Regioselective Synthesis of o-Benzenediboronic Acids via Ir-Catalyzed o-C-H Borylation Directed by a Pyrazolylaniline-Modified Boronyl Group

Article abstract of DOI:10.1021/acs.orglett.7b00041

Ir-catalyzed ortho-directed C-H borylation of pyrazolylaniline (PZA)-modified arylboronic acids with bis(pinacolate)diboron afforded o-benzenediboronic acids in which two boronyl groups are differentially modified by pinacol (PIN) and PZA. By using this borylation after nondirected Ir-catalyzed C-H borylation, o-benzenediboronic acids are conveniently synthesized from unfunctionalized arenes. The differentially modified o-benzenediboronic acids undergo selective oxidation and Suzuki-Miyaura cross-coupling at the PZA-modified boronyl groups, affording o-functionalized arylboronic acids selectively.

Full text of DOI:10.1021/acs.orglett.7b00041

Letter
pubs.acs.org/OrgLett
Regioselective Synthesis of o‑Benzenediboronic Acids via Ir-
Catalyzed o‑C−H Borylation Directed by a Pyrazolylaniline-Modified
Boronyl Group
Takeshi Yamamoto, Aoi Ishibashi, and Michinori Suginome*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Katsura,
Nishikyo-ku, Kyoto 615-8510, Japan
S
* Supporting Information
ABSTRACT: Ir-catalyzed ortho-directed C−H borylation of pyrazolylaniline (PZA)-
modified arylboronic acids with bis(pinacolate)diboron afforded o-benzenediboronic
acids in which two boronyl groups are differentially modified by pinacol (PIN) and
PZA. By using this borylation after nondirected Ir-catalyzed C−H borylation, o-
benzenediboronic acids are conveniently synthesized from unfunctionalized arenes.
The differentially modified o-benzenediboronic acids undergo selective oxidation and
Suzuki−Miyaura cross-coupling at the PZA-modified boronyl groups, affording o-
functionalized arylboronic acids selectively.
attracted much attention as a convenient route to o-
benzenediboronic acids.3b,c,8 Although these synthetic proto-
cols are highly efficient and selective, the requirement for 1,2-
difunctionalized arenes as starting material detracts much from
the synthetic efficacy of the approach.2a,b,9 Notably, high-
yielding, photoinduced dual C−H/C−X borylation of mono-
haloarenes C has been reported quite recently.10,11 However,
although predictable, the selectivity for the formation of 1,2-
diborylated products over 1,3-diborylated products depends to
a significant degree on the electronic effect of substituents on
the aromatic group. Furthermore, it is highly desirable to utilize
simple arylboronic acids D or even nonfunctionalized arenes E
as starting materials in the synthesis of o-benzenediboronic
acids through C−H activation without using functionalized
arenes bearing halogen or pseudohalogen leaving groups.
We previously reported Ru-catalyzed o-C−H silylation of
arylboronic acids by attaching a temporary directing group on
the boron atom of arylboronic acids.12 Modification of the
boronyl group with pyrazolylaniline or anthranilamide, which
leads to the formation of the Bpza or Baam group, respectively,
was found to be critical for the success of the highly selective
directed transformation. In this paper, we describe the use of
the PZA-modified boronyl groups as a temporary directing
group in Ir-catalyzed o-C−H borylation. Although o-C−H
borylation directed by several heteroatom functional groups
was achieved by using Ir13 and other transition-metal
catalysts,14 to our knowledge, boronyl-group-directed o-C−H
borylation has not been reported. By utilizing the directed
borylation, nonfunctionalized arenes are transformed into 1,2-
o-Benzenediboronic acid is an attractive structural motif not
only as a building block and synthetic intermediate for the
synthesis of natural products,1 polycyclic aromatic hydro-
carbons,2 and oligoarene derivatives3 but also as a bidentate
Lewis acid4 and key organic component of hydrogen-bonded
organic frameworks.5 In view of the rapid expansion of the
utilization of functionalized boronic acid derivatives in various
research fields including material science and organocatalysis, it
is important to develop efficient and convenient synthetic
access to o-benzenediboronic acids.
The synthesis of o-benzenediboronic acids A has generally
relied on the use of 1,2-difunctionalized benzene derivatives B
as starting materials (Scheme 1).4−6 In typical cases, o-
halobenzeneboronic acids or 1,2-dihalobenzenes are converted
into o-benzenediboronic acids through halogen−metal (Li or
Mg) exchange5,6d−g or palladium-catalyzed Miyaura boryla-
tion.1,2b,c,3a,7 Recently, catalytic diborylation of arynes gen-
erated from 1,2-difunctionalized benzene derivatives has
Scheme 1. Preparation of o-Benzenediboronic Acids
Received: January 5, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00041
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
benzenediboronic acid derivatives through nondirected C−H
borylation followed by Bpza-directed o-C−H borylation.
PZA-modified phenylboronic acid 1a, synthesized by
condensation of phenylboronic acid and 2-pyrazol-3-ylanili-
ne,12a reacted with diboron in the presence of catalytic amounts
of transition-metal complexes (Table 1). The resultant reaction
(14%) (entry 10). The requirement for the ortho-directing
group was confirmed by the observation that no product was
formed in the reactions of PhB(OH)2 or PhBpin under the
same reaction conditions (entries 11 and 12). Furthermore, the
use of PhBdan bearing a 1,8-diaminonaphthalene (DAN)-
masked boronyl group afforded no desired product (entry 13).
PhBaam underwent C−H borylation mainly at the anthranila-
mide group rather than at the o-C−H bond (entry 14). It was
also found that use of HBpin instead of B2pin2 as a boron
source successfully gave the o-borylation product in good yield
(entry 15). In this case, a higher yield was obtained by raising
the reaction temperature to 110 °C (entry 16). The primary
product 2, bearing Bpza and Bpin groups, was isolated by
crystallization, albeit in moderate yield, and found to be
hydrolytically unstable.
Table 1. o-C−H Functionalization of Phenylboronic Acid
a
Derivatives
Under the optimized reaction conditions, various PZA-
modified arylboronic acids were subjected to the directed C−H
borylation (Scheme 2). All the products were isolated after
a b
,
Scheme 2. Substrate Scope
yield (%) of
b
entry substrate (1)
catalyst
solvent
THF
3a
1
PhBpza (1a) [Ir(OMe)(cod)]2
(4)
85
c
2
1a
4, dtbpy
THF
<1 (15)
3
1a
[IrCl(cod)]2
THF
59
5
4
1a
[RhCl(cod)]2
THF
5
1a
[RhOH(cod)]2
THF
2
6
1a
4
4
4
4
4
4
4
4
4
4
4
cyclohexane
toluene
1,4-dioxane
60
57
67
68
74
0
7
1a
8
1a
d
9
1a
1,2-DME
e
10
11
12
13
14
15
16
1a
THF
THF
THF
THF
THF
THF
THF
PhB(OH)2
PhBpin
PhBdan
PhBaam
1a
0
0
0
a
f
Reaction conditions: 1 (0.30 mmol), B2pin2 (0.45 mmol), [Ir(OMe)-
70
86
b
ef
,
(cod)]2 (3.0 μmol), THF (3.0 mL), 80 °C, 18 h. NMR yield. Isolated
yields in parentheses. [Ir(OMe)(cod)]2 (7.5 μmol).
1a
c
a
Reaction conditions: 1 (0.10 mmol), B2pin2 (0.15 mmol), and
b
c
catalyst (1.0 μmol), THF (1.0 mL), 80 °C, 18 h. GC yield. NMR
yield of m- and p-diborylbenzenes. 1,2-Dimethoxyethane. Reaction
at 110 °C. HBpin (0.30 mmol) instead of B2pin2.
d
e
conversion into the corresponding bispinacolates after treat-
ment of the reaction mixtures with pinacol. The reaction of p-
substituted compounds bearing methoxy, trifluoromethyl, and
methyl groups afforded 4-substituted 1,2-diborylbenzenes 3b−
d. The directed C−H borylation of m-substituted arenes
proceeded at the less hindered o-positions, giving 4-substituted
1,2-diborylbenzenes 3b−g selectively. o-Substituted com-
pounds could also be employed in the C−H borylation, giving
the corresponding 3-substituted 1,2-benzenediboronates 3h−j
in high yields. 1-Naphthyl- and 2-naphthylboronic acids gave
1,2- and 2,3-diborylnaphthalenes 3k and 3l, respectively, in high
yield and with excellent selectivity.
The Bpza-directed o-borylation, in combination with non-
directed C−H borylation,15 allowed the synthesis of 1,2-
benzenediboronic acids from nonfunctionalized arenes
(Scheme 3). 1-Chloro-2-methoxybenzene was subjected to Ir-
catalyzed C−H borylation with B2pin2 in the presence of
[Ir(OMe)(cod)]2, giving a mixture of two regioisomers in a 1:1
ratio.16 The mixture was treated with 2-pyrazol-3-ylaniline and
subjected to the directed C−H borylation under the standard
reaction conditions. After treatment with pinacol, 3-chloro-4-
f
mixture was treated with pinacol for detection and
quantification of borylation product 2 in the form of pinacol
ester (3a). In the presence of 1.0 mol % [Ir(OMe)(cod)]2, o-
C−H borylation proceeded at 80 °C for 18 h, giving 3a in 85%
yield (entry 1). Notably, unreacted 1a and double borylated
product were recovered as PhBpin (10%) and 1,2,3-benzene-
triboronic acid pinacol ester (5a, 5%), respectively. Addition of
4,4′-di-tert-butyl-2,2′-bipyridyl (dtbpy), which is recognized as
the most effective ligand in nondirected C−H borylation,
resulted in m- or p-C−H borylation preferentially (15%, m:p =
1:2) (entry 2). The reaction with [IrCl(cod)]2 afforded 3a in
59% yield (entry 3). Although [RhCl(cod)]2 and [RhOH-
(cod)]2 showed low catalyst activities, C−H borylation
proceeded at the o-position selectively (entries 4 and 5). The
use of cyclohexane, toluene, 1,4-dioxane, or 1,2-dimethoxy-
ethane as solvent resulted in lower yields, with recovery of
unreacted 1a as PhBpin (entries 6−9). Performing the reaction
at 110 °C gave 3a in lower yield and with a larger amount of 5a
B
DOI: 10.1021/acs.orglett.7b00041
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Organic Letters
Letter
Scheme 3. Synthesis of o-Benzenediboronic Acid Derivatives
from Nonfunctionalized Arenes
Scheme 5. One-Pot Synthesis of o-Borylated Biaryls
a
a
Reaction conditions: (a) [Ir(OMe)(cod)]2 (1.5 mol %), dtbpy (3.0
mol %), B2pin2 (1.2 equiv), THF, rt, 18 h; (b) NaIO4 (3 equiv), THF,
H2O, 30 min, then HCl aq, 4 h; (c) H2pza, toluene, reflux; (d)
[Ir(OMe)(cod)]2 (1.0 mol %), B2pin2 (1.5 equiv), THF, 80 °C, 18 h;
(e) pinacol (2.0 equiv), PTSA·H2O (2.0 equiv), THF, 80 °C, 1 h; (f)
[Ir(OMe)(cod)]2 (0.5 mol %), dtbpy (1.0 mol %), B2pin2 (1.0 equiv),
toluene (30 equiv), rt, 30 h; (g) [Ir(OMe)(cod)]2 (2.0 mol %), B2pin2
(1.5 equiv), THF, 80 °C, 18 h.
borylation of p-TolBpza (p-1d) using 3 equiv of HBpin, the
reaction mixture was treated with isopropyl alcohol to
decompose the remaining HBpin. Suzuki−Miyaura cross-
coupling of the obtained crude product bearing Bpza and
Bpin groups with 1-bromonaphthalene or ethyl 2-bromoben-
zoate proceeded at the Bpza group with high selectivity, giving
biaryls 7a and 8a, bearing a Bpin group, along with the
formation of a small amount of regioisomers 7b and 8b. Under
the same reaction conditions, m-TolBpza (m-1d) was converted
into methyl-substituted biaryls 7b and 8b, bearing a Bpin
group, with high regioselectivity, in one-pot.
In conclusion, we have demonstrated a new Ir-catalyzed
directed C−H borylation of arylboronic acid derivatives by
attaching a removable directing group on the boron atoms. By
combining with the nondirected C−H borylation, the reaction
provides a new, convenient access to o-benzenediboronic acids
from nonfunctionalized arenes through conversion of the two
adjacent aromatic C−H bonds on the aromatic rings. The
unsymmetrically modified o-benzenediboronic acids with PZA
and PIN undergo selective conversion at the Bpza group in the
TMAO oxidation and Suzuki−Miyaura cross-coupling.
methoxy-1,2-benzenediboronate (3m) was isolated in good
overall yield as a single regioisomer. This four-step protocol was
also applicable to monosubstituted benzenes, as demonstrated
by the conversion of toluene into 4-methyl-1,2-benzenedibor-
onic acid (3d) (Scheme 2).
Our attention then turned to the reactivities of 2, bearing two
different masking groups, namely, PIN and PZA, on the boron
atoms. When m-TolBpza (m-1d) was subjected to the directed
C−H borylation and subsequent oxidation with trimethylamine
oxide (TMAO, 2.5 equiv), we observed selective oxidation of
one of the two different boron functional groups. The reaction
gave o-hydroxyarylboronic acid 6, which has been reported to
be an important coupling building block in iterative cross-
coupling for the synthesis of oligoarene derivatives, in a highly
chemoselective manner (Scheme 4).17,18 It is interesting to
Scheme 4. One-Pot Synthesis of o-Hydroxyarylboronic Acid
Derivatives
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.7b00041.
Detailed experimental procedures and compound char-
acterization data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: suginome@sbchem.kyoto-u.ac.jp.
ORCID
note that the Bpza group was oxidized selectively over the Bpin
group. When m-TolBpza and m-TolBpin were separately
treated with TMAO, we found that Bpza was more prone to
oxidation (see Supporting Information). Use of regioisomeric
TolBpza as a starting material allowed the synthesis of
regioisomeric products 6a and 6c with high selectivity.
Similarly, a pair of regioisomeric methoxy-substituted o-
hydroxyarylboronic acid derivatives (6b and 6d) was prepared
selectively.
Michinori Suginome: 0000-0003-3023-2219
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant Number
JP15H05811 in Precisely Designed Catalysts with Customized
Scaffolding and JP24750105 in Grant-in-Aid for Young
Scientists (B).
The Bpza selective conversion was also observed in Suzuki−
Miyaura cross-coupling (Scheme 5). After the directed o-C−H
C
DOI: 10.1021/acs.orglett.7b00041
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Organic Letters
Letter
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