Synthesis of sulfur-bridged polycycles via Pd-catalyzed dehydrogenative cyclization

Article abstract of DOI:10.1021/ol502127j

A general approach to sulfur-bridged polycycles by palladium-catalyzed double C(sp²)-H bond oxidative cyclization is presented. This protocol afforded diverse sulfur-bridged five-, six-, and seven-membered polycycles in moderate to good yields with a tolerance for a wide variety of functional groups. A sulfide-bridged six-membered pyrene-thienoacene compound was synthesized readily using this method, and excellent performance for photoluminescence quantum yield was observed.

Full text of DOI:10.1021/ol502127j

Letter
pubs.acs.org/OrgLett
Synthesis of Sulfur-Bridged Polycycles via Pd-Catalyzed
Dehydrogenative Cyclization
Binjie Wang,† Yue Liu,† Cong Lin,† Yiming Xu,† Zhanxiang Liu,† and Yuhong Zhang*,†,‡
†ZJU-NHU United R&D Center, Department of Chemistry, Zhejiang University, Hangzhou 310027, China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
S
* Supporting Information
ABSTRACT: A general approach to sulfur-bridged polycycles
by palladium-catalyzed double C(sp2)−H bond oxidative
cyclization is presented. This protocol afforded diverse
sulfur-bridged five-, six-, and seven-membered polycycles in
moderate to good yields with a tolerance for a wide variety of
functional groups. A sulfide-bridged six-membered pyrene−thienoacene compound was synthesized readily using this method,
and excellent performance for photoluminescence quantum yield was observed.
here has been great interest in sulfur-containing hetero-
cycles because of their potential biological activity,1
sulfur-bridged six- or seven-membered heterocycles still stands
as a challenge in organic synthesis.
T
pharmaceutical significance,2 and wide application in functional
materials.3 Driven by the growing demand of these structures
(Figure 1), great efforts have been devoted toward the
It is noteworthy that sulfur-based six-membered heterocycles
are known to possess interesting optoelectronic properties and
show more remarkable properties than aromatic thiophenes.3e
A recent study revealed that the oxidation state of the bridging
sulfur atom (sulfide, sulfoxide, and sulfone) had a decisive effect
on the quantum efficiency of the materials.3d However, the
application of sulfur-based six-membered heterocycles is
significantly restricted due to the lack of reliable preparation
protocols. Considering the very limited methodologies for
sulfur-based six- and seven-membered heterocycles,4g−i the
development of new efficient protocols for these heterocycles is
highly desirable.
Figure 1. Selected useful sulfur-bridged polycycles.
Our group has a long-standing interest in the C−H
functionalization directed by sulfur-containing functional
groups.8 We have developed the palladium-catalyzed olefina-
tion,8a,b arylation,8c and acetoxylation of arenes using sulfide or
sulfoxide as the directing groups. Herein, we report a novel
method for the synthesis of sulfoxide-bridged five-, six-, and
seven-membered fused polycycles by Pd-catalyzed intra-
molecular C(sp2)−H/C(sp2)−H oxidative coupling. The
transformation is supposed to be occurring through a
sulfoxide-assisted palladium-catalyzed C−H bond cleavage
process. The sulfoxide-bridged polycycles are able to be further
transferred into the corresponding sulfide- or sulfone-bridged
polycycles by easy reduction or oxidation. A sulfide-bridged six-
membered pyrene−thienoacene compound is readily prepared
using our method, and the preliminary study revealed its
excellent fluorescence performance to give a photolumines-
cence quantum yield as high as 0.48.
continual development of new and improved protocols.4 In
recent years, transition-metal-catalyzed oxidative cross-coupling
of two C(sp2)−H bonds has emerged as a powerful tool for the
synthesis of heterocycles.5 A wide variety of functionalized
xanthones,6a,e,f carbazoles,6b,c and furan derivatives6d have been
synthesized through the double C−H bond dehydrogenative
cyclization in order to both improve the efficiency and extend
the substrate scope. Despite the remarkable advances of C−H/
C−H coupling, engagement of sulfur-based heterocycle syn-
thesis by using this strategy has proven to be difficult.7
A recent breakthrough was achieved by the Antonchick
group, who employed sulfoxide as a new traceless directing
group that induced the formation of dibenzothiophenes by
palladium catalysis.4c Under their reaction conditions, the
initially formed six-membered cyclic sulfoxide possibly under-
went the Pummerer rearrangement to finally give the
dibenzothiophene derivatives. Very recently, Zhou et al.
reported a beautiful example of the synthesis of dibenzothio-
phenes from diaryl sulfides through Pd-catalyzed C(sp2)−H/
C(sp2)−H oxidative cyclization.4f Currently, the majority of
success was obtained for the synthesis of sulfide-bridged five-
membered heterocycles. A method for the preparation of
Initially, we chose to study the dehydrogenative cyclization
by the use of sulfoxide 1aa as the model substrate, which is
easily prepared from benzenethiol and benzyl bromide.
Received: July 19, 2014
Published: August 19, 2014
© 2014 American Chemical Society
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Encouragingly, in the presence of 10 mol % of PdCl2 and
AgOAc in 1,1,2,2-tetrachloroethane (TTCE) at 100 °C for 48
h, the sulfoxide-bridged six-membered polycycle 2aa was
isolated in 41% yield. Under this modified condition of
Antonchik’s work (see Supporting Information), a wide array of
sulfoxides were subjected to the reaction to give the
corresponding products as shown in Scheme 1. It was observed
products (Scheme 1, 2q−2s). The produced sulfur-based
polycycles might be used as organic semiconducting materials.3e
Dibenzothiophene-S-oxides are interesting triplet oxygen
precursors and were recently prepared by palladium catalysis
from 2-bromo-diarylsulfinyl moieties.1a To our delight, the
present method of direct C(sp2)−H/C(sp2)−H coupling could
be utilized for the synthesis of dibenzothiophene-S-oxides (five-
membered sulfur-bridged polycycles) (Scheme 2, 4a−4c),
Scheme 1. Synthesis of Six-Membered Sulfur-Bridged
a
Polycycles
Scheme 2. Synthesis of Five- and Seven-Membered Sulfur-
a
Bridged Polycycles
a
Reaction conditions: sulfoxide derivative (0.2 mmol), PdCl2 (0.02
mmol), AgOAc (0.8 mmol), iodobenzene (0.4 mmol), AcOH (0.8
mmol) in 2 mL TTCE at 100 °C for 48 h, in a sealed tube. b 120 °C,
c
d
e
24 h. 110 °C. isolated as isomers (1:1.8). Isolated as isomers
(1:1.5).
that substrates with both electron-withdrawing and -donating
groups in a sulfoxide aryl ring participated in the reaction to
give the cyclization product in moderate to good yields. Better
yields were achieved when the electron density of the aryl ring
was improved through the electron-donating substituent
(Scheme 1, 2aa−2af). However, the ortho-substituted deriva-
tives failed to afford the desired product, possibly owing to the
steric interactions between the sulfoxide group and the ortho
substituent (Scheme 1, 2ag).
The substrate generality of the benzyl ring was next
examined (Scheme 1, 2b−2s). We were pleased to find that
a variety of substituents, including −CH3, −OMe, −tert-butyl,
−OCF3, −F, −Cl, and −Br, were tolerated to give the desired
six-membered sulfur-bridged polycycles. Generally, the elec-
tron-rich substrates presented higher activity than that of the
electronic-deficient arenes. It should be noted that the selective
C(sp2)−H/C(sp2)−H cross-coupling is possible in the
presence of halogen functionality (Scheme 1, 2j−2p), providing
a useful handle for further cross-coupling reactions. Notably,
when 1-(p-tolylsulfinyl)naphthalene was used as the substrate,
the exclusive α-carbon−hydrogen bond coupling product was
generated (Scheme 1, 2q). In contrast, the β-C−H coupling
product was not observed, showing excellent regioselectivity.
Other acene groups such as phenanthryl and pyrenyl also
presented high regioselectivity to give the α-C−H coupling
a
Reaction conditions: sulfoxide derivative (0.2 mmol), PdCl2 (0.02
mmol), AgOAc (0.8 mmol), iodobenzene (0.4 mmol), AcOH (0.8
mmol) in 2 mL of TTCE at 100 °C for 48 h, in a sealed tube. 120
°C. 60 h.
b
c
which could be readily transferred to the useful dibenzothio-
phenes after reduction.8f Very importantly, the seven-
membered sulfur-bridged polycycle, which is difficult to be
constructed from simple starting materials, could be formed
under our reaction conditions with longer tether substrates
(Scheme 2, 4d−4n). For example, the reaction of o-, m-, and p-
methyl arenes resulted in the seven cycles in 45−67% yields
(Scheme 2, 4e−4g). Halogen-containing substrates tolerated
the reaction conditions to give the desired products, but a
longer reaction time was required (4i−4m). 2-Naphthalenyl
sulfoxide underwent the reaction smoothly to afford a 51%
yield.
To investigate the reaction mechanism, an intermolecular
isotope kinetic experiment was performed. Benzyl(p-tolyl)-
sulfoxide 1aa and its deuterated analogue 1aa-d5 were
equivalently subjected to the reaction (Scheme 3). A kinetic
isotope effect (KIE) value of 3.54 was observed, implicating
that the C(sp2)−H cleavage of the benzyl group might be the
rate-determining step in the catalytic cycle.
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Scheme 3. Isotope Kinetic Experiment
Scheme 5. Plausible Mechanism
To gain insight into the reaction mechanism, control
experiments were performed using the palladacycle complex
A (Scheme 4).8b It was found that the cyclization is not able to
Scheme 4. Mechanism Investigation
Pummerer rearrangement to afford dibenzothiophene 5 under
Antochik’s condition.4c
Pyrene is a well-known chromophore and has been used as
an emitting material for organic electronic devices due to its
high absorption coefficients and fluorescence quantum yield.
The utility of our methodology is illustrated by a rapid
synthesis of pyrene-thienoacene compound 6 as shown in
Scheme 6. The cyclization of sulfoxide 1s affords bathochromic
occur by simply heating the solution of palladacycle complex A,
showing the formation of intermediate D requires internal help
(Scheme 4, eq 1). No reaction was observed when 2 equiv of
iodobenzene were added in the solution of complex A (Scheme
4, eq 2), illustrating that acceleration of the reaction rate
through the formation of Pd(IV) by the oxidative addition of
the palladacycle complex A to iodobenzene is unlikely. In
contrast, when acetic acid or silver acetate was added, the
cyclized product was formed and the high yield could be
obtained by controlling the amount of acetic acid (Scheme 4,
eqs 3 and 4). It is interesting that the best reaction efficiency
was observed in the presence of both iodobenzene and acetic
acid (Scheme 4, eq 5).
Scheme 6. Synthesis of Pyrene Thienoacenes (PTAs)
Based on our previous studies, a plausible reaction
mechanism is proposed for this new C(sp2)−H/C(sp2)−H
coupling reaction as shown in Scheme 5. Directed by sulfoxide
as a chelation group, the ortho C(sp2)−H bond of the benzyl
group is activated to give the five-membered cyclopalladated
intermediate A, which experiences difficulty in undergoing the
subsequent intramolecular C(sp2)−H palladation in the
presence of iodobenzene or by simply heating. An electrophilic
palladation pathway is possible for this sulfoxide assisted
palladation because the lower reactivity of the substrates with
an electron-deficient aromatic ring partially is observed
(Scheme 1, entries 2j−2p). Acetic acid or silver acetate may
transfer the intermediate A to intermediate B, which is able to
undergo the second palladation. Since no strong electronic bias
of aromatic rings was observed for the second intramolecular
palladation (Scheme 1, entries 2aa−2af), a concerted
palladium−carbon/carbon−hydrogen bond formation/cleavage
pathway is reasonable.9 The reductive elimination of the
intermediate D liberates the sulfur-bridged polycycle 2aa with
the formation of Pd(0), which is oxidized by a silver salt to
regenerate the Pd(II) for the next catalytic cycle. It is also
reasonable to assume that iodobenzene promotes the formation
of intermediate D through a Pd(IV) intermediate after the
formation of intermediate B.4c The product 2aa went through
shifts for absorption at 354 to 385 nm in CH2Cl2, leading to a
drop in the photoluminescence quantum yield from 0.24
(compound 1s) to 0.17 (2s). Sulfide-bridged six-membered
pyrene−thienoacene 6 shows a pronounced quantum yield of
0.48, which is much higher than that for most of its sulfide-
bridged five-membered thiophene analogues reported in
literature,3e and also much better than that of parent pyrene.10
In contrast, sulfoxide-bridged six-membered pyrene−thienoa-
cene 2s gives a relatively lower photoluminescence quantum
yield. Compounds 1s, 6, and 2s exhibit good thermal and
oxidative stability in air.
In summary, we have developed an efficient sulfoxide-assisted
C(sp2)−H/C(sp2)−H coupling reaction that leads to the
straightforward synthesis of five-, six-, and seven-membered
sulfur-bridged polycycles by palladium catalysis. The precursors
for this ring-closing reaction are readily prepared by the
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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
Additional experimental data, characterization of new com-
pounds, and spectra data. This material is available free of
charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K. J. Org. Chem. 2008,
73, 5022. (d) Xiao, B.; Gong, T.-J.; Liu, Z.-J.; Liu, J.-H.; Luo, D.-F.; Xu,
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Leifert, D.; Studer, A. Org. Lett. 2013, 15, 928. (g) Ackermann, L.;
■
*E-mail: yhzhang@zju.edu.cn.
Notes
Jeyachandran, R.; Potukuchi, H. K.; Novak, P.; Buttner, L. Org. Lett.
́
̈
The authors declare no competing financial interest.
2010, 12, 2056. (h) Gallardo-Donaire, J.; Martin, R. J. Am. Chem. Soc.
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ACKNOWLEDGMENTS
■
Funding from NSFC (No. 21272205), NBRPC (No.
2011CB936003), and the Program for Zhejiang Leading
Team of S&T Innovation (2011R50007) is acknowledged.
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