Relayed Regioselective Alkynylation/Olefination of Unsymmetrical Cyclic Diaryliodonium Species Catalyzed by Cu and Pd: Affording Fluorescent Cytotoxic Benzoxazoles

Article abstract of DOI:10.1002/chem.201503791

Although cyclic diaryliodonium species have the potential to act as valuable synthons for cascade transformations, they still remain largely unexplored. The regioselectivity associated with unsymmetrical cyclic diaryliodonium species has previously been k

Full text of DOI:10.1002/chem.201503791

DOI: 10.1002/chem.201503791
Communication
&
Heterocycle Synthesis
Relayed Regioselective Alkynylation/Olefination of Unsymmetrical
Cyclic Diaryliodonium Species Catalyzed by Cu and Pd: Affording
Fluorescent Cytotoxic Benzoxazoles
Daqian Zhu,[a, b] Panpan Liu,[a] Wenhua Lu,[a] Haiwen Wang,[b] Bingling Luo,[a, b] Yumin Hu,[a]
Peng Huang,*[a] and Shijun Wen*[a, b]
Linear diaryliodonium species have been extensively exploit-
ed as arylating agents in the formations of CÀX bonds.[6] Re-
Abstract: Although cyclic diaryliodonium species have the
cently, significant achievements have been made in regioselec-
tive arylation with unsymmetrical linear diaryiodonium spe-
cies.[7] Compared to their linear analogues, cyclic diaryliodoni-
um species have not found broad applications in synthetic or-
ganic chemistry.[8] Our group is interested in the development
of novel transformations with cyclic diaryliodonium species to
construct important structural scaffolds. However, regioselec-
tivity associated with unsymmetrical cyclic diaryliodonium spe-
cies remained an unsolved problem to us in our previous
study.[9] Inspired by the directing group coordination effect
(Scheme 1a), we were eager to explore whether unsymmetrical
cyclic diaryliodonium species containing common DGs, for ex-
ample, an amido group, will exhibit the expected regioselectiv-
ity (Scheme 1b). Herein, we report a relayed regioselective al-
kynylation and olefination of unsymmetrical cyclic diaryliodoni-
um species by installing a directing amido group, leading to si-
multaneous benzoxazole formation. In these reactions, diverse
alkynes and olefins could be selectively introduced into un-
symmetrical cyclic diaryliodonium species and the directing
amide groups were converted into oxazole motifs through in-
tramolecular rearrangement. CÀC and CÀO bonds were formed
under dual relaying catalysis by CuI and Pd(OAc)2. Furthermore,
the fluorescent properties and anticancer activities of the ob-
tained products were also investigated.
potential to act as valuable synthons for cascade transfor-
mations, they still remain largely unexplored. The regiose-
lectivity associated with unsymmetrical cyclic diaryliodoni-
um species has previously been known to pose a chal-
lenge. A regioselective relayed alkynylation and olefination
of unsymmetrical cyclic diaryliodonium species has been
achieved by installation of a directing amido group. These
relayed transformations were delayed until an oxazole
ring had formed, delivering a series of unique fluorescent
benzoxazoles. Moreover, some of these synthetic benzoxa-
zoles showed apparent inhibitory activity against malig-
nant cancer cells. Further confocal visualization revealed
that benzoxazoles targeted cell nuclei. These findings
might provide a novel structural scaffold to develop desir-
able anticancer agents.
Transition metal-catalyzed regio- and site-selective cross-cou-
pling reactions are very powerful tools to form CÀC and CÀX
bonds and remain a long-standing challenge in organic
chemistry. In recent years, remarkable progress has been ach-
ieved in site-selective transformations by directed CÀH activa-
tion (Scheme 1a).[1] Generally, it is believed that functionaliza-
tion of aryl ortho CÀH bonds is possible through s-chelation-
assisted metalation with directing groups (DGs) such as pyri-
dines,[2] amides,[3] ketones,[4] and others.[5] With the assistance
of DGs, thermodynamically favorable six- or seven-membered
metal complex intermediates are formed and then subjected
to subsequent functionalization.
To assess our aforementioned hypothesis, a benzamido
group was installed ortho to the iodine center in cyclic diarylio-
donium 1a. Our initial efforts for the ortho-selective alkynyla-
tion of unsymmetrical cyclic diaryliodonium species were
guided by the reaction of 1a with p-tolylacetylene 2a cata-
lyzed by copper and palladium, a similar reaction system to
that developed in our previous study.[9] To our surprise, the ex-
pected product 3a’ was not obtained, although 2a was hy-
pothesized to be selectively introduced ortho to the directing
amido group. Instead, a new benzoxazole ring was formed and
a subsequent relayed alkynylation occurred to provide the
novel product 3a. The absolute configuration of 3a was then
determined by single-crystal X-ray diffraction (Figure 1).[10]
Benzoxazole frameworks are often applied in pharmaceuti-
cals, dyes, and functional materials.[11] Many endeavors have
been made to construct this type of aromatic heterocycle.[12]
However, to our knowledge, the synthesis of benzoxazoles
from diaryliodonium species has not been reported to date.
Thus, it was of interest to us to further investigate these find-
[a] D. Zhu,+ P. Liu,+ W. Lu, B. Luo, Dr. Y. Hu, Prof. P. Huang, Dr. S. Wen
Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in
South China, Collaborative Innovation Center for Cancer Medicine
Sun Yat-sen University 651 Dongfeng East Road, Guangzhou 510060
(China)
E-mail: huangpeng@sysucc.org.cn
wenshj@sysucc.org.cn
[b] D. Zhu,+ H. Wang, B. Luo, Dr. S. Wen
School of Pharmaceutical Sciences, Sun Yat-sen University
132 Waihuan East Road, Guangzhou 510006 (China)
[+] Both authors contributed equally to this work.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503791.
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Scheme 1. Strategies for site-selective functionalization enabled by directing groups. a) General strategy with ortho metalation; b) this work.
as the presence of a highly electron-poor amido group (penta-
fluorobenzamide) led to no conversion (data not shown).
To deliver structures with greater synthetic value and make
this methodology more general, we speculated that various
olefins could also be amenable to this dual metal relay cataly-
sis strategy (Scheme 3). To our satisfaction, in a screening of
olefination conditions (see the Supporting Information,
Table S2), methyl acrylate (4a) was effectively introduced with
1,2-bis(diphenylphosphino)ethane (dppe) as a ligand. In terms
of olefin compatibility, the reactions were tolerant of methyl
acrylate, tert-butyl acrylate, ethyl vinyl ketone, affording 5a,
5b, and 5c, respectively (Scheme 3). Aryl olefin substrates with
a variety of substituents including 2-nitro (5d), 3-nitro (5e), 4-
nitro (5 f), 4-cyano (5g), and 4-methoxycarbonyl (5h) were
readily coupled with 1a. Moreover, iodonium species bearing
diverse groups including trifluoromethyl (5i), methoxycarbonyl
(5j), phenyl (5k), and methoxy (5l, 5m) were well tolerated.
More importantly, other amido groups, including alkyl amides,
were also tolerated to some degree (5n, 5o).
For better insight into the reaction mechanism, we per-
formed some control experiments (Scheme 4). In the absence
of alkyne 2a, iodonium 1a was subjected to the standard con-
ditions for the formation of 3a with various catalysts. Inter-
mediate 6 was obtained in similarly good yields with CuI only
or with a combination of CuI and Pd(OAc)2. However, 6 was
not formed in the presence of only the palladium catalyst.
Next, 3a was readily generated in high yield through the reac-
tion of 6 with 2a under standard conditions. Based on these
observations, a potential mechanism of these transformations
was proposed, consisting of two reaction cycles (see the Sup-
porting Information, Scheme S1). The first intramolecular reac-
tion to form intermediate 6A was mediated by copper cata-
lysts. Then, a relayed intermolecular reaction of intermediate
6A with alkynes to form the final product 3 was catalyzed by
Pd or Pd/Cu. In these transformations, a radical pathway
cannot be excluded, as neither 6 nor 3a was formed in the re-
action of 1a and 2a under the standard conditions in the pres-
ence of the radical scavenger TEMPO. Further investigation to
elucidate the mechanism is still underway.
Figure 1. Single-crystal X-ray structure of 3a.[10]
ings, whereby a regioselective alkynylation took place and a di-
recting amide group was converted into an oxazole motif by
intramolecular rearrangement.
Firstly, we undertook screenings of catalysts, ligands, and
bases to optimize the reaction conditions for the formation of
3a (see the Supporting Information, Table S1). The optimal re-
action conditions were identified as CuI/Pd(OAc)2 as catalysts,
PPh3 and Na2CO3 as ligand and base, respectively, at 1008C
under Ar (Table S1, entry 1). It is worth noting that reactions
with single copper or palladium catalysts gave extremely poor
yield or no product (Table S1, entries 12 and 13), implying that
the Cu/Pd dual transition metal system is critical to the genera-
tion of 3a.
Then, the scope of both alkynes and cyclic diaryliodonium
species were investigated (Scheme 2). Aryl alkynes bearing
electron-donating groups (Me, OMe) or electron-withdrawing
groups (CO2Me, F, Cl) were found to perform well (3a–g). Grati-
fyingly, alkyl alkynes also gave the desired products in modest
yields (3h, 3i). Meanwhile, similar results were obtained for
cyclic diaryliodonium substrates in which the phenyl ring car-
ried various substituents (3j–m). To our delight, alkyl amide
group (pivalamide) also provided the desired benzoxazole 3n.
A substrate with the electron-rich amido group 3,4,5-trimeth-
oxybenzamide also underwent smooth conversion (3o), where-
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Scheme 2. Relayed alkynylation of unsymmetrical cyclic diaryliodonium species. Reaction conditions: 1 (0.27 mmol), 2 (1.5 equiv), Pd(OAc)2 (10 mol%), CuI
(10 mol%), PPh3 (20 mol%), Na2CO3 (3.0 equiv), DMF (1.4 mL), 1008C, 15 h, Ar.
Benzoxazole is an important structural motif that is present
in anticancer reagents.[13] In light of this, a preliminary antican-
cer screening was performed on these novel benzoxazoles
(Figure 2). To our delight, some of the products, including 5c,
5i, 5m, and 5o, demonstrated obvious inhibition activity on
colon cancer HCT-116 cells at 10 mm concentration. In addition,
malignant lung cancer A549 cells were also susceptible to
these benzoxazoles (Figure S1, Supporting Information). Our
findings suggest that these new obtained compounds may
provide a useful scaffold to develop anticancer agents.
the Supporting Information, Table S3). Small biologically active
molecules with fluorescence are highly valuable, due to a com-
bination of potential diagnostic and therapeutic abilities in
one molecule.[14]
Given the combined fluorescence and anticancer activity,
confocal experiments were carried out to determine a cellular
target of 5o (Figure 4). HCT-116 cells treated with 5o clearly
showed blue fluorescence, implying their potential target
might be the cell nuclei. Thus, a commercially available fluores-
cent selective cell nucleus marker, SYTO green, was employed
to validate our observation. Indeed, the blue subcellular fluo-
rescence of 5o was well overlaid with the green subcellular
fluorescence. These results imply that 5o might target cell
nuclei to cause its cytotoxic effects, although the exact mecha-
nism remains to be elucidated.
These synthetic benzoxazoles were also found to be fluores-
cent under irradiation at l=365 nm. Compounds 5h, 5j, 5m,
and 5o were selected for further study of their photophysical
properties by UV/Vis and fluorescence spectroscopy (Figure 3).
The UV/Vis absorption peak band of 5j was narrow compared
to those of the other compounds, whereas 5h and 5o showed
broader emission bands than 5j and 5m. The fluorescence
quantum yields were measured for 5h (0.16), 5j (0.234), 5m
(0.029) and 5o (0.094) using quinine sulfate as a standard (see
In summary, relayed regioselective alkynylation and olefina-
tion of unsymmetrical cyclic diaryliodonium species were suc-
cessfully realized under Cu/Pd dual-metal relay catalysis. These
transformations were delayed until the oxazole ring had
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Scheme 3. Relayed olefination of unsymmetrical cyclic diaryliodonium species. Reaction conditions: 1 (0.27 mmol), 4 (2.0 equiv), Pd(OAc)2 (10 mol%), CuI
(10 mol%), dppe (20 mol%), Na2CO3 (3.0 equiv), DMF (1.4 mL), 1008C, 24 h, Ar.
Scheme 4. Control experiments. Reaction conditions: Pd(OAc)2 or/and CuI (10 mol% if used), PPh3 (20 mol%), Na2CO3 (3.0 equiv), 1008C, DMF.
formed, providing a concise synthetic method to access
a series of novel fluorescent benzoxazoles. In subsequent bio-
logical evaluation, some compounds showed obvious antiproli-
ferative activity against malignant cancer cells. Moreover, the
compounds appeared to target the cell nuclei, according to
confocal experiments. These findings may provide a novel
structural scaffold to develop anticancer agents with unique
fluorescent properties. Further work on employing the current
transformation to develop benzoxazoles with long absorption
wavelengths and better cytotoxicities is currently underway in
our laboratory.
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Figure 4. Subcellular localization of 5o in HCT-116 cells. a) Fluorescent
image of cells treated with 5o (lEx =405 nm; lEm =430–470 nm); b) fluores-
cent image of cells treated with SYTO Green (lEx =500 nm; lEm =530 nm);
c) overlay of images (a) and (b). All images share the same scale bar (10 mm).
Figure 2. Preliminary anticancer screening of synthetic benzoxazoles
Figure 3. Photophysical properties of 5h, 5j, 5m, and 5o (0.5 mm in CHCl3, 258C). Left: UV/Vis absorption spectra; middle: emission spectra (measured after
their respective max excitation wavelength); right: luminescent colors of 5h (green), 5j (brown), 5m (blue), 5o (light blue) on irradiation at l=365 nm.
Experimental Section
Acknowledgements
This work was supported by Guangdong Department of Sci-
ence and Technology (2013B051000034, 2014A030313196),
Guangzhou Innovation Research Program (LCY201317), and
National Basic Research Program of China (2012CB967004).
General procedure for synthesis of 3, exemplified by 3a: To io-
donium 1a (150 mg, 267.2 mmol) in a flask was added Na2CO3
(85 mg, 802 mmol), Pd(OAc)2 (6.0 mg, 26.72 mmol), PPh3 (14 mg,
53.5 mmol), and CuI (5.1 mg, 26.72 mmol). The reaction flask was
evacuated and backfilled with argon three times, and a solution of
1-ethynyl-4-methylbenzene 2a (50.1 mL, 400.85 mmol) in DMF
(1.4 mL) was added via syringe. The reaction mixture was stirred at
1008C under Ar atmosphere for 15 h. The reaction mixture was
then diluted with EtOAc (3”15 mL), washed with H2O (2”5 mL)
and brine (2”5 mL), dried over anhydrous Na2SO4, and concentrat-
ed under reduced pressure. The residue was purified by column
chromatography on silica gel (petroleum ether (60–90)/EtOAc=
100:1–20:1) to give 3a (76 mg, 71% yield) as a white solid.
Keywords: alkynylation
·
fluorescence
·
iodonium
·
olefination · regioselectivity
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Received: September 21, 2015
Published online on November 24, 2015
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