Efficient synthesis of benzo fused tetrathia[7]helicenes

Article abstract of DOI:10.1021/ol202236r

An efficient route toward the synthesis of symmetrical and unsymmetrical benzo fused tetrathia[7]helicenes substituted with electron donor (ED) and electron acceptor (EA) groups is reported. A common, readily available precursor 1,2- bis-(2-thienyl)benzen

Full text of DOI:10.1021/ol202236r

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5516–5519
Efficient Synthesis of Benzo Fused
Tetrathia[7]helicenes
Deepali Waghray, Wienand Nulens, and Wim Dehaen*
Molecular Design and Synthesis, Department of Chemistry, Katholieke Universiteit
Leuven, Celestijnenlaan 200F, 3001 Leuven, Belgium
wim.dehaen@chem.kuleuven.be
Received August 18, 2011
ABSTRACT
An efficient route toward the synthesis of symmetrical and unsymmetrical benzo fused tetrathia[7]helicenes substituted with electron donor (ED)
and electron acceptor (EA) groups is reported. A common, readily available precursor 1,2- bis-(2-thienyl)benzene was used to synthesize different
helicenes through a Wittig reaction, Stille coupling, and modified oxidative photocyclization.
Helicenes constitute a fascinating class of ortho-annu-
lated polycyclic aromatic or heteroaromatic compounds
endowed with inherent chirality due to the helical shape
of their π-conjugated system.1 These nonplanar helical
molecules exhibit unique electronic2 and chiro-optical
properties.3 Enantiopure functionalized derivatives of
(hetera)helicenes can be isolated owing to their stability
and rigid helical framework. They are potential candidates
for chiral catalysts,4 helical ligands,5 and asymmetric
inducers6 and have been used as building blocks for helical
conjugated polymers.7 Since the synthesis of hexahelicene
in 1956 by Newman and Lednicer8 via FriedelꢀCrafts
cyclization, various synthetic routes have been described
for carbahelicenes. These include the widely used oxidative
photocyclization, also known as the Mallory reaction,9
and a few nonphotochemical routes10 such as DielsꢀAlder
reactions, cyclotrimerization of acetylenes, carbenoid cou-
pling, radical cyclization, and olefin metathesis.
(1) For reviews on synthesis of helicenes, see: (a) Rajca, A.; Miyasa-
ka, M. Synthesis and Characterization of Novel Chiral Conjugated
Materials, Functional Organic Materials: Syntheses and Strategies;
M€ueller, T. J. J., Bunz, U. H. F., Eds.; Wiley-VCH: Weinheim, Germany,
2007; pp 543ꢀ577. (b) Rajca, A.; Rajca, S.; Pink, M.; Miyasaka, M.
Synlett. 2007, 1799–1822. (c) Collins, S. K.; Vachon, M. P. Org. Biomol.
The synthesis of the first [7]helicene was reported by
Martin and co-workers in 1967, who employed the oxida-
tive photocyclization of stilbenes as the key process.11
Since then, the Mallory reaction has remained the method
Chem. 2006, 4, 2518–2524. (d) Torroba, T.; Garcıa-Valverde, M. Angew.
´
Chem., Int. Ed. 2006, 45, 8092–8096. (e) Urbano, A. Angew. Chem., Int.
Ed. 2003, 42, 3986–3989.
(2) Nuckolls, C.; Shao, R. F.; Jang, W. G.; Clark, N. A.; Walba,
(8) Newman, M. S.; Lednicer, D. J. Am. Chem. Soc. 1956, 78, 4765–
4770.
(9) (a) Laarhoven, W. H. Pure Appl. Chem. 1984, 56, 1225–1240.
(b) Jorgensen, K. B. Molecules 2010, 15, 4334–4358.
D. M.; Katz, T. J. Chem. Mater. 2002, 14, 773–776.
(3) (a) Verbiest, T.; Sioncke, S.; Persoons, A.; Vyklicky, L.; Katz,
T. J. Angew. Chem., Int. Ed. 2002, 41, 3882–3884. (b) Busson, B.;
Kauranen, M.; Nuckolls, C.; Katz, T. J.; Persoons, A. Phys. Rev. Lett.
2000, 84, 79–82.
(4) (a) Reetz, M. T.; Beuttenmuller, E. W.; Goddard, R. Tetrahedron
Lett. 1997, 38, 3211–3214. (b) Reetz, M. T.; Sostmann, S. J. Organomet.
Chem. 2000, 603, 105–109. (c) Dreher, S. D.; Katz, T. J.; Lam, K. C.;
Rheingold, A. L. J. Org. Chem. 2000, 65, 815–822.
(5) Fox, J. M.; Katz, T. J. J. Org. Chem. 1999, 64, 302–305.
(6) Ben Hassine, B.; Aloui, F.; El Abed, R. Tetrahedron Lett. 2008,
49, 1455–1457.
(7) (a) Sudhakar, A.; Katz, T. J.; Yang, B. W. J. Am. Chem. Soc.
1986, 108, 2790–2791. (b) Katz, T. J.; Sudhakar, A.; Teasley, M. F.;
Gilbert, A. M.; Geiger, W. E.; Robben, M. P.; Wuensch, M.; Ward,
M. D. J. Am. Chem. Soc. 1993, 115, 3182–3198.
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Katz, T. J. J. Org. Chem. 1998, 63, 7456–7462. (b) Carreno, M. C.;
Enriquez, A.; Garcia-Cerrada, S.; Sanz-Cuesta, M. J.; Urbano, A.;
Maseras, F.; Nonell-Canals, A. Chem.;Eur. J. 2008, 14, 603–620
. (c) Tanaka, K.; Fukawa, N.; Suda, T.; Noguchi, K. Angew. Chem.,
Int. Ed. 2009, 48, 5470–5473. (d) Dubois, F.; Gingras, M. Tetrahedron
Lett. 1998, 39, 5039–5040. (e) Gingras, M.; Goretta, S.; Tasciotti, C.;
Mathieu, S.; Smet, M.; Maes, W.; Chabre, Y. M.; Dehaen, W.; Giasson,
R.; Raimundo, J. M.; Henry, C. R.; Barth, C. Org. Lett. 2009, 11, 3846–
3849. (f) Pieters, G.; Gaucher, A.; Prim, D.; Marrot, J. Chem. Commun.
2009, 4827–4828. (g) Harrowven, D. C.; Guy, I. L.; Nanson, L. Angew.
Chem., Int. Ed. 2006, 45, 2242–2245. (h) Grandbois, A.; Collins, S. K.
Chem.;Eur. J. 2008, 14, 9323–9329.
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1967, 743. (b) Jorgensen, K. B. Molecules 2010, 15, 4334–4358.
r
10.1021/ol202236r
Published on Web 09/15/2011
2011 American Chemical Society

of choice for constructing the last ring(s) in the final
assembly and aromatization of the system for both carba-
and heterahelicenes. This method has been optimized and
is still widely applied. In 1991, Katz reported an improved
method for the oxidative photocyclization using iodine as
the oxidant and propylene oxide as a hydrogen iodide
scavenger which reduces side reactions such as photo-
reduction12 and increases the efficiency of the reaction.
In recent years, the preparation of heterohelicenes and in
particular tetrathia[7]helicene derivatives has become a
field of great interest in order to exploit their unique
properties. These molecules show interesting self-assem-
bling behavior in the solid state. Furthermore, they form
aggregates to give helical supramolecular architectures
potentially applicable to nonlinear optics and circularly
polarized luminescent materials.13 These helicenes are
potential candidates for studying one- or two-dimensional
molecular wires in the field of organic semiconductors.14
The ability of tetrathia[7]helicenes to be used as chiral
ligands has also been demonstrated.15
The potential of tetrathia[7]helicene and its derivatives
suffers from major drawbacks in their synthesis. The
literature procedures for the synthesis of tetrathia-
[7]helicenes describe the formation of stilbene-type pre-
cursors in the trans conformation or a mixture of cis and
trans isomers, where the trans isomer predominates,16
leading to poor solubility and inadequately functionalized
building blocks with low overall yield in the final photo-
cyclization step. As a result, the homochiral forms are not
readily available for investigating catalytic or material
properties. The important challenge in expanding the
potential of helicenes is therefore to develop synthetic
strategies that provide efficient access to a variety of helical
frameworks.
Figure 1. Benzo fused hetero[7]helicenes.
concentrations, and also low solubility are avoided, and
hence photocyclization can occur efficiently. The presence
of the ester functionality in helicene 2 and the maleimide
functionality in helicene 3 impart electron-withdrawing
character and can be used as handles for further
functionalization.
Our approach makes use of 1,2-bis(octyloxy)-4,5-bis(2-
thienyl)benzene 4 as a versatile building block for the
synthesis of heterohelicenes 1ꢀ3. This compound was
easily synthesized from catechol, according to slightly
modified literature procedures. Dibromination17 of cate-
chol using Br2/CHCl3, followed by dialkylation18 with
1-bromooctane employing 2-butanone as the solvent,
furnished dibromo-dialkoxy catechol in good yields which
was in agreement with the literature procedures. A final
coupling of two thiophene units to the dibromo-dialkoxy
compound via ZnCl2 and Pd(PPh3)4 promoted Negishi
coupling19 gave the compound 1,2-bis(octyloxy)-4,5-bis-
(2-thienyl)benzene 4 in 87% yield (see Supporting
Information). Compound 4 was subjected to oxidative
photocyclization using iodine as the oxidant, excess pro-
pylene oxide as the hydrogen iodide scavenger, and toluene
as the solvent. The reaction mixture was irradiated at room
temperature using a UV lamp to obtain the photocyclized
compound 5 in 82% yield.
Vilsmeier formylation of compound 5 using DMF,
POCl3, and dichloroethane as the solvent gave aldehyde
6 in 71% yield. Unfortunately, the conventional McMurry
coupling of the aldehyde to obtain the alkene did not work
on our substrate. The alternate route was via the Wittig
reaction. Aldehyde 6 was reduced to alcohol 6a in 89%
yield using sodium borohydride and THF/MeOH as the
solvent. The alcohol was subsequently converted to phos-
phonium salt 7 by reaction with triphenylphosphonium
bromide in refluxing CH3CN for 12 h with a yield of 67%.
Our main focus was to develop efficient routes to
helicenes that are amenable to scale-up and also provide
flexibility for functionalization and hence tuning of the
chiro-optical properties. Herein, we report progressively
efficient synthetic routes toward the new heterohelicenes
1ꢀ3 with benzo fusion to the tetrathia[7]helicene core
(Figure 1).
We have addressed the issues of solubility of the pre-
cursors and final products by introducing long alkoxy
chains and also devised an efficient method to obtain
substituted precursors which are conformationally in close
resemblance with the final helicene. Thus, the problems of
cisꢀtrans isomerization, [2 þ 2] cycloaddition at higher
(12) Liu, L. B.; Yang, B. W.; Katz, T. J.; Poindexter, M. K. J. Org.
Chem. 1991, 56, 3769–3775.
(13) Application of heterohelicenes: Nakano, K.; Hidehira, Y.;
Takahashi, K.; Hiyama, T.; Nozaki, K. Angew. Chem., Int. Ed. 2005,
44, 7136–7138.
(14) Rybacek, J.; Huerta-Angeles, G.; Kollarovic, A.; Stara, I. G.;
Stary, I.; Rahe, P.; Nimmrich, M.; Kuhnle, A. Eur. J. Org. Chem. 2011,
853–860.
(15) Kawasaki, T.; Suzuki, K.; Licandro, E.; Bossi, A.; Maiorana, S.;
Soai, K. Tetrahedron: Asymmetry 2006, 17, 2050–2053.
(16) (a) Groen, M. B.; Schadenb, H; Wynberg, H. J. Org. Chem.
1971, 36, 2797. (b) Maiorana, S.; Papagni, A.; Licandro, E.; Annunziata,
R.; Paravidino, P.; Perdicchia, D.; Giannini, C.; Bencini, M.; Clays, K.;
Persoons, A. Tetrahedron 2003, 59, 6481–6488.
(17) Fleming, M. J.; McManus, H. A.; Rudolph, A.; Chan, W. H.;
Ruiz, J.; Dockendorff, C.; Lautens, M. Chem.;Eur. J. 2008, 14, 2112–
2124.
(18) Ong, C. W.; Liao, S. C.; Chang, T. H.; Hsu, H. F. J. Org. Chem.
2004, 69, 3181–3185.
(19) Brooks, P.; Donati, D.; Pelter, A.; Poticelli, F. Synthesis 1999,
1303–1305.
Org. Lett., Vol. 13, No. 20, 2011
5517

Monolithiation of compound 5 at ꢀ78 °C using n-BuLi
(2.5 M in hexane) in dry THF, followed by treatment with
diethyl oxalate, furnished oxoester 9 in 65% yield while
12% of compound 5 was recovered. Wittig olefination of
oxoester 9 with Wittig reagent 7 gave alkene 10 as a 1:1
mixture of cisꢀtrans isomers in 52% yield. Unlike alkene8,
compound 10 was fully characterized by 1H and 13C NMR
spectroscopy owing to its better solubility. The ratio of the
isomers wasdeterminedby 1H NMR. Sharp singlets at δ =
7.87 and 6.81 ppm corresponded to the vinylic protons of
the cis and trans isomers respectively. Compound 10 was
subjected to oxidative photocyclization under the opti-
mized conditions mentioned in Scheme 1. The reaction was
run at high dilution conditions (0.45 mM) (Scheme 2).
Scheme 1. Wittig Reaction and Photocyclization
Scheme 2. Wittig Reaction with Oxoester and Photocyclization
Wittig olefination of 6 and 7 in the presence of t-BuOK as
base in dry THF at 0 °C gave the alkene 8 in 58% yield. The
alkene obtained could not be characterized by NMR
spectroscopy due to its poor solubility in various organic
solvents. This can be attributed to the fact that the trans
isomer predominates. Since in principle EꢀZ isomeriza-
tion occurs during the irradiation process, no specific
configuration of the alkene precursor was required. Thus,
we subjected the alkene obtained to oxidative photocycli-
zation using the same conditions as those for the synthesis
of compound 5. This afforded helicene 1 in 16% yield,
which was fully characterized by NMR spectroscopy and
HRMS and shows good solubility in a variety of medium-
polarity solvents such as CH2Cl2, ethyl acetate, and THF.
The 1H NMR spectrum of the helicene 1 is straightforward
and shows sharp signals for each proton. Singlets at δ =
7.99, 7.56, and 7.52 ppm corresponded to aromatic pro-
tons, and doublets at 6.94 and 6.74 ppm corresponded to
the terminal thiophene protons; these signals are indicative
of aromatization of the system. A major drawback en-
countered in the process is the poor solubility of the trans
alkene 8 which requires isomerization to the less stable cis
form and then cyclization, hence increasing the reaction
time. Furthermore, to avoid the [2πþ2π] dimerization the
reaction has to be run under high dilution conditions
(0.3 mM). The presence of alkoxy chains did not signifi-
cantly effect the solubility of the intermediates in this case.
To solve this problem, we proceeded with the approach
to obtain precursors which are in a cis conformation.20 We
devised a route which could lead us to a precursor with
better solubility and reduces the problems with cisꢀtrans
isomerization. To prove this we prepared the monoester
alkene 10 which has indeed better solubility in various
organic solvents and photocyclized efficiently in compar-
ison to the earlier alkene 8. The monoester alkene could
be easily obtained starting from building block 5.
As envisaged, the photocyclization proceeded efficiently
and with a significant increase in the yield of helicene 2 to
62% as compared to 16% of helicene 1. Interestingly, it
was the cis isomer that converted completely and a sig-
nificant amount of the unreacted trans isomer was recov-
ered from the reaction mixture. Monoester helicene 2 was
completely characterized by NMR spectroscopy and
1
HRMS. H NMR showed sharp singlets at δ = 8.76,
7.73, 7.55, and 7.54 ppm, and a multiplet at 6.8 ppm
corresponding with the terminal thiophene protons. These
signals give a clear indication of ring closure and final
aromatization of the system. The substitution on the
alkene with the ester group did prove to give better results,
and we could observe that the cis conformation of the
precursor indeed leads to better solubility and efficient
photocyclization.
Expanding on this, we expected that a precursor which is
locked in a cis conformation would have no options for
cisꢀtrans isomerization and hence would be able to be
photocyclized even more efficiently. This would reduce
both reaction time and the need for high dilution condi-
tions, allowing for a more efficient scale-up. Thus,
(20) Baldoli, C.; Bossi, A.; Giannini, C.; Licandro, E.; Maiorana, S.;
Perdicchia, D.; Schiavo, M. Synlett 2005, 1137–1141.
5518
Org. Lett., Vol. 13, No. 20, 2011

palladium-mediated coupling between dibromomaleimide
11 and the in situ prepared monostannyl derivative of
compound 5 was employed to give the highly conjugated
compound 12 in one step (Scheme 3). Compound 5 was
clearly indicated the occurrence of photocyclization and
final aromatization of the system.
The absorption spectra for helicenes 1, 2, and 3 in dilute
CHCl3 solutions are shown in Figure 2. We observed that
the absorption of helicenes 2 and 3 were red-shifted in
Scheme 3. Stille Coupling and Photocyclization
monolithiated using n-BuLi and then treated with tributyl
stannyl chloride to obtain the monostannyl derivative in
quantitative yield. Since protodestannylation was ob-
served to occur during chromatographic purification on
silica gel, the stannyl derivative was used without further
purification. The intensely violet compound 12, the key
precursor, was obtained in 74% yield by Stille coupling
between the monostannyl derivative and dibromo malei-
mide 11.21 This precursor 12 closely resembles the helicene
and has good solubility in various organic solvents. Com-
pound 12 was characterized by NMR and HRMS. The
1HNMR spectrum was straightforward, and a sharp sing-
let at δ = 8.52 ppm corresponded to the thiophene protons
attached to the maleimide group. Compound 12 was
subjected to irradiation using a 500 W high intensity lamp
(visible light) in the presence of iodine and propylene oxide
with toluene as the solvent (1.0 mM). In contrast to the
earlier compounds, which required morethan12h tofinish
the photocyclization, this reaction was completed in 1 h
and helicene 3 was obtained in 73% yield. The reaction
time was reduced drastically, the reaction concentration
could be increased, and as a result the efficiency of the
reaction increased. Helicene3 wasobtained inasubstantial
amount in three steps starting from building block 4. It was
characterized completely by spectroscopy. Disappearance
Figure 2. UVꢀvisible spectra of helicenes 1, 2, and 3 in dilute
CHCl3 solution.
comparison to helicene 1 which was due to the presence of
ester and maleimide functionalities.
In summary, we demonstrated an efficient route to new
hetero[7]helicenes which allows the synthesis of precursors
in a conformation closely resembling the final helicene.
Obtaining the precursors in a cis-helicene-like conforma-
tion by substituting the double bond assists in increasing
the solubility of the substrates, allows for easier character-
ization, and increases the efficiency of final photocycliza-
tion to the corresponding helicenes to a considerable
extent. The methodology used here can be amenable to
scale-up, especially for the maleimide derivatives and also
to a variety of modifications.
Acknowledgment. We thank the FWO (Fund for Scien-
tific Research - Flanders), the K.U. Leuven, and the Mini-
sterie voor Wetenschapsbeleid (IAP-IV-27) for continuing
financial support.
Supporting Information Available. Detailed experimen-
tal procedures, additional spectroscopic data, and NMR
spectra of all the synthesized compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
1
of the H NMR signal at δ = 8.52 ppm for helicene 3
(21) Nishide, Y.; Osuga, H.; Saito, M.; Aiba, T.; Inagaki, Y.; Doge,
Y.; Tanaka, K. J. Org. Chem. 2007, 72, 9141–9151.
Org. Lett., Vol. 13, No. 20, 2011
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