Hydrogen Bond-Accelerated meta-Selective C–H Borylation of

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Hydrogen Bond-Accelerated meta-Selective C-H Borylation of Aromatic Compounds and Expression of Functional Group and Substrate Specificities Xu Lu, Yusuke Yoshigoe, Haruka Ida, Mitsumi Nishi, Motomu Kanai, and Yoichiro Kuninobu ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b05005 • Publication Date (Web): 25 Jan 2019 Downloaded from http://pubs.acs.org on January 26, 2019

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ACS Catalysis

Hydrogen Bond-Accelerated meta-Selective C-H Borylation of Aromatic Compounds and Expression of Functional Group and Substrate Specificities Xu Lu,† Yusuke Yoshigoe,‡ Haruka Ida,‖ Mitsumi Nishi,‖,# Motomu Kanai,‖,# Yoichiro Kuninobu*,†,‡ †Department

of Molecular and Material Sciences, Interdisciplinary Graduate School of Engineering Sciences, Kyushu University, 6-1 Kasugakoen, Kasuga-shi, Fukuoka 816-8580, Japan ‡Institute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasugakoen, Kasuga-shi, Fukuoka 8168580, Japan ‖

Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan #ERATO, Japan Science and Technology Agency (JST), Kanai Life Science Catalysis Project, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

ABSTRACT: We found that meta-selective C-H borylation of aromatic compounds was accelerated when using urea moietycontaining bipyridine-type ligands unlike in cases involving a bipyridine-type ligand without the urea moiety. The acceleration was due to the recognition and capture of the aromatic substrates by the urea moiety of the ligand by hydrogen bonding. The acceleration was further enhanced by modifying the electronic and steric properties of the ligand. The functional group and substrate specificities were also observed using the urea moiety-containing ligands. KEYWORDS: C-H activation, hydrogen bond, meta-selectivity, substrate specificity, reaction rate

Acceleration of reactions and expression of functional group and substrate specificities are important functions of enzymes,1 the tertiary structures of which play an important role in the expression of the functionalities. Enzymes recognize and capture substrates, which have suitable structures for the cavity of the enzymes,2 by secondary interactions such as hydrogen bonding. The enzymes then accelerate the desired reactions efficiently by decreasing the activation energy of the reactions by utilizing proximity of the substrates to the catalytic active sites and orientation effects.3 The functional groups in the cavity and the shape of the cavity recognize a substrate selectively, leading to the functional group and substrate specificities. If acceleration of reactions and expression of functional group and substrate specificities can be realized in artificial catalysts4,5 modeled on enzymes, their functionalities can lead to the development of highly efficient synthetic organic reactions. For example, Breslow reported intramolecular aldol condensation by the acceleration of enolization of aryl ketones using imidazole-bearing cyclodextrin catalysts.6 In this catalytic system, the cyclodextrin moiety captures the aromatic ring of the substrate and two imidazolyl groups can promote the enolization of the carbonyl group. Hamilton and co-workers succeeded in the acceleration of a phosphate diester transesterification by bis(arylguanidinium)receptors containing an appended general base.7 The phosphate diesters are captured by the two

alkylguanidinium moieties by hydrogen bonding, and the electrophilicity of the phosphorus atom of the phosphate diesters is increased owing to hydrogen bonding. The appended amino group works as a base to promote the transesterification. Examples of metal-containing artificial enzymes including zinc(II)-macrocyclic polyamine complexes reported by Kimura et al as models for phosphatases.8 In such a system, the OH anion is formed from H2O by coordination of H2O to the zinc ion, and the OH anion accelerates hydrolysis of phosphates. Komiyama succeeded in the synthesis of artificial restriction enzymes.9 Iminodiacetate complexes of lanthanide(III) ions (lutetium, europium, thulium, and lanthanum), attached to the 5′-end of a 15-mer DNA, hydrolyze a 39-mer RNA selectively at the 3′-side of its 15-mer sequence. However, to the best of our knowledge, there has been no report of the acceleration of reactions and expression of functional group and substrate specificities for C-H transformations controlled by secondary interactions such as hydrogen bonding.10 We recently reported meta-selective C-H borylation of aromatic compounds by recognizing and capturing substrates using hydrogen bonding between a ligand (Cy-Ubpy) of a catalyst and a substrate (Figure 1a).11-17 We thought the reaction could be accelerated by increasing the reactivity of the iridium-boryl species, decreasing the activation energy of the reaction, and tuning the hydrogen bonding ability of the urea moiety by increasing the electron density of the

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iridium center, adjusting the structure of the ligand to fit to the structure of the transition state, and changing the substituent of the urea moiety (Figure 1b). In addition, we also expected expression of functional group and substrate specificities due to differences in the electronic and steric properties of the functional groups of the substrates, which can be recognized by the urea moiety of the ligand using hydrogen bonding.

planes should be twisted as shown in Figure 1a when the borylation occurs in the iridium/4a-catalyzed meta-selective C-H borylation. Therefore, we introduced a methyl group on the ortho-phenylene moiety (ligand 4c) to twist the dihedral angle of the ortho-phenylene and bipyridyl moieties, and to accelerate the reaction. By using ligand 4c, the C-H borylation was accelerated by 2.1 times compared with the rate obtained using ligand 4a (Scheme 1, entry 4). This result indicated that the meta-selective C-H borylation Scheme 1. Initial reaction rate constants of C-H borylation using bipyridine-type ligand 3 and urea-containing bipyridine-type ligands 4a

Figure 1. Hydrogen bond-controlled meta-selective C-H borylation: (a) our previous work; and (b) design of ligand to accelerate the reaction

We first investigated if Cy-Ubpy (4a) accelerated the C-H borylation of benzamide 1a when compared to the performance of the 5-phenyl-2,2’-bipyridine (Ph-bpy) ligand 3, which has no urea moiety (Scheme 1, entries 1 and 2). A mixture of B2pin2 and catalytic amounts of [Ir(OMe)(cod)]2 and ligand 3 or 4a was stirred at 25 °C for 1 h to generate the catalytically active species, and the reaction mixture was treated with benzamide 1a to give the borylated product 2a. The yields of 2a were checked at the early stage of the reaction to measure the initial reaction rates. The reaction rate of the C-H borylation using 4a was found to be 3.3 times faster than that of the reaction using 3, suggesting that ligand 4a accelerated the C-H borylation by capturing 1a with the urea moiety of ligand 4a. We next investigated further acceleration of the C-H borylation by improving the ligand structure (Scheme 1, entries 3-6). An iridium/bipyridine-catalyzed C-H borylation of aromatic compounds is generally accelerated by the introduction of electron-donating group(s) on the bipyridine ligand.18 Thus, we prepared ligand 4b with a tert-butyl (electron-donating) group on the bipyridyl moiety of 4a, and investigated the differences between the reactivity of this reaction and the one undertaken with 4a (Scheme 1, entry 3): ligand 4b slightly accelerated the reaction. Molecular modeling suggested that the ortho-phenylene and bipyridyl

aFor

the reaction time in the second step, see Figure S2 in the Supporting Information.

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ACS Catalysis proceeded via the twisted structure. As we expected, the CyUbpy-type ligand 4d with both tert-butyl and methyl groups at the bipyridyl and ortho-phenylene moieties, respectively, further accelerated the C-H borylation reaction (Scheme 1, entry 5). We finally tuned the catalytic activity by changing the substituent on the urea moiety from the cyclohexyl group to an n-hexyl group (ligand 4e). As a result, the reaction rate increased (Scheme 1, entry 6). In summary, ligand 4e accelerated the C-H borylation reaction by 26 and 7.9 times of the rates obtained using ligands 3 and 4a, respectively. In addition, C-H borylation was accelerated using ligand 4e instead of ligand 4f without tert-butyl and methyl groups (Scheme 1, entry 7). The yield of borylated product 2b was improved using a urea moiety-containing series of ligands 4 (Scheme 2). NMethylbenzamide 1b was treated with B2pin2 in the presence of an iridium/3 or iridium/4a catalyst to give the meta-borylated product 2b in 8% and 20% yields, respectively. The meta-borylated benzamide 2b was formed in 55% yield when using ligand 4d. By changing the ligand to 4e, the yield of 2b increased dramatically (85%). These results showed that the ligand series 4, especially 4e, can accelerate the C-H borylation of aromatic substrates with a low reactivity, such as 1b. Scheme 2. Improvement of yield of meta-borylated Nmethylbenzamide 2b using ligand 4

Scheme 3. Competition reaction between benzamide 1a and benzoate 5

We then investigated the intramolecular functional group specificity of aromatic compound 7 with amide and ester groups (Scheme 4). In this reaction, the C-H borylation occurred at the meta-positions of the amide group regioselectively in the case of ligands 4a, 4d, and 4e, and metaborylated product 8 was obtained as a major product, with the 8/9 ratio being low in the case of ligand 3. These results showed that the urea-containing set of ligands 4, especially 4e, expressed functional group specificity. Scheme 4. Intramolecular competition reaction between amide and ester groups of aromatic substrate 7

In the following several competition reactions, we investigated the functional group and substrate specificity of our catalytic system. The reaction of a 1:1 mixture of benzamide 1a and benzoate 5 with B2pin2 in the presence of an iridium/3 catalyst afforded ca. 1:1 mixture of meta-borylated products 2a and 6 in 36% combined yield (Scheme 3). On the other hand, ligands 4a, 4d, and 4e produced the meta-borylated product 2a in good to excellent yields as the major product, and the ratio (2a/6) was 10.4 in the case of ligand 4e (Scheme 3).19 These results showed that the urea-containing ligand series 4, especially 4e, expressed functional group specificity. In addition, we investigated titration experiments to determine the association constants of ligand 4a to an amide or an ester. These results showed that the strength of the hydrogen bonding between the urea moiety of the ligand and a functional group of the substrate was correlated with the functional group specificity (for the details, see the Supporting Information).

Next, we investigated a competition reaction between N,N-dimethylbenzamide 1a and N,N-diphenylbenzamide 1c (Scheme 5). We noted that meta-borylated N,N-dimethyl benzamide 2a was formed as a major product using ligands 4a and 4d whereas the yields of meta-borylated products 2a and 2c were almost the same as in the case of ligand 3. The 2a/2c ratio decreased by using ligand 4e (2a/2c = 2.5), probably due to the decreased steric hindrance compared to that in the case involving ligand 4d (the hexyl group of 4e

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is smaller than the cyclohexyl group of 4d). Therefore, we synthesized a urea-containing ligand with a bulkier substituent on the urea moiety 4g. As a result, the 2a/2c ratio increased dramatically (2a/2c = 10.3), indicating that ligands with a urea moiety, 4a, 4d, 4e, and 4g (especially 4g), exhibited a substrate specificity.

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General experimental procedures and characterization data for ligands, substrates, and borylated products. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author [email protected]

Scheme 5. Competition reaction between N,N-dimethylbenzamide 1a and N,N-diphenylbenzamide 1c

ORCID Motomu Kanai: 0000-0003-1977-7648 Yoichiro Kuninobu: 0000-0002-8679-9487

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was partially supported by JSPS KAKENHI Grant Numbers JP 26288014, JP 17H03016, and 18H04656, and ERATO from JST.

REFERENCES

In summary, we found that bipyridine-type ligands with a urea moiety accelerated the iridium-catalyzed meta-selective C-H borylation of aromatic amides and expressed functional group and substrate specificities in the reaction. The C-H borylation was accelerated by a urea moiety-containing bipyridine-type ligand (Cy-Ubpy) compared to the case involving a bipyridine-type ligand without the urea moiety. The reaction rate was further accelerated by introducing tert-butyl and methyl groups on the bipyridine and orthophenylene moieties of Cy-Ubpy, respectively. The acceleration must be due to increased the electron density on the iridium center and the twisted structure of the ortho-phenylene and bipyridyl moieties. By using the urea moietycontaining ligands, the yield of C-H borylation of a less reactive substrate such as N-methylbenzamide improved dramatically. Functional group specificity was expressed in intermolecular and intramolecular competition reactions between amide and ester groups when using the urea moietycontaining bipyridine-type ligands. In addition, substrate specificity was exhibited in the competition reaction between N,N-dimethylbenzamide and N,N-diphenylbenzamide by using a newly designed urea moiety-containing bipyridine-type ligand with a bulky substituent on the urea moiety. We hope that these results will provide a useful insight toward improvement of the reaction rate and expression of the functional group and substrate specificities as well as control of the regioselectivity in C-H transformations and other reactions.

ASSOCIATED CONTENT Supporting Information

(1) Enzyme Specificity and Selectivity. Encyclopedia of Life Sciences (ELS) [online]; John Wiley & Sons, Ltd, Posted February 2010. https://onlinelibrary.wiley.com/doi/pdf/10.1002/9780470015902.a0000716.p ub2 (accessed in Nov 30th, 2018) (2) Fischer, E. Ueber die optischen Isomeren des Traubenzuckers, der Gluconsäure und der Zuckersäure. Ber. Dtsch. Chem. Ges. 1890, 23, 2611-2624. (b) Fischer, E. Einfluss der Configuration auf die Wirkung der Enzyme. Ber. Dtsch. Chem. Ges. 1894, 27, 29852993. (c) Koshland, Jr. D. E. The Key–Lock Theory and the Induced Fit Theory. Angew. Chemie. Int. Ed. Engl. 1994, 33, 2375-2378. (3) Fersht, A., Enzyme Structure and Mechanism; W.H. Freeman: San Francisco; 1985; pp 50–52. (b) Cox, M. M.; Nelson, D. L. Chapter 6.2: How enzymes work. In Lehninger Principles of Biochemistry, 6th ed.; W. H. Freeman; New York, 2013; p 195. (4) Breslow, R.; Overman, L. E. An "Artificial Enzyme" Combining a Metal Catalytic Group and a Hydrophobic Binding Cavity. J. Am. Chem. Soc. 1970, 92, 1075-1077. (5) For several reviews of artificial enzymes, see: (a) Murakami, Y.; Kikuchi, J.-i.; Hisaeda, Y.; Hayashida, O. Artificial Enzymes. Chem. Rev. 1996, 96, 721-758. (b) Dong, Z.; Luo, Q.; Liu, J. Artificial Enzymes Based on Supramolecular Scaffolds. Chem. Soc. Rev. 2012, 41, 7890-7908. (6) Desper, J. M.; Breslow, R. Catalysis of an Intramolecular Aldol Condensation by Imidazole-Bearing Cyclodextrins. J. Am. Chem. Soc. 1994, 116, 12081-12082. (7) Jubian, V.; Veronese, A.; Dixon, R. P.; Hamilton, A. D. Acceleration of a Phosphate Diester Transesterification Reaction by Bis(alkylguanidinium) Receptors Containing an Appended General Base. Angew. Chem. Int. Ed. Engl. 1995, 34, 1237-1239. (8) Koike, T.; Kimura, E. Roles of Zinc(II) Ion in Phosphatases. A model Study with Zinc(II)-Macrocyclic Polyamine Complexes. J. Am. Chem. Soc. 1991, 113, 8935-8941. (9) Matsumura, K.; Endo, M.; Komiyama, M. Lanthanide Complex–Oligo-DNA Hybrid for Sequence-Selective Hydrolysis of RNA. J. Chem. Soc., Chem. Commun. 1994, 2019-2020. (10) Mote, N. R.; Chikkali, S. H. Hydrogen‐Bonding‐Assisted Supramolecular Metal Catalysis. Chem. Asian J. 2018, 13, 3623-3646. (11) Kuninobu, Y.; Ida, H.; Nishi, M.; Kanai, M. A meta-Selective C– H Borylation Directed by a Secondary Interaction Between Ligand and Substrate. Nature Chem. 2015, 7, 712-717. (12) For examples of ion pair-directed meta-selective C-H borylation, see: (a) Davis, H. J.; Mihai, M. T.; Phipps, R. J. Ion Pair-Directed Regiocontrol in Transition-Metal Catalysis: A Meta-Selective C–H Borylation of Aromatic Quaternary Ammonium Salts. J. Am. Chem.

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ACS Catalysis Soc. 2016, 138, 12759-12762. (b) Davis, H. J.; Genov, G. R.; Phipps, R. J. meta‐Selective C−H Borylation of Benzylamine‐, Phenethylamine‐, and Phenylpropylamine‐Derived Amides Enabled by a Single Anionic Ligand. Angew. Chem. Int. Ed. 2017, 56, 13351-13355. (13) For an example of meta-selective C-H borylation controlled by the interaction between a boryl group on the iridium center and a substrate, see: Bisht, R.; Chattopadhyay, B. Formal Ir-Catalyzed Ligand-Enabled Ortho and Meta Borylation of Aromatic Aldehydes via in Situ-Generated Imines. J. Am. Chem. Soc. 2016, 138, 84-87. (14) For an example of para-selective C-H borylation controlled by the coordination bond of a carbonyl group of substrates to a potassium cation, see: Hoque, M. E.; Bisht, R.; Haldar, C.; Chattopadhyay, B. Noncovalent Interactions in Ir-Catalyzed C–H Activation: LShaped Ligand for Para-Selective Borylation of Aromatic Esters. J. Am. Chem. Soc. 2017, 139, 7745-7748. (15) For an example of meta-selective C-H borylation controlled by the cation- interaction between an amide group of substrates and a potassium cation, see: Bisht, R.; Hoque, M. E.; Chattopadhyay, B. Amide Effects in C−H Activation: Noncovalent Interactions with L‐Shaped Ligand for meta Borylation of Aromatic Amides. Angew. Chem. Int. Ed. 2018, 57, 15762-15766. (16) We also reported ortho-selective C-H borylation controlled by Lewis acid-base interaction between the ligand and substrate.

See: Li, H.-L.; Kuninobu, Y.; Kanai, M. Lewis Acid-Base InteractionControlled ortho-Selective C−H Borylation of Aryl Sulfides. Angew. Chem. Int. Ed. 2017, 56, 1495-1499. (17) For pioneering examples of iridium/bipyridine-catalyzed CH borylation of aromatic compounds, see: (a) Cho, J.-Y.; Tse, M. K.; Holmes, D.; Maleczka Jr., R. E.; Smith, M. R. III Remarkably Selective Iridium Catalysts for the Elaboration of Aromatic C-H Bonds. Science 2002, 295, 305-308. (b) Ishiyama, T.; Takagi, J.; Ishida, K.; Miyaura, N.; Anastasi, N. R.; Hartwig, J. F. Mild Iridium-Catalyzed Borylation of Arenes. High Turnover Numbers, Room Temperature Reactions, and Isolation of a Potential Intermediate. J. Am. Chem. Soc. 2002, 124, 390-391. (18) Ishiyama, T.; Nobuta, Y.; Hartwig, J. F.; Miyaura, N. Room Temperature Borylation of Arenes and Heteroarenes Using Stoichiometric Amounts of Pinacolborane Catalyzed by Iridium Complexes in an Inert Solvent. Chem. Commun. 2003, 2924-2925. See also ref. 17b. (19) We determined the initial reaction rate constant of ester 5 using ligand 4a. The value of 5 (k = 0.79) was lower than that of amide 1a (k = 1.81, Scheme 1, entry 2). The difference was correlated with the ratio between 2a and 6. For the details, see the Supporting Information.

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