Rh-Catalyzed C-H Amination/Annulation of Acrylic Acids and Anthranils by Using -COOH as a Deciduous Directing Group: An Access to Diverse Quinolines

Article abstract of DOI:10.1021/acs.orglett.0c00539

A method for the synthesis of diverse polysubstituted quinolines from readily available acrylic acids and anthranils has been developed. The weakly coordinating -COOH directing group, which can be tracelessly removed in the cascade cyclization, is essential for this reaction. Diverse polysubstituted quinolines were obtained under mild reaction conditions with simple H₂O and CO₂ as byproducts. More importantly, 1,2,3,4-tetrahydroacridine, which is the core skeleton of tacrine (an Alzheimer's disease drug), was conveniently synthesized.

Full text of DOI:10.1021/acs.orglett.0c00539

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Letter
Rh-Catalyzed C−H Amination/Annulation of Acrylic Acids and
Anthranils by Using −COOH as a Deciduous Directing Group: An
Access to Diverse Quinolines
Yang Gao,* Jianhong Nie, Yibiao Li, Xianwei Li, Qian Chen, Yanping Huo, and Xiao-Qiang Hu*
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ABSTRACT: A method for the synthesis of diverse polysubstituted
quinolines from readily available acrylic acids and anthranils has been
developed. The weakly coordinating −COOH directing group, which can
be tracelessly removed in the cascade cyclization, is essential for this
reaction. Diverse polysubstituted quinolines were obtained under mild
reaction conditions with simple H2O and CO2 as byproducts. More
importantly, 1,2,3,4-tetrahydroacridine, which is the core skeleton of tacrine (an Alzheimer’s disease drug), was conveniently
synthesized.
he selective activation of C−H bonds by transition metal
in one pot to deliver a bifunctional product is still unknown
(Scheme 1c).
T
catalysts has evolved into a robust tool for organic
synthesis, and various efficient catalytic systems have been
established.1 Nevertheless, directing groups (DG) are still
indispensable for most reactions to control the reactivity and
regioselectivity.2 Thence, additional reaction steps are needed
to remove the directing groups, and as a result, the practicality
and efficiency of the reaction are greatly affected. The use of
traceless directing groups, which can be deciduously removed
after facilitating the C−H functionalization without the need
for additional steps, is a promising solution to this issue.3
Pioneered by the groups of Larossa, Gooßen, Su,
Ackermann, and others, the weakly coordinating −COOH
group has been developed as a traceless directing group in C−
H couplings of benzoic acids to access useful functionalized
arenes (Scheme 1a).4 In principle, the application of the same
Quinoline is a ubiquitous structural motif that has wide
application in natural product synthesis, drug discovery, and
materials science.8 Traditional methods to construct this
scaffold include numerous named reactions such as the
Combes synthesis, the Friedlander reaction, and the Povarov
reaction.9 However, the regioselectivity issue and the harsh
reaction conditions limited the scope and application of these
methods. Afterwards, a series of transition-metal-catalyzed
methods have been developed to synthesize quinolines.10
Recently, anthranils have been established as versatile synthons
for the construction of N-containing compounds, and formal
[4 + 2] annulation reactions have been developed to construct
quinolines.11 In 2019, Knochel reported a cobalt-catalyzed
electrophilic amination/enamine annulation protocol for the
construction of polysubstituted quinolines by treating
anthranils with alkenylzinc pivalates (Scheme 2a).12 Consid-
ering that anthranils have served as electrophilic aminating
reagents in Rh/Co-catalyzed C−H amination reactions,13 we
envisioned that the related enamines could be obtained
through a directing-group-assisted C−H amination of alkenes
with anthranils. Ideally, a traceless directing group could
facilitate this process. Thus, the expected quinoline products
could be obtained through a cascade intramolecular cyclo-
isomerization (Scheme 2b). To our delight, we observed that
the weakly coordinating −COOH group could enable the
Scheme 1. Decarboxylative C−H couplings of carboxylic
acid
strategy to acrylic acids, which are readily available feedstocks
and naturally occurring products,5 could provide efficient
routes for the synthesis of functionalized alkenes (Scheme
1b).6 However, to our knowledge, only a few specific examples
have achieved decarboxylative C−H functionalization of acrylic
acids.7 In particular, a more efficient reaction model that can
merge the C−H functionalization and decarboxylative coupling
Received: February 10, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00539
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
Scheme 2. Strategies to Synthesize Quinolines from
Anthranils
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
additive
T (°C) yield (%)
1
2
3
4
5
[RhCp*Cl2]2/AgSbF6
[RhCp*Cl2]2/AgOAc
[RhCp*Cl2]2/AgNTf2
[RhCp*Cl2]2/−
″
″
K2CO3
″
″
″
″
″
100
100
100
100
110
90
35
63
44
68
65
71
6
c
7
″
″
80
86 (82 )
8
9
″
″
″
−
70
80
73
0
10
11
12
13
14
15
16
17
″
″
″
″
KOAc
Et3N
K3PO4
Na2CO3
K2CO3
″
80
80
80
80
80
80
80
80
24
0
32
38
0
32
0
0
−
[Cp*Rh(MeCN)3][SbF6]2
[IrCp*Cl2]2
[{Ru(p-cymene)Cl2}]2
″
″
a
direct amination of acrylic acids with anthranils and, more
importantly, that decarboxylation could occur in the
subsequent intramolecular condensation process (Scheme
2c). Herein we report our recent findings on a Rh-catalyzed
C−H amination/annulation of acrylic acids and anthranils for
the diverse synthesis of polysubstituted quinolines by using the
carboxyl group as a deciduous directing group.
Reaction conditions: 1a (0.2 mmol), 2a (0.25 mmol), metal catalyst
(4 mol %), silver salt (16 mol %), and additive (0.2 mmol) in DCM
b
(2 mL) at the indicated reaction temperature for 8 h. Yields were
determined by 1H NMR analysis with 1,3,5-trimethoxybenzene as the
c
internal standard. Isolated yield.
c
Scheme 3. Substrate Scope of Acrylic Acids
Our initial studies focused on identifying the optimal
conditions by selecting anthranil (2a) and cyclohex-1-ene-1-
carboxylic acid (1a) as the model substrates. As shown in
Table 1, the reaction was firstly conducted under the
previously reported conditions (entry 1).13f To our delight,
the expected product 3aa was obtained in 35% 1H NMR yield.
When AgSbF6 was switched to AgOAc or AgNTf2 (entries 2
and 3), 3aa was detected in 63% and 44% yield, respectively.
Interesting, this reaction proceeded smoothly even without a
silver salt as a Cl− scavenger, as 3aa was obtained in 68% yield
(entry 4). Then the reaction temperature was screened, and
the yield of 3aa increased to 86% when the temperature was
reduced to 80 °C (entries 5−8). This temperature is worth
highlighting because of the generally higher temperatures
(>120 °C) in decarboxylation processes.4 The base also played
an important role in this reaction (entry 9). Among the various
bases tested (entries 10−13), K2CO3 gave the best yield. Other
transition metal catalysts were examined (entries 14−17), and
[Cp*RhCl2]2 was the most efficient catalyst for this reaction.
The evaluation of different solvents and other parameters
showed that DCM was the best choice and that the optimal
substrate ratio was 2a/1a = 1.25/1 (see Table S1 for details).
Next, the substrate scope of this transformation was
investigated. As displayed in Scheme 3, various acrylic acids
are compatible with the reaction, and diverse quinolines with
different substituent types were successfully obtained in
generally good yields. Cyclopent-1-ene-1-carboxylic acid
furnished the corresponding product 3ba in 40% yield,
probably as a result of the unfavorable configuration of the
rhodacycle intermediate. N/O-containing cyclic acrylic acids
were compatible, and 3ca−fa were isolated in 59−75% yield.
Notably, naturally occurring perillic acid reacted smoothly with
anthranils to produce 3ga and 3ha in 85% and 86% yield,
a
Conditions A: 1 (0.2 mmol), 2 (0.25 mmol), K2CO3 (0.2 mmol),
b
and [Cp*RhCl2]2 (4 mol %) in DCM (2 mL) at 80 °C. Conditions
B: 1 (0.2 mmol), 2 (0.25 mmol), K2CO3 (0.2 mmol), AgOAc (16 mol
%), and [Cp*RhCl2]2 (4 mol %) in HFIP (2 mL) at 100 °C. Isolated
yields are given. OBz = benzoate.
c
B
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respectively. Acyclic acrylic acids were also effective substrates
under the modified reaction conditions (see Table S2 for the
optimization of the reaction conditions). When R1 ≠ R2, 3ka
and 3la were obtained with specific regioselectivity using the
present approach. To our knowledge, these substrates are
problematic for the traditional methods9 because of the
regioselectivity issue. When R2 = H, various 3-substitued
quinolines were obtained (3ma−ra), and −CO2Me was well-
tolerated as a functional group (3ka). Additionally, this
reaction could be scaled up to 5 mmol, and 3aa (0.69 g)
was obtained in 75% yield. However, at the current stage, α-
unsubstituted acrylic acids (R1 = H) are not compatible with
this reaction.
Scheme 5. Synthetic Applications
1,2,3,4-Tetrahydroacridine is the core skeleton of tacrine,
which is a drug for treating Alzheimer’s disease. As shown in
Scheme 4, this C−H amination/annulation protocol was
a
Scheme 4. Substrate Scope of Anthranils
condensation of 3aa and benzaldehyde afforded derivative 4
in 85% yield (Scheme 5a).16 The direct acylation of 3aa could
be achieved through a radical process, furnishing the expected
product 5 in 78% yield (Scheme 5b).17 Derivative 6 was
synthesized in 80% yield through a catalyst-free tandem
conjugate addition/decarboxylation of 3aa and coumarin-3-
carboxylic acid (Scheme 5c).18 More importantly, tacrine and
analogues could be synthesized from 1,2,3,4-tetrahydroacridine
(3aa) (Scheme 5d).19 Thus, the present method could supply
an alternative efficient route to tacrine derivatives for drug
discovery.
Control experiments were conducted to understand the
reaction mechanism (Scheme 6). When the corresponding
Scheme 6. Mechanistic Studies
a
Reaction conditions: 1a (0.2 mmol), 2 (0.25 mmol), K2CO3 (0.2
mmol), and [Cp*RhCl2]2 (4 mol %) in DCM (2 mL) at 80 °C.
b
Isolated yields are given. With additional B(C6F5)3 (20 mol %).
carried out for the synthesis of various 1,2,3,4-tetrahydroacri-
dine scaffolds. A broad range of functional groups such as
fluorine (3ab) chlorine (3ac), bromo (3ad), methoxy (3ae),
allyl (3af), benzyl (3ag), OBz (3ah), and acetal (3ai) were
well-tolerated, and the desired 1,2,3,4-tetrahydroacridine
products were obtained in good yields (68−83%). These
functional groups provided easy handles for additional
synthetic elaboration. Notably, the allyl group remained inert
in this reaction (3af), and side reactions such as the Heck
reaction or C−H allylation were not observed.14 The 3-
substituent (R3) of the anthranil could be an alkyl group, and
the corresponding product 3ak was obtained in 75% yield.
When 3-aryl-substituted anthranils were tested, low yields were
observed under the present reaction conditions. Boron
reagents were used as Lewis acids to activaate anthranils in
You’s work.15 To our delight, when 20 mol % B(C6F5)3 was
added, a significant increase in yield was observed, as 3al and
3am were obtained in 68% and 70% yield, respectively.
carboxester and carboxamide were used as substrates, the
desired product was not obtained, and even the C−H
amination did not occur (Scheme 6a). Therefore, −COOH
may be an indispensable directing group for this reaction. Next,
a H/D exchange experiment was conducted with D2O as the D
source (Scheme 6b), and 33% deuteration was observed within
30 min, thereby implicating a reversible cyclometalation
process. The reaction of 1a and 2a was performed with
additional D2O (Scheme 6c). Very low D incorporation (<5%)
was detected in the recovered acrylic acid 1a, which suggesting
that the amination step is sufficiently fast to outcompete the
reverse C−H activation step. The kinetic isotope effect (KIE)
The potential applications of this transformation were
investigated. As displayed in Scheme 5, InCl3-catalyzed
C
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was determined through parallel experiments with non- and
deuterated acrylic acid, and kH/kD = 2.3 was observed. This
result suggested that C−H activation might be the rate-
determining step (Scheme 6d).
Accordingly, a plausible reaction pathway is proposed in
Scheme 7. First, rhodacycle intermediate A is formed via
Chemistry and Materials Science, South-Central University for
Nationalities, Wuhan 430074, China; orcid.org/0000-
0001-9094-2357; Email: huxiaoqiang@mail.scuec.edu.cn
Authors
Jianhong Nie − School of Chemical Engineering and Light
Industry, Guangdong University of Technology, Guangzhou
510006, China
Scheme 7. Proposed Mechanism
Yibiao Li − School of Biotechnology and Health Sciences, Wuyi
University, Jiangmen, Guangdong 529090, China;
orcid.org/0000-0001-8249-5630
Xianwei Li − School of Chemical Engineering and Light
Industry, Guangdong University of Technology, Guangzhou
510006, China; orcid.org/0000-0002-4014-6712
Qian Chen − School of Chemical Engineering and Light
Industry, Guangdong University of Technology, Guangzhou
510006, China; orcid.org/0000-0002-0818-6028
Yanping Huo − School of Chemical Engineering and Light
Industry, Guangdong University of Technology, Guangzhou
510006, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00539
Notes
[Cp*RhCl2]2-catalyzed C(sp2)−H activation of potassium
cyclohex-1-ene-1-carboxylate (1a′). Coordination of inter-
mediate A and anthranil 2a affords intermediate B. Then the
key Rh−nitrene intermediate C is generated through N−O
bond cleavage of anthranil. Subsequently, insertion of the Rh−
nitrene into the Rh−C bond affords intermediate D.13c,d The
reaction of 1a′ with intermediate D releases intermediate E
with the regeneration of rhodacycle intermediate A. The
intramolecular condensation of E is initiated by nucleophilic
attack of the enamine to the formyl group, and the final
product G is formed through a collaborative dehydration/
decarboxylation process.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (21901045 and 21901258) and the Guangdong Natural
Science Foundation (2018A030310570) for financial support.
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In conclusion, a Rh-catalyzed C(sp2)−H amination/
annulation protocol of acrylic acids and anthranils for the
synthesis of diverse polysubstituted quinolines has been
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The Supporting Information is available free of charge at
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Detailed experimental procedures and NMR spectra for
all compounds(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Yang Gao − School of Chemical Engineering and Light Industry,
Guangdong University of Technology, Guangzhou 510006,
China; orcid.org/0000-0001-9513-6899;
Email: gaoyang@gdut.edu.cn
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