Iridium/Bipyridine-Catalyzed ortho-Selective C-H Borylation of Phenol and Aniline Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b02936

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 electron-withdrawing 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.

Full text of DOI:10.1021/acs.orglett.7b02936

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
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 electron-
withdrawing substituent on the bipyridine-type ligand and a methyl-
thiomethyl 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.
henol and aniline derivatives are useful compounds as
dyes, pigments, and agricultural chemicals.1 Phenols and
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 boryla-
tion was also recently reported.8 Several groups reported ortho-
selective 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
P
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
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 methyl-
thiomethyl 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 para-
C−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
Figure 1. Bioactive compounds containing phenol and aniline
moieties.
Received: September 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02936
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Scheme 1. Ligand Screening
Scheme 2. Investigation of Substrate Scope of Aromatic
a
Compounds
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 electron-
withdrawing 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 meta-
position.
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
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-
B
DOI: 10.1021/acs.orglett.7b02936
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Letter
functional groups and/or loss of the functional groups.18 The
reaction with substrate 1r with a cyano substituent at the meta-
position afforded a di-ortho-borylated product, even at the
sterically hindered ortho-position.
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.
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 methylthio-
methylene (−CH2SCH3, MTM) was replaced by methoxy-
methylene (−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).
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 ortho-
borylated 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). Condensa-
tion 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).
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
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-(trifluoro-
methyl)phenyl)-2,2′-bipyridine whereas C−H borylation oc-
Figure 2. Two possible mechanisms of ortho-selective C−H
borylation.
C
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curs meta- and para-selectively when using a 4,4′-di-tert-butyl-
2,2′-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.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02936.
General experimental procedures and characterization
data for substrates 1, ligands L6−L13, ortho-borylated
products 3, and products 6 and 8 (PDF)
(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 ortho-
diborylated 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.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: kanai@mol.f.u-tokyo.ac.jp.
*E-mail: kuninobu@cm.kyushu-u.ac.jp.
ORCID
Motomu Kanai: 0000-0003-1977-7648
Yoichiro Kuninobu: 0000-0002-8679-9487
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was partially supported by ERATO from JST and
JSPS KAKENHI Grant Number JP 26288014.
■
(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.
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DOI: 10.1021/acs.orglett.7b02936
Org. Lett. XXXX, XXX, XXX−XXX