Selective Preparation of C 2v -Symmetric Hexaphenylbenzene Derivatives through Sequential Suzuki Coupling

Article abstract of DOI:10.1055/s-0037-1610024

We have developed effective reaction conditions for the Suzuki cross-coupling of chlorinated hexaphenylbenzene derivatives. A chloro group on a hexaphenylbenzene framework exhibits a low reactivity to Suzuki cross-coupling, and only nickel catalysts bearing alkyl-substituted phosphine ligands achieved the coupling. With this as a key step, we succeeded in the selective preparation of a C _2v -symmetric hexaphenylbenzene derivative containing two kinds of aryl group.

Full text of DOI:10.1055/s-0037-1610024

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
K. Ogata et al.
Letter
Synlett
Selective Preparation of C2v-Symmetric Hexaphenylbenzene
Derivatives through Sequential Suzuki Coupling
OMe
very inert against
oxidative addition
Kazuho Ogata
Tatsuo Kojima*
Shuichi Hiraoka*
Cl
B(OH)2
B(OH)2
Department of Basic Science, Graduate School of Arts
and Sciences, The University of Tokyo, 3-8-1 Komaba,
Meguro-ku, Tokyo, 153-8902, Japan
OMe
chiraoka@mail.ecc.u-tokyo.ac.jp
ckojima@mail.ecc.u-tokyo.ac.jp
Pd(PPh3)4
93%
Ni(PCy3)2Cl2
44%
Br
Br
available through
selective alternate trilithiation
C2v-symmetric hexaphenylbenzene
Received: 04.02.2018
Accepted after revision: 24.04.2018
Published online: 29.05.2018
substituents in a desired arrangement. Among the various
substitution patterns for HPB, a C2v-symmetric one with
two kinds of substituent in an alternate pattern is interest-
ing for its potential use as a building unit for polyphenylene
dendrimers.3 This C2v-symmetric pattern has also been
used in HPB-based amphiphiles.4 Despite their utility, C2v-
symmetric HPB derivatives are difficult to prepare by con-
ventional methods5 or even by modern protocols.6
We recently developed a method for the selective alter-
nate trilithiation of brominated HPB derivatives through a
thermodynamically controlled halogen dance,7 and have
overcome the synthetic hurdle for C2v-symmetric HPB de-
rivatives (Scheme 1). One of the products, with both bromo
and chloro groups on the HPB framework, could serve as a
common precursor to various C2v-symmetric HPB deriva-
tives, owing to the different reactivities of aryl bromide and
aryl chloride groups in metal-catalyzed cross-coupling
reactions.8,9 However, we encountered a low reactivity of
the C–Cl moiety on the HPB framework in the Suzuki cross-
coupling reaction. Here, we report an effective method for
DOI: 10.1055/s-0037-1610024; Art ID: st-2018-b0074-l
Abstract We have developed effective reaction conditions for the
Suzuki cross-coupling of chlorinated hexaphenylbenzene derivatives. A
chloro group on a hexaphenylbenzene framework exhibits a low reac-
tivity to Suzuki cross-coupling, and only nickel catalysts bearing alkyl-
substituted phosphine ligands achieved the coupling. With this as a key
step, we succeeded in the selective preparation of a C2v-symmetric
hexaphenylbenzene derivative containing two kinds of aryl group.
Key words hexaphenylbenzene, Suzuki coupling, cross-coupling,
nickel catalysis, aryl chlorides, regioselectivity
Hexaphenylbenzene (HPB) is a rigid C6-symmetric mo-
lecular framework that has been adopted as a core struc-
ture of various materials.1 It is also important as a precursor
of large polycyclic aromatic hydrocarbon derivatives such as
hexa-peri-benzocoronene.2 To maximize the potential of
the HPB framework, it is crucial to introduce appropriate
This work
R2
Cl
Cl
B(OH)2 B(OH)2
Br
Br
Br
Br
selective
alternate
trilithiation
R1
R2
Suzuki Suzuki
ref. 7
R1
R1
Br
Br
Br
1
2
3
Scheme 1 Selective preparation of a C2v-symmetric HPB derivative containing two kinds of aryl group through selective alternate trilithiation of HPB
derivative 1 and sequential Suzuki coupling
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
K. Ogata et al.
Letter
Synlett
Suzuki cross-coupling of the chloro group on the HPB
framework. By using this condition, we selectively prepared
a C2v-symmetric HPB derivative containing two kinds of
aryl group (Scheme 1).
compound 4. Our attention then shifted to Ni catalysts,
which are known to promote oxidative addition more read-
ily than do Pd catalysts.15 Whereas Ni catalysts with aryl-
substituted phosphine ligands such as DPPP,16 PPh3,17 or DP-
PF18 did not work at all (entries 4–8), more-electron-rich Ni
catalysts with alkyl-substituted phosphine ligands, such as
We screened several sets of conditions for the Suzuki
cross-coupling of the chlorinated HPB 4 with phenylboronic
acid (Table 1).10 No cross-coupling reaction of a chloro
group on HPB has previously been reported. We found that
compound 4 was completely recovered in the presence of
palladium catalysts bearing bulky or electron-rich phos-
phines such as SPhos,11 PCy3,12,13 or P(t-Bu)3,13 which are
known to be effective in Suzuki cross-coupling reactions of
aryl chlorides (Table 1, entries 1–3). Taking successful ex-
amples of Suzuki cross-coupling reaction of brominated
HPB derivatives14 into consideration, we attributed this low
reactivity to difficult oxidative addition of the C–Cl moiety of
19
PCy3 or 1,2-bis(dicyclohexylphosphino)ethane (DCYPE),20
afforded the coupled product 5 when an appropriate base
and solvent were used (entries 9–13). The optimized condi-
tions involved a combination of Ni(PCy3)2Cl2 and K3PO4 in
THF or 1,4-dioxane (entries 9 and 10). The moderate yields
under these conditions are due to the recovery of the start-
ing material 4 (34% for entry 9, 45% for entry 10). Although
the reason for this is unclear, no further improvement of the
conversion was achieved, even on doubling the amount of
the Ni catalyst.
The inertness of compound 4 against oxidative addition
of a metal center might be related to the geometrical struc-
ture of the HPB framework (Figure 1). HPB derivatives adopt
a propeller conformation because of steric repulsion be-
tween the adjacent aryl groups, especially around the cen-
tral part of the framework.21 During oxidative addition of a
metal center to an aryl halide, the metal center approaches
the C–X bond, interacting with the π-orbitals of the aryl
ring of an aryl halide.22 In the case of the HPB derivatives
such as compound 4, both sides of the π-orbitals of the aryl
rings are sterically covered by the adjacent aryl groups. This
geometrical characteristic of the HPB framework, combined
with the intrinsic low reactivity of aryl chlorides, hampers
oxidative addition of a metal catalyst, thereby demanding
electron-rich Ni catalysts.
Table 1 Optimization of a Suzuki Coupling of HPB Derivative 4a
B(OH)2
Cl
(2 equiv)
Catalyst
Base (4 equiv)
Solvent
4
5
Entry Catalyst (mol%)
Base
Solvent
Temp Time
Yieldb
(%)
steric repulsion
MLn
(°C)
(h)
1c
2e
3e
Pd(OAc)2 (5)
SPhos (10)
K3PO4
K3PO4
K3PO4
toluene
1,4-dioxane
THF
100
14
0
0
0
d
Cl
Pd2(dba)3 (2.5)
PCy3·HBF4 (6)
80
80
22
30
Pd2(dba)3 (2.5)
P(t-Bu)3·HBF4 (6)
Figure 1 Difficult oxidative addition of a metal catalyst to a C–Cl bond
on the HPB framework
4
Ni(dppp)Cl2 (5)
Ni(dppp)Cl2 (5)
Ni(dppp)Cl2 (5)
K3PO4
K3PO4
K3PO4
1,4-dioxane
THF
100
80
66
42
42
44
62
60
51
28
38
75
0
5
0
6
toluene
THF
100
80
0
7
Ni(PPh3)2Cl2 (10) K3PO4
Ni(dppf)Cl2 (10) K3PO4
0
We selectively prepared a C2v-symmetric HPB derivative
8 possessing two kinds of aryl group on the HPB framework
(Scheme 2). HPB derivative 1 was selectively trilithiated in
an alternate pattern to afford compound 6 containing three
TMS groups.7 The introduction of the TMS groups enabled
us to isolate compound 6 by crystallization. The TMS
groups in 6 were then protodesilylated under acidic condi-
tions.23 Though the direct protonation of the trilithio spe-
cies deriving from compound 1 afforded compound 2 as the
main product, it was difficult to separate compound 2 from
small amounts of its isomers generated during the lithia-
tion step. Compound 2 was then subjected to sequential
8
THF
80
0
9
Ni(PCy3)2Cl2 (10) K3PO4
Ni(PCy3)2Cl2 (10) K3PO4
Ni(PCy3)2Cl2 (10) K3PO4
Ni(PCy3)2Cl2 (10) CsF
Ni(dcype)Cl2 (10) K3PO4
THF
80
66
55
0
10
11
12
13
1,4-dioxane
toluene
THF
100
100
80
0
THF
80
25
a Compound 4 (0.10 g) and solvent (1 mL) were used.
b Determined by 1H NMR.
c With 1.1 equivalents of PhB(OH)2.
d With 2.0 equivalents of K3PO4.
e With 1.5 equivalents of PhB(OH)2.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
K. Ogata et al.
Letter
Synlett
Cl
Cl
Cl
Br
Br
Br
TMS
1) t-BuLi (6 equiv)
MesBr (2.7 equiv)
2) TMSCl
TMS
TsOH (6 equiv)
THF
–98 °C to r.t.
ref. 7
AcOH
reflux
Br
Br
Br
Br
Br
Br
TMS
1
6: 76%
2: 90%
OMe
Cl
MeO
B(OH)2
(2 equiv)
Ni(PCy3)2Cl2 (10 mol%)
K3PO4 (4 equiv)
PhB(OH)2 (3 equiv)
Pd(PPh3)4 (10 mol%)
K2CO3 (6 equiv)
THF
80 ºC
THF/water
80 ºC
7: 93%
8: 44%
Scheme 2 Preparation of HPB derivative 8
Suzuki cross-coupling. The first coupling with phenyl-
boronic acid in the presence of Pd(PPh3)4 as a catalyst
occurred exclusively at the Br moieties, even with excess
phenylboronic acid, and the diarylated HPB derivative 7 was
obtained in high yield.24 The second Suzuki coupling be-
tween the C–Cl moiety of compound 7 and 4-methoxy-
phenylboronic acid afforded the C2v-symmetric HPB deriva-
tive 8 (44%) with 30% recovery of compound 7.25 This result
demonstrates the utility of our protocol in selectively af-
fording C2v-symmetric HPB derivatives containing two
kinds of aryl group, which are difficult to prepare by other
protocols.
In conclusion, we have developed effective reaction con-
ditions for the Suzuki cross-coupling of chlorinated HPB
derivatives. The aryl chloride moiety on the HPB framework
exhibits a low reactivity to Suzuki cross-coupling, and only
Ni catalysts bearing alkyl-substituted phosphine ligands
were capable of inducing this reaction. With this as a key
step, we succeeded in the selective introduction of two
kinds of aryl group onto the periphery of a HPB skeleton to
give a C2v-symmetric HPB derivative. This protocol should
be applicable to the development of new HPB derivatives
bearing multiple functional groups or HPB-based large
carbon clusters.
Funding Information
This research was supported by JSPS Grants-in-Aid for Scientific
Research on Innovative Areas ‘Dynamical Ordering of Biomolecular
Systems for Creation of Integrated Functions’ (25102005 and
25102001) and by The Asahi Glass Foundation.
)(
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610024.
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References and Notes
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Soc. 2010, 132, 13223.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
K. Ogata et al.
Letter
Synlett
(7) (a) Kojima, T.; Hiraoka, S. Org. Lett. 2014, 16, 1024. (b) Kojima,
T.; Hiraoka, S. Chem. Commun. 2014, 50, 10420.
(8) Stanforth, S. P. Tetrahedron 1998, 54, 263.
(9) A combination of an aryl bromide and an aryl iodide is not
applicable for the selective sequential Suzuki coupling because
both substrates are reactive in the lithiation step.
(10) Suzuki Coupling Reactions of Compound 4; General
Procedure
1H NMR (500 MHz, CDCl3, 298 K): δ = 6.98 (d, J = 8.8 Hz, 4 H),
6.92–6.89 (m, 9 H), 6.83 (d, J = 8.6 Hz, 2 H), 6.78–6.75 (m, 6 H),
6.71 (d, J = 8.6 Hz, 2 H), 6.66 (d, J = 8.6 Hz, 4 H). 13C NMR (125
MHz, CDCl3, 298 K): δ = 140.66, 140.57, 139.91, 139.89, 139.48,
139.43, 139.39, 138.90, 132.98, 132.61, 131.45, 131.25, 130.00,
127.21, 127.08, 125.90, 119.75. HRMS (ESI-TOF): m/z [M]+ calcd
for C42H2779Br235Cl: 724.0182; found: 724.0168.
(24) Compound 7
A suspension of compound 4 (0.100 g, 0.176 mmol, 1.0 equiv),
the appropriate arylboronic acid, base, and catalyst were stirred
in a Schlenk tube under N2 while the reaction was monitored
and the yield was determined by 1H NMR.
A solution of compound 2 (0.200 g, 0.275 mmol, 1.0 equiv),
PhB(OH)2 (0.101 g, 0.825 mmol, 3.0 equiv), K2CO3 (0.228 g, 1.65
mmol, 6.0 equiv), and Pd(PPh3)4 (31.8 mg, 27.5 μmol, 10 mol%)
in THF (2 mL) and H2O (2 mL) was stirred at 80 °C for 6 h under
N2. The mixture was then extracted with EtOAc (3 × 5mL). The
combined organic layer was dried (MgSO4), filtered, and con-
centrated in vacuo. The crude product was purified by column
chromatography [silica gel, hexane to hexane–EtOAc (20:1)] to
give a colorless solid; yield: 0.186 g (93%); mp 284–286 °C.
1H NMR (500 MHz, CDCl3, 298 K): δ = 7.44 (d, J = 7.2 Hz, 4 H),
7.33 (t, J = 7.5 Hz, 4 H), 7.24 (t, J = 7.4 Hz, 2 H), 7.13 (d, J = 8.4 Hz,
4 H), 6.90–6.80 (m, 21 H), 6.77 (d, J = 8.6 Hz, 2 H). 13C NMR (125
MHz, CDCl3, 298 K): δ = 140.91, 140.80, 140.55, 140.49, 140.40,
140.31, 139.69, 139.33, 139.27, 137.56, 132.80, 131.90, 131.51,
131.47, 131.29, 128.68, 127.03, 126.92, 126.81, 125.62, 125.50,
125.29. HRMS (ESI-TOF): m/z [M]+ calcd for C54H3735Cl:
720.2576; found: 724.2584.
(11) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685.
(12) Shen, W. Tetrahedron Lett. 1997, 38, 5575.
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(14) (a) Shen, X.; Ho, D. M.; Pascal, R. A. Jr. Org. Lett. 2003, 5, 369.
(b) Wunderlich, K.; Grigoriadis, C.; Zardalidis, G.; Klapper, M.;
Graf, R.; Butt, H.-J.; Müllen, K.; Floudas, G. Macromolecules 2014,
47, 5691.
(15) (a) Han, F.-S. Chem. Soc. Rev. 2013, 42, 5270. (b) Tasker, S. Z.;
Standley, E. A.; Jamison, T. F. Nature 2014, 509, 299.
(16) Zhao, Y.-L.; Li, Y.; Li, S.-M.; Zhou, Y.-G.; Sun, F.-Y.; Gao, L.-X.;
Han, F.-S. Adv. Synth. Catal. 2011, 353, 1543; Corrigendum: ibid.
2011, 353: 2881.
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3950.
(20) Muto, K.; Yamaguchi, J.; Itami, K. J. Am. Chem. Soc. 2012, 134,
169.
(25) Compound 8
A solution of compound 7 (0.100 g, 0.139 mmol, 1.0 equiv), 4-
methoxyphenylboronic acid (42.2 mg, 0.278 mmol, 2.0 equiv),
K3PO4 (0.118 g, 0.556 mmol, 4.0 equiv), and Ni(PCy3)2Cl2 (9.60
mg, 13.9 μmol, 10 mol%) in THF (1 mL) was stirred at 80 °C for
one week under N2. The mixture was then extracted with EtOAc
(3 × 5 mL). The combined organic layer was dried (MgSO4), fil-
tered, and concentrated in vacuo. The crude product was puri-
fied by column chromatography [silica gel, hexane to hexane–
EtOAc (10:1)] to give a colorless solid [yield: 48 mg (44%)],
together with a mixture of compound 7 and 4,4′-dimethoxybi-
phenyl. Compound 7 [yield: 30 mg (30%); mp 252–253 °C] was
recovered after washing this mixture with hexane.
(21) Gust, D. J. Am. Chem. Soc. 1977, 99, 6980.
(22) (a) Sundermann, A.; Uzan, O.; Martin, J. M. L. Chem. Eur. J. 2001,
7, 1703. (b) Senn, H. M.; Ziegler, T. Organometallics 2004, 23,
2980. (c) Ahlquist, M.; Fristrup, P.; Tanner, D.; Norrby, P.-O.
Organometallics 2006, 25, 2066. (d) Barder, T. E.; Biscoe, M. R.;
Buchwald, S. L. Organometallics 2007, 26, 2183. (e) Li, Z.; Fu, Y.;
Guo, Q.-X.; Liu, L. Organometallics 2008, 27, 4043. (f) McMullin,
C. L.; Jover, J.; Harvey, J. N.; Fey, N. Dalton Trans. 2010, 39,
10833.
1H NMR (500 MHz, CDCl3, 298 K): δ = 7.45 (d, J = 7.4 Hz, 4 H),
7.38 (d, J = 9.0 Hz, 2 H), 7.33 (t, J = 7.8 Hz, 4 H), 7.24 (t, J = 7.4 Hz,
2 H), 7.13 (d, J = 8.5 Hz, 4 H), 7.09 (d, J = 8.5 Hz, 2 H), 6.90–6.80
(m, 23 H), 3.80 (s, 3 H). 13C NMR (125 MHz, CDCl3, 298 K):
δ = 158.97, 140.88, 140.71, 140.69, 140.67, 140.60, 140.30,
140.22, 139.94, 139.21, 137.47, 137.09, 133.45, 132.00, 131.97,
131.61, 128.68, 127.82, 127.01, 126.89, 126.82, 125.40, 125.26,
124.79, 114.11, 55.47. HRMS (ESI-TOF): m/z [M]+ calcd for
(23) Compound 2
A suspension of compound 6 (0.500 g, 0.530 mmol) and TsOH
(604 mg, 3.18 mmol) in AcOH (5 mL) was refluxed for 1.5 h. H2O
(5 mL) was then poured into the mixture and the resulting pre-
cipitate was collected by filtration and washed with MeOH to
afford compound 2 as a colorless solid; yield: 0.346 g (90%); mp
>300 °C.
C
61H44O: 792.3392; found: 792.3395.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D