Diverse functionalization of corannulene: Easy access to pentagonal superstructure

Article abstract of DOI:10.1021/ol8028127

A variety of functionalized penta-arylcorannulene derivatives were prepared in high yields and high chemoselectivity by a cross-coupling reaction between sym-pentachlorocorannulene and substituted arylboronic acids using Fu's Pd(0) catalyst. This approach

Full text of DOI:10.1021/ol8028127

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1063-1066
Diverse Functionalization of Corannulene:
Easy Access to Pentagonal Superstructure
Doron Pappo,† Tom Mejuch,† Ofer Reany,† Ephrath Solel,† Mahender Gurram,‡
and Ehud Keinan*,†,‡
Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Technion City,
Haifa 32000, Israel, and Department of Molecular Biology and The Skaggs Institute
for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
keinan@technion.ac.il
Received December 5, 2008
ABSTRACT
A variety of functionalized penta-arylcorannulene derivatives were prepared in high yields and high chemoselectivity by a cross-coupling reaction
between sym-pentachlorocorannulene and substituted arylboronic acids using Fu’s Pd(0) catalyst. This approach provides a general entry to penta-
substituted corannulene derivatives, which are useful building blocks for various structures of high complexity, such as pentagonal dendrimers,
synthetic capsids, and discotic liquid crystals. This was demonstrated here by the facile synthesis of a third generation pentagonal dendrimer.
The notion that molecular containers1 can be obtained by
total synthesis and assembly of small molecules is largely
inspired by the fascinating architecture of the virus particles,
particularly the spherical viral capsids.2 We have recently
proposed a general strategy to meet the challenge of
constructing non-protein molecular capsids having the icosa-
hedral geometry by synthesis and assembly of 12 pentagonal
tiles that bear appropriate “sticky” devices.3 The icosahedron
has been extensively used by Nature at all scales for the basic
physical property of encapsulation because this architecture
exploits the economy of the sphere in terms of both surface-
area-to-volume ratio and genetic efficiency of subunit-based
symmetric assembly.4
For the synthesis of the desired pentagonal tiles we have
chosen the corannulene molecule as the core skeleton due
to its bowl shape, rigid polycyclic aromatic nature, and 5-fold
symmetry.5 These properties render corannulene a useful
building block not only for the synthesis of chemical capsids
but also for the construction of large molecular6 and
† Technion-Israel Institute of Technology.
‡ The Scripps Research Institute.
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75, 393–413. (c) Hof, F.; Craig, S. L.; Nuckolls, C.; Rebek, J., Jr. Angew.
Chem., Int. Ed. 2002, 41, 1488–1508. (d) Turner, D. R.; Pastor, A.; Alajarin,
M.; Steed, J. W. In Structure and Bonding; Mingos, D. M. P., Ed.; Springer-
Verlag: Heidelberg, 2004; Vol. 108, pp 97-168.
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10.1021/ol8028127 CCC: $40.75
Published on Web 02/04/2009
2009 American Chemical Society

supramolecular architectures, such as pentagonal dendrim-
ers,7 single-wall nanotubes, light emitters,8 and discotic liquid
crystals.9
in the synthesis of penta-arylcorannulenes bearing functional
groups that are needed to achieve the desired architectures.
For example, our attempts to couple 1 with various arylzinc
or arylboronic acid partners bearing various functional groups
failed to produce the corresponding penta-arylcorannulenes
in satisfactory yield. Consequently, we searched for a more
general cross-coupling approach.
Here we report that a broad variety of functionalized penta-
arylcorannulene derivatives can be obtained in high yields
under mild conditions from 1 and the appropriate arylboronic
acids using Fu’s bulky phosphine ligand, tri(tert-butyl)phos-
phine.19
Our general procedure for the cross-coupling reactions of
1 at 0.1 mmol scale (Scheme 1)20 employ the substituted
arylboronic acid (8 equiv, 1.6 equiv per site), catalytic
amounts of Pd[P(t-Bu)3]2 (20%, 4% per site), and CsF (15
equiv, 3 equiv per site) in dioxane at 80 °C. The resulting
penta-arylcorannulenes, 2, 5, 8 and 11, were obtained under
these conditions in 59-83% yields.
The isolation and characterization of symmetrical coran-
nulene derivatives is not easy because of their low solubility
in most organic solvents.21 A typical example is 1,3,5,7,9-
penta(4-methoxycarbonylphenyl)corannulene, 2, which is
obtained by reacting 1 with 4-(methoxycarbonyl)phenylbo-
ronic acid. The procedure reported by Scott for another penta-
arylcorannulene,17 which involves filtration through a short
bed of silica-gel, afforded only traces of 2. Nevertheless,
avoiding the filtration and chromatographic purification
yielded a crude solid product that was purified by recrys-
tallization from chloroform, affording 2 in 41% yield.
Significantly higher yields were obtained with Fu’s catalytic
system,19 leading to pure 2 in 59% yield without recrystal-
lization (Scheme 1).
The synthetic difficulties en route to penta-functional
corannulene derivatives have been significantly reduced
owing to the available synthesis of corannulene.10 Further-
more, the challenge of symmetrical activation of all five
edges in the molecule has been satisfactorily met by Scott’s
discovery that the reaction of corannulene with ICl proceeds
with high regioselectivity to produce 1,3,5,7,9-pentachloro-
corannulene, 1.10b,11 Consequently, the main challenge
became the attachment of the desired functional groups and
binding devices onto the corannulene edges. This is a non-
trivial task considering the low reactivity of aryl chlorides
in cross-coupling reactions12 and the need to perform the
reaction five times on the same molecule.
Previous efforts to meet this challenge were based on
various methods of metal-catalyzed cross-coupling reactions.
Siegel’s protocol, which employs trialkyl aluminum com-
pounds under nickel(II) catalysis, can convert 1 into penta-
alkylcorannulenes in 30-50% yields.14 However, the analo-
gous nickel(II)-catalyzed reactions with metallo-aryl reactants,
including those of aluminum, magnesium, boron, and tin,
were met with partial success.
Some successful approaches have been found. For ex-
ample, Siegel has used the Negishi chemistry to achieve
several sym-penta-arylcorannulenes in 28-49% yield via
nickel-catalyzed cross-coupling of 1 with arylzinc chlo-
ride.13,14 Also Eberhard’s pincer catalyst15 was found useful
for these cross-coupling transformations with metallo-alkynyl
reactants.10b,16 Further advances by Scott offered the cross-
coupling of 1 with 2-chloroarylboronic acid using the
Suzuki-Miyaura protocol under Nolan’s conditions.17,18
We found that although the above-mentioned methods
work well for some aryl groups, their efficiency is limited
Compound 2 was successfully transformed into other
useful penta-arylcorannulenes. Thus, hydrolysis with KOT-
MS in refluxing THF for 16 h afforded 1,3,5,7,9-penta(4-
carboxyphenyl)corannulene, 3, in 86% yield. Reduction of
2 with DIBAL-H in THF at room temperature afforded
1,3,5,7,9-penta(4-hydroxymethylphenyl)corannulene, 4, in
65%. Avoiding filtration/chromatography workup in all other
reactions afforded numerous penta-arylcorannulenes, 2-14,
in good yields. All products exhibited low solubility in
common organic solvents, such as toluene, chloroform, and
ethyl acetate.
(5) (a) Wu, Y. T.; Siegel, J. S. Chem. ReV. 2006, 106, 4843–4867. (b)
Sygula, A.; Rabideau, P. W. In Carbon-Rich Compounds: From Molecules
to Materials; Haley, M., Tykwinski, R., Eds.; Wiley-VCH: Weinheim,
Germany, 2006; p 529. (c) Sygula, A.; Xu, G.; Marcinow, Z.; Rabideau,
P. W. Tetrahedron 2001, 57, 3637–3644. (d) Sygula, A.; Rabideau, P. W.
J. Am. Chem. Soc. 2000, 122, 6323–6324. (e) Hirsch, A. Top. Curr. Chem.
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Seiders, T. J.; Siegel, J. S. Chem. Br. 1995, 31, 307–312.
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For example, 1,3,5,7,9-penta(4-methoxyphenyl)corannu-
lene, 5,14,22 and 1,3,5,7,9-penta(4-tert-butylthiophenyl)coran-
nulene, 8, were obtained in 83% and 59% yields, respec-
tively. While the pentaether 5 and pentathioether 8 exhibited
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E. J.; Keinan, E. J. Org. Chem. 1993, 58, 3821–3827. (c) Keinan, E.; Kumar,
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L. T. J. Am. Chem. Soc. 2007, 129, 484–485.
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(20) The coupling reaction was successfully performed on larger scale
as well (0.4 mmol in the case of pentaester 2).
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Org. Lett., Vol. 11, No. 5, 2009

Scheme 1. Preparation of Penta-arylcorannulenes 2-14
partial solubility in organic solvents, such as tetrachloroet-
hane, their correponding pentaphenol, 6, and pentathiophenol,
9, were found to be insoluble for characterization by solution
NMR. Compound 6 was obtained in 87% yield by treatment
of 5 with BBr3 in CH2Cl2 at room temperature for 18 h.
Similarly, 8 was converted to 9 in 90% yield by treatment
with triflic acid and TFA in toluene at 80 °C for 16 h. In
order to determine their structures, 6 and 9 were allylated
by treatment with allylbromide and NaH in DMF at room
temperature for 24 h. The allylated products, 1,3,5,7,9-
penta(4-allyloxy-phenyl)corannulene, 7, and 1,3,5,7,9-penta(4-
allylthio-phenyl)corannulene, 10, were obtained as yellow
solids in 65% and 82% yield, respectively, sufficiently
soluble for characterization by NMR.23
1,3,5,7,9-Penta(4-formyl)phenylcorannulene, 12, was pre-
pared in two steps. First, coupling of 4-(1,3-dioxan-2-
yl)phenylboronic acid with 1 afforded 1,3,5,7,9-penta(4-(1,3-
diox-an-2-yl)phenyl)corannulene, 11, in 61%. Acid-catalyzed
hydrolysis (TFA, CH2Cl2-H2O, 85% yield) afforded the
corresponding penta-aldehyde, 12. The latter derivative
represents a potential candidate for the synthesis of a
chemical capsid using imine chemistry according to the
concept of dynamic covalent chemistry.24,25
methoxypyridin-3-yl)corannulene, 13, was obtained in 51%
yield using catalytic Pd[P(t-Bu)3]2 and K3PO4 in dioxane-
H2O at 80 °C for 72 h. Similarly, 1,3,5,9-penta(pyridin-4-
yl)corannulene, 14, was prepared in 24% yield using catalytic
Pd[P(t-Bu)3]2 and K3PO4 in DMF-H2O at 100 °C for 72 h.
The latter two derivatives represent the first example of
corannulene substituted with heteroaromatic groups, which
may lead to icosahedral capsids by metal-mediated self-
assembly. The metal coordination strategy has been suc-
cessfully used by Stang and others for the construction of
large supramolecular architectures.26
The above-described functionalized corannulene deriva-
tives represent attractive building blocks for the synthesis
of new dendrimers that have 5-fold symmetry.27 Such
monodispersed macromolecules could have interesting ap-
plications, including medicinally relevant compounds,28
sensors,29 catalysts,30 and molecular encapsulators.31
(23) Whereas compound 7 has sufficient solubility in C2D2Cl4 for
1
performing both H and 13C NMR experiments, compound 10 has poor
solubility and its carbon chemical shifts could not be measured.
(24) (a) Rowan, S. J.; Cantrill, S. J.; Cousins, G. R. L.; Sanders, J. K. M.;
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2006, 45, 901–904. (c) Liu, Y.; Liu, X.; Warmuth, R. Chem. Eur. J. 2007,
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For the cross-coupling of heteroaryl boronic acids with 1
we used slightly modified conditions.19d 1,3,5,7,9-Penta(6-
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Org. Lett., Vol. 11, No. 5, 2009
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Scheme 2. Preparation of Third Generation Fre´chet-Type Dendrimer 17
Thus, applying the divergent growth approach, a third
generation Fre´chet-type dendrimer, 17 (Scheme 2), was
prepared from 6 in three steps, utilizing “click” chemis-
try.32,33 The penta-phenol, 6, was reacted with the substituted
benzylic bromide, 18,34 to produce the corresponding penta
ether, 15, in nearly quantitative yield. The 10 terminal
acetylene groups of compound 15 underwent high-yield,
copper-catalyzed 1,3-dipolar cycloaddition with excess azide
19 to produce the icosaphenol, 16. Without any purification
of either 15 or 16, the latter underwent another etherification
with 18 to produce dendrimer 17 in 75% overall yield for
the three steps from 6. Whereas compounds 15 and 16 still
suffered from low solubility that characterizes many other
penta-arylcorannulene derivatives, the third generation den-
drimer, 17, having 40 terminal acetylene groups, exhibited
excellent solubility in common organic solvents, including
CH2Cl2 and ethyl acetate. Its structure was confirmed by both
1H and 13C NMR and MS (MALDI-TOF; m/z 7316.7 M+,
calcd 7317.6).
acids provides a general entry to penta-substituted corannu-
lene derivatives with high yields and high chemoselectivity.
The reaction works equally well with arylboronic acids
bearing variety of useful functional groups, including
electron-rich (OMe, S-t-Bu, 1,3-dioxan-2-yl) and electron-
deficient (CO2Me) substituents to produce the penta-
substituted derivatives in 50-83% yield (87-96% per site).
For the cross-coupling of sym-pentachlorocorannulene with
aryls, Fu’s catalyst was found to be more efficient and more
general than Nolan’s catalyst with a carbene ligand. The high
reactivity of Fu’s catalyst allows for low catalyst loading
(20%, 4% per site) and only a small excess of the coupled
boronic acid (1.6 equiv per site). Considering the low
solubility of the corannulene derivatives, the recommended
workup procedure avoids chromatographic purification. It
simply involves treatment of the crude product with toluene,
collecting the precipitate and washing it with other organic
solvents.
This work demonstrates that functionalized penta-aryl-
corannulenes are useful building blocks for various structures
of high complexity, such as pentagonal dendrimers. Further
efforts toward other molecular and supramolecular architec-
tures, including synthetic capsids3 and discotic liquid crystals,
are currently underway in our laboratories.
In conclusion, the palladium-catalyzed cross-coupling
reaction of 1 with a broad variety of substituted arylboronic
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Acknowledgment. This study was supported by the Israel
Science Foundation, the German-Israeli Project Cooperation
(DIP), the Institute of Catalysis Science and Technology,
Technion, and the Skaggs Institute for Chemical Biology.
E.K. is the incumbent of the Benno Gitter & Ilana Ben-Ami
Chair of Biotechnology, Technion.
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