Differentially protected benzenediboronic acids: Divalent cross-coupling modules for the efficient synthesis of boron-substituted oligoarenes

Article abstract of DOI:10.1021/ol702420x

On the basis of the boron-masking strategy, new divalent cross-coupling modules have been designed for the efficient synthesis of boronsubstituted oligoarenes. The modules, i.e., monoprotected o-, m-, and p-benzenediboronic acid derivatives, undergo highly selective SuzukiMiyaura coupling with sp ² iodides, bromides, chlorides, and triflates, affording coupling products in which the protected boronyl groups are left intact.

Full text of DOI:10.1021/ol702420x

ORGANIC
LETTERS
2008
Vol. 10, No. 3
377-380
Differentially Protected
Benzenediboronic Acids: Divalent
Cross-Coupling Modules for the Efficient
Synthesis of Boron-Substituted
Oligoarenes
Hiroyoshi Noguchi, Takayuki Shioda, Chih-Ming Chou, and Michinori Suginome*
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of
Engineering, Kyoto UniVersity, Katsura, Kyoto 615-8510, Japan
suginome@sbchem.kyoto-u.ac.jp
Received October 19, 2007
ABSTRACT
On the basis of the boron-masking strategy, new divalent cross-coupling modules have been designed for the efficient synthesis of boron-
substituted oligoarenes. The modules, i.e., monoprotected o-, m-, and p-benzenediboronic acid derivatives, undergo highly selective Suzuki
−
Miyaura coupling with sp2 iodides, bromides, chlorides, and triflates, affording coupling products in which the protected boronyl groups are
left intact.
Much effort has been devoted to the exploration of new
synthetic routes to organoboron compounds because of their
increasing utilization in synthetic organic chemistry directed
toward both material sciences and pharmaceutical sciences.1
In particular, the chemistry of organoboronic acids2 is
growing rapidly in recognition of their reasonable stability
and controllable reactivity in a variety of transition-metal-
catalyzed reactions, such as Suzuki-Miyaura coupling
(SMC).3 Therefore, efficient synthetic routes to organo-
boronic acid derivatives are in great demand, including those
having multiple B(OH)2 functional groups.4 While the
majority of the newly developed methods involve boron-
carbon bond formation as the key step,5,6 it seems to be
highly desirable to develop synthetic methods in which boron
groups are retained intact. Although the potential of boronyl
(3) (a) Miyaura, N. Top. Curr. Chem. 2002, 219, 11. (b) Suzuki, A.;
Brown, H. C. Organic Synthesis Via Boranes: Aldrich: Milwaukee, 2003;
Vol. 3. (c) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457.
(4) (a) James, T. D. In Boronic Acids; Hall, D., Ed.; Wiley: Weinheim,
2005; p 441. (b) Sandanayake, K. R. A. S.; James, T. D.; Shinkai, S. Chem.
Lett. 1995, 503.
(5) (a) Suginome, M.; Yamamoto, A.; Murakami, M. J. Am. Chem. Soc.
2003, 125, 6358. (b) Suginome, M.; Yamamoto, A.; Murakami, M Angew.
Chem., Int. Ed. 2005, 44, 2380. (c) Suginome, M.; Yamamoto, A.;
Murakami, M J. Am. Chem. Soc. 2005, 127, 15706.
(1) Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents; Academic
Press: London, 1988.
(2) Hall, D. Boronic Acids; Wiley: Weinheim, 2005.
10.1021/ol702420x CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/10/2008

protection in organic synthesis has been successfully dem-
onstrated by the studies of organotrifluoroborates, which are
tolerable toward various reactions including oxidation, they
are still reactive in SMC.7 It seems likely that the develop-
ment of effective protective groups for boronyl groups in
SMC shall open up the new possibilities for the synthesis of
new organoboron compounds.
Scheme 2. Synthesis of Monoprotected Benzenediboronic
Acid Derivatives
In this paper, we report benzenediboronic acid derivatives
of which boronyl groups are differentially protected as new
divalent cross-coupling modules for the convenient synthesis
of oligoarene derivatives (Scheme 1).8 The modules have
Scheme 1. Synthesis of Oligoarenes by Using Monoprotected
Benzenediboronic Acid Derivatives as Divalent Coupling
Modules
p- and o-derivatives, requiring the modified catalyst system
(Pd(dba)2/PCy3) to obtain a reasonable yield of m-2.
The monoprotected p-benzenediboronic acid derivative p-2
was subjected to SMC with p-bromotoluene under various
reaction conditions (Table 1). The reaction rate was greatly
two boronyl-derived substituents whose reactivities were
differentiated by the introduction of a temporary protective
group onto one of the two boron atoms. The temporary
protection of otherwise reactive boronyl groups was achieved
by 1,8-diaminonaphthalene, which we recently established
as a masking group for boronyl groups in iterative SMC.9-11
Our initial attempts at preparing the requisite monopro-
tected modules by simple condensation of benzenediboronic
acids with 1,8-diaminonaphthalene resulted in nonselective
formation of mixtures of monoprotected and diprotected
diboronic acids. We then turned our attention to use of
boronyl-protecteded haloarylboronic acid derivatives as start-
ing materials. Protected haloarylboronic acids p-, m-, and
o-1 were subjected to palladium-catalyzed borylation with
bis(pinacolato)diboron (Scheme 2).12 Reactions of p- and o-1
proceeded in the presence of PdCl2(dppf) in DMSO, giving
benzenediboronic acid derivatives p- and o-2, respectively,
whose boron atoms are unsymmetrically substituted with 1,8-
diaminonaphthalene and pinacol. On the other hand, m-1
showed an apparently lower reactivity than the corresponding
Table 1. Optimization of Suzuki-Miyaura Coupling Reaction
Conditionsa
entry
X
catalyst
base
KF
CsF
% yieldb
1
2
3
4
5
6
7
Br Pd[P(t-Bu)3]2
Br Pd[P(t-Bu)3]2
Br Pd[P(t-Bu)3]2
Br Pd[P(t-Bu)3]2
Br Pd[P(t-Bu)3]2
Br Pd(OAc)2/PPh3 (1/2)
Br Pd(OAc)2/dppf (1/1)
37
51
Na2CO3 58
K3PO4
NaOH
NaOH
NaOH
NaOH
NaOH
97
99 (99)
99
99
8c Cl
9c Cl
10
Pd[P(t-Bu)3]2
Pd(OAc)2/PPh3 (1/2)
92 (90)
N.R.
(94)
OTf Pd(OAc)2/(2-biphenyl)PCy2 (1/2) NaOH
a A mixture of aryl halide (0.14 mmol), p-2 (0.14 mmol), a catalyst (2.7
µmol), and base (0.41 mmol) was stirred at 60 °C for 4 h. b NMR yield.
Isolated yield in the parentheses. c 3 mol % of catalyst at 80 °C for 24 h.
(6) (a) Beletskaya, I.; Moberg, C. Chem. ReV. 1999, 99, 3435. (b)
Ishiyama, T.; Nishijima, K.-i.; Miyaura, N.; Suzuki, A. J. Am. Chem. Soc.
1993, 115, 7219. (c) Marder, T. B.; Norman, N. C. Top. Catal. 1998, 5,
63. (d) Ishiyama, T.; Miyaura, N. J. Organomet. Chem. 2000, 611, 392.
(7) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275.
(8) (a) Tour, J. M. Chem. ReV. 1996, 96, 537. (b) Berresheim, A. J.;
Mu¨ller, M.; Mu¨llen, K. Chem. ReV. 1999, 99, 1747. (c) Segura, J. L.; Martin,
N. J. Mater. Chem. 2000, 10, 2403.
influenced by bases: K3PO4 and NaOH were found to be
most effective in promoting the reaction in dioxane/H2O in
the presence of Pd[P(t-Bu)3]2 as a catalyst, whereas KF, CsF,
and Na2CO3 resulted in a slower reaction at 60 °C. After
prolonged reaction time (18 h), however, almost quantitative
yields were attained even with the less effective bases (entries
1-5). It should be noted that the 1,8-diaminonaphthalene
protective group was found to be perfectly tolerable toward
strong bases in the presence of water.9 The high tolerance
toward bases is characteristic of the 1,8-diaminonaphthalene
(9) Noguchi, H.; Hojo, K.; Suginome, M. J. Am. Chem. Soc. 2007, 129,
758.
(10) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc. 2007, 129, 6716.
(11) (a) Liess, P.; Hensel, V.; Schlu¨ter, A.-D. Liebigs Ann. 1996, 1037.
(b) Blake, A. J.; Cooke, P. A.; Doyle, K. J.; Gair, S.; Simpkins, N. S.
Tetrahedron Lett. 1998, 39, 9093. (c) Read, M. W.; Escobedo, J. O.; Willis,
D. M.; Beck, P. A.; Strongin, R. M. Org. Lett. 2000, 2, 3201. (d) Spivey,
A. C.; Turner, D. J.; Turner, M. L.; Yeates, S. Org. Lett. 2002, 4, 1899. (e)
Ishikawa, S.; Manabe, K. Chem. Lett. 2006, 35, 164.
(12) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
7508. (b) Ishiyama, T.; Ishida, K.; Miyaura, N. Tetrahedron 2001, 57, 9813.
378
Org. Lett., Vol. 10, No. 3, 2008

protective group in comparison with a recently reported
tridentate protective group, which is reported to be depro-
tected easily even by weak bases.10 For the cross-coupling
with aryl bromides, PPh3 and DPPF ligands are active enough
to attain high yields (entries 6 and 7). In the coupling of
aryl chloride, however, use of a t-Bu3P-based catalyst system
rather than a PPh3-based system was essential to obtain high
yields (entries 8 and 9). In the coupling of p-tolyl triflate,
(2-biphenyl)PCy2 was found to be most active,13 while the
t-Bu3P-based catalyst resulted in almost no reaction under
the same reaction conditions (entry 10). In general, use of
NaOH as a base was preferable, and even in the presence of
the strong base, there was no appreciable decomposition of
the protected boronyl group during the reaction.
reactions of p-2 and m-2, reactions of o-2 in the presence of
NaOH resulted in significant decomposition of the protected
boronyl group during the reaction. Using K3PO4 as a base,
however, the cross-coupling of o-2 proceeded cleanly, giving
the corresponding products in high yields (entries 13-17).
Note that cross-coupling of o-2 with ortho-substituted aryl
bromide gave sterically demanding coupling products in high
yields (entries 16 and 17).
SMC of p-2 with alkenyl bromide proceeded as well,
giving the boron-substituted trans-stilbene 3r in good yield
(Scheme 3).
Scheme 3
Under the optimized reaction conditions, p-, m-, and o-2
were subjected to the cross-coupling reaction with various
aryl halides (Table 2). Coupling of aryl iodides proceeded
Table 2. Pd-Catalyzed Suzuki-Miyaura Coupling of Aryl
Halides with Benzenediboronic Acid Derivativesa
To demonstrate the synthetic utility of the new divalent
coupling module, reactions of di- and trihaloarene derivatives
with p-2 were carried out (Scheme 4). In the coupling of
p-dibromobenzene derivatives 4a and 4b, 4,4′′-diboronylter-
phenyl derivatives 5a and 5b, respectively, were obtained
aryl halide
entry
Ar
X
2
product
% yieldb
Scheme 4. Synthesis of Boron-Substituted Oligoarene
1c
2
3
4
5
6c
Ph
I
I
I
p-2
p-2
p-2
p-2
p-2
p-2
p-2
p-2
p-2
m-2
m-2
m-2
o-2
o-2
o-2
o-2
o-2
3b
3c
3d
3e
3f
3g
3h
3i
3d
3j
3k
3l
3m
3n
3o
3p
3q
94
92
88
99
93
85
96
98
93
94
95
95
96
94
99
99
94
Derivatives
4-MeOC6H4
4-NO2C6H4
4-FC6H4
2,6-Me2C6H3
1-Naphthyl
2-Pyridyl
2-Thienyl
4-NO2C6H4
4-MeC6H4
4-MeOC6H4
4-MeC(O)C6H4
4-MeC6H4
4-MeOC6H4
4-MeC(O)C6H4
2-MeC6H4
Br
Br
Br
Br
Br
Cl
Br
Br
Br
Br
Br
Br
Br
Br
7
8
9d
10
11
12c
13e
14e
15e
16e
17e
1-naphthyl
a A mixture of aryl halides (0.14 mmol), 1 (0.14 mmol), Pd[P(t-Bu)3]2
(2.7 µmol), and 5 N NaOH aq (0.41 mmol) was stirred at 60 °C for 4 h,
unless otherwise noted. b Isolated yield. c Reaction in a 1.0 mmol scale.
d At 80 °C. e K3PO4 as a base.
in high yields under the reaction conditions optimized for
aryl bromides, regardless of the electronic nature of the
p-substituents on the aromatic rings (entries 1-3). Products
could be isolated in high yields by silica gel column
chromatography. Cross-coupling of p-2 with substituted aryl
bromides, heteroaryl bromides, and aryl chlorides afforded
the corresponding coupling products in high yields (entries
4-9). Under the same reaction conditions as p-2, m-2 reacted
with aryl bromides to give the corresponding coupling
products in good yields (entries 10-12). In contrast to the
Org. Lett., Vol. 10, No. 3, 2008
379

As demonstrated in the previous report, the diaminonaph-
thalene protective group features facile deprotection in the
presence of aqueous acid (Scheme 5). For example, boronyl-
substituted stilbene 12, teraryl-1,4′′-diboronic acid 13 and
2,5-di(4-boronylphenyl)thiophene derivative 14 were ob-
tained in high yields by acid hydrolysis. Triply protected
derivative 11b also underwent clean deprotection of the
diaminonaphthalene group at room temperature, giving
triboronic acid 12 in high yield. Because cyclic boronates
such as a pinacolate often meet with difficulty in clean
deprotection,14,15 the present boron-protecting strategy is
attractive in that highly elaborated boronic acids are readily
obtained at the final stage of their synthetic process.
In summary, we have developed new divalent cross-
coupling modules for the synthesis of boron-substituted
oligoarene derivatives, which can be further transformed into
higher oligoarenes via a second cross-coupling. The mono-
protected divalent modules undergo cross-coupling with sp2
iodides, bromides, chlorides, and triflates under the optimized
reaction conditions. The new reaction system provides
convenient access to oligoarene derivatives bearing multiple
boronyl groups through coupling with polyhalogenated
haloarenes followed by clean deprotection of the protecting
group.
Scheme 5. Synthesis of Boronic Acids via Hydrolysis
Acknowledgment. H.N. thanks the Japan Society for the
Promotion of Science for the fellowship support.
in high yields. Likewise, m-dibromobenzene derivative 6 was
coupled with p-2, giving meta-linked terphenyl 7 in high
yield. The coupling system could be applied to dibromothio-
phene derivative 8 to give 2,5-di(p-boronylphenyl)thiophene
derivative 9 in high yield. In an additional example, tri-
bromobenzene derivatives 10 afforded tri(p-boronylphenyl)-
benzene derivatives 11a and 11b in high yields.
Supporting Information Available: Experimental pro-
cedures and spectral data for new compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL702420X
(14) (a) Decicco, C. P.; Song, Y.; Evans, D. A. Org. Lett. 2001, 3, 1029.
(b) Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1999, 64, 2976. (c) Yuen,
A. K. L.; Hutton, C. A. Tetrahedron Lett. 2005, 46, 7899.
(15) (a) Murphy, J. M.; Tzschucke, C. C.; Hartwig, J. F. Org. Lett. 2007,
9, 757. (b) Coutts, S. J.; Adams, J.; Krolikowaski, D.; Snow, R. J.
Tetrahedron Lett. 1994, 35, 5109.
(13) (a) Nguyen, H. N.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 11818. (b) Ishikawa, S.; Manabe, K. Chem. Commun. 2006,
2589.
380
Org. Lett., Vol. 10, No. 3, 2008