Synthesis of arylethynylated cyclohexa-m-phenylenes via sixfold Suzuki coupling

Article abstract of DOI:10.1016/j.tetlet.2008.05.150

A one-step, one-pot assembly of arylethynylated cyclohexa-m-phenylenes from meta-dibromide and meta-diboronic acids has been accomplished using a sixfold Suzuki macrocyclization, without the need for high dilution or slow-addition techniques.

Full text of DOI:10.1016/j.tetlet.2008.05.150

Tetrahedron Letters 49 (2008) 4912–4914
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of arylethynylated cyclohexa-m-phenylenes
via sixfold Suzuki coupling
*
Julian M. W. Chan, Timothy M. Swager
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-step, one-pot assembly of arylethynylated cyclohexa-m-phenylenes from meta-dibromide and
meta-diboronic acids has been accomplished using a sixfold Suzuki macrocyclization, without the need
for high dilution or slow-addition techniques.
Received 22 April 2008
Revised 28 May 2008
Accepted 30 May 2008
Available online 5 June 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Cyclohexa-m-phenylenes are cyclic oligomers possessing the
same benzene ring-based backbone as poly(p-phenylene)s (PPPs).
Since the first syntheses of cyclohexa-m-phenylenes by Staab in
the 1960s1 and some later work on cyclohexa-m-phenylene-based
cation hosts by Cram et al.,2 there has generally been little atten-
tion given to these interesting macrocycles. With the exception
of a recent paper3 by the Klaus Müllen group, there have been no
reports of cyclohexa-m-phenylenes bearing functional groups
more complex than alkyl and alkoxy substituents. Furthermore,
all previous strategies for cyclohexa-m-phenylene syntheses
involve the cumbersome pre-synthesis of terphenyl precursors
prior to the final macrocyclization step (reductive coupling). The
terphenyl strategy restricts the diversity of symmetries that can
be achieved in the final product, and the harsh conditions of the
final coupling step also restrict the range of functional groups that
can be present. Given recent interest in designing various novel
functional materials, more efficient syntheses are needed to
advance the development of cyclohexa-m-phenylenes.
described in previous work performed in our group,4 whilst the
diboronic acid had to be prepared in two steps (Scheme 1). The first
step involved a simple O-methylation, followed by a nickel-cata-
lyzed double borylation in the second step, using a method
described by Tour and co-workers.5 It is worth noting that the
use of pinacol protecting groups enabled the complete purification
of the diboronic acid coupling partner by column chromatography,
in contrast to a structurally similar but unprotected 1-alkoxyphe-
nyl-2,6-diboronic acid employed by Cram et al.,2a which could only
be used in a subsequent step without further purification. In our
macrocyclization step (Scheme 2), equimolar amounts of both cou-
pling partners were mixed together with catalytic Pd(PPh3)4
(6 mol %), cesium carbonate and toluene (water was excluded),
and refluxed for 27 h to give the desired cyclohexa-m-phenylene
in 13% isolated yield (as a white powder),9 along with some oligo-
meric byproducts (ca. 37%). Increasing the scale of the reaction ten-
fold appears to decrease the yield to about 9–10%. Empirically, this
set of conditions appears to be crucial to the success of the reac-
tion. Following the isolation of the less polar cyclohexa-m-pheny-
lene, the majority of the oligomeric mixture was successfully
flushed out of the silica gel column, and subsequently analyzed
by NMR and gel permeation chromatography (GPC). Chemical
shifts from the 1H NMR spectrum suggested that the functionality
present in the oligomers was the same as those present in the
In this Letter, we report an efficient approach for the one-step
assembly of the cyclohexa-m-phenylene framework via a sixfold
Suzuki coupling between meta-difunctionalized, monobenzenoid
building blocks. For the macrocyclization experiment, we prepared
the two necessary building blocks, namely pinacol-protected dibo-
ronic acid 1 and dibromide 2. The synthesis of the dibromide is
O
OH
OMe
O
B
OMe O
B
BH
Br
Br
Br
Br
O
MeI, K2CO3
O
O
acetone, reflux
overnight
cat. Ni(dppp)Cl2, Et3N
PhMe, 100 C, 24 h
˚
98%
1
50%
Scheme 1. Synthesis of the protected diboronic acid precursor.
* Corresponding author. Tel.: +1 617 253 4423; fax: +1 617 253 7929.
E-mail address: tswager@mit.edu (T. M. Swager).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.150

J. M. W. Chan, T. M. Swager / Tetrahedron Letters 49 (2008) 4912–4914
4913
OC12H25
OC12H25
C12H25
O
OC12H25
2
O
O
O
O
B
OMe O
Br
Br
B
C12H25
O
OC12H25
O
O
Pd(PPh3)4, Cs2CO3,
PhMe, 110 C, 27 h
˚
13%
3
C12H25
O
OC12H25
Scheme 2. Synthesis of hexa-m-phenylene via sixfold Suzuki coupling.
cyclohexa-m-phenylene. The GPC results indicated a number-aver-
age molecular weight of 4400 amu, and a polydispersity index of
about 1.2. This corresponds to species containing about six repeat
units (or 12 benzene rings) in their structure. The use of high-dilu-
tion/slow-addition techniques was found to be unnecessary (and
in fact detrimental) to macrocycle formation. When such condi-
tions were applied, a grand mixture of inseparable products was
obtained, with the distinctive absence of the desired cyclohexa-
m-phenylene. A multitude of emissive (under UV) and non-emis-
sive spots was observed on TLC, with the dibromide starting mate-
rial being one of the components in the crude mixture. The
emissive species were presumed to be oligomers, and subsequent
analysis of the crude mixture by MALDI-TOF did reveal the pres-
ence of molecules in the 4900–4950 amu mass range, which could
correspond to oligomers containing about 6.5 repeat units. Trials
employing tetrahydrofuran or dioxane as solvent did not give suc-
cesful reactions. The use of cesium carbonate under anhydrous
conditions was also found to be effective compared with the use
of potassium and sodium carbonates in the presence of water.
The introduction of water to the reaction mixture proves deleteri-
ous to the formation of cyclohexa-m-phenylene. For example,
when K2CO3/H2O was used instead of Cs2CO3, no macrocycle was
obtained. Instead, up to 60% of the starting dibromide could be
recovered after column chromatography, and an analysis of the
remaining mixture of substances by MALDI-TOF revealed only very
low molecular weight species (i.e., <1150 amu). It is highly likely
that under protic conditions, hydrolytic deborylation of the pina-
colboronate ester predominates, leading to very little coupling
being effected. An additional experiment in which the methoxy
group of the diboronic acid component was deliberately omitted
was performed, keeping all other reaction conditions unchanged.
In this case (Table 1, entry 4), no macrocycle was detected by either
TLC or MALDI-TOF. Instead, numerous unresolvable emissive spots
were observed on TLC. After partial purification and attempted
Table 1
Scope of the one-step macrocyclization
R
R
R'
R
R
R''
O
B
R''
O
B
Br
Br
R
R'' R''
R
O
O
Pd(PPh3)4, Cs2CO3,
PhMe, 110 C, 27 h
˚
R'
R'
R
R
Entry
1
R
R0
R00
Yielda (%)
13
H
OMe
OC12H25
OC12H25
2
3
Me
H
OMe
OMe
H
ca. 5b
15
–n-C10H21
4
H
0
OC12H25
a
Isolated yields based on 0.14 mmol scale.
Yield could not be determined with sufficient accuracy.
b

4914
J. M. W. Chan, T. M. Swager / Tetrahedron Letters 49 (2008) 4912–4914
tions promoted by electrophilic additions to the acetylene groups.7
The appeal of these reactions is that they would provide an effi-
cient synthesis of Kekulene structures.8 Unfortunately, to date
our efforts via various electrophilic cyclizations have been unsuc-
cessful, giving complex inseparable mixtures.
In summary, we have discovered a one-step Suzuki coupling-
based construction of arylethynylated cyclohexa-m-phenylenes
from simple building blocks. Compared with previous preparations
of oligophenylene macrocycles, all carbon–carbon bond formations
can be accomplished within a single step. Besides allowing for the
quick assembly of the cyclohexa-m-phenylene framework, the rel-
atively mild conditions used also accommodate the introduction of
complex functionality, and thus provides access to a wide range of
potentially useful materials.
311 nm
388 nm
1.0
0.5
0.0
250
300
350
400
450
500
550
600
Acknowledgments
Wavelength (nm)
This work was supported by the National Science Foundation.
References and notes
Figure 1. Normalized absorbance (blue line) and emission (pink line) spectra of 3.
separation by silica gel column chromatography, several (emissive)
fractions were analyzed by NMR and MALDI. The 1H NMR spectra
of the partially purified mixtures showed typical aromatic peaks
between 6.5 and 8.0 ppm, as well as signals around 3.5 and
4.0 ppm (OCH2), suggesting the kind of functionality that would
be expected in any oligomer or macrocycle formed. MALDI studies
on these fractions indicated the presence of numerous species with
exact masses ranging from 1100 to 4900 amu. These could corre-
spond to oligomers containing between 2 and 7 repeat units. When
the methoxy groups were kept in place, macrocyclization occurred
even as the ethynyl substituents were varied. Isolated yields
tended to be below 20%, with greater steric hindrance (bulkier sub-
stituents) resulting in lower yields. Finally, a macrocyclization
reaction between pinacolboronate 1 and 1,3-dibromobenzene
was attempted. This reaction did not proceed cleanly, leading to
the formation of numerous products. TLC showed no less than
ten unresolvable non-emissive spots, and MALDI analysis failed
to show any peak that would correspond to the desired target.
Thus, the reaction appears to be quite sensitive to the type of
substituents employed in the coupling partners.
1. (a) Staab, H. A.; Binnig, F. Chem. Ber. 1967, 100, 293–305; (b) Staab, H. A.; Binnig,
F. Tetrahedron Lett. 1964, 5, 319–321.
2. (a) Cram, D. J.; Kaneda, T.; Helgeson, R. C.; Brown, S. B.; Knobler, C. B.; Maverick,
E.; Trueblood, K. N. J. Am. Chem. Soc. 1985, 107, 3645–3657; (b) Cram, D. J.;
Carmack, R. A.; Helgeson, R. C. J. Am. Chem. Soc. 1988, 110, 571–577; (c) Cram, D.
J.; Lein, G. M. J. Am. Chem. Soc. 1985, 107, 3657–3658; (d) Lein, G. M.; Cram, D. J. J.
Chem. Soc., Chem. Commun. 1982, 5, 301–304; (e) Cram, D. J.; Lein, G. M.; Kaneda,
T.; Helgeson, R. C.; Knobler, C. B.; Maverick, E.; Trueblood, K. N. J. Am. Chem. Soc.
1981, 103, 6228–6232; (f) Trueblood, K. N.; Knobler, C. B.; Maverick, E.;
Helgeson, R. C.; Brown, S. B.; Cram, D. J. J. Am. Chem. Soc. 1981, 103, 5594–5596;
(g) Cram, D. J.; Kaneda, T.; Helgeson, R. C.; Lein, G. M. J. Am. Chem. Soc. 1979, 101,
6752–6754.
3. Pisula, W.; Kastler, M.; Yang, C.; Enkelmann, V.; Müllen, K. Chem. Asian J. 2007, 2,
51–56.
4. Goldfinger, M. B.; Crawford, K. B.; Swager, T. M. J. Am. Chem. Soc. 1997, 119, 4578.
5. Morgan, A. B.; Jurs, J. L.; Tour, J. M. J. Appl. Polym. Sci. 2000, 76, 1257–1268.
6. Fujioka, Y. Bull. Chem. Soc. Jpn. 1984, 57, 3494–3506.
7. (a) Goldfinger, M. B.; Crawford, K. B.; Swager, T. M. J. Org. Chem. 1998, 63, 1676;
(b) Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 12230; (c) Yao, T.; Campo,
M. A.; Larock, R. C. J. Org. Chem. 2005, 70, 3511; (d) Mamane, V.; Hannen, P.;
Fürstner, A. Chem. Eur. J. 2004, 10, 4556–4575.
8. (a) Staab, H. A.; Diederich, F. Chem. Ber. 1983, 116, 3487–3503; (b) Steiner, E.;
Fowler, P. W.; Acocella, A.; Jenneskens, L. W. Chem. Commun. 2001, 7, 659–660;
(c) Jiao, H.; Schleyer, P. v. R. Angew. Chem., Int. Ed. 1996, 35, 2383–2386; (d)
Aihara, J. J. Am. Chem. Soc. 1992, 114, 865–868; (e) Cioslowski, J.; O’Connor, P. B.;
Fleischmann, E. D. J. Am. Chem. Soc. 1991, 113, 1086–1089.
9. Typical experimental details: Preparation of cyclohexa-m-phenylene 3. A two-
neck round-bottomed flask containing a magnetic stir-bar was charged with
1,5-dibromo-2,4-bis(p-dodecyloxyphenylethynyl)benzene (0.112 g, 0.14 mmol),
1-methoxy-2,6-benzenedipinacolboronate (0.050 g, 0.14 mmol), tetrakis-
(triphenylphosphine)palladium (4.8 mg, 0.0042 mmol), cesium carbonate
(0.113 g, 0.35 mmol), and dry toluene (8 mL). After sparging the stirred
mixture with argon gas over 10 min, the reaction mixture was refluxed under
argon at 110 °C for 27 h. Upon cooling, the crude mixture was partitioned
between diethyl ether and deionized water. After three rounds of extraction
with diethyl ether, the combined organic extracts were dried over anhydrous
magnesium sulfate, before being concentrated in vacuo to give a viscous brown
oil. This was then subjected to flash chromatography on a silica gel column (3:2
v/v hexane/dichloromethane). Upon the complete removal of solvent from the
desired fractions, the target cyclohexa-m-phenylene 3 (13.7 mg, 0.0061 mmol)
is obtained as an off-white solid. 1H NMR (300 MHz, CH2Cl2-d2): d 7.96 (s, 3H),
7.94 (s, 3H), 7.81 (d, 6H, J = 7.8 Hz) 7.38 (d, 12H, J = 9.0 Hz), 7.29 (t, 3H,
J = 7.8 Hz), 6.85 (d, 12H, J = 9.0 Hz), 3.97 (t, 12H, J = 6.6 Hz), 3.33 (s, 9H), 1.80 (m,
12H), 1.2–1.6 (108H), 0.90 (t, 18H, J = 6.9 Hz). 13C NMR (300 MHz, CH2Cl2-d2): d
159.62, 138.76, 133.96, 133.09, 131.39, 120.84, 115.29, 114.71, 93.22, 87.37,
68.35, 32.17, 29.94, 29.91, 29.86, 29.70, 29.62, 29.49, 26.26, 22.94, 14.14. HRMS
(MALDI-TOF): m/z calcd for C159H198O9 2253.2680, found 2252.9891 (M+).
Cyclohexa-m-phenylene 3 was characterized by 1H NMR, 13C
NMR, high-resolution mass spectrometry (MALDI-TOF), UV/vis,
and fluorescence spectroscopy. The 1H NMR spectrum showed all
the expected splitting patterns and chemical shifts. The three sets
of methoxy protons within the macrocycle cavity turned out to be
magnetically equivalent (d = 3.33 ppm), suggesting a symmetrical
optimum conformation that placed the internal substituents in
identical environments, or that the ring system was reasonably
fluxional. Figure 1 shows the normalized absorbance and emission
spectra of 3, with the absorption and emission maxima at 311 nm
and 388 nm, respectively. The large bandgap of the material
(3.4 eV) suggests the lack of conjugation between the rings of the
cyclic system due to twisting relative to each other, not unlike
the rings of unsubstituted cyclohexa-m-phenylene (band-
gap = 3.9 eV, based on its 320 nm band edge).6 Further synthetic
manipulations involving the cyclohexa-m-phenylene targets are
envisioned and we were particularly interested in cyclization reac-