Anthranilamide-masked o-iodoarylboronic acids as coupling modules for iterative synthesis of ortho-linked oligoarenes

Article abstract of DOI:10.1246/cl.130136

Anthranilamide (AAM)-masked o-iodoarylboronic acids were prepared from AAM-masked arylboronic acids via Rucatalyzed o-C-H silylation, followed by iododesilylation with ICl. The Suzuki-Miyaura coupling of AAM-masked o-haloarylboronic acids with arylboronic acids proceeded under ligandfree conditions. Oligo(o-phenylene)s and oligo(naphthalene-2,3-diyl)s were synthesized via iterative Suzuki-Miyaura coupling sequences.

Full text of DOI:10.1246/cl.130136

doi:10.1246/cl.130136
Published on the web May 5, 2013
541
Anthranilamide-masked o-Iodoarylboronic Acids as Coupling Modules
for Iterative Synthesis of ortho-Linked Oligoarenes
Masashi Koyanagi, Nils Eichenauer, Hideki Ihara, Takeshi Yamamoto, and Michinori Suginome*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering,
Kyoto University, Katsura, Kyoto 615-8510
(Received February 19, 2013; CL-130136; E-mail: suginome@sbchem.kyoto-u.ac.jp)
Anthranilamide (AAM)-masked o-iodoarylboronic acids
were prepared from AAM-masked arylboronic acids via Ru-
catalyzed o-C-H silylation, followed by iododesilylation with
ICl. The Suzuki-Miyaura coupling of AAM-masked o-haloaryl-
boronic acids with arylboronic acids proceeded under ligand-
free conditions. Oligo(o-phenylene)s and oligo(naphthalene-2,3-
diyl)s were synthesized via iterative Suzuki-Miyaura coupling
sequences.
R
ortho-
silylation
R
B(aam)
B(aam)
SiR'3
1
2
halo-
desilylation
R5
R
R4
B(aam)
R3
R1
iterative
coupling
X
3
Interest in the synthesis and structure of ortho-linked
oligoarenes and hetarenes has been increasing.1-4 They cannot
adopt planar structure, but they form helical structures due to the
steric repulsion of the substituents on the aromatic rings. In
addition to their static helical structures, the dynamic change in
the helical structures has attracted increasing attention from the
viewpoint of application to functional materials.5 For instance,
we have recently established solvent-dependent, reversible
switch of helical conformation of poly(quinoxaline-2,3-diyl)s
with high molecular weight.6 This system was successfully
applied to a new chiral catalyst system in which either
enantiomer can be produced with high enantioselectivity from
a single chiral catalyst.7 Although attractive, ortho-linked
oligoarenes and hetarenes have not been explored in detail yet,
mainly because of paucity of robust synthetic approaches.
Therefore, it is highly desirable to establish general, efficient
synthetic methods that would also allow the synthesis of
functionalized oligoarenes in a sequence-selective manner.
We have been interested in the development of cross-
coupling-based organic synthesis, including iterative synthesis
of oligoarene derivatives on the basis of boron-masking strategy
using 1,8-diaminonaphthalene (DAN) as a highly effective
masking group.8 We subsequently established a removable
ortho-directing group (o-DG), which is attached to the boron
atom of the boronyl group and allows Ru-catalyzed o-silylation.9
Although pyrazolylaniline (PZA) was reported also as the first-
generation o-DG, we subsequently showed that anthranilamide
(AAM) exhibited higher ability of o-direction as well as higher
stability, which allowed us to utilize AAM as a protective group
in the Suzuki-Miyaura coupling.10 We envisioned that AAM-
protected o-haloarylboronic acids 3 may serve as highly
convenient building modules in the synthesis of helical
oligo(o-arene)s via iterative Suzuki-Miyaura cross-coupling
(Figure 1). The modules 3 may be obtained directly by
halodesilylation of AAM-protected o-silylarylboronic acids 2,
which in turn are conveniently prepared by o-silylation of AAM-
protected arylboronic acids 1. It should be noted that a report on
direct ortho-iodination of unprotected arylboronic acids has
appeared recently.11,12 The direct iodination, however, still
requires the use of silver salt to promote the reaction and
R2
HN
B
HN
B(aam)
=
O
oligo(o-arene)s
Figure 1. Synthetic strategies of oligo(o-arene)s.
encounters difficulty in iodination of electron-poor and electron-
neutral arenes. In this paper, we demonstrate the convenient
synthesis of AAM-protected o-iodoarylboronic acids and their
use in the iterative Suzuki-Miyaura coupling for the synthesis of
oligo(o-phenylene)s and oligo(naphthalene-2,3-diyl)s.
AAM-protected o-silylarylboronic acids 2 were prepared
according to the reported procedure for Ru-catalyzed o-silylation
of arylboronic acids.10 In addition to the o-silylboronic acids 2a,
2b, 2d, 2g, and 2k reported in the previous paper, we also
synthesized new derivatives in good yields from the corre-
sponding AAM-protected arylboronic acids (Table 1). Iodode-
silylation was accomplished efficiently by use of ICl at a low
temperature.12 Attempted use of I2 or Br2 failed to give the
corresponding o-halogenated products in reasonable yields. In
the iododesilylation, the use of the electron-deficient AAM
group, rather than the electron-rich PZA group, was essential to
avoid undesirable iodination on the masking group. The present
synthesis of o-iodoarylboronic acids through iododesilylation
was found to be complementary to Hall’s silver-mediated direct
iodination, which requires electron-donating substituents such as
alkoxy and amino groups on the aromatic rings. Our method
could successfully be applied to alkyl- (Entries 2 and 8), aryl-
(Entry 10), chloro- (Entries 5 and 11), and even fluoro-
substituted arylboronic acids (Entry 6), in addition to alkoxy-
substituted arylboronic acids (Entries 3 and 9).13 Note that
attempted iododesilylation of the phenyldimethylsilyl group on
the electron-deficient aromatic ring failed (Entry 4), leading to
iodination at the phenyl group of the PhMe2Si group. This
problem was overcome by use of Et3Si derivative (Entries 5, 6,
7, and 11). It should also be noted that AAM-masked 5,8-
dimethyl-2-naphthylboronic acid, which was used for the
Chem. Lett. 2013, 42, 541-543
© 2013 The Chemical Society of Japan
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542
Table 1. Iododesilylation of AAM-protected o-silylarylboronic
acids produced by Ru-catalyzed o-directed silylation of AAM-
protected arylboronic acidsa
Table 2. Optimization of cross-coupling of o-halophenylbo-
ronic acid 3a¤ with p-tolylboronic acid
B(aam)
B(aam)
(HO)2
B
B(aam)
Ru cat.
+
+
R
R
R
HSiR3
B(aam)
Br
3a′
B(aam)
SiR'3
Me
B(aam)
I
ICl
Me
norbornene
Me
1b
toluene
135 °C
CH2Cl2,
–78 °C, 18 h
4
undesirable product
1
2
3
Entry Reaction conditions
% yield 4 (1b)a
Yieldd
Yieldf
/%
Entry
1
Product 2
Product 3
1
2
3
4
Pd(OAc)2 (3 mol %), SPhos (6 mol %),
K3PO4 (2 equiv), THF, rt, 89 h
Pd(OAc)2 (3 mol %), SPhos (6 mol %),
K3PO4 (2 equiv), THF, 50 °C, 62 h
Pd(PtBu3)2 (5 mol %), CsF (2 equiv),
THF, rt, 19 h
/%
0 (98)
0 (65)
0 (0)
B(aam)
B(aam)
I
80e
87
SiMe2Ph
(3a)
(2a)
B(aam)
B(aam)
88e
90
2
3
96
90
Me
SiMe Ph (2b)
Me
I
2
(3b)
Pd(OAc)2 (3 mol %), K3PO4 (2 equiv),
THF, rt, 19 h
B(aam)
B(aam)
96 (0)
C6H13
O
C6H13
O
I
SiMe Ph (2c)
(3c)
2
aIsolated yield of 4. NMR yield of 1b is in the parenthesis.
B(aam)
B(aam)
e
4
0
95
94
91
Cl
Cl
F
SiMe2Ph
Cl
I
(2d)
(3d)
R
B(aam)
B(aam)
Pd(OAc)2 (5 mol%)
K3PO4 (2 equiv)
1) HCl (5 N)
3a
THF, r.t., 20 h
5b
6b
82
65
3d
+
SiEt3
THF, 50 °C, 11 h
2) ArBr (0.83 equiv)
Pd(OAc)2 (3 mol%)
SPhos (6 mol%)
(2d′)
PhB(OH)2
(1.2 equiv)
B(aam)
B(aam)
I
5 (92%)
K3PO4 (1.5 equiv)
6a (R = Me) 96%
6b (R = OMe) 96%
6c (R = CF3) 98%
THF, 60 °C, 20 h
SiEt3
F
(3e)
(2e′)
B(aam)
B(aam)
7c
8
53
71
94
94
Scheme 1. Synthesis of ter(o-phenylene)s via iterative
Suzuki-Miyaura coupling.
F3C
Me
SiEt3
F3C
Me
I
(3f)
(2f′)
B(aam)
B(aam)
I
e
81
SiMe2Ph
under the reaction conditions utilized for the coupling of AAM-
protected p- and m-bromophenylboronic acids completely failed,
giving no desired coupling products. In fact, the attempted
coupling of AAM-protected o-bromophenylboronic acid 3a¤
in the presence of SPhos14 (P/Pd = 2) as a ligand at room
temperature resulted in transfer of the AAM group from 3a¤ to p-
tolylboronic acid, giving AAM-protected p-tolylboronic acid 1b
with no formation of the coupling product (Entry 1, Table 2).
Applying a higher reaction temperature did not improve the
reaction outcome at all (Entry 2). Use of the t-Bu3P/CsF
system15 gave no desirable product, although no AAM-transfer
product was formed either (Entry 3). We finally found that a
ligand-free palladium catalyst worked efficiently in the cross-
coupling of 3a¤, giving the AAM-protected biarylboronic acid 4
in high isolated yield (Entry 4). The reaction conditions were
successfully applied to the cross-coupling of o-iodo derivative
3a, giving the corresponding biaryl product 5 in high yield
(Scheme 1).16 The thus-obtained AAM-protected biarylboronic
acid 5 was cross-coupled with various aryl bromides after
deprotection of the AAM group by acidic hydrolysis, giving
teraryls 6a-6c in high yields.
Having established the basis for the preparation and
reactivities of AAM-masked o-iodoarylboronic acids, we pur-
sued the iterative synthesis of oligo(naphthalene-2,3-diyl)s using
our AAM system. Cross-coupling conditions for the synthesis of
oligonaphthalene were further optimized on the basis of the
optimization of the biaryl synthesis shown in Table 2. We again
observed better outcome with the ligand-free palladium catalyst
in the coupling of AAM-masked 3-iodo-2-naphthylboronic acid
3k with 6-ethoxy-2-naphthylboronic acid (7) (Scheme 2). After
(2g)
(3g)
MeO
B(aam)
MeO
B(aam)
9
87
63
SiMe Ph(2h)
I
2
(3h)
Me
Me
B(aam)
B(aam)
10
92
SiMe2Ph
I
(3i)
(2i)
Cl
B(aam)
Cl
B(aam)
b
83
97
84
11
SiEt3
I
(3j)
(2j′)
B(aam)
B(aam)
90e
72
12
13
SiMe Ph (2k)
I
2
(3k)
Me
Me
B(aam)
B(aam)
I
86
SiMe2Ph
(2l)
(3l)
Me
Me
a2 (0.1 mmol), ICl (0.2 mmol), CH2Cl2 (0.5 mL), ¹78 °C, 18 h.
¹78 to ¹9 °C. ¹78 °C to room temperature. Isolated yield
of 2 in Ru-catalyzed ortho-silylation of the corresponding
b
c
d
e
f
ArB(aam). Reported in ref 10. Isolated yield.
synthesis of 2l (Entry 13) was conveniently prepared from 1,4-
dimethylnaphthalene via Ir-catalyzed aromatic C-H borylation.
This example demonstrates that the synthetic utility of the ortho-
C-H silylation is significantly enhanced by combining it with
the C-H borylation chemistry.
We then examined cross-coupling of AAM-protected o-
halophenylboronic acids with arylboronic acids. An initial trial
Chem. Lett. 2013, 42, 541-543
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

543
3k (1.0 equiv)
Pd(OAc)2 , K3PO4
THF, 50 °C, 11 h
1) HCl aq, THF, rt
2) dried under
vacuum
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B(aam)
(aam)B
B(OH)2
90%
EtO
OEt
7 (1.2 equiv)
8
1) H2O (0.92 equiv)
THF, 50 °C, 15 min
3k (0.77 equiv)
Pd(OAc)2 , K3PO4
THF, 60 °C, 15 h
2)
O
B
3
88%
(3 steps)
OEt
OEt
9
10
2
1) HCl aq, THF, rt
2) Pd(OAc)2 , K3PO4
dioxane/H 2O, 110 °C, 24 h
3
4
Oligo(quinoline-2,3-diyl)s: M. Suginome, H. Noguchi, M.
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Br
Oligo- and poly(quinoxaline-2,3-diyl)s: a) Y. Ito, E. Ihara, M.
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11880.
(2 equiv)
80%
(2 steps)
OEt
11
Scheme 2. Synthesis of quater(naphthalene-2,3-diyl) via iter-
ative Suzuki-Miyaura coupling.
5
a) H. Yuki, Y. Okamoto, I. Okamoto, J. Am. Chem. Soc. 1980,
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the coupling, the AAM group remaining untouched was
removed by acidic treatment. However, use of the unmasked
binaphthylboronic acid in cross-coupling with 3k resulted in ill-
reproducible results. It turned out that the presence of even a
small amount of water led to AAM transfer from 3k to the
binaphthylboronic acid, whereas complete dehydration then led
to the formation of boroxine 9, which was totally unreactive
toward cross-coupling. Indeed, the degree of dehydration after
the unmasking step significantly affected the result of the
subsequent cross-coupling step. We could finally adapt the
procedure in which boroxine 9, obtained by complete dehy-
dration, was hydrolyzed to binaphthylboronic acid by adding
a stoichiometric amount of water prior to the coupling step.
According to this procedure, AAM-masked ternaphthylboronic
acid 10 was isolated in high yield. The iterative coupling
sequence was terminated by coupling with 2-naphthyl bromide,
giving quaternaphthalene 11 bearing a terminal ethoxy group.
In summary, we have established a new synthetic route to
o-iodoarylboronic acid derivatives via Ru-catalyzed o-directed
silylation of AAM-masked arylboronic acids followed by
iododesilylation with ICl. The present synthesis of o-iodo-
arylboronic acids is complementary to the ortho-directed, Ag-
mediated iodination of arylboronic acids,11 and it shows wider
applicability to electronically unactivated arylboronic acids.
Application to iterative synthesis of oligo(o-phenylene)s and
oligo(naphthalene-2,3-diyl)s has also been demonstrated. Syn-
thesis of more densely functionalized oligo(o-phenylene)s and
oligo(naphthalene-2,3-diyl)s, including those adapting nonrace-
mic helical structures, are now being undertaken in this
laboratory.17
6
7
8
9
H. Ihara, M. Suginome, J. Am. Chem. Soc. 2009, 131, 7502.
10 H. Ihara, M. Koyanagi, M. Suginome, Org. Lett. 2011, 13, 2662.
11 R. M. Al-Zoubi, D. G. Hall, Org. Lett. 2010, 12, 2480.
12 For nondirected halogenation of organoboronic acids and esters,
see: a) H. G. Kuivila, L. E. Benjamin, C. J. Murphy, A. D. Price,
J. H. Polevy, J. Org. Chem. 1962, 27, 825. b) D. Qiu, F. Mo, Z.
Zheng, Y. Zhang, J. Wang, Org. Lett. 2010, 12, 5474.
13 General procedure: ICl (10 ¯L, 0.2 mmol) was added to a solution
of ArB(aam) (0.1 mmol) in CH2Cl2 at ¹78 °C. After 18 h, 2-
methyl-2-butene (32 ¯L, 0.3 mmol) was added to the solution,
which was stirred for 5 min at room temperature. The mixture was
subjected to column chromatography on Florisilμ (eluent:
hexane-AcOEt (10:1) to pure chloroform), giving o-iodonated
product 3.
14 a) T. Ishiyama, J. Takagi, K. Ishida, N. Miyaura, N. R. Anastasi,
J. F. Hartwig, J. Am. Chem. Soc. 2002, 124, 390. b) T. Ishiyama,
J. Takagi, J. F. Hartwig, N. Miyaura, Angew. Chem., Int. Ed. 2002,
41, 3056.
15 A. F. Littke, C. Dai, G. C. Fu, J. Am. Chem. Soc. 2000, 122, 4020.
16 A mixture of 3a (69.6 mg, 0.20 mmol), phenylboronic acid
(29.3 mg, 0.24 mmol), Pd(OAc)2 (2.24 mg, 0.01 mmol), and
K3PO4 (84.8 mg, 0.40 mmol) in THF (0.4 mL) was stirred for
11 h at 50 °C. The solvent was evaporated in vacuo. The coupling
product 5 (55.1 mg, 92%) was isolated by column chromatog-
raphy on silica gel (eluent: hexane-AcOEt (10:1) to pure
chloroform).
This work was supported by JST, CREST. N.E. acknowl-
edges the fellowship support from JSPS.
References and Notes
1
Oligo(o-phenylene)s: a) H. J. S. Winkler, G. Wittig, J. Org.
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17 Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.html.
Chem. Lett. 2013, 42, 541-543
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/