Repetitive synthetic method for o, o, p-oligophenylenes using C-H arylation

Article abstract of DOI:10.1021/ol303327k

A synthetic method for the preparation of o,o,p-oligophenylenes has been developed. It involves Miura's C-H arylation of 2-biphenols with aryl nonaflates as the key step. Oligophenylenes with defined lengths are successfully synthesized using this method.

Full text of DOI:10.1021/ol303327k

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
Repetitive Synthetic Method for
o,o,p‑Oligophenylenes Using CꢀH Arylation
Kei Manabe* and Takeshi Kimura
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku,
Shizuoka 422-8526, Japan
manabe@u-shizuoka-ken.ac.jp
Received December 5, 2012
ABSTRACT
A synthetic method for the preparation of o,o,p-oligophenylenes has been developed. It involves Miura’s CꢀH arylation of 2-biphenols with aryl
nonaflates as the key step. Oligophenylenes with defined lengths are successfully synthesized using this method.
Oligophenylenes, which are composed of benzene rings
connected through a single bond, constitute an important
class of oligomers1 and are widely used architectures
in electronic devices2 and as self-assembling molecules,3
biologically active compounds,4 and catalytic molecules.5
However, the ability to design and synthesize oligophenylenes
with well-defined secondary structures, except for helix-
forming o-6 and m-oligophenylenes,3d in which benzene
rings are connected only at the ortho- and meta-positions,
respectively, is still in a primitive state. We seek to construct
a new type of secondary structure using the proper com-
binations of the possible connectivities (o-, m-, and p-).
Preliminary investigations of the combinations by the Merck
Molecular Force Field (MMFF) molecular mechanics
method7 revealed that o,o,p-oligophenylenes, unknown in
the literature,8 adopt a helical conformation with six benzene
units per helical turn (Figure 1; the structure was optimized
using density functional theory (DFT) calculations7,9 after a
conformational search at the MMFF level).10 This folding
structure maximizes stacking and T-shape contacts among
benzene rings and provides novel scaffolds for the develop-
ment of functional molecules. To explore the chemistry of
this oligomer, it is necessary to develop a method that enables
the efficient synthesis of oligomers with a specific chain
length and substituents at the desired positions.11 Herein,
we describe a versatile method of o,o,p-oligophenylene
(1) (a) Tour, J. M. Chem. Rev. 1996, 96, 537. (b) Berresheim, A. J.;
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In Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
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A. C.; Mullen, K. Angew. Chem., Int. Ed. 2005, 44, 5592. (e) Hoeben,
F. J. M.; Jonkheijm, P.; Meijer, E. W.; Schenning, A. P. H. J. Chem. Rev.
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(2) Li, C.; Liu, M.; Pschirer, N. G.; Baumgarten, M.; Mullen, K.
Chem. Rev. 2010, 110, 6817.
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Tetrahedron Lett. 1998, 39, 9093. (b) He, J.; Crase, J. L.; Wadumethrige,
S. H.; Thakur, K.; Dai, L.; Zou, S.; Rathore, R.; Hartley, C. S. J. Am.
Chem. Soc. 2010, 132, 13848. (c) Mathew, S. M.; Hartley, C. S. Macro-
molecules 2011, 44, 8425. (d) Hartley, C. S.; He, J. J. Org. Chem. 2010, 75,
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(7) Molecular calculations were performed using Spartan ’10,
Wavefunction, Inc., Irvine, CA.
(8) m,m,p-Oligophenylenes have been reported: (a) Diebold, C.;
Weekes, D. M.; Navarrete, M. T.; Mobian, P.; Kyritsakas, N.; Henry, M.
Eur. J. Org. Chem. 2010, 6949. A sexiphenyl with o-, m-, and
p-connectivities has been reported: (b) Nehls, B. S.; Galbrecht, F.; Bilge,
A.; Brauer, D. J.; Lehmann, C. W.; Scherf, U.; Farrell, T. Org. Biomol.
Chem. 2005, 3, 3213.
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W.; Parr, R. G. Phys. Rev. B 1988, 37, 785.
(10) Reviews on artificial molecules with well-defined secondary
structures including helices: (a) Lehn, J.-M. Supramolecular Chemistry:
Concepts and Perspectives; VCH: Weinheim, 1995; Chapter 9, p 139.
(b) Gellman, S. H. Acc. Chem. Res. 1998, 31, 173. (c) Hill, D. J.; Mio,
M. J.; Prince, R. B.; Hughes, T. S.; Moore, J. S. Chem. Rev. 2001, 101,
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(e) Foldamers; Hecht, S., Huc, I., Eds.; Wiley-VCH: Weinheim, 2007.
r
10.1021/ol303327k
XXXX American Chemical Society

synthesis for preparing a variety of oligomers for further
research.
sulfonates such as triflates, as the arylating agents, instead
of aryl iodides or bromides, because the former can be
easily prepared from the corresponding phenols, the key
synthetic intermediates in our route. However, the instabil-
ity of aryl triflates under basic reaction conditions at high
temperature was a severe drawback in this strategy. Triflyl
migration to the hydroxy group of 2-biphenol occurred,
together with hydrolysis of the triflates by adventitious
moisture, resulting in low yields of the desired arylated
products and the substantial production of byproducts.
Therefore, we tested arylating agents other than aryl
triflates and found that aryl nonafluorobutanesulfonates
(nonaflates)15 were better. Aryl nonaflates are less prone
to OꢀSO2 cleavage than triflates.16 In addition, they are
easily prepared from phenols and nonafluorobutanesulfo-
nyl fluoride, which is usually less expensive than the
commonly used triflating agent, triflic anhydride. Thus,
we decided to use aryl nonaflates in our synthesis.
Figure 1. (a) o,o,p-Oligophenylene. (b) Side view of the DFT
(B3LYP/6-31(d))-optimized structure of a 13-mer. (c) Top view.
Next, we screened various ligands to Pd in the reaction
of nonaflate 1 with 2-biphenol in refluxing mesitylene
(Table 1), determined to be the best solvent in our pre-
liminary studies. When PPh3 was used, the desired product
(2) was obtained in an unsatisfactory yield (entry 1), along
with a small amount of [1,10:20,100-terphenyl]-2-ol, which
was probably formed because PPh3 acted as the phenylat-
ing agent.14 We further tested various phosphines, includ-
ing monodentate and bidentate phosphines with different
steric and electronic properties, and found that PCy3 in a
Pd/P ratio of 1:2 gave the best result (entry 10). Bisaryla-
tion at the 20- and 60-position of the biphenols, which is
known to occur in the presence of excess arylating agent,14
was not observed when using 1.5 equiv of biphenol, as
shown in Table 1. A methoxy-substituted biphenol was
also arylated in good yield (entry 11).
Previously, we developed a synthetic method for the
preparation of oligophenylenes via repetitive Suzukiꢀ
Miyaura (SM) coupling12 of hydroxyphenylboronic acids
and sebsequent triflation of the hydroxy group to afford
oligophenylenes with a specific chain length and substitu-
ents at the desired positions (Scheme 1a).13 On this basis,
we designed a new synthetic route to o,o,p-oligopheny-
lenes. It involves CꢀH arylation of 2-biphenols, developed
by Miura et al.,14 as the key step in the construction of an
o,o-connected moiety. Repetition of CꢀH arylation and the
subsequent sulfonation/SM coupling (with a p-hydroxyphe-
nylboronic acid)/sulfonation procedure gives o,o,p-oligo-
phenylenes (Scheme 1b). Since using biphenols instead of
boronic acids is a more atom-economical approach, this
method is superior to the previous one.
With the optimized CꢀH arylation conditions in hand,
we explored the feasibility of the synthetic strategy shown
in Scheme 1b, starting with nonaflate 4 (Scheme 2). The
Scheme 1. Repetitive Synthetic Methods of Oligophenylenes
(11) Examples of oligophenylene synthesis: (a) Cheng, W.; Snieckus,
€
V. Tetrahedron Lett. 1987, 28, 5097. (b) Liess, P.; Hensel, V.; Schluter,
A. D. Liebigs Ann. 1996, 1037. (c) Galda, P.; Rehahn, M. Synthesis 1996,
ꢀ
614. (d) Malenfant, P. R. L.; Groenendaal, L.; Frechet, J. M. J. J. Am.
Chem. Soc. 1998, 120, 10990. (e) Kirschbaum, T.; Azumi, R.; Mena-
€
Osteritz, E.; Bauerle, P. New J. Chem. 1999, 241. (f) Read, M. W.;
Escobedo, J. O.; Willis, D. M.; Beck, P. A.; Strongin, R. M. Org. Lett.
2000, 2, 3201. (g) Kanibolotsky, A. L.; Berridge, R.; Skabara, P. J.;
Perepichka, I. F.; Bradley, D. D. C.; Koeberg, M. J. Am. Chem. Soc.
2004, 126, 13695. (h) Noguchi, H.; Hojo, K.; Suginome, M. J. Am.
Chem. Soc. 2007, 129, 758. (i) Gillis, E. P.; Burke, M. D. J. Am. Chem.
Soc. 2007, 129, 6716. (j) Nakao, Y.; Chen, J.; Tanaka, M.; Hiyama, T.
J. Am. Chem. Soc. 2007, 129, 11694. See also ref 6. For reviews, see:
(k) Wang, C.; Glorius, F. Angew. Chem., Int. Ed. 2009, 48, 5240. See also
ref 5.
(12) (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(b) Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6723.
(13) (a) Ishikawa, S.; Manabe, K. Chem. Lett. 2006, 35, 164.
(b) Ishikawa, S.; Manabe, K. Chem. Commun. 2006, 2589.
(14) (a) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew.
Chem., Int. Ed. 1997, 36, 1740. (b) Satoh, T.; Inoh, J.-i.; Kawamura, Y.;
Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71,
2239.
(a) Our previous method for oligoarene synthesis. (b) Method invol-
ving CꢀH arylation of 2-biphenol as a key step.
Miura et al. reported arylation at the 20-position of
2-biphenol with aryl iodides or bromides in the presence
of a Pd catalyst and a base.14 To apply this reaction to our
synthetic scheme, it was much more beneficial to use aryl
€
(15) Hogermeier, J.; Reissig, H.-U. Adv. Synth. Catal. 2009, 351,
2747.
(16) (a) Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999,
121, 7600. (b) Ikawa, T.; Nishiyama, T.; Nosaki, T.; Takagi, A.; Akai, S.
Org. Lett. 2011, 13, 1730.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Effect of Ligands in CꢀH Arylation of Biphenols with
Nonaflate 1
Scheme 2. Synthesis of o,o,p-Oligophenylene 9-Mer 13
entry
R
ligand (mol %)
PPh3 (20)
yield (%)
1
H
35
5
2
H
P(C6H4-4-CF3)3 (20)
DPPF (20)
3
H
36
44
13
30
33
36
68
76
78
4
H
Xantphos (10)
5
H
P(t-Bu)3 HBF4 (10)
3
6
H
(2-biphenyl)PCy2 (10)
XPhos (10)
7
H
8
H
SPhos (10)
9
H
PCy3 (20)
demonstrated the feasibility of the strategy shown in
Scheme 1b.
10
11
H
PCy3 (10)
OMe
PCy3 (10)
CꢀH arylated product 5 was obtained in 64% yield.
Nonaflation of the hydroxy group of 5 gave nonaflate 6,
which was then converted to7 in high yield by SM coupling
with p-hydroxyphenylboronic acid in the presence of the
PdꢀSPhos catalyst.17 Nonaflation of 7 afforded the sub-
strate for the next CꢀH arylation step, which proceeded
well to give 9 in reasonable yield. Subsequent nonaflation,
SM coupling, nonaflation, and CꢀH arylation afforded
o,o,p-oligophenylene 9-mer 13. Thus, repeated use of CꢀH
arylation, nonaflation, and SM coupling in the appropri-
ate sequence allowed for the facile synthesis of o,o,p-
oligophenylenes. While only unsubstituted biphenol was
used in the CꢀH arylation steps, substituted biphenols
should also be tolerated under the present reaction condi-
tions, considering that methoxybiphenol underwent CꢀH
arylation with a similar yield (Table 1, entry 11). To the
best of our knowledge, this is the first example of the use of
repeated CꢀH arylation to synthesize oligophenylenes
with a defined chain length.18
The synthetic strategy shown in Scheme 2 was also
applicable to the elongation of both ends of the symmetric
oligomers, as shown in Scheme 3. p-Dichlorobenzene
reacted with 2-biphenol to give symmetric 5-mer 14. While
the yield of 14 was modest, to the best of our knowledge,
this is the first example of CꢀH arylation of 2-biphenol
with chlorobenzenes, demonstrating the versatility of
our CꢀH arylation conditions. Repetition of the elonga-
tion process including nonaflation, SM coupling, and
CꢀH arylation afforded symmetric 11-mer 18 from
p-dichlorobenzene in five steps. This synthesis further
Scheme 3. Synthesis of o,o,p-Oligophenylene 11-Mer 18
1H and 13C NMR spectra of o,o,p-oligophenylenes longer
than 6-mers were complicated, suggesting the existence
of rotamers that slowly interconverted at rt on the NMR
timescale. Althoughdetailed conformationalstudiesofthe
o,o,p-oligophenylenes have not been conducted, prelimi-
nary variable-temperature-NMR studies of 7-mer 11 were
conducted (Figure 2). Since the predicted structure of
o,o,p-oligophenylene (Figure 1) has a helical conformation
with six benzene units per helical turn, 7-mers are the shortest
1
possible oligomers having a complete helical turn. The H
NMR spectrum of 11 at 25 °C in DMSO-d6 exhibited two
singlets corresponding to the methoxy protons, at ∼3.6ꢀ
3.7 ppm (Figure 2a). These two sets of signals coalesced at
high temperatures. For example, increasing the temperature
from 25 to 100 °C in DMSO-d6 resulted in coalescence of the
methoxy signals into a single peak (Figure 2d), with a
coalescence temperature of ∼70 °C (Figure 2c). The signals
in the aromatic region (6.2ꢀ7.4 ppm) also coalesced to some
extent at high temperatures.
(17) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2005, 127, 4685.
(18) Synthesis of polymers having a polyphenylene skeleton using
multiple CꢀH arylation has been reported: Lu, W.; Kuwabara, J.;
Kanbara, T. Macromolecules 2011, 44, 1252.
While complete assignment of the species observed in
the NMR spectra is yet to be achieved, DFT-optimized
Org. Lett., Vol. XX, No. XX, XXXX
C

quaterphenyl units, a process that is expected to be slower.19
Therefore, we assume that the two sets of signals observed in
the NMR spectra at 25 °C correspond to the averaged
signals of (M,M)-cisoid-1,2 and (M,M)-transoid-1,2 and
those of (M,P)-cisoid-1,2 and (M,P)-transoid-1,2 (as well
as those of the enantiomer series). From the coalescence
behavior shown in Figure 2, the energy barrier of the
interconversion was calculated to be 72 kJ molꢀ1 at 70 °C.
Figure 3. Eight conformers of 19 and their relative energies
calculated by the DFT method (B3LYP/6-31G(d)).
Figure 2. 1H NMR spectra of 11 in DMSO-d6 at (a) 25, (b) 50,
(c) 70, and (d) 100 °C.
Conformer 19a is very similar to the substructure of the
helix shown in Figure 1. Figure 3 indicates that 19b,c,g are
as stable as 19a, suggesting that conformers other than the
helix should also exist for o,o,p-oligophenylenes. In fact,
oligomers with more than six benzene units yielded com-
plicated NMR spectra at rt, indicating that the oligomers
existed as mixtures of several conformers that interconvert
slowly on the NMR time scale. While it maybe necessaryto
introduce appropriate substituents that stabilize the helix
more effectively,20 our synthetic strategy seems applicable
to oligomers with various substituents and hence may allow
for the efficient preparation of a new helical motif.
In conclusion, a new synthetic route to o,o,p-oligophe-
nylenes involving Pd-catalyzed CꢀH arylation of aryl
nonaflates with 2-biphenols has been developed. The
proposed synthetic strategy is suitable for obtaining oligo-
mers with substituents. Further studies to develop oligo-
phenylenes with well-defined secondary structures are
currently underway.
structures7 found in the conformation search of unsubsti-
tuted 7-mer 19 shed light on the conformational behavior
of 7-mer 11. Eight conformers were found (Figure 3),
which can be categorized into four groups that differ in
the helicity of the o,o-connected quaterphenyl units
(defined as P and M) and in the positions of the terminal
benzene rings A and G relative to the central benzene ring
D (defined as cisoid and transoid). In each group, there are
two conformers that differ mainly in the dihedral angle
between rings D and E. The enantiomers of these con-
formers also exist, although they are omitted for clarity.
Interconversion among 19a, 19b, 19c, and 19d or among
19e, 19f, 19g, and 19h should occur rapidly because of the
possible fast rotation of a single bond connected at the
p-disubstituted ring D. On the other hand, interconversion
among 19a,b and 19e,f or among 19c,d and 19g,h occurs
through changes in the helicity of the o,o-connected
Acknowledgment. We thank Keisuke Mori (University
of Shizuoka) for his assistance in computational studies.
(19) For a studyonrotation barriersofan o-connected quinquephenyl,
see ref 6d.
(20) Examples of substituents that stabilize helical structures: (a)
Marqusee, S.; Baldwin, R. L. Proc. Natl. Acad. Sci. U.S.A. 1986, 84,
8898. (b) Ruan, F.; Chen, Y.; Hopkins, P. B. J. Am. Chem. Soc. 1990,
112, 9403. (c) Ghadiril, M. R.; Choi, C. J. Am. Chem. Soc. 1990, 112,
1630. (d) Jackson, D. Y.; King, D. S.; Chmielewski, J.; Singh, S.; Schultz,
P. G. J. Am. Chem. Soc. 1991, 113, 9391. (e) Blackwell, H. E.; Grubbs,
R. H. Angew. Chem., Int. Ed. 1998, 37, 3281. (f) Walensky, L. D.; Kung,
A. L.; Escher, I.; Malia, T. J.; Barbuto, S.; Wright, R. D.; Wagner, G.;
Verdine, G. L.; Korsmeyer, S. J. Science 2004, 305, 1466.
Supporting Information Available. Experimental and
computational procedures and characterization data of
new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
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