A versatile approach for the synthesis of para -substituted arenes via palladium-catalyzed C-H functionalization and protodecarboxylation of benzoic acids

Article abstract of DOI:10.1055/s-0035-1560579

While a great number of ortho C-H functionalization reactions have been developed and several breakthroughs have been achieved in meta C-H activation, para C-H functionalization is still in its infancy stage. In this article, a versatile strategy for the synthesis of para-substituted arenes has been developed via a tandem process consisting of palladium-catalyzed C-H functionalization and subsequent copper-catalyzed protodecarboxylation of benzoic acids. Both electron-withdrawing and electron-donating functionalities can be introduced into the para positions of arenes bearing a variety of substituents.

Full text of DOI:10.1055/s-0035-1560579

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© Georg Thieme Verlag Stuttgart · New York
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Letter
Synlett
A Versatile Approach for the Synthesis of para-Substituted Arenes
via Palladium-Catalyzed C–H Functionalization and Protodecar-
boxylation of Benzoic Acids
O
OH
Shulei Pan
R2
Bo Zhou
para-selective functionalization
R1
Yanghui Zhang*
Changdong Shao
Guangfa Shi
R1
O
OH
R2
Cu-catalyzed
decarboxylation
Pd-catalyzed C–H
functionalization
Shanghai Key Laboratory of Chemical Assessment and Sustainability,
Department of Chemical, and UNEP-Tongji Institute of Environment for
Sustainable Development, Tongji University, 1239 Siping Road,
Shanghai 200092, P. R. of China
no isolation
R1
R1 = Me, Ph, CF3, COMe, CO2Me, F, Cl, Br, OMe, OH, NO2, NHAc
R2 = Ar (16 examples, yield 25%–85%)
zhangyanghui@tongji.edu.cn
ArCO (13 examples, yield 45%–80%)
OH (9 examples, yield 40%–88%)
Received: 01.08.2015
Accepted after revision: 20.09.2015
Published online: 21.10.2015
activation,3 primarily including selective meta C–H activa-
tion controlled by electronic or steric effects,4 copper-cata-
lyzed meta-selective arylation of anilides and β-aryl car-
bonyl compounds,5 ruthenation-dictated functionalization
of meta C–H bonds,6 remote meta C–H activation directed
by a U-shaped nitrile-containing template,7 and nor-
bonene-mediated meta C–H functionalization (Scheme 1,
b).8 para-C–H Functionalization still remains to be investi-
gated. Very few examples of para-selective C–H functional-
ization reactions have been reported.9 In the reported reac-
tions, the site selectivity resulted primarily from steric or
electronic factors, and the reactions were applicable to a
limited substrate scope.
DOI: 10.1055/s-0035-1560579; Art ID: st-2015-w0600-l
Abstract While a great number of ortho C–H functionalization reac-
tions have been developed and several breakthroughs have been
achieved in meta C–H activation, para C–H functionalization is still in its
infancy stage. In this article, a versatile strategy for the synthesis of
para-substituted arenes has been developed via a tandem process con-
sisting of palladium-catalyzed C–H functionalization and subsequent
copper-catalyzed protodecarboxylation of benzoic acids. Both electron-
withdrawing and electron-donating functionalities can be introduced
into the para positions of arenes bearing a variety of substituents.
Key words C–H activation, palladium, decarboxylation, arenes, regio-
selectivity
Recently, an intriguing traceless directing-group strate-
gy for achieving meta C–H functionalization of arenes is
arousing attention of organic chemists (Scheme 1, c).10 For
this strategy, ortho-substituted benzoic acids are function-
alized at the other ortho positions via carboxylate-directed
C–H activation in the first step. Subsequently, the carboxyl
group is removed to give meta-substituted arenes. When
we surveyed carboxylate-directed C–H functionalization
reactions, we found that C–H activation took place at the
less-hindered ortho positions for the majority of meta-sub-
stituted benzoic acids.11 Therefore, we envisioned that
para-functionalized products could be formed after the car-
boxyl groups are removed (Scheme 1, d). It should be men-
tioned that this type of reactions were observed in carbox-
ylate-directed C–H alkoxylation with concomitant proto-
decarboxylation, which was reported by the Gooßen
group.10e
In the past few decades, transition-metal-catalyzed C–H
functionalization has attracted great attention and is
emerging as a powerful methodology in organic synthesis.1
As C–H bonds are ubiquitous in organic molecules, it is cru-
cial to activate desirable C–H bonds selectively for develop-
ing synthetically applicable C–H functionalization reac-
tions. However, controlling site selectivity is a great chal-
lenge because the C–H bonds often have very subtle
difference in intrinsic reactivity. At present, the most com-
mon strategy to achieve site selectivity is to use directing
groups.2 The directing groups chelate with transition-metal
catalysts, and as a consequence, only C–H bonds at the ap-
propriate positions can be cleaved through the formation of
a cyclic pretransition state, which is normally a five- or six-
membered ring. This strategy usually leads to ortho selec-
tivity for the C–H functionalization of arenes. Currently, the
vast majority of work in the literature has focused on ortho
C–H functionalization via the directing-group strategy
(Scheme 1, a), and the activation of meta and para C–H
bonds remain comparatively underdeveloped. However,
several breakthroughs were recently achieved in meta C–H
During the preparation of this manuscript, the Chang
group reported the synthesis of para-substituted (N-sulfo-
nyl)aniline derivatives via the traceless directing-group
strategy.10h
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S. Pan et al.
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The Daugulis and Larrosa group reported palladium-
catalyzed ortho C–H arylation of benzoic acids inde-
pendently.14 Based on these excellent works, we first inves-
tigated the synthesis of para-arylated arene derivatives.
Therefore, the benzoic acids in Figure 1 were subjected to
the Larrosa conditions as shown in Scheme 2, yielding the
corresponding 2-phenylbenzoic acid derivatives. We aimed
to develop a tandem approach, so the subsequent proto-
decarboxylation was examined with the crude products
without purification. After screening several current proto-
decarboxylation conditions,15 we found that the ortho-phe-
nylated benzoic acid crude products underwent protocar-
boxylation smoothly under the catalytic system discovered
by the Gooßen group which comprises catalyst Cu2O and li-
gand Phen.16 All of the intermediates from benzoic acids in
Figure 1 were converted into the corresponding para-ary-
lated arene products. While the reactions of the benzoic ac-
ids bearing meta-electron-donating groups occurred effi-
ciently, the overall yields for the benzoic acids with elec-
tron-withdrawing groups were much lower. The poor
overall yields resulted primarily from the low efficiency of
ortho-C–H functionalization
DG DG
a)
R
meta-C–H functionalization
b)
c)
DG
DG
1. Cu-catalyzed
2. ruthenation-dictated
3. end-on template-directed
4. norbonene-mediated
5. sterically or electronically controlled
R
O
OH
O
OH
R1
R2
R1
R1
R2
removable directing-group-relayed meta-C–H functionalization
this work:
para-C–H functionalization
d)
O
OH
O
OH
R2
R2
R1
R1
R1
1) Pd(OAc)2, Ag2CO3
para-C–H functionalization via a removable directing-group-relay
strategy
K2CO3, AcOH
120 °C, 24 h
R
COOH
H
R
+
ArI
Scheme 1 Strategies for regioselective C–H functionalization of arenes
2) Cu2O, Phen
quinoline, NMP
170 °C, 24 h, N2
Ar
a
n
na
(3 equiv)
We aimed to develop a versatile approach for the syn-
thesis of para-substituted arenes. This approach should
have broad substrate scopes and its para selectivity should
be independent of the nature of the substituents. Benzoic
acids are a very common class of organic molecules and
widely exist in nature.12 Carboxylate-directed C–H func-
tionalization and decarboxylation reactions have been ex-
tensively investigated.12,13 As para-functionalized products
are expected to be obtained via carboxylate-directed ortho
C–H functionalization and protodecarboxylation of meta-
substituted benzoic acids, this traceless directing-group
strategy is ideal for developing a versatile approach for the
synthesis of para-substituted arenes.
O
Ph
F3C
Ph
Ph
Ph
Ph
Ph
1a, 80%
MeOOC
2a, 80%
3a, 55%
4a, 35%
8a, 60%
F
Cl
Ph
Ph
Ph
5a, 30%
6a, 65%
MeO
7a, 40%
HO
Br
O2N
Ph
Ph
Ph
Ph
9a, 60%
AcHN
10a, 75%
11a, 78%
12a, 25%
To develop a general method, we selected a range of
meta-substituted benzoic acids, including those bearing C-,
O-, and N-linked substituents and halides (Figure 1). The
substituents also cover the majority of common electron-
donating and electron-withdrawing functionalities.
Ph
OMe
F
13a, 40%
14a, 80%
15a, 85%
O
OH
Cl
a Yields based on isolated produts on a 0.5 mmol scale.
1 R = Me
2 R = Ph
3 R = CF3
4 R = COMe
5 R = COOMe
6 2-naphthoic
acid
7 R = F
8 R = Cl
9 R = Br
10 R = OMe
11 R = OH
12 R = NO2
13 R = NHAc
16a, 81%
R
Scheme 2 Formal para-C–H arylation of arenes; yields based on isolat-
ed products on a 0.5 mmol scale.
Figure 1 meta-Substituted benzoic acid substrates
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 277–281

279
S. Pan et al.
Letter
Synlett
the first C–H arylation steps. Substituted phenyl iodides
were also examined. Therefore, m-toluic acid was allowed
to react with 4-methoxy, 4-fluoro-, or 4-chlorophenyl io-
dide under the standard conditions. The reactions formed
the corresponding para-functionalized toluenes in high
yields.
Next, we sought to develop a general protocol for the
synthesis of para-substituted arenes bearing an electron-
withdrawing group. The carbonyl group is a typical elec-
tron-withdrawing group and can be transformed into a va-
riety of other functionalities, so it is a desirable example to
be studied. Gratefully, the Ge and Gooßen group disclosed
carboxylate-directed carbonylation reaction with α-oxocar-
boxylic acids and acetic anhydrides, respectively.17 Thus,
the benzoic acids were benzoylated following the Ge’s con-
ditions, and the resulting crude products were subjected to
the same protodecarboxylation conditions as that em-
ployed for the decarboxylation of 2-phenylbenzoic acids
(Scheme 3). As shown in Scheme 3 most of the benzoic ac-
ids were converted into para-substituted benzophenones.
The substrates bearing MeCO, OH, or NO2 were not reactive,
also because the first step failed to form carbonylated prod-
ucts. Substituted 2-oxo-2-phenylacetic acids were also re-
active. Therefore, 2-oxo-2-phenylacetic acids bearing a me-
thoxy, fluoro, or chloro group reacted with m-toluic acid, af-
fording the corresponding benzophenones in medium
yields.
Having successfully developed methods for the synthe-
sis of para-substituted arenes with a phenyl (almost neutral
and weakly electron donating) or carbonyl group (electron
withdrawing), we turned to investigate the synthetic means
for para-substituted electron-rich arenes. The hydroxyl
group, a strong electron-donating group, is an ideal target
because phenols are a type of important organic molecules
and versatile synthetic intermediate. The Yu group dis-
closed an intriguing C–H hydroxylation reaction of benzoic
acids with O2.18 Therefore, following the Yu’s conditions and
the previous protodecarboxylation protocol, the benzoic
acids underwent a tandem procedure of C–H hydroxylation
and subsequent protodecarboxylation, affording a range of
para-substituted phenols (Scheme 4). Benzoic acids with
meta-MeCO, NHAc, Br, or OH failed to form the correspond-
ing products, because the hydroxylation in the first step did
not occur. As the former two reactions, the decarboxylation
steps were high-yielding, and the overall yields depended
on the efficiency of the hydroxylation step. Based on the
Yu’s work, the yield of the hydroxylation reaction increased
1) Pd(TFA)2, Ag2CO3
DME,150–165 °C
24–48 h
R
O
R
COOH
OH
+
Ar
Ar
2) Cu2O, Phen
quinoline, NMP
170 °C, 24 h, N2
H
O
O
n
nb
b
(3 equiv)
O
F3C
Ph
1) Pd(OAc)2, KOAc
BQ, DMA
Ph
Ph
Ph
Ph
R
COOH
H
R
115 °C, 15 h
O
O
O
4b, 75%
+
O2
c
O
1b, 80%a
MeO2C
2b, 60%a
2) Cu2O, Phen
quinoline, NMP
220 °C, 12 h, N2
3b, 0%
OH
n
nc
F
Cl
(1atm)
Ph
Ph
Ph
Ph
Ph
O
F3C
Ph
O
O
O
O
5b, 55%b
6b, 50%
7b, 75%
8b, 65%
OH
OH
OH
OH
OH
Br
MeO
HO
Ph
O2N
Ph
2c, 88%a
1c, 80%
MeOOC
3c, 0%
4c, 45%
Ph
F
Cl
O
O
O
O
9b, 60%c
10b, 65%
11b, 0%
12b, 0%
OH
OH
OH
OH
AcHN
OMe
F
8c, 84%a
5c, 45%
6c, 60%
MeO
7c, 45%
11c, 0%
Ph
Br
HO
O2N
O
O
O
14b, 70%b
15b, 60%
OH
OH
OH
13b, 45%
Cl
9c, 0%
10c, 70%
12c, 40%
AcHN
O
OH
13c, 0%
16b, 50%
Scheme 3 Formal para C–H benzoylation of arenes; yields based on
isolated products on a 0.5 mmol scale. a Conditions: 165 °C, 24 h. b
Conditions: 165 °C, 48 h. c Conditions: 130 °C, 24.
Scheme 4 Formal para C–H hydroxylation of arenes; yields based on
isolated products on a 0.5 mmol scale. a Conditions: 5 atm O2.
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when O2 (5.065 bar) was employed, so the overall yields of
this protocol should be able to be improved by using O2
(5.065 bar).
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Soc. 2014, 507, 215. (g) Yang, G.; Lindovska, P.; Zhu, D.; Kim, J.;
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M.; Yu, J.-Q. Nature (London, U.K.) 2015, 519, 334. (b) Dong, Z.;
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Commun. 2013, 49, 7653.
In summary, we have developed a versatile approach for
the synthesis of para-substituted arenes.19–21 In this ap-
proach, meta-substituted benzoic acids were first function-
alized at the less hindered ortho positions via palladium-
catalyzed C–H activation. The resulting intermediates un-
derwent copper-catalyzed protodecarboxylation to give
para-substituted arenes. Three classes of substituents, in-
cluding phenyl group, electron-withdrawing benzoyl, and
electron-donating hydroxyl, were introduced via palladi-
um-catalyzed C–H functionalization reaction. A variety of
functionalities were compatible with the protocols. Other
removable directing group may also be utilized to develop
synthetic approaches for para-substituted arenes.
Acknowledgment
The work was supported by the National Natural Science Foundation
of China (No. 21372176), the Program for Professor of Special Ap-
pointment (Eastern Scholar) at Shanghai Institutions of Higher Learn-
ing, Tongji University 985 Phase III funds, and Shanghai Science and
Technology Commission (14DZ2261100).
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560579.
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(20) Synthesis of para-Benzoylated Arenes
A mixture of m-toluic acid (27.2 mg, 0.20 mmol), benzoylformic
acid (90.1 mg, 0.60 mmol), Pd(TFA)2 (6.6 mg, 0.020 mmol), and
Ag2CO3 (165.5 mg, 0.60 mmol) in DME (2 mL) was heated at
150–165 °C for 24–48 h. After cooling down to r.t., the reaction
mixture was diluted by addition of EtOAc (10 mL) and then fil-
tered through a pad of Celite. The filtrate was concentrated in
vacuo to afford 2-benzoylbenzoic acid derivatives. A mixture of
the crude product, Cu2O (1.4 mg, 0.010 mmol), and 1,10-
phenanthroline (3.6 mg, 0.020 mmol) in a solution of NMP (1.5
mL) and quinoline (0.5 mL) was heated under an atmosphere of
N2 at 170 °C for 24 h. The reaction mixture was quenched by
addition of 0.2 M aq HCl (10 mL), diluted with EtOAc (10 mL),
and then filtered through a pad of Celite. The filtrate was
washed with brine (10 mL), dried over Na2SO4, and concen-
trated in vacuo. The residue was purified by silica gel prepara-
tive TLC to give phenyl(p-tolyl)methanone. 1H NMR (400 MHz,
CDCl3): δ = 7.78 (d, J = 7.1 Hz, 2 H), 7.72 (d, J = 8.1 Hz, 2 H), 7.58
(t, J = 7.4 Hz, 1 H), 7.48 (t, J = 7.5 Hz, 2 H), 7.28 (d, J = 7.9 Hz, 2
H), 2.44 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 196.50, 143.22,
137.95, 134.87, 132.13, 130.29, 129.91, 128.95, 128.18, 21.64.
HRMS (ESI-TOF): m/z calcd for C14H12NaO+: 219.0780 [M + Na]+;
found: 219.0774.
(16) Thiel, W. R.; Rodríguez, N.; Linder, C.; Melzer, B.; Gooßen, L. J.
Adv. Synth. Catal. 2007, 349, 2241.
(17) (a) Miao, J.; Ge, H. Org. Lett. 2013, 15, 2930. (b) Mamone, P.;
Danoun, G.; Gooßen, L. J. Angew. Chem. Int. Ed. 2013, 52, 6704;
Angew. Chem. 2013, 125, 6836.
(18) Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 14654.
(19) Synthesis of para-Arylated Arenes
A mixture of m-toluic acid (68.0 mg, 0.50 mmol), iodobenzene
(167.2 μL, 1.50 mmol), Ag2CO3 (76.0 mg, 0.28 mmol), K2CO3
(35.0 mg, 0.25 mmol), and Pd(OAc)2 (2.3 mg, 0.01 mmol) in
AcOH (130.0 μL) was heated under an atmosphere of N2 at
120 °C for 24 h. After cooling down to r.t., the reaction mixture
was quenched by addition of 2.0 M aq HCl (10 mL), diluted with
EtOAc (10 mL), and then filtered through a pad of Celite. The fil-
trate was washed with brine, dried over Na2SO4, and concen-
trated in vacuo, yielding crude 2-phenylbenzoic acid deriva-
tives. A mixture of the crude product, Cu2O (3.6 mg, 0.025
mmol), and 1,10-phenanthroline (9.0 mg, 0.050 mmol) in a
solution of NMP (1.5 mL) and quinoline (0.5 mL) was heated
under an atmosphere of N2 at 170 °C for 24 h. The reaction
mixture was quenched by addition of 0.2 M aq HCl (10 mL),
diluted with EtOAc (10 mL), and then filtered through a pad of
Celite. The filtrate was washed with brine (10 mL), dried over
Na2SO4, and concentrated in vacuo. The residue was purified by
silica gel preparative TLC to give 4-methylbiphenyl. 1H NMR
(400 MHz, CDCl3): δ = 7.59–7.57 (m, 2 H), 7.51–7.49 (m, 2 H),
7.45–7.41 (m, 2 H), 7.34–7.31 (m, 1 H), 7.26–7.24 (m, 2 H), 2.40
(s, 3 H). 13C NMR (100 MHz, CDCl3): δ = 141.14, 138.34, 136.99,
129.45, 128.68, 126.97, 126.95, 21.08. HRMS (ESI-TOF): m/z
calcd for C13H13+: 169.1012 [M + H]+; found: 169.0938.
(21) Synthesis of para-Hydroxylated Arenes
A 50 mL Schlenk-type tube (with a Teflon high-pressure valve
and side arm) was charged with m-toluic acid (68.0 mg, 0.50
mmol), benzoquinone (54.0 mg, 0.50 mmol), KOAc (98.0 mg,
1.00 mmol), Pd(OAc)2 (11.2 mg, 0.050 mmol), and N,N-dimethyl-
acetamide (1.5 mL). The reaction tube was evacuated and back-
filled with O2 (3×, ballon). After the reaction mixture was
stirred at 115 °C for 15 h, it was allowed to cool down to r.t. The
reaction mixture was diluted with EtOAc (10 mL) and then fil-
tered through a pad of Celite. The filtrate was concentrated in
vacuo to yield crude 2-hydroxylbenzoic acid. A mixture of the
crude product, Cu2O (3.6 mg, 0.025 mmol), and 1,10-phenan-
throline (9.0 mg, 0.050 mmol) in a solution of NMP (1.5 mL) and
quinoline (0.5 mL) was heated under an atmosphere of N2 at
220 °C for 12 h. The reaction mixture was quenched by addition
of 0.2 M aq HCl (10 mL), diluted with EtOAc (10 mL), and then
filtered through a pad of Celite. The filtrate was washed with
brine (10 mL), dried over Na2SO4, and concentrated in vacuo.
The residue was purified by silica gel preparative TLC to give p-
cresol. 1H NMR (400 MHz, CDCl3): δ = 7.05 (d, J = 8.3 Hz, 2 H),
6.75 (d, J = 8.3 Hz, 2 H), 4.95 (br, 1 H), 2.29 (s, 3 H). 13C NMR (100
MHz, CDCl3): δ = 153.18, 130.03, 129.92, 115.06, 20.43. HRMS
(ESI-TOF): m/z calcd for C7H9O+: 109.0648 [M + H]+; found:
109.0657.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 277–281