A fragment-based approach toward substituted trioxa[7]helicenes

Article abstract of DOI:10.1021/ol3023209

A series of novel substituted trioxa[7]helicenes have been successfully prepared by a one-pot palladium catalyzed C-H arylation reaction starting from readily prepared dibenzofuran fragments. The dinitro-substituted helicene was analyzed by X-ray crystallography revealing the occurrence of two distinct enantiomers in the asymmetric unit, which forms interesting supramolecular motifs in the crystal, based on weak H-bonding interactions.

Full text of DOI:10.1021/ol3023209

ORGANIC
LETTERS
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Vol. XX, No. XX
000–000
A Fragment-Based Approach toward
Substituted Trioxa[7]helicenes
†
Hans Kelgtermans, Liliana Dobrzanska, Luc Van Meervelt, and Wim Dehaen*
†
‡
,†
ꢀ
Molecular Design and Synthesis, Department of Chemistry, Katholieke Universiteit
Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium, and Biomolecular Architecture,
Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan 200F,
3001 Leuven, Belgium
wim.dehaen@chem.kuleuven.be
Received August 20, 2012
ABSTRACT
A series of novel substituted trioxa[7]helicenes have been successfully prepared by a one-pot palladium catalyzed CꢀH arylation reaction starting
from readily prepared dibenzofuran fragments. The dinitro-substituted helicene was analyzed by X-ray crystallography revealing the occurrence
of two distinct enantiomers in the asymmetric unit, which forms interesting supramolecular motifs in the crystal, based on weak H-bonding
interactions.
For over a century now, chemists have been inspired
by the peculiar shape of helicenes.1 Formed by a sequential
ortho-annulation of (hetero)aromatic rings, helicenes are
endowed with a unique π-conjugated backbone which
is twisted into a helical shape due to a progressive
steric hindrance between the terminal rings. The resulting
inherently chiral skeleton is responsible for an astonishing
number of diverse and fascinating applications, covering
domains such as chiral catalysis,2 self-assembly,3 liquid
crystals,4 and biomolecular recognition.5 Not surprisingly,
these recent developments have led to a rapid increase in
the number of different synthetic methodologies that avoid
the more common, and up until now widely used, oxidative
photocyclizations of stilbene-like precursors.6 Compelling
examples of these novel synthetic routes include the well-
known DielsꢀAlder approach introduced by Katz et al.,7
carbenoid couplings,8 FriedelꢀCrafts type cyclizations,9
† Molecular Design and Synthesis.
‡ Biomolecular Architecture.
(1) (a) Shen, Y.; Chen, C.-F. Chem. Rev. 2012, 112, 1463. (b)
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Ed. 2011, 50, 3684. (c) Rybacek, J.; Huerta-Angeles, G.; Kollarovic, A.;
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r
10.1021/ol3023209
XXXX American Chemical Society

and olefin metathesis.10 Another well established proce-
selected as a terminal substituent on the helicene since, in
general, they are inaccessible using photocyclization-based
methods due to their quenching effect and will most likely
enhance the electro-optical properties of the helicene by
creating a more pronounced D-π-A system.17 Both substi-
tuted dibenzofurans were readily prepared on a multigram
scale starting from commercially available compounds. A
nucleophilic aromatic substitution followed by a CꢀH
arylation catalyzed by Pd(OAc)2 and PPh3 yielded ester
3, which wasreduced using DIBAL and finally brominated
with PBr3, resulting in the formation of 4 in good yields.
Using a similar strategy, 2-methoxy-8-nitrodibenzofuran 7
was obtained. After demethylation of 7 and subsequent
iodination using an iodineꢀmorpholine charge-transfer
complex,18 the targeted phenolic substrate 8 was acquired
in excellent yields (Scheme 2).
dure is based on the intramolecular [2 þ 2þ2] cycloisome-
ꢀ
ꢀ
rization of triynes, first reported by Stary and Stara in
1998,11 and currently one of the most employed methods
for preparing helicenes both racemically12 and enantio-
selectively.13 Although several different helical frame-
works have been created using this technique, the rather
cumbersome preparation of the starting materials and the
relatively high cost of the transition metals and ligands
are still limiting factors in this methodology. On the other
hand, only a few palladium-catalyzed arylation approaches
toward helicenes are reported to date,14 despite the major
advances that have been made in this field.15 Prompted
by these findings, we were eager to investigate whether it
would be possible to extend the well-known palladium
mediated CꢀH arylations to sterically more demanding
structures, particularly by using substituted dibenzofuran
units.
Scheme 2. Synthesis of the Starting Materials 4 and 8
Scheme 1. Overview of Past and Current Work
In previous work16 we described the synthesis and char-
acterization of oxa-helicenes in which two dibenzofuran
blocks are linked via a pyrrole moiety, constructed by means
of a double BuchwaldꢀHartwig N-arylation (Scheme 1).
For this study a pyran ring as a linking group was selected
due to its relatively facile preparation and increased ring
size, which will extend the sterical overlap between the
terminal rings and improve the thermal racemization
stability.
Scheme 3. CꢀH Arylation toward Helicene 10
The study was initiated with the preparation of suitable
starting materials 4 and 8 (Scheme 2). A nitro group was
(10) (a) Grandbois, A.; Collins, S. K. Chem.;Eur. J. 2008, 14, 9323.
(b) Collins, S. K.; Grandbois, A.; Vachon, M. P.; Cote, J. Angew. Chem.,
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Tichy, M. J. Org. Chem. 1998, 63, 4046.
ꢁ ꢀ ꢁ ꢀ
(12) Songis, O.; Mısek, J.; Schmid, M. B.; Kollarovic, A.; Stara, I.;
´
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Saman, D.; Cısarova, I.; Stary, I. J. Org. Chem. 2010, 75, 6889.
´
(13) (a) Shibata, T.; Uchiyama, T.; Yoshinami, Y.; Takayasu, S.;
Tsuchikama, K.; Endo, K. Chem. Commun. 2012, 48, 1311. (b) Sehnal,
The reaction between 4 and 8 was characterized by the
formation of a white precipitate after only a few minutes at
100 °C. Although the low solubility of 9 was expected,
ꢀ
ꢀ
ꢀ
ꢀ
ꢁ
P.; Krausova, Z.; Teply, F.; Stara, I.; Stary, I.; Rulısek, L.; Saman, D.;
ꢁ
´
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Cı
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sarova, I. J. Org. Chem. 2008, 73, 2074.
(14) (a) Nakano, K.; Hidehira, Y.; Takahashi, K.; Hiyama, T.;
Nozaki, K. Angew. Chem., Int. Ed. 2005, 44, 7136. (b) Kamikawa, K.;
Takemoto, I.; Takemoto, S.; Matsuzaka, H. J. Org. Chem. 2007, 72,
7406.
(15) Ackermann, L. Modern Arylation Methods; Wiley-VCH: Weinheim,
(17) (a) Champagne, B. Chem. Phys. Lett. 2012, Article ASAP (doi:
10.1016/j.cplett.2012.03.015). (b) Bossi, A.; Licandro, E.; Maiorana, S.;
Rigamonti, C.; Righetto, S.; Stephenson, G. R.; Spassova, M.; Botek,
E.; Champagne, B. J. Phys. Chem. C 2008, 112, 7900.
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34, 3389.
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W. Org. Lett. 2012, 14, 1500.
B
Org. Lett., Vol. XX, No. XX, XXXX

isolation and characterization of the dimeric intermediate
9 remained very difficult, even after the introduction of
a bulky tert-butyl substituent on 8. However, addition of
Pd(OAc)2 to the reaction mixture in combination with
triphenyl phosphine resulted in the rapid disappearance
of the precipitate and formation of a ring-closed prod-
uct (according to mass spectrometry); thus the synthetic
protocol was carried out as a one-pot process. After the
reaction, two major compounds could be separated which
corresponded to the two possible isomers 10 and 11
(Scheme 3).
By investigating the NMR spectroscopic data, the major
component of the mixture (79%) was identified as helicene
10. This was clearly indicated by a significant upfield shift
for the innermost hydrogens, caused by the shielding effect
of the neighboring dibenzofuran system (see Supporting
Information (SI)). The linearly fused isomer 11, which
Figure 1. Two crystallographically independent molecules of
13 present in the asymmetric unit with labeled heteroatoms.
Displacement ellipsoids are drawn at the 50% probability level;
hydrogen atoms have been omitted for clarity.
Table 1. Scope of the CꢀH Arylation Approach toward Substituted Trioxa[7]helicenes
a Isolated yields. b The linearly fused isomers were formed in trace amounts but could not be isolated in a pure form.
Org. Lett., Vol. XX, No. XX, XXXX
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actually is a [5]helicene by itself, was only formed in small
amounts (6ꢀ7%) despite the fact that it is less sterically
strained than its helical counterpart.
(calculated as the sum of torsion angles) of the molecular
structures I and II with respective absolute values of 69.0°
and 74.2°. These indicate a larger distortion in compound
13 than in the dioxa-aza[7]helicene (53.2°) we reported
earlier,16 as a result of introducing the pyran ring and
perhaps the presence of the nitro functions. The value in
II approaches the one reported for oxa[7]helicene (78.9°).14a
Moreover, due to the presence of the nitro groups,
Interestingly, during the optimization process it became
clear that the nature of the phosphine ligand was irrelevant
to the outcome of the reaction, which could mean that it
is not participating in the ring closure mechanism. These
observations were confirmed by running an experiment
under ligand-free conditions, which revealed a reaction
outcome comparable to that when PPh3 was used. Perform-
ing the second step without the addition of a palladium
source left the starting material unchanged, proving the
necessity of the catalyst. So in general, the synthetic protocol
could be carried out as a high-yielding, scalable, one-pot
process starting from readily obtained dibenzofuran build-
ing blocks and a relatively inexpensive source of palladium.
With these reaction conditions in hand, we were eager
to test the scope of this new CꢀH arylation approach.
Several substituted dibenzofuran moieties were success-
fully prepared and coupled (Table 1) following a similar
strategy as before, clearly demonstrating the versatility of
this approach. Both electron-donating and -withdrawing
functionalities were readily combined by connecting the
corresponding dibenzofuran fragments, making this meth-
od an ideal tool for fine-tuning the helicene backbone.
Crystals of rac-13 suitable for an X-ray diffraction study
were obtainedby slow evaporation from dichloromethane.
The compound crystallizes in the centrosymmetric triclinic
space group P1, with two crystallographically independent
molecules of opposite helical handedness in the asym-
metric unit (see Figure 1). The geometrical parameters of
these two solid-state enantiomers (I and II) differ slightly
(rmsd was calculated as 0.115 A, with a maximum distance
between two atoms of 0.266 A).
CꢀH O weak H-bonding interactions lead to the for-
3 3 3
mation of 1D zigzag chains consisting of one type of
conformer that are further interconnected into 2D supra-
molecular layers (see Supporting Information (SI) for a
detailed analysis of the packing).
In summary we have successfully explored the synthesis
of a novel trioxa[7]helicene scaffold. Several substitution
patterns were readily constructed by starting from differ-
ent dibenzofuran building blocks, which could be com-
bined in a one-pot reaction under palladium catalysis to
form the helical framework. One of the helicenes was
characterized by X-ray crystallography analysis, revealing
the importance of nitro functionalities in the supramole-
cular assembly. We demonstrated the flexibility of the
approach by combining electron-donating and -withdraw-
ing functional groups, a vital feature during the forth-
coming study of the electro-optical properties of these
helicenes.
Acknowledgment. The Instituut voor de aanmoediging
van innovatie door Wetenschap en Technologie in
Vlaanderen (IWT) is acknowledged for a fellowship to
H.K. We thank the Fonds voor Wetenschappelijk
Onderzoek (FWO - Vlaanderen) and the University of
Leuven for financial support.
For example, there isa small difference inthe orientation
of the N29 and N67 nitro groups with the corresponding
torsion angles C11ꢀC10ꢀN29ꢀO30 = 174.7(2)° (I) and
C49ꢀC48ꢀN67ꢀO68 = 179.4(2)° (II), as well as a notice-
able shortening of the NꢀO bonds for N67. The conforma-
tional divergence is also reflected in the different distortions
Supporting Information Available. Additional X-ray
data and experimental procedures, copies of 1H and 13
NMR spectra and UV spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
C
The authors declare no competing financial interest.
D
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