Synthesis of functionalized dioxa-aza[7]helicenes using palladium catalyzed arylations

Article abstract of DOI:10.1021/ol300236t

Despite the recent reports on transition-metal catalyzed cycloisomerization strategies toward helicenes, the amount of palladium catalyzed routes remains rather scarce. Within this letter the successful preparation and characterization of novel dioxa-aza[

Full text of DOI:10.1021/ol300236t

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1500–1503
Synthesis of Functionalized
Dioxa-aza[7]helicenes Using
Palladium Catalyzed Arylations
†
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 January 30, 2012
ABSTRACT
Despite the recent reports on transition-metal catalyzed cycloisomerization strategies toward helicenes, the amount of palladium catalyzed routes
remains rather scarce. Within this letter the successful preparation and characterization of novel dioxa-aza[7]helicenes using palladium mediated
coupling reactions is presented.
During the past decades, helicenes gained a consider-
able amount of attention, and not only by synthetic
chemists. Their unique helical shaped backbone, which
is formed by a successive annulation of (hetero)
aromatic rings, has led to an impressive number of
diverse applications, mostly based on the inherently
chiral conformation.1 Remarkable examples of this
applicability include chiral catalysis,2 self-assembly,3
and biomolecular recognition.4
The recently increased interest in these areas is most
likely caused by the inspiring discoveries made during the
pursuit toward new synthetic approaches that avoid
photochemical cyclizations,5 a field now dominated by
the cycloisomerization-based methods first reported by
6
ꢀ
ꢀ
Stary and Stara in 1998. However, despite this sudden
growth in transition-metal based procedures, synthetic
routes using palladium catalyzed coupling reactions as a
crucial step in the formation of a helicene are rare, probably
due to the challenging preparation of an appropriate pre-
cursor. Notable examples thus far include a Buchwaldꢀ
Hartwig arylation7 and a double CꢀH activation8
(Scheme 1). However, both approaches are suffering from
certain drawbacks. First, compounds like 1 are not readily
† Molecular Design and Synthesis.
‡ Biomolecular Architecture.
(1) For some recent reviews, see: (a) Urbano, A. Angew. Chem., Int.
Ed. 2003, 42, 3986. (b) Shen, Y.; Chen, C.-F. Chem. Rev. 2011, article
ASAP (doi:10.1021/cr200087r).
(2) (a) Crittall, M. R.; Rzepa, H.; Carbery, D. R. Org. Lett. 2011, 13,
1250. (b) Takenaka, N.; Sarangthem, R. S.; Captain, B. Angew. Chem.,
Int. Ed. 2008, 47, 9708.
(3) (a) Kaseyama, T.; Furumi, S.; Zhang, X.; Tanaka, K.; Takeuchi,
M. Angew. Chem., Int. Ed. 2011, 50, 3684. (b) Shcherbina, M. A.; Zeng,
X.-B.; Tadjiev, T.; Ungar, G.; Eichhorn, S. H.; Philips, K. E. S.; Katz,
T. J. Angew. Chem., Int. Ed. 2009, 48, 7837. (c) Murguly, E.; McDonald, R.;
Branda, N. Org. Lett. 2000, 2, 3169.
(4) (a) Shinohara, K.-I.; Sannohe, Y.; Kaieda, S.; Tanaka, K.-I.;
Osuga, H.; Tahara, H.; Xu, Y.; Kawase, T.; Bando, T.; Sugiyama, H.
J. Am. Chem. Soc. 2010, 132, 3778. (b) Xu, Y.; Zhang, Y.; Sugiyama, H.;
Umano, T.; Osuga, H.; Tanaka, K. J. Am. Chem. Soc. 2004, 126, 6566.
(c) Honzawa, S.; Okubo, H.; Anzai, S.; Yamaguchi, M.; Tsumoto, K.;
Kumagai, I. Bioorg. Med. Chem. 2002, 10, 3213.
(5) (a) Waghray, D.; Nulens, W.; Dehaen, W. Org. Lett. 2011, 13,
5516. (b) Pearson, M. S. M.; Carbery, D. R. J. Org. Chem. 2009, 74,
5320. (c) Bossi, A.; Maiorana, S.; Graiff, C.; Tiripicchio, A.; Licandro,
E. Eur. J. Org. Chem. 2007, 28, 4499.
ꢁ ꢁ ꢀ
(6) (a) Songis, O.; Mısek, J.; Schmid, M. B.; Kollarovic, A.; Stara,
´
ꢁ ꢀ
ꢀ
I. G.; Saman, D.; Cısarova, I.; Stary, I. J. Org. Chem. 2010, 75, 6889.
´
ꢀ
ꢀ
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(b) Stara, I. G.; Stary, I.; Kollavoric, A.; Teply, F.; Saman, D.; Tichy, M.
ꢀ
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J. Org. Chem. 1998, 63, 4046.
(7) Nakano, K.; Hidehira, Y.; Takahashi, K.; Hiyama, T.; Nozaki,
K. Angew. Chem., Int. Ed. 2005, 44, 7136.
(8) Kamikawa, K.; Takemoto, I.; Takemoto, S.; Matsuzaka, H.
J. Org. Chem. 2007, 72, 7406.
r
10.1021/ol300236t
Published on Web 02/24/2012
2012 American Chemical Society

accessible, hampering further derivatization; second, the
double CꢀH arylations experience low yields caused by
the increasing steric hindrance and dehalogenation. These
findings prompted us to investigate other, more effi-
cient and general routes using these palladium-mediated
methods.
Scheme 2. Synthesis of Dioxa-aza[7]helicene 9
Scheme 1. Examples of Palladium Catalyzed Routes towards
Helicenes
triclinic space group P1, with one molecule in the asymmetric
unit, as depicted in Figure 1. The distortion of the molecular
structure (53.2°), defined by the sum of the five dihedral
angles, namely, C16ꢀC12ꢀC9ꢀC3, C12ꢀC9ꢀC3ꢀC4,
C9ꢀC3ꢀC4ꢀC17, C3ꢀC4ꢀC17ꢀC21, C4ꢀC17ꢀC21ꢀ
C24, is substantially smaller than the value reported
by Nozaki et al. (83.6°) for the phenanthrene analogue 2
(X = N-Ph)7 due to the presence of the furan rings
(smaller overlap between the outer rings leads to a re-
duced steric repulsion). Viewed down the a-axis, the mol-
ecules form columns of alternating opposite enantiomers
(see Supporting Information), held together by different
kinds of weak interactions. πꢀπ stacking occurring between
pyrrole rings and the benzene rings (C2ꢀC9) is followed by
πꢀπ stacking between the former pyrrole rings and ben-
zene rings (C4ꢀC20), with centroidꢀcentroid distances of
In addition, we will be focusing on the implementation
of oxygen-based heterocycles (i.e., dibenzofuran), as this
could open an opportunity to study the electro-optical
properties of the otherwise uncommon oxa-helicenes.
The classic approach toward dimeric structures like bis-
phenanthrol 1 depends on the oxidative coupling of
an appropriate phenolic unit. Earlier we reported
such a strategy to yield a novel scaffold; H8-1,10-
bis(dibenzofuran-2-ol) or H8-BIFOL 5,9 an ideal candidate
for exploring further reaction conditions as it can be
prepared in large amounts. Initial optimization studies re-
vealedthatoxidation of thesaturatedringsprior to the final
N-arylation step was essential to ensure acceptable yields of
the helicene. Several oxidation agents were screened. How-
ever, only dichlorodicyanobenzoquinone (DDQ) could
convert 5 into its aromatized analogue 6. Removal of the
tert-butyl groups of 6 was achieved using conventional
conditions, allowing an effortless substitution of diphenol
7 with nonafluorobutanesulfonyl fluoride (NfF), providing
bis-nonaflate 8 as a benchtop stable compound (Scheme 2).
Due to the higher racemization barrier of an aza-helicene
compared with the corresponding oxa-helicene,7,10 a dou-
ble N-arylation was selected to bridgethe two dibenzofuran
units, creating the novel dioxa-aza[7]helicene 9 in good
yields.
3.705(1) and 3.618(1) A respectively. CꢀH π interactions
3 3 3
involving the nonfused benzene ring and the furan rings
(C29ꢀH29 Cg1; Cg1 = centroid of the O10 furan ring,
3 3 3
and C33ꢀH33 Cg2, Cg2 = centroid of the O23 furan ring;
3 3 3
C29 Cg1 = 3.440(2) A and C33 Cg2 = 3.331(2) A)
combined with CꢀH O hydrogen bonds (C33ꢀH33
3 3 3
3 3 3
3 3 3
3 3 3
O23 with C O = 3.370(2) A) further support the
columnar formation. A similar packing feature was ob-
3 3 3
served for thiohelicenes.11 Additional CꢀH O inter-
3 3 3
actions between isochiral molecules (C7ꢀH7 O23 with
3 3 3
a C O distance of 3.379(2) A) interlink the columns,
resulting in a 3-D assembly.
3 3 3
However, in order to be applicable in new useful materi-
als, 9 has to be further functionalized. Considering the
electron-rich carbazole segment, it would be advantageous
toimplement electron-deficient functionalitiesonthe outer
rings, which should improve the electro-optical properties
significantly.12 For this purpose, a series of substituted
dibenzofuran moieties was prepared starting from the
Crystals of rac-9suitable for X-ray analysis were obtained
by vapor diffusion, from a chloroformꢀpentane system.
The racemic compound crystallizes in the centrosymmetric
ꢀ
(9) Kelgtermans, H.; Dobrzanska, L.; Van Meervelt, L.; Dehaen, W.
Tetrahedron 2011, 67, 3685.
(10) Groen, M. B.; Schadenberg, H.; Wynberg, H. J. Org. Chem.
(11) Caronna, T.; Sinisi, R.; Catellani, M.; Malpezzi, L.; Meille, S.;
Mele, A. Chem. Commun. 2000, 1139.
(12) Clays, K.; Wostyn, K.; Persoons, A.; Maiorana, S.; Papagni, A.;
1971, 36, 2797.
Daul, C.; Weber, V. Chem. Phys. Lett. 2003, 372, 438.
Org. Lett., Vol. 14, No. 6, 2012
1501

Scheme 4. Alternative Approach to Bis-dibenzofuranol Deriv-
atives
the dibenzofuran units for several reasons. First, it is
readily prepared on a large scale by oxidative coupling of
BHA, a cheap, commercially available reagent. Second,
the bulky tert-butyl substituents control both the nucleo-
philic aromatic substitution and the CꢀH arylation step
toward the desired regioisomers. As expected, demethyla-
tion using BBr3 afforded the bis-hydroquinone 16 in
quantitative yields (Scheme 5). Although two of the hydro-
xyl groups are obstructed by the tert-butyl substituents,
careful regulation of the temperature seemed crucial to
prevent the formation of oversubstituted products, allow-
ing yields up to 78% of the targeted disubstituted com-
pound 17.
Figure 1. Molecular structure of 9. Displacement ellipsoids are
drawn at the 50% probability level.
commercially available compounds 10ꢀ12 (Scheme 3). A
nucleophilic aromatic substitution followed by a palla-
dium catalyzed arylation provided the appropriate phe-
nolic dibenzofuran units 13 and 14 after quantitative
deprotection using BBr3. Unfortunately, none of the con-
ditions that were investigated for the oxidative dimerization
of these building blocks was able to provide the desired
coupled products (Scheme 3). A plausible reason for the
lack of reactivity is the increased oxidation potential due to
the presence of these electron-withdrawing groups.
Scheme 5. Synthesis of Substituted Bis-dibenzofuran 18
Scheme 3. Synthesis and Oxidative Coupling of Substituted
Dibenzofuran Moieties
Investigation of the palladium catalyzed CꢀH arylation
revealed that the use of Pd(OAc)2 in combination with
PCy3 (added as the air-stable tetrafluoroborate salt) were
optimal conditions for the ring closure to 18, which is in
good agreement with earlier reports concerning the palla-
dium mediated intramolecular arylation of biaryl chlorides
by Fagnou et al.13 As assumed, the structural flexibility of
the biaryl system did not hamper the double CꢀH activa-
tion, resulting in a near-quantitative conversion without
any trace of dehalogenation or partially reacted material
(Scheme 5).
An obvious, yet unprecedented way to avoid this kind of
problem is to reverse the approach, that is by starting with
an oxidative coupling of less complex, electron-rich seg-
ments, followed by an extension to the substituted diben-
zofuran moieties (Scheme 4).
Due to the analogy with the biaryl system 6 prepared
earlier, similar conditions could be employed for the synthesis
of helicene 21. Again, good yields were found for the
The known compound, bis-tert-butylated hydroxyani-
sole (bis-BHA) 15, was selected as a scaffold to construct
(13) Campeau, L.-C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am.
Chem. Soc. 2006, 128, 581.
1502
Org. Lett., Vol. 14, No. 6, 2012

In summary we have discovered efficient routes toward
a novel helical scaffold, dioxa-aza[7]helicene. Both ap-
proaches made use of palladium catalyzed arylations to
construct the crucial bonds in the helicene backbone.
Although the oxidative coupling of the dibenzofuranol
unit could not be used for substituted derivatives, an
alternative route was found by reversing this first strategy.
We believe that these approaches will form a constructive
addition to the field of helicene synthesis. Further func-
tionalization and resolution of the new scaffold is currently
ongoing and will be reported in due course.
Scheme 6. Synthesis of 2,13-Dinitrodioxa-aza[7]helicene 21
Acknowledgment. The Instituut voor de aanmoedig-
ing van innovatie door Wetenschap en Technologie
in Vlaanderen (IWT) is acknowledged for a fellowship
to H.K. We thank the Fonds voor Wetenschappelijk Onder-
zoek (FWO - Vlaanderen; special acknowledgment by L.D.)
and the University of Leuven for financial support.
dealkylation to 19 and double BuchwaldꢀHartwig amination
starting from the corresponding dinonaflate 20 (Scheme 6).
2,13-Dinitro-dioxa-aza[7]helicene 21 was obtained as a bright
yellow solid with no visible fluorescence due to the quenching
effect of the nitro substituents, which can be a useful advan-
tage during second-order NLO measurements.
Supporting Information Available. Additional X-ray
data, copies of 1H and 13C NMR spectra and UV spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
1503