bidentate L,X-type ligands to promote ortho-selective CH bond borylation of a variety of benzamides.[11c] This approach is also compatible with substrates containing other directing groups. However, this poses a limitation to performing chemoselective transformations in complex settings where numerous functional groups are present. Indeed, in heteroaromatic substrates the directing effect of the carboxamide is overridden by the intrinsic electronics of the heterocycles. As part of our research in CH activation chemistry,[18] we have now discovered that introducing a CF3substituent in position 5 of a 2,2’-bipyridine ligand induces a complete change in regioselectivity in the borylation of aromatic amides from meta/parato ortho-selective. The change in selectivity by such a subtle change in a L,L-type of ligand is intriguing, and therefore we conducted a detailed experimental and computational study to uncover the underlying basis for the directing effect. Our results suggest that the selectivity originates from unusual non-covalent attractions between the benzamide group of the substrate and the bipyCF3ligand (Figure 1d). Results and Discussion Influence of the Bipyridine Substituents in the Borylation Our interest in this reaction was prompted by the observation that the borylation of N,N-dimethylbenzamide (1a) under iridium catalysis led to a different result when moving from the standard bipyridine ligand to one that contains a phenyl substituent at the 5 position of one of the pyridines. The reaction with the common ligands 4,4’-di-tert-butyl-2,2’- bipyridine (dtbpy, L1) and 2,2’-bipyridine (bipy, L2) produced a mixture of meta and para monoand diborylated products (Table 1, entry 1, 2).[19] However, using the phenyl containing ligand L3, we observed a small amount of the ortho-substituted product (entry 3), which further increased when using L5 (entry 5). Replacing the aryl by a methyl substituent in the bipyridine (L6, entry 6) led to a similar result than with 2,2’- bipyridine, whereas with halogen substituted bipyridines (L7 and L8) we observed a slightly higher ortho-borylation (entries 7, 8). Surprisingly, when a CF3substituent was introduced (ligand L9), we observed the exclusive formation of ortho monoand diborylated products (entry 9). Ligands with other electron-withdrawing substituents at position 5, such as L10 (C6F5) and L11 (CN), also afforded the orthoborylated compounds as the major products, but were less selective than L9, and the detected diborylated products consisted of mixtures of regioisomers (entries 10 and 11). With L12 (entry 12), featuring a CHF2substituent, we also observed mixtures, with partial ortho borylation. The perfluorinated derivative (L13, entry 13) and the symmetric ligand L14, with CF3substituents at the 5 positions of each Figure 1. a) Accepted mechanistic profile for the iridium-catalyzed borylation reactions; b) Previous works on directed ortho-borylations controlled by outer-sphere non-covalent interactions; c) Hbond directed, ortho-borylation of secondary benzamides; d) Strategy presented in this manuscript. Angewandte Chemie Research Articles Angew. Chem. Int. Ed. 2023, e202214510 (2 of 10) © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202214510 by Consorcio Interuniversitario Do Sistema Universitario De Galicia (Cisug), Wiley Online Library on [23/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License ring also led to ortho products (entry 14). These results suggest that the stereoelectronic characteristics of the CF3 group are especially effective in imparting the desired regiocontrol. Ortho-borylation was also detected even when no ligand was used (entry 15), but conversion was much lower.[11d] The optimized conditions for the ortho borylation using L9 as ligand consists of: 1 equiv benzamide, 1.5 equiv B2pin2, 3 mol% [Ir(OMe)(COD)]2and 6 mol% L9 in THF (0.2 M) at 65°C, and gave product 2a after 1.5 hours in 83% yield, with only 7% yield of the diborylated byproduct (entry 16). With the electron-deficient phosphine ligand L15, which is known to favor ortho borylations by allowing a direct coordination of the carbonyl group to the metal,[8] product 2a was also formed; however, the reaction was slower and less efficient than with L9 (58% yield after 1.5 h, entry 17). As an initial hypothesis to explain the striking effect of the CF3substituents at C-5, we considered that electron deficient bipyridine ligands might favor the formation of IrI complexes, and therefore change the catalytic process from the standard IrIII/IrVcycle to one involving IrI/IrIII intermediates, which might allow chelation of the amide. However, when running the reaction with positional isomers L16 and L17, we observed lower conversions and the formation of meta and para-substituted products (Figure 2). This drastic change in reactivity and regioselectivity by just moving the CF3groups from the meta to the ortho or para positions in the bipyridine is astonishing, and raised intriguing mechanistic questions. Kinetic Studies To gain mechanistic insights, we performed comparative kinetic studies using the standard bipyridine L2, and the CF3-substituted derivatives L9 and L17. Ligand L9 leads to almost full conversion after 1.5 h at 65°C, generating the ortho borylated product exclusively, while the borylations with L2 and L17, which yielded a mixture of meta and para borylated products, are faster and slower respectively (Figure 3a). Monitoring the reactions kinetics at different temperatures revealed substantially different apparent activation enthalpies (DH� obs) and entropies (DS� obs) for the reactions carried out with L9, than for those involving L2 or L17 (Figures S1–S5). These dissimilar numbers in the activation parameters depending on the ligand, are likely associated to Table 1: Ligand effects on regioselectivity.[a,b] Entry LConv [%] 2a [%] 3a [%] 4a [%] 5[%] 1L1 100 0 18 30 52 2L2 99 0 28 37 34 3L3 99 14 28 11 53 4L4 99 11 25 10 53 5L5 98 42 11 3 42 6L6 99 4 35 23 37 7L7 99 4 31 19 45 8L8 87 12 40 23 12 9L9 100 20 0 0 80[c] 10 L10 100 49 3 1 47 11 L11 99 46 4 2 47 12 L12 98 28 27 13 29 13 L13 100 62 0 0 38[c] 14 L14 100 19 0 0 81[c] 15 – 8 8 0 0 0 16[d] L9 97 90 (83) 0 0 7 17[d] L15 58 58 0 0 0 Reaction conditions: [a] 1a (0.25 mmol), B2pin2(0.375 mmol, 1.5 equiv), [Ir(OMe)(COD)]2(3 mol%), L (6 mol%), THF (0.2 M), 80°C, 3 h. [b] Diborylated product 5 consists of a mixture of isomers, unless otherwise stated. [c] Exclusively the di-ortho-borylated regioisomer. [d] 65°C for 1.5 h, isolated yield of 2a in parenthesis. Note: Conversion and % of products were determined by GC/MS analysis. For more details about 5 isomers see the Supporting Information (Table S1). Figure 2. Regioselectivity changes depending on the position of the CF3 substituents in the bipy ligand. Reaction conditions: 1a (0.25 mmol), B2pin2(0.375 mmol, 1.5 equiv), [Ir(OMe)(COD)]2(3 mol%), ligand L (6 mol%), THF (0.2 M), 65°C, 1.5 h. Angewandte Chemie Research Articles Angew. Chem. Int. Ed. 2023, e202214510 (3 of 10) © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202214510 by Consorcio Interuniversitario Do Sistema Universitario De Galicia (Cisug), Wiley Online Library on [23/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License different stabilities of precatalytic iridium species formed in the initial reaction mixture,[6] but they are not necessarily informative on the origin of the regioselectivity. Importantly, parallel kinetic experiments using 1a and its d5-deuterated analogue as substrates, and L9 as a ligand, revealed a KIE of 4.5, similar to that obtained with bipy (L2),[6a] and consistent with a canonical mechanism involving a turnover-determining CH activation (Figure 3b). Solvent Effects We also evaluated the effect of different solvents on the reaction outcome (Table S2). Non-polar hydrocarbon solvents like hexane or cyclohexane decreased reactivity, and, remarkably, led to regioisomeric mixtures. Weakly polar ethereal solvents such as dibutyl ether led to a different result than the more polar THF, with formation of meta and para borylated products as major products. Therefore, there is an important influence of the solvent in the regioselectivity, which started to suggest the existence of non-covalent interactions in the regio-determining step. Reaction Scope Before going into further mechanistic details, it was essential to find out whether the ortho-borylation reaction can be generalized. Gratifyingly, many other tertiary amides participated in the process (Scheme 1). Ortho-monoborylated products 2a–2g were obtained in high yields and excellent regioselectivities, as no other mono-borylated side products were detected when using L9 as a ligand. As expected, using L2 instead of L9, we did not detect ortho-borylated products, but only mixtures of other regioisomers (See Supporting Information for more details, Figure S9). The results obtained with amides featuring phenyl substituent at the nitrogen atom (1c,1i), which pose a chemoselectivity challenge (i.e. two aryl rings can be functionalized), are remarkable. Using L2 we observed mixtures of meta and para substituted products in the Figure 3. a) Reaction monitoring using different ligands. Conversion of substrate 1a with ligands L2 (green), L9 (dark purple) and L17 (orange), and formation of ortho-monoborylated product 2a with ligand L9 (light purple) are shown. b) Kinetic isotope effect (KIE) determined from parallel reactions of substrates 1a (dark purple) and 1a-d5(light purple). Scheme 1. Borylation of benzamides and related precursors. Reaction conditions: substrate (0.25 mmol), B2pin2(0.375 mmol, 1.5 equiv), [Ir(OMe)(COD)]2(3 mol%), L9 (6 mol%), THF (0.2 M), 65°C, 1.5 h. 1H NMR yield using CH2Br2as IS (mean value of 3 parallel reactions), isolated yield described between parenthesis [a] Reaction time 1 h. [b] Reaction time 2 h. [c] Reaction time 4 h. [d] Reaction time 24 h. [e] Reaction temperature 80°C. [f] Reaction temperature 100°C. [g] Liigand L14 was used. Note: only traces of diborylated products were detected. Angewandte Chemie Research Articles Angew. Chem. Int. Ed. 2023, e202214510 (4 of 10) © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202214510 by Consorcio Interuniversitario Do Sistema Universitario De Galicia (Cisug), Wiley Online Library on [23/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License benzamide ring, and partial borylation of the phenyl substituent attached to the N atom. However, with L9, the reaction was completely chemoselective towards the benzamide phenyl ring (products 2c or 2d were obtained in excellent yields). We were pleased to find that the reaction also works with secondary amides, affording ortho borylated products 2h–2j in good yields. As with tertiary benzamides, the presence of additional phenyl rings in the substrates was tolerated, if ligand L9 is used. Interestingly, a C6F5 substituent at the nitrogen slowed down the reaction, suggesting an important effect of the stereoelectronic properties of the amide on the reaction rate. Other heteroatom substituents at the nitrogen such as OMe (Weinreb amide) or SO2 R, are also compatible, and products 2k and 2l could be formed in good yields with no other borylation products detected. The same chemoselectivity was observed with a substrate featuring an indole moiety (2m). The amino acid containing product 2n was also produced with high selectivity, which suggests that the method might be used for late-stage functionalization of short peptides with benzamide substituents. Overall, our results confirm that the ortho-borylation is widely applicable. Control reactions with some of these substrates using L2 instead of L9 as a ligand, failed to give the ortho-borylated products (Figure S9). When B2pin2was replaced with bis(hexyleneglycolato)diboron we obtained the expected product 6a. As discussed before, the orthodiborylated product 5a can be obtained using L14 and an excess of B2pin2. The observed reactivity is not limited to benzamides; methylbenzoate reacted to give the ortho borylation product 2o, although the reaction required heating up to 100°C and the use of ligand L14. Acetophenone also reacted to give the expected product, with only traces of a secondary hydroborylation. In addition, N-Me-tosylsulfonamide was an effective substrate for the reaction, obtaining the expected product 2q in excellent yield. When bipyridine (L2) was used as a ligand no ortho borylation was observed. Ortho-borylation is effective on benzamides exhibiting different types of substituents at the aryl ring. The reaction is successful with substrates featuring both EDG (Me or OMe) or EWG (CF3)para to the amide, giving the expected products (2aa–2ac) in good yields (Scheme 2). Halogen groups such as Cl and Br, which might be sensitive to the metal reagent, were also tolerated. Importantly, the reaction can also be performed in the presence of unprotected alcohols or amines (products 2af and 2ag). Meta-substituted precursors also react, to give products borylated at the less hindered ortho position relative to the amide group, as in 2ai and 2aj. Substrates bearing ortho substituents, which have proven difficult to functionalize in the past,[11c] reacted very efficiently to give the expected products (2ak–2an) in excellent yields. Disubstituted benzamides also gave the expected ortho borylated products (2ao–2aq). It is important to note that when using L2 as a ligand many of these functionalized precursors underwent poor conversions (likely because of steric hinderance) and gave mixtures of products (metasubstituted, see Figure S9). Therefore, 3,5-dimethoxy-N,Ndimethylbenzamide failed to react using L2 as a ligand; however, L9 led to good yields of the expected products (2ao). Interestingly, 2,6-dimethyl-N,N-dimethylbenzamide (ortho-disubstituted amide) led to no conversion (2as) under standard conditions with L9; however, with L2 we observed the para-borylated product with excellent conversions (See Figure S9). Along the same lines, it is important to highlight that substrates like anisole or toluene remained essentially unchanged under standard conditions in the presence of L9. However, they react in the presence of L2 (65°C, 1.5 h),[19] to give meta/para borylation products (See Table S4). When Scheme 2. Borylation of substituted benzamides. Reaction conditions: substrate (0.25 mmol), B2pin2(0.375 mmol, 1.5 equiv), [Ir(OMe)- (COD)]2(3 mol%), L9 (6 mol%), THF (0.2 M), 65°C, 1.5 h. 1H NMR yield using CH2Br2as IS (mean value of 3 parallel reactions), isolated yield described between parenthesis. [a] Reaction time 1 h. [b] Reaction time 1.25 h. [c] Reaction time 2 h. [d] Reaction time 24 h. [e] Reaction temperature 80°C. Note: only traces of diborylated products were detected. Angewandte Chemie Research Articles Angew. Chem. Int. Ed. 2023, e202214510 (5 of 10) © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202214510 by Consorcio Interuniversitario Do Sistema Universitario De Galicia (Cisug), Wiley Online Library on [23/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License the reaction with L9 is carried out at higher temperatures (100°C) we start to see reactivity, to give the same regioisomers than with L2. All these results confirm that with L9 the reaction is both chemo- (only substrates bearing a substituted carbonyl/ sulfonyl directing group work), and regioselective (ortho orientation). Other substrates lacking a proper carbonyl-like directing group failed to undergo the ortho-borylation (see Supporting Information). Interestingly, phthalimide and naphthalimide reacted in presence of L9, but to give the meta and the para borylated products, respectively, with no ortho-borylation. These results may be explained by the rigid planar conformation of the carbonyl group (see Supporting Information). Precursors with extended aromatic systems were also borylated only at the ortho position of the amide group. Therefore, the ortho-borylated biphenyl amides 2ah,2aj and 2am were obtained in excellent yields when using L9, whereas with L2 we observed mixture of products. Likewise, a naphthalene amide substrate was borylated at the ortho position of the amide (2ar). Next, we assessed whether the ortho borylations could be extended to challenging heterocyclic systems containing amide functionalities. As shown in Scheme 3a, the reaction proceeds with excellent yields on different heterocycles such as indoles (2r), pyrroles (2s and 2t), furans (2u), and even thiophenes (2v). Importantly, in all the cases, the regioselectivity of the reaction is governed by the amide directing group, which contrasts with related borylations using other ligands.[11c] The data presented above supports a highly regioand chemoselective transformation, with the substituted amide playing a key role as reaction-promoting and ortho-directing group, when combined with ligand L9. In agreement with the prevalent directing effect of the amide, we observed that disubstituted precursors containing other potential directing groups, gave exclusively mono-borylated products ortho to the amide (2at–2aw). A substrate exhibiting competing dimethyl and diphenyl amides gave the product borylated ortho to the dimethyl amide (2ax). More complex substrates like indomethacine (7), benzocaine (9), or the insect repellent 11, can also be borylated with excellent selectivity using L9, while the reaction with L2 affords a mixture of products borylated at multiple positions (Scheme 4). Overall, the chemo and regiodirecting effect of CF3-containing ligand L9 is very robust and covers a wide variety of substrates. Synthetic Application Finally, the synthetic potential of the method is underscored by its application to a straightforward synthesis of fungicide 14 (43% overall, only two synthetic operations, (Scheme 5)), while the patented process involves 5 different steps, and it is less efficient.[21] Computational Assessment of the CH Activation Step The clean selectivity outcomes of the above borylations suggest a key role for the amide group in the CH activation step. However, a direct interaction of this group with the IrIII reagent (complex Ain scheme 1) saturates the metal center, and would hamper the CH activation. To gain further insights into the origins of the observed ortho regioselectivity with L9 we performed a thorough quantum mechanical study on the CH activation step (see computational details in the Supporting Information). First, the possibilities that an electron deficient bipy ligand such as L9 could enable an IrI/IrIII mechanistic pathway (Figures S11 and S12), or act as an hemilabile ligand allowing direct coordination of the amide to the metal,[9] were discarded due to the very high activation barriers calculated for the CH activation (ΔG� ortho =43– 51 kcalmol1, Figure S13). Importantly, the barriers when decoordinating the pyridine ring in L9 are similar to those calculated with L2. We therefore focused our attention on a canonical CH activation mechanism, with bipyridines acting as bidentate ligands (Figure 1a). Off-cycle IrIII and IrVcomplexes with Scheme 3. Borylation of heterocycles, and of substrates with competing DGs (directing group). Reaction conditions: substrate (0.25 mmol), B2pin2(0.375 mmol, 1.5 equiv), [Ir(OMe)(COD)]2(3 mol%), L9 (6 mol%), THF (0.2 M), 65°C, 1.5 h. Isolated yields. [a] Reaction time 15 min. [b] Reaction time 1 h. [c] Reaction time 2 h. [d] Reaction time 24 h. [e] Reaction temperature 80°C. [f] Ligand L14 was used a) Borrylation of heterocyclic substrates. b) Chemoand regioselective borylations demonstrate the selectivity of the amide moiety over competing DG. Angewandte Chemie Research Articles Angew. Chem. Int. Ed. 2023, e202214510 (6 of 10) © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202214510 by Consorcio Interuniversitario Do Sistema Universitario De Galicia (Cisug), Wiley Online Library on [23/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License either three Bpin and one THF molecule (L2_THF and L9_ THF) or five Bpin units (L2_IrV and L9_IrV) coordinated to Ir, were calculated to be energetically feasible (Figure S15). These 18 electron species in equilibrium could be considered as catalyst resting state(s) before the TOFdetermining CH activation step, affecting the effective concentration of the reactive catalyst and thus the global reaction rate.[22] The calculations indicate that complexes with ligand L9 are systematically more stable than those with L2. This might be the reason behind the relatively large activation enthalpy and more favorable activation entropy observed for L9. More stable saturated species could impose an enthalpic penalty to the CH activation, while their necessary dissociation of some ligand to form the active catalyst might provide an entropic driving force. We then analyzed the CH activation step in detail by considering all possible regioisomers (ortho,meta and para), and conformers of relevant stationary points at each potential energy surface (Figures S13 to S17). Importantly, the IrIII(bipy)(Bpin)3complexes entering the catalytic cycle are considerably more stable (>4 kcalmol1) when bound to the substrate via agostic CH···Ir interactions (L2_RC and L9_RC), than when coordinated to the amide carbonyl (L2_RCDG and L9_RCDG). Regarding the regioselectivity-determining transition states, the computed activation energies (�30 kcalmol1) and 2D/1H KIEs with ligand L9 (Figure S8), agree with the observed reactivity. Most importantly, only ligand L9 showed a clear preference for oxidative addition at ortho vs. meta or para positions (calculated o:m:pratio=81:15:4, Figure 4). On the contrary, for the isomeric trifluromethylated ligands L16 (calculated o:m:pratio=31:67:2) and L17 (calculated o:m:pratio=26:73:0), the meta-borylation was preferred. This was also the case with unsubstituted bipyridine L2 (calculated o:m:pratio=6:94:0). Overall, these trends are in consonance with the observed selectivities. The Role of Non-Covalent Interactions on the Regioselectivity of the CH Activation A close inspection of the calculated structures reveals that although the geometry of the lowest energy ortho and meta TS with ligands L2 and L9 are almost identical (Figure 4), their relative energies are significantly different, leading to an inversion of regioselectivity. This strongly suggests that outer-sphere substrate-ligand non-covalent interactions in the ortho oxidative addition transition states drive the regioselectivity. Exhaustive non-covalent interaction analyses (Figures 5, S24–S28 and Tables S6–S9) unveiled an extended network of attractive interactions between the carbonyl group of the benzamide and the CF3-pyridine ring of ligand L9 in the ortho TS; these interactions are weaker for the unsubstituted bipyridine ligand L2 (Figure 5). NBO[23] analysis suggests that dispersion contacts between the amide carbonyl group and the CF3-pyridine ring of L9 (especially the interaction πC=O!π*CC) are predominant (Figure S25), resulting in a shorter CO···CC distance and a more stable transition structure (L9_TS_o) than with L2 (L2_TS_o, Figure 5). The polarizing (i.e. electron withdrawing) effect of the CF3substituent in L9 (Figure S29), exacerbates the intensity of outer-sphere substrate-ligand attractions, which seems key for the preferred ortho orientation. This was confirmed by an energy decomposition analysis of these interactions (EDA, Figure S26), which suggests that both polar, but especially dispersion contributions increase with ligand L9. The calculated non-covalent interactions appear to involve also contacts between the Scheme 4. Borylation of biologically-relevant molecules. Scheme 5. Three step-synthesis of fungicide 14. a) (COCl)2(1.5 equiv), DMF, CH2Cl2, 0°C to r.t., 2 h; then pyrrolidine 0°C to r.t., 16 h; b) B2pin2 (1.5 equiv), [Ir(OMe)(COD)]2(3 mol%), L9 (6 mol%), THF, 65°C, 1.5 h; then H2O, degassed and Pd(PPh3)4, K2CO3, 3,4(dimethoxy)iodobenzene, 100°C, 16 h. Angewandte Chemie Research Articles Angew. Chem. Int. Ed. 2023, e202214510 (7 of 10) © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202214510 by Consorcio Interuniversitario Do Sistema Universitario De Galicia (Cisug), Wiley Online Library on [23/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License amide substituents and the CF3group at position 5 (Figures 5, S24 and S28). On the contrary, in the other CF3containing ligands, the more distal location of the CF3group in L17 or the deplanarization of the bipy-Ir chelate in L16, reduce the intensity of substrate-ligand interactions in the TS, and thus the ortho-selectivity vanishes, as observed experimentally. Importantly, our model is fully consistent with the absence of ortho-borylation in phthalimide and naphthalimide, due to the inability of their carbonyls to adopt the required conformation for such non-covalent contacts with the ligand (Figures S20–S22). Calculations also predicted that borylation of toluene would occur at the meta position, with both ligands L2 and L9 (Figure S18). The absence of the benzamide group destabilizes the ortho borylation TS with L9 by ca. 5 kcalmol1. These predictions are in consonance with the experimental observations (Table S4), and further demonstrate the crucial role of outer-sphere interactions in both reactivity and ortho-regioselectivity. Loss of regioselectivity was also predicted and experimentally verified for the borylation of benzonitrile, whose cyano group cannot engage in the non-covalent interactions described for the benzamide group (Figures S19, S27 and S28). Besides these unusual substrate-bipyridine interactions, calculations revealed an intriguing trend: in all cases entropy opposes and sometimes even supersedes enthalpy as the regioselectivity determining factor. Hence, relative activation enthalpies (ΔΔH�) always favor the ortho pathways, while the meta orientation is driven by entropy (TΔΔS�) (Figure S23). Conclusion In summary, we have discovered that the introduction of CF3groups at position 5 of bipyridine ligands (Ligand L9), triggers a complete change in regioselectivity in the iridiumcatalyzed borylations of benzamides, from meta/para to ortho. Importantly, the presence of the amide directing group is critical to observe reactivity, which provides exquisite selectivity in polysubstituted and heteroaromatic substrates. This represents a substantial advantage with respect to other methods based on different ligand types. Experimental data together with DFT calculations on the CF3and non-CF3containing ligands support a canonical IrIII/IrVmechanism with a rate-determining CH activation. Calculations suggest that the regioselectivity of the reactions stems from a subtle interplay of enthalpic and entropic contributions. While the ortho orientation tends to be penalized by steric and entropic factors, with 5-CF3substituted ligand L9, a significant enthalpic stabilization arises from unusual non-covalent interactions between the substrate’s benzamide group and the polarized ring(s) of the bipyridine. This type of dispersion, non-covalent interactions Figure 4. Low energy outer-sphere transition states (TS) calculated for the oxidative addition step between N,N-dimethylbenzamide (1a) and IrIII(ligand)(Bpin)3(ligand=L2 (a), L9 (b), L6 (c) and L17 (d); o=ortho,m=meta,p=para). Relative activation free energies (ΔΔG� QH) calculated with SMDTHF/M06/6-311G(2d,p)+SDD(Ir)//M06/6-31G(d)+LANL2DZ(Ir) are given in kcal mol1. Metal-ligand and breaking/forming CH, IrC and IrH bonds are represented as blue dashed lines, respectively. Non-reactive hydrogens have been omitted for clarity. Angewandte Chemie Research Articles Angew. Chem. Int. Ed. 2023, e202214510 (8 of 10) © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202214510 by Consorcio Interuniversitario Do Sistema Universitario De Galicia (Cisug), Wiley Online Library on [23/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License has rarely been invoked and should be taken into account in the future for other types of chemical reactions. Acknowledgements This research was funded by AEI (Spain) through projects PID2019-106184GB-I00 (to J.L.M.), PID2021-125946OB-I00 and RTI2018-099592-B-C22 (to G.J.O) and Severo Ochoa Excellence Accreditations (CEX2021-001136-S and SEV2016-0644 to CIC bioGUNE). D.M. thanks MECD for a FPU fellowship (FPU18/04495) and Fulbright España for a US-Spain Fulbright grant. C.V. and F.P. thank MINECO for Juan de la Cierva Formación (FJCI-2017-33168) and Incorporación (IJC2020-045506-I) funding. We also want to thank Xunta de Galicia (2015-CP082, ED431C-2021/25 and Centro Singular de Investigación de Galicia accreditation 20192022, ED431G 2019/03) and ERDF. The Orfeo-Cinqa network is also acknowledged. The authors thank Dr. M. Marcos and Dr. N. Atanes from CACTI (Universidade de Vigo) for their excellent technical assistance and essential contributions to the kinetic studies and the characterization of products. Conflict of Interest The authors declare no conflict of interest. Data Availability Statement The data that support the findings of this study are available in the Supporting Information of this article. Keywords: Bipyridine Ligands ·Borylation ·CH Activation · Iridium ·Non-Covalent Interactions [1] a) T. Gensch, M. N. Hopkinson, F. Glorius, J. Wencel-Delord, Chem. Soc. Rev. 2016,45, 2900–2936; b) M. Gulías, J. L. Mascareñas, Angew. Chem. Int. Ed. 2016,55, 11000–11019; Angew. Chem. 2016,128, 11164–11184; c) R. H. Crabtree, A. Lei, Chem. Rev. 2017,117, 8481–8482; d) D. F. Fernández, J. L. Mascareñas, F López, Chem. Soc. Rev. 2020,49, 7378–7405; e) N. Y. S. Lam, K. Wu, J. Q. Yu, Angew. Chem. Int. Ed. 2021, 60, 15767–15790; Angew. Chem. 2021,133, 15901–15924; f) U. Dutta, S. Maiti, T. Bhattacharya, D. Maiti, Science 2021,372, 6543; g) T. Dalton, T. Faber, F. Glorius, ACS Cent. Sci. 2021,7, 245–261; h) E. Fernández, Topics in Organometallic Chemistry, Springer, Cham, 2021, ISBN 978-3-030-69083-0. [2] a) Z. Chen, B. Wang, J. Zhang, W. Yu, Z. Liu, Y. Zhang, Org. Chem. Front. 2015,2, 1107–1295; b) C. Sambiagio, D. Schönbauer, R. Blieck, T. Dao-Huy, G. Pototschnig, P. Schaaf, T. Wiesinger, M. F. Zia, J. Wencel-Delord, T. Besset, B. U. W. Maes, M. Schnürch, Chem. Soc. Rev. 2018,47, 6603–6743; c) L. Ping, D. S. Chung, J. Bouffard, S. Lee, Chem. Soc. Rev. 2017, 46, 4299–4328. [3] a) G. Meng, N. Y. S. Lam, E. L. Lucas, T. G. Saint-Denis, P. Verma, N. Chekshin, J. Q. Yu, J. Am. Chem. Soc. 2020,142, 10571–10591; b) V. K. Tiwari, M. Kapur, Org. Biomol. Chem. 2019,17, 1007–1026. [4] a) “Boronic Acids: Preparation and Applications”: D. G. Hall, Organic Synthesis and Medicine, Wiley-VCH, Weinheim, 2005; b) S. Namirembe, J. P. Morken, Chem. Soc. Rev. 2019,48, 3464–3474; c) S. Darses, J. P. Genet, Chem. Rev. 2008,108, 288–325; d) D. Leonori, V. K. Aggarwal, Acc. Chem. Res. 2014, 47, 3174–3183; e) E. C. Neeve, S. J. Geier, I. A. I. Mkhalid, S. A. Westcott, T. B. Marder, Chem. Rev. 2016,116, 9091–9161; f) R. Bisht, C. Haldar, M. M. M. Hassan, M. E. Hoque, J. Chaturvedi, B. Chattopadhyay, Chem. Soc. Rev. 2022,51, 5042–5100; g) C. Haldar, M. E. Hoque, J. Chaturvedi, M. M. M. Hassan, B. Chattopadhyay, Chem. Commun. 2021, 57, 13059–13074. [5] a) S. A. Iqbal, J. Pahl, M. J. Ingleson, Chem. Soc. Rev. 2020,49, 4564–4591; b) Y. Kuroda, Y. Nakao, Chem. Lett. 2019,48, 1092–1100; c) Y. Li, X. Wu, Angew. Chem. Int. Ed. 2020,59, 1770–1774; Angew. Chem. 2020,132, 1786–1790; d) P. Nguyen, H. P. Blom, S. A. Westcott, N. J. Taylor, T. B. Marder, J. Am. Chem. Soc. 1993,115, 9329–9330. [6] a) T. M. Boller, J. M. Murphy, M. Hapke, T. Ishiyama, N. Miyaura, J. F. Hartwig, J. Am. Chem. Soc. 2005,127, 14263– 14278; b) H. Tamura, H. Yamazaki, H. Sato, S. Sakaki, J. Am. Chem. Soc. 2003,125, 16114–16126. Figure 5. Substrate-ligand non-covalent interactions (NCI) occurring in low energy outer-sphere transition states (TS) calculated for the oxidative addition step between N,N-dimethylbenzamide (1a) and IrIII(ligand)(Bpin)3(ligand=L2 and L9;o=ortho,m=meta). Activation free energies (ΔG� QH) calculated with SMDTHF and IEF-PCMTHF (in parentheses) and M06/6-311G(2d,p)+SDD(Ir)//M06/6-31G(d)- +LANL2DZ(Ir) are given in kcal mol1. Metal-ligand and breaking/ forming CH, IrC and IrH bonds are represented as pale red and yellow lines, respectively. Contacts between the substrate carbonyl O and bipyridine N and C atoms are represented as red dashed lines. Note the larger extension of non-covalent interactions[24] in the ortho transition states, especially with ligand L9. Angewandte Chemie Research Articles Angew. Chem. Int. Ed. 2023, e202214510 (9 of 10) © 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH 15213773, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/anie.202214510 by Consorcio Interuniversitario Do Sistema Universitario De Galicia (Cisug), Wiley Online Library on [23/03/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License