English

• Regioselective C—H bond activation of arenes provides an efficient approach for obtaining functionalized aromatics in organic synthesis [1-3]. The directed ortho-selective C—H functionalization of arenes is well established through transition-metal catalysis [4-7]. Compared with proximal ortho-C-H bonds, the meta- and para-C-H bonds are away from the directing group but are adjacent to each other, leading to more difficulties in achieving the high regioselectivity [8,9]. In recent years, quite a few elegant methods are developed to control remote selective C—H activation, such as σ-bond activation-assisted functionalization [10-13], template strategy [14-22], noncovalent interaction direction [23-33], Pd(Ⅱ)/norbornene cooperative catalysis [34-36], traceless directing group strategy [37], and catalyst or reagent controlled strategy [38-43]. Recently, noncovalent interaction directed iridium-catalyzed borylation becomes a robust approach [44-47] because the borylated products can be served as versatile synthetic building blocks in chemical and industrial synthesis [48-51].

  In 2015, Kanai and coworkers reported a meta-selective C—H borylation of arenes using a bipyridine-derived ligand with a urea moiety [23]. Aromatic amides, phosphonates and phosphine oxides are suitable for this reaction, but the ratios of meta-selectivity highly depend on the substrates, ranging from 30:1 to 0.5:1. The authors claimed that hydrogen bond interaction between ligand and substrate placed the iridium center in close proximity to the meta-C-H bond of substrates and controlled the regioselectivity (Fig. 1A). The mechanism of Ir-catalyzed C—H borylation of arenes has been established by Sakaki [52], Hartwig [53], Houk [54] and Ke [55] groups, in which the rate-determining step is C—H bond oxidative addition (Fig. 1B). Sunoj and coworkers reported a computational study on Kanai's work, and they also proved that the aromatic C—H activation is the regioselectivity-determining step. In addition, they demonstrated that the observed high meta-selectivity was predominantly attributed to a good number of noncovalent interactions between catalyst/ligand and substrate [56]. However, through a combined computational and experimental study, we found that the origin of meta-selectivity is much more complex than expected.

  Figure 1

  

  Figure 1.  (A) Hydrogen bond interaction directed meta-selective C-H borylation proposed by Kanai and coworkers. (B) Catalytic cycle for the Ir-catalyzed borylation of arenes using B₂pin₂.

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  We first explored the electronic effect of substituents in the urea moiety of ligand to validate the important role of hydrogen bond interaction in controlling regioselectivity. We used 2,2′-bipyridine (bpy) as ligand to evaluate the intrinsic borylation selectivity of benzamide 1a, which gave a meta to para ratio of 0.7:1 (Fig. 2). Meanwhile, ligands L1-L5 were synthesized and tested in the iridium-catalyzed borylation of benzamide 1a. As shown in Fig. 2, for L1 and L2, with electron-donating groups (OMe and Me), the ratios of meta to para were 2.9:1 and 3.2:1, respectively. For ligand L3, a slightly increased meta-selectivity (3.9:1) was observed. However, ligands L4 and L5 with electron-withdrawing groups (Cl and CF₃) exhibited even lower meta-selectivities (1.4:1 and 1.1:1). Especially for L5, the selectivity of borylated products was very close to that using bpy ligand without hydrogen bond interaction. It is well known that ureas bearing electron-withdrawing groups are better hydrogen bond donors than those with electron-donating groups, and it should enhance the hydrogen bond interaction between ligand and substrate [57]. With stronger hydrogen bonds, the meta-selectivity would have been further improved, rather than becoming much worse. What is the deeper reason behind this unusual experimental phenomenon?

  Figure 2

  

  Figure 2.  The electronic effect of substituents in the urea moiety of ligand on the regioselectivity.

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  To answer this question, DFT calculations were conducted using L5 as ligand (Fig. 3). According to Kanai's hydrogen bond recognition model shown in Fig. 1A, we located the meta- and para-C-H activation transition states TS1-meta and TS1-para directed by hydrogen bond interaction. Computational results showed that the free energy of TS1-meta is 3.6 kcal/mol lower than that of TS1-para, implying that L5 favors meta-selectivity greatly. This result was obviously inconsistent with our experimental data, in which only 1.1:1 of meta to para selectivity was obtained. We then conducted extensive conformational search and discovered another two non-directed transition states TS1-meta-ND and TS1-para-ND with even lower energies, which were not reported in previous study by Sunoj and coworkers [56]. In the non-directed pathway, the urea moiety in ligand recognizes the O atom in Bpin bound to iridium center via N—H⋯O hydrogen bonding, rather than the C=O group in substrate. Taking these four transition states into account (Fig. 3), it is now clear that the non-directed TS1-meta-ND and TS1-para-ND control the ratio of the meta- and para-borylated products. As their free energy difference is only 0.6 kcal/mol, predicting an approximate 1:1 mixture of meta- and para-borylated products, this is in good agreement with the experimental result (L5, m: p = 1.1, Fig. 2). These calculations indicated that the previouly overlooked non-directed pathway played a critical role in determining regioselectivity, even overriding the directed pathway.

  Figure 3

  

  Figure 3.  DFT-computed geometries and Gibbs free energies for the C-H activation transition states of 1a-Me using B₂pin₂ and L5 as ligand, computed with SMD(p-xylene)-ωB97X-D/6–311+G(d, p)[SDD for Ir]//M06/6–31G(d)[SDD for Ir]. For improved clarity, most hydrogen atoms are omitted. All distances are in Å.

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  As shown in Scheme 1, Kanai and coworkers reported that, in the presence of B₂pin₂, the borylation of 1a gave a 13:1 ratio of meta to para using ligand L6 [23]. We speculated that the non-directed pathway would also exist in this case, and that it would become predominant when the B₂pin₂ was replaced by a smaller diboron reagent, which favors the hydrogen bond interaction between the boron group and the urea moiety of ligand, leading to deteriorated meta-selectivity. To test the steric effect of the boron group, DFT calculations were carried out using the less bulky diboron reagent DB-1 (Scheme 1), and four transition states were located (Fig. 4). As expected, both non-directed transition states TS2-meta-ND and TS2-para-ND had lower free energies than two directed transition states TS2-meta and TS2-para, indicating that the regioselectivity was again determined by the non-directed pathway. The negligible energy difference of 0.2 kcal/mol predicted a poor regioselectivity. To confirm this prediction, DB-1 was synthesized and tested using the same ligand L6. Indeed, it delivered meta- and para-borylated products as a 1:1 isomeric mixture (Scheme 1). On the other hand, the diboron reagent with bulkier substituent was also investigated. B₂Epin₂ (DB-2), a more stable boronic ester than B₂pin₂, was synthesized via two steps from 3-pentanone according to a known procedure [58]. Unfortunately, B₂Epin₂ exhibited poor reactivity in the borylation of 1a using L6 (conv. < 5%). Therefore, ligand evolution may be a more promising approach to improve the meta-selectivity.

  Scheme 1

  

  Scheme 1.  Influence of diboron reagents on regioselectivity. ^a data from Ref. [23]. ^b Conversion of 1a. ^c At 50 ℃, m:p = 0.5:1, 90% conversion of 1a.

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  Figure 4

  

  Figure 4.  DFT-computed geometries and Gibbs free energies for the C—H activation transition states of 1a-Me using DB-1 and L6 as ligand, computed with SMD(p-xylene)-ωB97X-D/6–311+G(d, p)[SDD for Ir]//M06/6–31G(d)[SDD for Ir]. For improved clarity, most hydrogen atoms are omitted. All distances are in Å.

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  With the computational and experimental results in hand, we then focus on how to utilize our findings to improve the previously reported suboptimal results. Kanai and coworkers reported the borylation of heteroaromatic amide 2a using L6 as ligand, which gave a moderate regioselectivity (m: p = 6.4:1, Scheme 2). We located the meta- and para-C-H activation transition states of this reaction (Fig. 5A). Among them, TS3-meta and TS3-para-ND were responsible for generating the meta- and para-borylated product. The preference of meta- over para-C-H borylation is 1.2 kcal/mol, in accordance with the reported selectivity (m: p = 6.4:1). Due to its more electron-withdrawing aromatic ring, amide 2a is a poorer hydrogen bond acceptor than benzamide. As a result, its carbonyl group has less advantage against the O atom of Bpin to interact with the urea moiety of ligand, further favoring the non-directed pathway. We envisioned that, through increasing the steric repulsion between the urea moiety of ligand and the Bpin group bound to iridium center, the non-directed pathway would be inhibited. Therefore, we changed the cyclohexyl to a much bulkier 2-adamantyl and designed ligand L7. Further DFT calculations showed that the steric repulsion between the urea moiety and Bpin increased the energies of non-directed transiton states TS4-meta-ND and TS4-para-ND by 3–5 kcal/mol, impeding the non-directed pathway effectively (Fig. 5B). Meanwhile, as the free energy of directed transition state TS4-meta is much lower than those of three other transition states, a higher meta-selectivity is anticipated. When the 2-adamantyl-bearing ligand L7 was synthesized and used in the C—H borylation reaction, it indeed gave a higher selectivity (m: p = 12:1, Scheme 2). This realized the control of meta-selectivity through inhibiting the non-directed para-C-H borylation by inceasing the size of substituent on the urea moiety.

  Scheme 2

  

  Scheme 2.  Steric effect of ligands on the meta-selective borylation of 2a. ^* data from Ref. [23].

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  Figure 5

  

  Figure 5.  DFT-computed geometries and Gibbs free energies for the C—H activation transition states of 2a using B₂pin₂ and L6 or L7 as ligand, computed with SMD(p-xylene)-ωB97X-D/6–311+G(d, p)[SDD for Ir]//M06/6–31G(d)[SDD for Ir]. For improved clarity, most hydrogen atoms are omitted. All distances are in Å.

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  Encouraged by this positive result, ligand L7 was used for the substrates with poor meta-selectivities in Kanai's work (Scheme 3) [23]. In the borylation of benzamide 3a, a 6.9:1 ratio of meta to para was reported by using L6, while an enhanced selectivity (m: p = 12:1) was obtained by using our ligand L7. Previously, N-methylisoindolin-1-one 4a showed a meta-regioselectivity of only 3.3:1. This selectivity was as high as 15:1 when L7 was used as ligand. Finally, for aryl phosphonate 5a, the para-borylated product was generated as major product (m: p = 0.5:1) using L6, which was similar to the result using dtbpy, a typical ligand exhibiting intrinsic selectivity of substrates in the Ir-catalyzed borylation [59,60]. Significantly, our ligand L7 enabled the meta-selective borylation of 5a, delivering the desired meta-product with a high selectivity (m: p = 12:1).

  Scheme 3

  

  Scheme 3.  The comparison of meta-selectivity in the C—H borylation of arenes by using ligands L6 and L7. ^* data from Ref. [23].

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  In summary, this work combines calculations and experiments to elucidate the origin of regioselectivity in hydrogen bond interaction directed meta-selective C—H borylation of benzamides. The non-directed pathway, in which the ligand recognizes Bpin instead of substrate, is disclosed. We find that the non-directed para-borylation pathway plays an important role in controlling regioselectivity through competing with the meta-borylation pathways. This study demonstrates that the electronic and steric effects of ligand and the size of diboron reagent affect the regioselectivity by tuning the barriers of directed and non-directed pathways. Based on these findings, the ligand is improved and applied into some previously reported unsuccessful arenes, giving excellent performance. This work is a cornerstone of our ligand design in the remote C—H activation, which leads to the tunable meta- and para-selective C—H borylation of arenes bearing a variety of multi-transformable directing groups [61,62].

  Declaration of competing interest

  The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

  Acknowledgments

  We are grateful for financial support from the Fundamental Research Funds for the Central Universities (Nos. 020514380253, 020514380277), the Natural Science Foundation of Jiangsu Province (No. BK20211555), and the Jiangsu Innovation & Entrepreneurship Talents Plan. We thank the High Performance Computing Center (HPCC) of Nanjing University for doing the numerical calculations in this paper on its blade cluster system.

  
  
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• 

  Figure 1  (A) Hydrogen bond interaction directed meta-selective C-H borylation proposed by Kanai and coworkers. (B) Catalytic cycle for the Ir-catalyzed borylation of arenes using B₂pin₂.

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  Figure 2  The electronic effect of substituents in the urea moiety of ligand on the regioselectivity.

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  Figure 3  DFT-computed geometries and Gibbs free energies for the C-H activation transition states of 1a-Me using B₂pin₂ and L5 as ligand, computed with SMD(p-xylene)-ωB97X-D/6–311+G(d, p)[SDD for Ir]//M06/6–31G(d)[SDD for Ir]. For improved clarity, most hydrogen atoms are omitted. All distances are in Å.

  下载: 全尺寸图片 幻灯片
  

  Scheme 1  Influence of diboron reagents on regioselectivity. ^a data from Ref. [23]. ^b Conversion of 1a. ^c At 50 ℃, m:p = 0.5:1, 90% conversion of 1a.

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  Figure 4  DFT-computed geometries and Gibbs free energies for the C—H activation transition states of 1a-Me using DB-1 and L6 as ligand, computed with SMD(p-xylene)-ωB97X-D/6–311+G(d, p)[SDD for Ir]//M06/6–31G(d)[SDD for Ir]. For improved clarity, most hydrogen atoms are omitted. All distances are in Å.

  下载: 全尺寸图片 幻灯片
  

  Scheme 2  Steric effect of ligands on the meta-selective borylation of 2a. ^* data from Ref. [23].

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  Figure 5  DFT-computed geometries and Gibbs free energies for the C—H activation transition states of 2a using B₂pin₂ and L6 or L7 as ligand, computed with SMD(p-xylene)-ωB97X-D/6–311+G(d, p)[SDD for Ir]//M06/6–31G(d)[SDD for Ir]. For improved clarity, most hydrogen atoms are omitted. All distances are in Å.

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  Scheme 3  The comparison of meta-selectivity in the C—H borylation of arenes by using ligands L6 and L7. ^* data from Ref. [23].

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•