Palladium-Catalyzed Base-Promoted Arylation of Unactivated C(sp3)–H Bonds by Aryl Iodides: A Practical Approach To Synthesize β-Aryl Carboxylic Acid Derivatives

Article abstract of DOI:10.1002/ejoc.201701215

A highly efficient protocol for the β-arylation of carboxylic amides by aryl iodides under PdCl₂(CH₃CN)₂/CsOAc catalysis was developed. This method was found to tolerate a broad scope of substrates and was successfully employed in the preparation of a variety of β-aryl α-amino and γ-amino acid derivatives. The utility of this method was further illustrated in the synthesis of the psychotropic drug (±)-phenibut and β-aryl bile acid analogues.

Full text of DOI:10.1002/ejoc.201701215

DOI: 10.1002/ejoc.201701215
Communication
C–H Activation
Palladium-Catalyzed Base-Promoted Arylation of Unactivated
C(sp3)–H Bonds by Aryl Iodides: A Practical Approach To
Synthesize ꢀ-Aryl Carboxylic Acid Derivatives
Quan Gou,[a][‡] Gang Liu,[a][‡] Lanxiu Zhou,[a] Suiyun Chen,*[b] and Jun Qin*[a]
Abstract: A highly efficient protocol for the ꢀ-arylation of carb- aration of a variety of ꢀ-aryl α-amino and γ-amino acid deriva-
oxylic amides by aryl iodides under PdCl2(CH3CN)2/CsOAc catal- tives. The utility of this method was further illustrated in the
ysis was developed. This method was found to tolerate a broad synthesis of the psychotropic drug ( )-phenibut and ꢀ-aryl bile
scope of substrates and was successfully employed in the prep- acid analogues.
Introduction
bond arylation as arylation reagents was also reported by differ-
ent groups.[9] Our method operated under the assistance of 8-
aminoquinoline, a removable bidentate directing group that
was first introduced by Daugulis in the ꢀ-arylation of carboxylic
acid derivatives and subsequently employed in other C–H acti-
vation reactions.[3] During studies on the mechanism of this
reaction, we found that aryl iodides resulting from the decom-
position of (diacetoxyiodo)arenes were actually the arylation re-
agents for this reaction. Although a variety of (diacetoxyiodo)-
arenes are commercially available, they require extra steps to
prepare from aryl iodides and are more expensive than aryl
iodides. On the basis of this discovery, we wondered whether
aryl iodides could replace (diacetoxyiodo)arenes as arylation re-
agents to achieve a general scope of the reaction. Herein, we
report this newly developed palladium-catalyzed arylation of
carboxylic amides by using aryl iodides for the synthesis of a
variety of ꢀ-aryl carboxylic acid derivatives.
In recent years, the direct arylation of C(sp3)–H bonds has
emerged as a powerful method for the construction of C(sp2)–
C(sp3) bonds, as it eliminates the need to prefunctionalize the
substrate and, therefore, shortens the synthetic sequence.[1]
Significant advances have been made in the transition-metal-
catalyzed arylation of C(sp3)–H bonds, including palladium,[2–4]
iron,[5] and nickel.[6] In the palladium-catalyzed arylation of
C(sp3)–H bonds, the arylation reagents are usually aryl halides,
and the reactions generally require the assistance of a stoichio-
metric amount of a silver salt as a halide scavenger for success
of the transformation.[2,3] As a result, the reactions generate a
significant amount of silver metal waste, which increases the
cost and difficulty of the synthetic process. To avoid those dis-
advantages, many laboratories have been developing non-silver
salt conditions for the arylation of C(sp3)–H bonds, as exempli-
fied by several recent reports.[7] Nevertheless, the utility of
those protocols were demonstrated with limited substrate
scope and/or harsh reaction conditions. The development of
new methods to expand the scope and limitations of current
protocols is highly desired.
Results and Discussion
Our investigation of the arylation of C(sp3)–H bonds by using
aryl iodides commenced with a model reaction between N-
(quinolin-8-yl)butyramide (1a) and PhI (2a). Upon screening
various bases in the presence of PdCl2(CH3CN)2 as the catalyst
in mesitylene as the solvent at 110 °C (Table 1, entries 1–5), we
found that CsOAc afforded desired product 3aa in 98 % yield
(Table 1, entry 1). Other bases including NaOAc, Cs2CO3,
Na2CO3, and Et3N were inferior to CsOAc (Table 1, entries 2–5).
We further investigated the effects of different palladium cata-
lysts on the reaction efficiency (Table 1, entries 6–8). We found
that PdCl2(CH3CN)2 remained the best. Afterwards, we exam-
ined the solvent effects of the reaction (Table 1, entries 9–14).
Polar aprotic solvents such as DMF and CH3CN had a detrimen-
tal effect on the reaction and afforded the products in much
lower yields (Table 1, entries 9 and 10). A protic solvent such as
tBuOH was tolerated and resulted in a slight decrease in the
yield of 3aa (Table 1, entry 11). Nonpolar solvents such as diox-
In our program to develop new C–H activation/C–C bond-
formation reactions,[8] we recently reported a method for the
palladium-catalyzed arylation of ꢀ-C(sp3)–H bonds of carboxylic
amides by using (diacetoxyiodo)arenes as the arylation rea-
gents.[8b] The application of (diacetoxyiodo)arenes in C(sp3)–H
[a] Key Laboratory of Medicinal Chemistry for Natural Resource,
Ministry of Education, School of Chemical Science and Technology,
Yunnan University,
Kunming 650091, P. R. China
E-mail: qinjun@ynu.edu.cn
[b] Plant Science Institute, School of Life Sciences, Yunnan University,
Kunming 650091, P. R. China
E-mail: chensuiyun@ynu.edu.cn
[‡] These authors contributed equally to this work.
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.201701215.
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ane, 1,2-dichloroethane (DCE), and toluene were inferior to
mesitylene (Table 1, entries 12–14). The temperature had a min-
imal impact on the reaction (Table 1, entries 15 and 16). Lower-
ing the loading of PdCl2(CH3CN)2, 2a, or CsOAc resulted in a
decrease in the yield of 3aa (Table 1, entries 17–19). Ultimately,
the optimal reaction conditions were determined to include the
use of PdCl2(CH3CN)2 (5 mol-%), CsOAc (3.0 equiv.), and 2a
(2.5 equiv.) in mesitylene at 110 °C.
Table 2. Substrate scope of the aryl iodides.[a,b]
Table 1. Optimization of the reaction conditions.[a]
Entry
Pd catalyst
Base
Solvent
Yield[b] [%]
1
2
3
4
5
6
7
8
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(COD)
CsOAc
NaOAc
Cs2CO3
Na2CO3
Et3N
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
DMF
CH3CN
tBuOH
dioxane
DCE
98
9
11
38
0
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
93
91
90
14
57
90
95
87
94
92
94
90
87
91
Pd(OAc)2
PdCl2
9
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
10
11
12
13
14
15[c]
16[d]
17[e]
18[f]
19[g]
toluene
mesitylene
mesitylene
mesitylene
mesitylene
mesitylene
[a] Reaction conditions: 1a (0.20 mmol), 2a (0.50 mmol), catalyst (5 mol-%),
and base (0.60 mmol) in solvent (0.2 mL) at 110 °C for 24–48 h with TLC
control. [b] Determined by analysis of the crude mixture by 400 MHz 1H NMR
spectroscopy with benzyl bromide as an internal standard. [c] Temperature:
100 °C. [d] Temperature: 120 °C. [e] PdCl2(CH3CN)2: 2 mol-%. [f] Substrate 2a:
0.25 mmol. [g] CsOAc: 0.40 mmol.
With the optimal reaction conditions in hand, we investi-
gated the scope of the aryl iodides in the arylation of N-(quin-
olin-8-yl)butyramide (1a) (Table 2). To our delight, para-substi-
tuted aryl iodides containing electron-withdrawing groups such
as F, Cl, Br, CN, CF3, CO2CH3, COCH3, and OCF3 and para-substi-
tuted aryl iodides containing electron-donating groups such as
CH3, Ph, OCH3, CH2OCOCH3, and p-methoxybenzyloxy (OPMB)
all afforded desired arylation products 3ab–ai and 3aj–an in
good to excellent yields. In addition, meta-substituted aryl iod-
ides bearing electron-rich or electron-deficient groups also per-
formed well and gave desired products 3ao–aq in excellent
yields. Notably, sterically hindered ortho-substituted aryl iod-
ides also delivered desired products 3ar–as in moderate to
good yields. Moreover, disubstituted aryl iodides bearing either
electron-poor or electron-rich groups also afforded arylation
products 3at–ax in excellent yields. Notably, functional groups
such as Br, CO2CH3, COCH3, CN, and OPMB were well tolerated
and could be a useful handle for further derivatization.
[a] Optimal reaction conditions: 1a (0.20 mmol), 2 (0.50 mmol), PdCl2(CH3CN)2
(5 mol-%), and CsOAc (0.60 mmol) in mesitylene (0.2 mL) at 110 °C for 24–
48 h with TLC control. [b] Yield of isolated product.
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Afterwards, the reaction scope of the aliphatic amides was forded a mixture of mono- and diarylation products 3la in a 1:7
examined in the arylation with 2a under the reaction conditions ratio. Arylation of cyclopropanecarboxylic amide also gave a
(Table 3). Substrates containing simple aliphatic chains were mixture of mono- and diarylation products 3ma in a 1:1.8 ratio.
well tolerated and afforded desired arylation products 3ba–da However, both cyclopentanecarboxylic and cyclohexanecarbox-
in excellent yields. Phenyl, benzyl, and indolyl analogues also ylic amides delivered diarylation products 3na and 3oa exclu-
participated in the arylation without incident to afford products sively in excellent yields under the reaction conditions.
3ea–ga in excellent yields. In addition, substrates contained
useful functional groups such as ether, amine, and ester groups
were well tolerated and afford desired products 3ha–ka in
good to excellent yields. The arylation of propionamide af-
γ-Aminobutyric acid (GABA) is
a key neurotransmitter
present in the human brain. It plays an important role in signal
transmission. It has therapeutic properties and acts as an anti-
anxiety and antihypertensive agent in medicinal chemistry.[10]
To demonstrate further the utility of this method, we explored
the arylation of GABA substrate 1p with different aryl iodides
under the reaction conditions. We were delighted to find that
diverse aryl iodides were well tolerated and generated a variety
of unnatural ꢀ-aryl γ-aminobutyric acid derivatives in moderate
to good yields (Table 4, see products 3pa–pl). As another illus-
tration of the synthetic utility of the method shown in
Scheme 1, arylation product 3pa was successfully transformed
into the psychotropic drug ( )-phenibut in two steps, including
Table 3. Substrate scope of the carboxylic amides.[a,b]
Table 4. Arylation of GABA analogue 1p with aryl iodides.[a,b]
[a] Optimal reaction conditions: 1p (0.20 mmol),
2 (0.50 mmol),
PdCl2(CH3CN)2 (5 mol-%), and CsOAc (0.60 mmol) in mesitylene (0.2 mL) at
110 °C for 24–48 h with TLC control. [b] Yield of isolated product.
[a] Optimal reaction conditions: 1 (0.20 mmol), 2a (0.50 mmol), PdCl2(CH3CN)2
(5 mol-%), and CsOAc (0.60 mmol) in mesitylene (0.2 mL) at 110 °C for 24–
48 h with TLC control; NPhth = phthalimido, Boc = tert-butoxycarbonyl.
[b] Yield of isolated product.
Scheme 1. Synthesis of ( )-phenibut.
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acid-mediated cleavage of the 8-aminoquinolinyl and Boc
groups and hydrogenative debenzylation.
Table 6. Arylation of bile acid analogue 1w with aryl iodides.[a,b]
Following that, we turned our attention to examine the
scope of the α-amino carboxylic amides in the arylation with
2a (Table 5). An alanine substrate afforded diarylation product
3qa exclusively in good yield. Longer aliphatic α-amino carb-
oxylic amides produced monoarylation products 3ra–sa in
moderate yields. Phenyl and benzyl substrates also underwent
monoarylation in good yields (Table 5, see products 3ta and
3ua). Notably, a functional α-amino carboxylic amide such as a
lysine derivative was also well tolerated and afforded desired
product 3va in a useful yield.
Table 5. Arylation of α-amino carboxylic amides with aryl iodides.[a,b]
[a] Optimal reaction conditions: 1w (0.20 mmol),
2 (0.50 mmol),
PdCl2(CH3CN)2 (5 mol-%), and CsOAc (0.60 mmol) in mesitylene (0.2 mL) at
110 °C for 24–48 h with TLC control. [b] Yield of isolated product.
intramolecular KIE = 4.04; see the Supporting Information] sug-
gested that cleavage of the ꢀ-C(sp3)–H bond of the substrate
occurred as part of the reaction pathway but was not the rate-
limiting step.[12] In light of our previous study[8b] and the limited
amount of data available, a reaction mechanism was proposed,
as shown in Scheme 2. Complexation of substrate 1 with the
palladium catalyst results in the formation of intermediate A,
which further undergoes ꢀ-C(sp3)–H bond activation under the
assistance of CsOAc to give B. Subsequently, oxidative addition
of B into ArI takes place to afford C. Further reductive elimina-
[a] Optimal reaction conditions: 1 (0.20 mmol), 2a (0.50 mmol), PdCl2(CH3CN)2
(5 mol-%), and CsOAc (0.60 mmol) in mesitylene (0.2 mL) at 110 °C for 24–
48 h with TLC control. [b] Yield of isolated product.
Late-stage functionalization of natural products or medici-
nally active agents produces analogues that could have im-
proved pharmacodynamics or pharmacokinetic profiles. How-
ever, the complexity of natural products can cause issues of
chemo- or regioselectivity if C–H activation/functionalization
takes place. Bile acid derivatives have demonstrated their me-
dicinal applications as FXR agonists in the treatment of dyslipi-
demia such as nonalcoholic steatohepatitis (NASH), as exempli-
fied by recent global approval of obeticholic acid (Ocaliva).[11]
However, to the best of our knowledge, very few ꢀ-aryl bile
acid derivative have been reported,[8b] and their pharmacologi-
cal value as FXR agonists remains valuable to explore. Therefore,
we were particularly interested in applying this method to pre-
pare ꢀ-aryl bile acid analogues. Remarkably, arylation of the ꢀ-
C(sp3)–H bond of 1w by a variety of electron-rich and electron-
poor aryl iodides proceeded efficiently under the reaction con-
ditions to afford the desired ꢀ-aryl bile acid derivatives in good
to excellent yields (Table 6; see products 3wa–wy, 72–93 %
yield). The reaction demonstrated excellent regioselectivity in
the presence of a number of other C(sp3)–H bonds within the
molecule.
Kinetic isotope experiments [parallel intermolecular kinetic
isotope effect (KIE) = 1.28, one-pot intermolecular KIE = 3.13,
Scheme 2. Proposed reaction mechanism.
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Chen, S.-Q. Zhang, J.-W. Xu, F. Hu, B.-F. Shi, Chem. Commun. 2014, 50,
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stored after ligand exchange of PdIXL2 with CsOAc.
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Conclusions
In conclusion, we disclosed an efficient protocol for the ꢀ-aryl-
ation of carboxylic amides by aryl iodides under PdCl2(CH3CN)2/
CsOAc catalysis. This method operated without the assistance
of silver salts or other oxidants. The reaction demonstrated a
broad substrate scope of carboxylic amides and aryl iodides to
produce a variety of ꢀ-aryl α-amino or γ-amino acid derivatives.
The utility of the method was further illustrated in the synthesis
of the psychotropic drug ( )-phenibut and bile acid analogues
as FXR agonists. Further investigation of the synthetic applica-
tion of this method is currently in progress.
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Experimental Section
General Procedure: A 5.0 mL Teflon-capped vial was charged with
1 (0.20 mmol), 2 (0.50 mmol), Pd(CH3CN)2Cl2 (5 mol-%), CsOAc
(0.60 mmol), and mesitylene (0.2 mL) under an air atmosphere. The
vial was then tightly capped. The mixture was stirred at room tem-
perature for 1 min to mix the reactants properly and was then
heated at 110 °C with vigorous stirring for 24–48 h. The progress of
the reaction was monitored by TLC. Upon completion of the reac-
tion, the vial was cooled to room temperature, and the mixture was
diluted with ethyl acetate and filtered through a short pad of Celite.
The filtrate was concentrated in vacuo, and the residue was purified
by flash chromatography (silica gel, ethyl acetate/petroleum ether)
to afford desired product 3.
Acknowledgments
We gratefully acknowledge financial support from the Program
of High-End Science and Technology Talents of Yunnan Prov-
ince (2012HA003), Postdoctoral Science Foundation of China,
Program of Hundred Oversea High-Level Talents of Yunnan
Province (W8110305), Yunnan University (XT412003), and Pro-
gram for Changjiang Scholars and Innovation Research Team in
University (IRT13095).
Keywords: Arylation · C–H activation · Palladium ·
Regioselectivity · Carboxylic acids
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Received: August 30, 2017
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