Highly Selective Palladium-Catalyzed Arene C-H Acyloxylation with Benzothiadiazole as a Modifiable Directing Group

Article abstract of DOI:10.1021/acs.orglett.8b02414

An efficient protocol for the palladium-catalyzed direct arene C-H acyloxylation of benzothiadiazole-arene derivatives is reported for the first time. The key strategy is the employment of benzothiadiazole as a modifiable directing group. The highly selective mono- or bis-acyloxylation can be achieved by tuning the reaction conditions, affording various acyloxylated benzothiadiazole derivatives, which could offer a rational tailoring of their electronic properties and be applied in organic electronic and optoelectronic materials. Finally, by diversity-oriented modification of the benzothiadiazole directing group, the acyloxylated products can be readily converted into various valuable functionalized (hetero)biaryls.

Full text of DOI:10.1021/acs.orglett.8b02414

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Highly Selective Palladium-Catalyzed Arene C−H Acyloxylation with
Benzothiadiazole as a Modifiable Directing Group
Jie Guo,† Hui He,† Zenghui Ye,† Kai Zhu,† Yanqi Wu,‡ and Fengzhi Zhang*,†
†College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, P. R. China
‡Institute of Information Resource, Zhejiang University of Technology, Hangzhou 310014, P. R. China
S
* Supporting Information
ABSTRACT: An efficient protocol for the palladium-
catalyzed direct arene C−H acyloxylation of benzothiadia-
zole−arene derivatives is reported for the first time. The key
strategy is the employment of benzothiadiazole as a modifiable
directing group. The highly selective mono- or bis-
acyloxylation can be achieved by tuning the reaction
conditions, affording various acyloxylated benzothiadiazole
derivatives, which could offer a rational tailoring of their electronic properties and be applied in organic electronic and
optoelectronic materials. Finally, by diversity-oriented modification of the benzothiadiazole directing group, the acyloxylated
products can be readily converted into various valuable functionalized (hetero)biaryls.
eteroaromatic moties are found throughout many organic
materials for organic electronics and optoelectronics, such
the direct ortho-arylation of difluoro-BTD under palladium
catalysis (Scheme 1, eq 1). In these examples, although the
H
as donor (D)/acceptor (A) polymers used in bulk hetero-
junction solar cells,1 D−A compounds for dye-sensitized solar
cells (DSC),2 D−A second-order nonlinear optical chromo-
phores,3 A−D−A two-photon absorption (2PA) dyes,4 and
electron-transport materials, etc.5 Among them, electron-
withdrawing 2,1,3-benzothiadiazole (BTD) has been widely
incorporated into polymers6 and small molecules7 used as DSC
sensitizers,8 2PA chromophores,9 or emitters in organic light-
emitting diodes (Figure 1).10 For example, polyfluorene (PF)
Scheme 1. Double Functions of BTD Derivatives as Both a
Modifiable Directing Group and an Important Fragment of
Functional Materials
Figure 1. Representative BTD-containing molecules used in optoelec-
tronic materials.
monofluoro-BTD and nonfluorinated BTD substrates are much
less effective probably due to the unfavorable cyclopalladation,
we are still inspired to develop a more general and efficient arene
C−H functionalization strategy for the diversified modification
of the valuable functionalized BTD molecules, which would
offer a rational tailoring of their electronic properties by
combining the double functions of BTD as both a modifiable
directing group for C−H activation14 and one of the most
important cores for functional materials (Scheme 1, eq 2).
Transition-metal-catalyzed, ligand-directed C−H acyloxyla-
tion has emerged as a powerful tool for the direct conversion of
arenes into various valuable oxygenated aromatic derivatives.15
Recently, the Mei group reported the oxime-directed sp3 C−H
acyloxylation under electrochemical paladium catalysis.16
based materials have been explored as blue light emitting
materials in polymer light emitting diodes (PLEDs) due to their
superior properties, and BTD, which is a narrow bandgap
moiety, has often been incorporated into the PF backbone or
side chain to tune the emission colors.11
Although BTD moieties are among the most important cores
in organic materials for optoelectronics, studies concerning their
efficient synthesis or structure modification are relatively
limited. Because of the synthetic challenges, most of these
studies have been only focused on the preparation and
investigation of the photophysical properties of 4,7-diaylated
BTD derivatives. Moreover, to our knowledge, there are only
two similar examples that employ BTD as a modifiable directing
group for the direct C−H functionalization of the BTD ring,
which were reported by Marder12 and Zhang,13 respectively, for
Received: July 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02414
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Although a variety of other directing groups such as pyridine,17
pyrimidine,18 pyrazole,19 oxazoline,20 amide,21 diphenylphos-
phine oxide,22 and pyridyldiisopropylsilyl (PyDipSi)23 have
been shown to be efficient in these reactions, there are still some
challenges that need to be addressed. First, the acyloxylation of
strong electron-withdrawing substrates is much less effective.
Second, the control of reaction selectivity between mono- and
bis-acyloxylation is still problematic. Third, the examples about
iterative double C−H acyloxylation of arenes are very rare.
Finally, the removal or conversion of most directing groups into
other desired functionalities is not trivial. Due to the important
applications of functionalized BTD derivatives in material
chemistry, we are interested in addressing these problems by
employing the BTD moiety as a modifiable directing group for
the direct arene C−H acyloxylation.
when the reaction was conducted at rt (Table 1, entry 9). No
reaction occurred in the absence of either the palladium catalyst
or oxidant (Table 1, entries 10 and 11). Finally, to demonstrate
the scalability of this reaction, a 5 mmol gram scale reaction was
conducted, and the monoacetate 2a was isolated almost
exclusively in very good yield (Table 1, entry 12).
With the optimum conditions in hand, we first examined the
scope of this novel monoacyloxylation reaction (Scheme 2).
Scheme 2. Mono-acetoxylation of BTD-arene Derivatives
We initiated the investigation by reacting the readily available
4-methyl-7-phenyl-BTD 1a with PhI(OAc)2 (PIDA) under
palladium catalysis at 120 °C (Table 1).
a
Table 1. Reaction Optimization
b
c
entry
PIDA (equiv)
solvent
MeCN
DCE
Ac2O
AcOH
AcOH/Ac2O (1:1)
AcOH/Ac2O (1:1)
AcOH/Ac2O (1:1)
AcOH/Ac2O (1:1)
AcOH/Ac2O (1:1)
AcOH/Ac2O (1:1)
AcOH/Ac2O (1:1)
AcOH/Ac2O (1:1)
yield (%)
2a/3a
1
2
3
4
5
3.0
3.0
3.0
3.0
3.0
3.0
2.0
1.0
1.0
1.0
42
62
70
72
91
99
98
88
91
1:1
1:35
1:45
1:10
1:3
d
6
7
8
9
6:1
20:1
e
f
10
11
12
g
1.0
82
40:1
a
Reaction conditions: 0.2 mmol of 1a, Pd(OAc)2 (5 mol %), PIDA (x
b
c
equiv), solvent (2.0 mL), 120 °C, 16 h. Isolated overall yield. The
ratio of 2a to 3a was determined by the isolated yields of the products.
a
b
c
d
e
f
60 °C. PhI(OAc)2 (1.2 equiv), 120 °C, 16 h. PhI(OAc)2 (3.0
150 °C. The reaction was conducted at rt for 36 h. In the absence
g
equiv), 120 °C, 16 h.
of Pd cat. 5 mmol gram scale.
With MeCN as the solvent, the acetate was obtained in 42%
yield (Table 1, entry 1). The yield could be improved to 62%
with DCE as the solvent (Table 1, entry 2). With Ac2O as the
solvent, it was found that a 1:1 mixture of mono- and bis-acetates
was isolated in 70% yield (Table 1, entry 3). By switching the
solvent from Ac2O to AcOH, the selectivity was improved to
1:35 with the bis-acetate 3a as the major product (Table 1, entry
4). Pleasingly, the selectivity could be further improved to 1:45
with a 91% overall yield with a mixture of AcOH/Ac2O (1:1) as
the solvent (Table 1, entry 5). It was found that both the yield
and selectivity were decreased by further changing the ratio of
solvents (not shown). By raising the reaction temperature to 150
°C, the selectivity was decreased significantly, although the
overall yield was improved to 99% (Table 1, entry 6). By
reducing the amounts of PIDA (1.0 equiv), the amount of
isolated bis-acetate 3a decreased, and the major compound
isolated was the monoacetoxylated 2a (Table 1, entries 7 and 8).
The selectivity can be improved to 20:1 in 91% overall yield
First, the substrates with a substituent on the para-position of
the phenyl ring were tested. Simple alkyl (2b,c), strong electron-
donating (2d), strong electron-withdrawing (2e−g), and
halogen substituents (2h,i) were all tolerated under the reaction
conditions, affording the corresponding products in good yields.
For the substrates with a substituent on the ortho-position of the
phenyl ring, all gave the corresponding products in good to
excellent yields (2j−k and 2n−o) except the substrates with
strong electron-withdrawing substituents (2l−m) by conduct-
ing the reactions at an elevated temperature (120 °C). For the
substrates with a substituent on the meta-position of the phenyl
ring, surprisingly, the substrates with electron-withdrawing
substituents (2q−s and 2tb) gave the corresponding products
in much higher yields than those with electron-donating
substituents (2p and 2ta), whereas in the literature the
acyloxylation of strong electron-withdrawing substrates was
normally much less extensively reported.15−22 The BTD-
naphthalene 2u and quinolone 2v substrates were effective as
B
DOI: 10.1021/acs.orglett.8b02414
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Organic Letters
Letter
well. If there is no substituent on the 4-position of BTD, the
acetoxylation still took place regioselectively on the 7-phenyl
ring (2w−x) other than the BTD ring itself. Both fluoro- and
bromo- functional groups were tolerated on the BTD ring under
the reaction conditions, which could work as functional handles
for further transformations (2y). For the symmetrical BTD-
arene substrate, the monoacetoxylation still can be achieved very
well under the optimized conditions (2z).
acyloxy group could come from the solvent directly other than
the oxidant.
We already demonstrated that the BTD moiety, as both an
important fragment in material chemistry and C−H activation
directing group, is effective for selective mono- and bis-
acyloxylation. We next want to further demonstrate that the
iterative double C−H acyloxylation can be achieved as well
(Scheme 4). First, with a mixture of AcOH and Ac2O as the
The substrate scopes for the bis-acyloxylation were then
examined under the optimized reaction conditions (Scheme 3).
Scheme 4. Iterative Double Acyloxylation of BTD-arene
Derivatives
Scheme 3. Bis-acyloxylation of BTD-arene Derivative
solvent the monoacetate 2a was obtained under the optimized
conditions at rt. Then the compound 2a was treated with the
palladium-catalyzed acyloxylation conditions again in the
presence of different solvent at 120 °C, and various asymmetric
bis-acyloxylated BTD-arene products 4a−c were obtained
successfully.
Finally, we demonstrate that the BTD directing group can be
easily modified and the acyloxylated product 2a could be
transformed into various valuable functionalized (hetero)biaryls
(Scheme 5).24 It was found that the acetoxyl group of 2a can be
Scheme 5. Further Diversity-Oriented Transformations into
Various Valuable (Hetero) Biaryls
a
b
Yield of monoacyloxylated product. n-PrCO2H was used as the
c
solvent. t-BuCO2H was used as the solvent.
The substrates with simple alkyl substituents gave the bis-
acetates almost exclusively in very good yields by using 3.0 equiv
of PIDA (3a−c). For the substrate with a strong electron-
donating methoxy group, a separable mixture of bis- and
monoacetylated products (5.3:1) was obtained in 82% overall
yield (3d). Interestingly, both sp3 and sp2 C−H acetoxylation
occurred for the substrate with a methylthio group (3e).
Surprisingly, the monoacetate was obtained as the major
product for the substrate with a cyano group (3f). For the
substrates with other strong electron-withdrawing groups, a
separable mixture of products was obtained in excellent overall
yields with the bis-acetate as the major one (3g,h). The reactions
gave an almost 1:1 separable mixture of bis- and monoacetates in
excellent yields for the substrates with halogen substituents (3i−
k). The bis-acetoxylation still can be achieved if there is no
substituent on the 4-position of BTD (3l). For the symmetrical
BTD-arene substrate, tetra-acetate was obtained in an
unoptimized 41% yield (3m). Finally, we showed that the
other acyloxylated products can be obtained as well in almost
quantitative yield by changing the solvent to the other acids,
respectively (3n,o), which demonstrated in this study that the
selectively reduced to give the hydroxylated BTD product 5 in
the presence of CoCl2·6H2O and NaBH4. With LAH as the
reducing reagent, both the acetoxyl group and BTD moiety were
reduced in one pot to give the diaminobiphenyl 6. Starting with
compound 6, a diversity-oriented synthesis of various valuable
functionalized heterobiaryls 7−11 can be achieved readily. For
example, by reacting 6 with glyoxal the quinoxaline derivative 7
was prepared in good yield, which could be employed as a
PFKFB3 inhibitor. The azabicyclic compounds 9−11 were also
obtained successfully under different reaction conditions, which
could be used as BET inhibitors.25
C
DOI: 10.1021/acs.orglett.8b02414
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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In summary, we have developed an efficient protocol for the
highly selective arene C−H mono- and bis-acyloxylation of BTD
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both an important fragment of material chemistry and a
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02414.
Experimental procedures and spectroscopic character-
ization data (PDF)
AUTHOR INFORMATION
■
́
X.; Dimitrijevic, E.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 3466.
Corresponding Author
*E-mail:zhangfengzhi@zjut.edu.cn.
ORCID
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1141. (b) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am.
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Chem. Soc. 2006, 128, 78. (c) Ackermann, L.; Novak, P. Org. Lett. 2009,
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(b) Tobisu, M.; Ano, Y.; Chatani, N. Org. Lett. 2009, 11, 3250. (c) Gou,
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Fengzhi Zhang: 0000-0001-9542-6634
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This research was supported by the Natural Science Foundation
of China (Grant No. 21871234) and Zhejiang Provincial
Natural Science Foundation of China for Distinguished Young
Scholars (Grant No. LR15H300001). We also thank the
Zhejiang Provincial Thousand-Talent Program and Zhejiang
University of Technology for financial support.
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DOI: 10.1021/acs.orglett.8b02414
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