Bipyridine-Catalyzed ortho-Selective C–H Borylation of Phenol

Letter Cite This: Org. Lett. 2017, 19, 5944-5947

pubs.acs.org/OrgLett

Iridium/Bipyridine-Catalyzed ortho-Selective C−H Borylation of Phenol and Aniline Derivatives Hong-Liang Li,† Motomu Kanai,*,†,‡ and Yoichiro Kuninobu*,‡,§ †

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 § Institute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasugakoen, Kasuga-shi, Fukuoka 816-8580, Japan ‡

S Supporting Information *

ABSTRACT: An iridium-catalyzed ortho-selective C−H borylation of phenol and aniline derivatives has been successfully developed. Iridium/ bipyridine-catalyzed C−H borylation generally occurred at the meta- and para-positions of aromatic substrates. Introduction of an electronwithdrawing substituent on the bipyridine-type ligand and a methylthiomethyl group on the hydroxy and amino groups of the phenol and aniline substrates, however, dramatically altered the regioselectivity, affording exclusively ortho-borylated products. The reaction proceeded in good to excellent yields with good functional group tolerance. C−H borylation was applied to the synthesis of a calcium receptor modulator.

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occurs at the meta- and para-positions of the aromatic compounds to avoid steric hindrance between substituent(s) of the aromatic substrates and the iridium active species. Regiocontrol of C−H borylation has recently received increased attention. We achieved hydrogen-bond-controlled meta-selective C−H borylation.7 para-Selective C−H borylation was also recently reported.8 Several groups reported orthoselective C−H borylation: (1) using a directing group;9 (2) by a silyl-directed method;10 (3) by outer sphere direction;11 (4) by Lewis acid−base interaction between two substrates;12 (5) by Lewis acid−base interaction between a ligand and a substrate;13 (6) by electrostatic interaction between a ligand and a substrate;14 (7) using a N,B-bidentate boryl ligand;15 and (8) using a Si,P-bidentate ligand.16 We report herein iridium/bipyridine-catalyzed ortho-selective C−H borylation of phenol14 and aniline11b derivatives by protecting the hydroxy and amino groups with a methylthiomethyl group, and introducing an electron-withdrawing group into bipyridine-type ligands. First, we investigated several ligands in a reaction between aromatic substrate 1a and bis(pinacolato)diboron (2) (Scheme 1). Ligand L1 (dtbpy) gave a mixture of ortho-, meta-, and paraC−H borylated products in 88% yield, but the [ortho/(meta + para)] ratio was low (0.83). The use of bipyridine ligands L2 and L3 with electron-withdrawing groups improved the [ortho/ (meta + para)] ratio, but the yields of the C−H borylated products were lower. The use of 5-phenyl-2,2′-bipyridine (L6) as a ligand afforded a mixture of C−H borylated products in 72% yield [ortho/(meta + para) = 9.3]. The [ortho/(meta + para)] ratio was dramatically improved by the use of borylated

henol and aniline derivatives are useful compounds as dyes, pigments, and agricultural chemicals.1 Phenols and anilines are also versatile building blocks in numerous natural products, bioactive compounds, and pharmaceuticals (Figure 1).2 Therefore, the development of a site-selective C−H functionalization of phenol and aniline derivatives is an important goal. C−H borylation is a direct and convenient reaction for the synthesis of organoboron compounds, which are useful starting materials in organic syntheses,3 organic functional materials,4 and drugs.5 A pioneering example of C−H borylation is iridium/bipyridine-catalyzed C−H borylation of aromatic compounds.6 In these reactions, the C−H borylation generally

Figure 1. Bioactive compounds containing phenol and aniline moieties. © 2017 American Chemical Society

Received: September 19, 2017 Published: October 18, 2017 5944

DOI: 10.1021/acs.orglett.7b02936 Org. Lett. 2017, 19, 5944−5947

Letter

Organic Letters Scheme 1. Ligand Screeninga

Scheme 2. Investigation of Substrate Scope of Aromatic Compoundsa

a Yield was determined by 1H NMR using 1,1,2,2-tetrachloroethane as an internal standard. Ratio of ortho to (meta + para) was reported in square brackets.

ligands L4 and L5, but the yield of a mixture of C−H borylated products was not satisfactory. Several substituents on the phenyl group were screened for their effects to improve the yield. Both the yield and [ortho/(meta + para)] ratio were improved as the electron-withdrawing ability of the substituent increased, and trifluoromethylated ligand L11 provided the best yield and [ortho/(meta + para)] ratio (90% yield17 [ortho/ (meta + para) = >30]). However, the yields of the products decreased when using bipyridine-type ligands L12 and L13 with an electron-withdrawing group on the pyridine ring. Next, we investigated the substrate scope of aromatic compounds 3 (Scheme 2). In all entries, the ortho-selectivity was dramatically improved by using ligand L11 instead of dtbpy, and the [ortho/(meta + para)] ratio of the borylated products was >30. The ortho-C−H borylation proceeded well when using phenol derivatives 1b and 1c with an electronwithdrawing or -donating substituent at the ortho-position. There are two possible reaction sites in the case of aromatic substrates with a substituent (electron-donating group (3j, 3k) and electron-withdrawing group (3f, 3g, 3h, 3i)) at the metaposition. The C−H borylation proceeded only at an ortho-position with less steric hindrance and gave ortho-borylated products 3d−3l without loss of the functional groups when L11 was used. These results were in sharp contrast to results of the reaction when using the dtbpy ligand, in which the C−H borylation reaction predominately occurred at the meta-

a

2a (0.50 equiv). A: Isolated yield of monoborylated products (as a mixture of ortho-, meta- and para-products) using ligand L11. Ratio of ortho to (meta + para) is reported in square brackets. B: Isolated yield of monoborylated products using dtbpy ligand. Ratio of ortho to (meta + para) is reported in square brackets

positions of phenol derivatives. Noteworthy is that the C−H borylation reaction also worked well using 3i as a substrate with a ketone moiety, which is usually reduced to a hydroxy group during the reaction.8e In addition, the ortho-selective C−H borylation also proceeded smoothly when using aniline derivatives 1m−1t and gave the corresponding ortho-borylated products 3m−3t in good yield without inhibition by the 5945

DOI: 10.1021/acs.orglett.7b02936 Org. Lett. 2017, 19, 5944−5947

Letter

Organic Letters functional groups and/or loss of the functional groups.18 The reaction with substrate 1r with a cyano substituent at the metaposition afforded a di-ortho-borylated product, even at the sterically hindered ortho-position. This result indicates that HBpin, which must be formed after the first borylation, also worked as a borylation reagent. The C−H borylation gave poor ortho-selectivity when methylthiomethylene (−CH2SCH3, MTM) was replaced by methoxymethylene (−CH2OCH3, MOM) to protect the hydroxy or amino group, such as when using (methoxymethoxy)benzene as the substrate (L11: 61% [ortho/(meta + para) < 0.01]; dtbpy: 50% [ortho/(meta + para) < 0.01]). Interestingly, the yield of borylated products and the [ortho/(meta + para)] ratio were improved using an electron-poor ligand compared with dtbpy in many entries. This finding indicated that a sulfur atom at the α-position to the oxygen or nitrogen atom of phenol or aniline derivatives and a ligand with an electron-withdrawing group are important for controlling the ortho-regioselectivity. The C−H borylation reaction proceeded in good yield with high ortho-selectivity, even in gram scale (Scheme 3).

B).9,21 The results of ligand screening in Scheme 1 supported both pathways: that is, an electron-withdrawing group on the phenyl ring of Ar-bipyridine ligands enhanced the reaction rate and improved the yield of 3a. The reaction pathway, however, is not clear. Finally, we applied the reaction to the synthesis of a calcium receptor modulator (Scheme 5).22 Treatment of aromatic Scheme 5. Application to the Synthesis of Calcium Receptor Modulator

Scheme 3. Gram-Scale Reaction

Treatment of 1.00 g of phenol derivative1a with diboron 2 in thepresence of an iridium/L11 catalyst gave 1.21 g of orthoborylated product 3a in 77% yield ([ortho/(meta + para)] > 30). We also investigated the removal of a protecting group (Scheme 4). Treatment of ortho-borylated product 3a (0.500 g, 1.79 mmol) with I2 (0.454g, 1.0 equiv) in MeOH at 55 °C gave 0.45 g of deprotection product 4 in 83% yield.19,20

substrate 1u with a combination of tert-butyl imine and bis(pinacolato)diboron (2) in the presence of catalytic amounts of iridium complex [Ir(OMe)(cod)]2 and ligand L11 gave ortho-C−H borylated product 3u in 64% yield without loss of the formyl group.23−25 Coupling product 6 was obtained in 85% yield by a Suzuki−Miyaura cross-coupling reaction between 3u and 5-bromo-1-methyl-1H-indole (5). Condensation of 6 with (R)-1-phenylethan-1-amine (7) and successive reduction and elimination of a methylthio group produced the calcium receptor modulator 8 in 80% yield. In the present method, there are two significant points to enhance the synthetic efficiency: (1) ortho-borylated compound 3u was obtained by a “one-pot” reaction from 1u to 3u (aldimine formation and successive ortho-selective C−H borylation) without loss of the formyl group; (2) final product 8 was obtained by reduction of the imino group and elimination of a methylthio group at the same time (from 6 to 8). In summary, we successfully developed an ortho-selective C− H borylation of phenol and aniline derivatives. Several examples of ortho-selective C−H borylation of aromatic compounds have recently been reported, but the examples of phenol and aniline derivatives are still rare. Key to the success was the introduction of a methylthio group at the α-position to the oxygen or nitrogen atom of the phenol or aniline derivatives and the use of a bipyridine-type ligand with an electron-withdrawing group. The regioselectivity was dramatically altered by changing the substituent(s) on the bipyridine core: the C−H borylation proceeds with high ortho-selectivity when using 5-(4-(trifluoromethyl)phenyl)-2,2′-bipyridine whereas C−H borylation oc-

Scheme 4. Deprotection

We considered two possible reaction mechanisms (Figure 2): (1) C−H borylation proceeds via an outer-sphere Lewis acid− base interaction between a boryl ligand of an iridium center and a sulfur atom of a substrate (Mechanism A);11a (2) C−H borylation proceeds via the coordination of a sulfur atom of a substrate to an iridium center as a directing group (Mechanism

Figure 2. Two possible mechanisms of ortho-selective C−H borylation. 5946

DOI: 10.1021/acs.orglett.7b02936 Org. Lett. 2017, 19, 5944−5947

Letter

Organic Letters

ACS Catal. 2016, 6, 7536. (c) Zhu, L.; Qi, X.; Li, Y.; Duan, M.; Zou, L.; Bai, R.; Lan, Y. Organometallics 2017, 36, 2107. (d) Yang, L.; Semba, K.; Nakao, Y. Angew. Chem., Int. Ed. 2017, 56, 4853. (e) Hoque, M. E.; Bisht, R.; Haldar, C.; Chattopadhyay, B. J. Am. Chem. Soc. 2017, 139, 7745. (9) (a) Kawamorita, S.; Ohmiya, H.; Hara, K.; Fukuoka, A.; Sawamura, M. J. Am. Chem. Soc. 2009, 131, 5058. (b) Ishiyama, T.; Isou, H.; Kikuchi, T.; Miyaura, N. Chem. Commun. 2010, 46, 159. (c) Ros, A.; Estepa, B.; López-Rodríguez, R.; Á lvarez, E.; Fernández, R.; Lassaletta, J. M. Angew. Chem., Int. Ed. 2011, 50, 11724. (d) Kawamorita, S.; Miyazaki, T.; Ohmiya, H.; Iwai, T.; Sawamura, M. J. Am. Chem. Soc. 2011, 133, 19310. (e) Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134, 134. (f) Crawford, K. M.; Ramseyer, T. R.; Daley, C. J.; Clark, T. B. Angew. Chem., Int. Ed. 2014, 53, 7589. (g) Hale, L. V. A.; McGarry, K. A.; Ringgold, M. A.; Clark, T. B. Organometallics 2015, 34, 51. (10) Boebel, T. A.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 7534. (11) (a) Roosen, P. C.; Kallepalli, V. A.; Chattopadhyay, B.; Singleton, D. A.; Maleczka, R. E., Jr.; Smith, M. R., III J. Am. Chem. Soc. 2012, 134, 11350. (b) Preshlock, S. M.; Plattner, D. L.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E., Jr.; Smith, M. R., III Angew. Chem., Int. Ed. 2013, 52, 12915. (12) Kuninobu, Y.; Omura, T.; Iwanaga, T.; Takai, K. Angew. Chem., Int. Ed. 2013, 52, 4431. (13) Li, H.-L.; Kuninobu, Y.; Kanai, M. Angew. Chem., Int. Ed. 2017, 56, 1495. (14) Chattopadhyay, B.; Dannatt, J. E.; Andujar-De Sanctis, I. L.; Gore, K. A.; Maleczka, R. E., Jr.; Singleton, D. A.; Smith, M. R., III J. Am. Chem. Soc. 2017, 139, 7864. (15) Wang, G.; Liu, L.; Wang, H.; Ding, Y.-S.; Zhou, J.; Mao, S.; Li, P. J. Am. Chem. Soc. 2017, 139, 91. (16) Ghaffari, B.; Preshlock, S. M.; Plattner, D. L.; Staples, R. J.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E.; Smith, M. R., III J. Am. Chem. Soc. 2014, 136, 14345. (17) This is a total yield of ortho-borylated product 3a and orthodiborylated product of 1a. 3a and ortho-diborylated product of 1a were obtained in 66% and 16% isolated yields, respectively. (18) ortho-Borylated product 3m and ortho-diborylated product of 1m were obtained in 78% and 8% yields, respectively. (19) Keith, J. M. Tetrahedron Lett. 2004, 45, 2739. (20) Results of deprotection of other borylated products: 3f, 72% yield; 3k, 85% yield; 3p, 60%; 3s, 68% yield. (21) For an example of κ-1 bipyridine coordination to an iridium center, see ref 9c. (22) Kelly-Michael, G.; Xu, S.; Xi, N.; Miller, P.; Kincaid, J. F.; Ghiron, C. Calcium receptor modulating arylalkylamines, WO 03099776, 2003. (23) Bisht, R.; Chattopadhyay, B. J. Am. Chem. Soc. 2016, 138, 84. (24) ortho-Diborylated product of 1u was formed in 10% yield. (25) HBpin was not used in this case, because the yield of 3u decreased in the presence of HBpin. Probably, undesired reduction of the imine intermediate proceeded as a side reaction in the presence of HBpin.

curs meta- and para-selectively when using a 4,4′-di-tert-butyl2,2′-dipyridine (dtbpy) ligand. The desired products were obtained in good to excellent yields, even in gram scale, without loss of the functional groups. The protecting group of phenol and aniline derivatives can easily be removed after C−H borylation. The C−H borylation was applied to the synthesis of a calcium receptor modulator. This reaction is expected to become a useful method to synthesize ortho-borylated phenol and aniline derivatives and provides meaningful insight into synthetic organic chemistry.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b02936. General experimental procedures and characterization data for substrates 1, ligands L6−L13, ortho-borylated products 3, and products 6 and 8 (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

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

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was partially supported by ERATO from JST and JSPS KAKENHI Grant Number JP 26288014. REFERENCES

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DOI: 10.1021/acs.orglett.7b02936 Org. Lett. 2017, 19, 5944−5947