A repetitive one-step method for oligoarene synthesis using catalyst-controlled chemoselective cross-coupling

Article abstract of DOI:10.1021/ol200676k

Chemical equations presented. A method for oligoarene synthesis involving chemoselective cross-coupling as the key reaction was developed. Boronic acids with a chloro or trifluoromethanesulfonyloxy group were used as the monomer precursors with either of

Full text of DOI:10.1021/ol200676k

ORGANIC
LETTERS
2011
Vol. 13, No. 9
2436–2439
A Repetitive One-Step Method for
Oligoarene Synthesis Using
Catalyst-Controlled Chemoselective
Cross-Coupling
Kei Manabe,* Mai Ohba, and Yuji Matsushima
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku,
Shizuoka 422-8526, Japan
manabe@u-shizuoka-ken.ac.jp
Received March 14, 2011
ABSTRACT
A method for oligoarene synthesis involving chemoselective cross-coupling as the key reaction was developed. Boronic acids with a chloro or
trifluoromethanesulfonyloxy group were used as the monomer precursors with either of two chemoselective catalytic systems: Pd with P(t-Bu)3,
and Pd with 1,10-bis(diphenylphosphino)ferrocene (DPPF). This method enabled elongation by one benzene unit in every step and thus reduced
the number of steps required for elongation of oligoarene chains with well-defined lengths and sequences of substituted benzene rings.
Oligomers with well-defined chain lengths and struc-
tures are of interest as functional molecules, and the
development of efficient methods for oligomer synthesis
has been an important subject in organic chemistry.1
Oligoarenes, which are composed of aromatic monomer
units such as benzene rings connected through a single
bond (Figure 1a), constitute an important class of
oligomers,2 and those with functional groups are
widely used in electronic devices3 and as self-assem-
bling molecules,4 biologically active compounds,5 and
catalytic molecules.6 Herein, we report a new synthetic
method that halves the number of steps required for
elongation of oligoarene chains.
Oligopeptides are an important class of oligomers, and
their established synthetic method involves the repetition
of two steps: amide formation using N-protected amino
acids and deprotection of the amino group. This has been a
model in developing synthetic methods for other types of
oligomers in which sequences of connected monomer units
must be controlled. Oligoarenes with well-defined chain
lengths and sequences have also been synthesized by
methods in which two (or sometimes three)5 steps required
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r
10.1021/ol200676k
Published on Web 04/07/2011
2011 American Chemical Society

chemoselective cross-coupling.12 For example, Fu and co-
workers reported an intriguing example of catalyst-controlled
chemoselectivity between chloro and TfO groups in Suzukiꢀ
Miyaura coupling,13ꢀ15 finding that a Pd catalyst bearing
P(t-Bu)3 reacted with chloroarenes preferentially over
aryl triflates, which are known to be more reactive than
chloroarenes in most cross-coupling reactions. Thus, we
assumed that this chemoselective SuzukiꢀMiyaura cou-
pling would be applicable to our repetitive one-step method
for oligoarene synthesis (Figure 1c, Y = (HO)2B, X1 = Cl,
X2 = TfO).
As there have been no reports of chemoselective Suzukiꢀ
Miyaura coupling of chloroarenes with phenylboronic
acids bearing a TfO group on the benzene ring, we first
optimized the reaction conditions for cross-coupling based
on those used by Fu and co-workers.13 Phenylboronic
acids bearing a TfO group were easily prepared from
iodophenyl triflates through IꢀMg exchange reactions.16
Some boronic acids (e.g., 2) were isolated as their trimeric
anhydride forms (boroxines). Optimization of a model
reaction of 4-chlorotoluene (1) with 2 led to the conditions
shown in eq 1. As in Fu’s examples,13 the TfO group of the
boronic acid remained intact under these conditions, and
longer oligoarene byproducts were not produced. While
KF also worked as a base, K3PO4 was found to be slightly
more active, giving 3 in higher yield.
Figure 1. (a) General representation of an oligoarene. (b) The
repetitive two-step method for oligoarene synthesis. X and Y are
functional groups that form a carbonꢀcarbon bond under
cross-coupling conditions. Z is a group that remains intact
under the cross-coupling conditions but can be converted to X in
the subsequent step. (c) The repetitive one-step method using
chemoselective cross-coupling: see text for details.
for elongation by one arene unit are repeated.7 These
methods involve repetition of two steps: cross-coupling
and the subsequent functional group transformation
(Figure1b). Thistype ofstepwisesynthesisallowsthe cons-
truction of multisubstituted oligoarenes with various sub-
stituents in a specific sequence. While these repetitive two-
step methods may be improved to establish an efficient
synthetic method, we envisioned the development of a more
efficient method using chemoselective cross-coupling. The
concept of this “repetitive one-step method” is shown in
Figure 1c. Underconditions in whichone catalyst promotes
the reaction of Y with X1 but not with X2, while another
promotes the reaction with X2 but not with X1, the mole-
cule can be elongated by one benzene unit in every step.
Without chemoselectivitybetween X1 and X2, uncontrolled
polymerization would take place, producing a mixture of
compounds with various molecular weights.8 While chemo-
selective reactions have been utilized inrepetitive one-step
synthesis of oligosaccharides9 and dendrimers10;often
called orthogonal synthesis;repetitive one-step synthesis
of oligoarenes has not yet been achieved.11 In the litera-
ture, there are several examples of catalyst-controlled
There are some examples in the literature of reactions of
aryl triflates with phenylboronic acids bearing a Cl
group.17 Screening of catalytic conditions for a model
reaction of 4 with 5 showed that the conditions shown in
eq 2 were optimal. A combination of Pd(OAc)2 (3 mol %)
(8) (a) Yamamoto, T.; Hayashi, Y.; Yamamoto, Y. Bull. Chem. Soc.
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arylenevinylene unit has been reported: Ishida, N.; Shimamoto, Y.;
Murakami, M. Org. Lett. 2010, 12, 3179.
(12) (a) Kamikawa, T.; Hayashi, T. Tetrahedron Lett. 1997, 38, 7087.
(b) Espino, G.; Kurbangalieva, A.; Brown, J. M. Chem. Commun. 2007,
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Bauerle, P. New J. Chem. 1999, 241. (g) Read, M. W.; Escobedo, J. O.;
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Org. Lett., Vol. 13, No. 9, 2011
2437

and PCy3 (6 mol %) also gave 6 in good yield (75%),
but a small amount of the terphenyl byproduct was for-
med through an overreaction (over-cross-coupling) at the
Cl group. Therefore, we decided to use 1,10-bis(diphenyl-
phosphino)ferrocene (DPPF) for this chemoselective
cross-coupling.17b
in the steps (93ꢀ99%) were higher than those in the
previous synthesis (Scheme 1). Although the reason for
the higher yields is unclear, we assume that slight differ-
ences in the solubility of the substrates are responsible.
Scheme 2. Synthesis of Quinquephenyl 16
We then applied the reaction conditions to oligomer
synthesis, as shown in Scheme 1. The synthesis began with
chloroarene 7. Alternating use of the Cl-selective and TfO-
selective conditions afforded 12 in 4 steps, demonstrating
that the repetitive one-step method really worked. The
yields in each step were not excellent (72ꢀ83%), but over-
cross-coupling was not observed. Slight modifications of
the conditions in eqs 1 and 2 were required for some steps:
the third and fourth steps were found to require higher
temperatures, greater amounts of the catalysts, and larger
volumes of solvents to increase the fluidity of the reaction
mixtures. While the target quinquephenyl was arbitrarily
chosen, this result strongly suggests that the method under
discussion is applicable to the synthesis of various types of
oligoarene.
We next carried out the synthesis of multisubstituted
oligoarenes using boronic acids with substituents. An
example is shown in Scheme 3. Multisubstituted quater-
phenyl 22 was produced in good yield. It should be
mentioned that the cross-coupling conditions for chloro-
arene 18 had to be modified in this synthesis. When 18 was
subjected to the conditions described above (Pd2(dba)3,
Scheme 1. Synthesis of Quinquephenyl 12
P(t-Bu)3 HBF4, K3PO4), some aldehydes and a byproduct
3
in which the Cl group was substituted with H were obtained
(7ꢀ9%). These byproducts are likely to be produced
through Pd-mediated oxidation of the hydroxymethyl
Scheme 3. Synthesis of Quaterphenyl 22
In this repetitive one-step method, the alternating use of
triflates and chlorides in a different order was expected to
work equally well. To demonstrate this, we started with
aryl triflate 4, instead of 7, with the aim of synthesizing the
same quinquephenyl backbone as 12 (Scheme 2). In this
way, quinquephenyl 16 was produced in 4 steps by using
the two catalytic systems alternately. In this case, the yields
2438
Org. Lett., Vol. 13, No. 9, 2011

extent. Therefore, we used KF as the base, albeit slightly
less active, throughout the synthetic route. The result
shown in Scheme 3 demonstrates that various functional
groups, including ester, free hydroxy, alkoxy, and fluoro
groups, can be installed into oligoarene structures.
Another example of multisubstituted oligoarene synthe-
sis is shown in Scheme 4. The third step from 24 to 25
resulted in modest yield. In addition, 25 and remaining 24
could not be separated. Therefore, the mixture (24:25 =
ca. 2:3) was subjected to the next reaction with 17 without
isolation of 25. The reaction preferentially occurred at the
TfO group of 25 over the Cl group of 24 to produce
sexiphenyl 26, which was now isolated with ease. The
results of synthesis of these arbitrarily chosen oligoarenes
strongly suggest that combinatorial uses of monomer
precursors should enable preparation of various oligo-
arenes by this method.
Scheme 4. Synthesis of Sexiphenyl 26
In conclusion, we have developed a repetitive one-step
method for synthesizing multisubstituted oligoarenes. The
key reaction is catalyst-controlled chemoselective Suzukiꢀ
Miyaura coupling. The monomer precursors were phenyl-
boronic acids bearing a Cl group or a TfO group, which
were used in an alternating fashion to elongate the oligoar-
ene chain by one benzene unit in every step. In principle, by
using various monomer precursors and combining them in
different ways, a variety of oligoarenes should be produced
with ease. Combinatorial syntheses of functional mole-
cules are now underway in our laboratory.
group and Pd-mediated reduction of the Cl group with the
hydride generated by the oxidation step.18 However, we
were pleased to find that the use of KF instead of K3PO4
suppressed the formation of these byproducts to a significant
Supporting Information Available. Experimental proce-
dures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(18) Kesharwani, T.; Larock, R. C. Tetrahedron 2008, 64, 6090.
Org. Lett., Vol. 13, No. 9, 2011
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