Acid-promoted iron-catalysed dehydrogenative [4 + 2] cycloaddition for the synthesis of quinolines under air

Article abstract of DOI:10.1039/c8ra06826g

An acid-promoted iron-catalysed dehydrogenative [4 + 2] cycloaddition reaction was developed for the synthesis of quinolines using air as a terminal oxidant. Acetic acid was the best cocatalyst for the cycloaddition of N-alkyl anilines with alkenes or alk

Full text of DOI:10.1039/c8ra06826g

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Acid-promoted iron-catalysed dehydrogenative [4
+ 2] cycloaddition for the synthesis of quinolines
under air†
Cite this: RSC Adv., 2018, 8, 31603
*
Jinfei Yang,
and Fei Sun
Xiao Meng, Kai Lu, Zhihao Lu, Minliang Huang, Chengniu Wang
*
An acid-promoted iron-catalysed dehydrogenative [4 + 2] cycloaddition reaction was developed for the
synthesis of quinolines using air as a terminal oxidant. Acetic acid was the best cocatalyst for the
cycloaddition of N-alkyl anilines with alkenes or alkynes under air. Various quinoline derivatives were
obtained in satisfactory-to-excellent yields, and no other byproducts besides water were produced in
the reaction. The zebrafish model has become an important vertebrate model for evaluating drug
effects. We tested the activity of 3n in zebrafish. The test results showed that 1 mg mLꢀ1 3n treatments
resulted in morphological malformation, and 0.01–0.1 mg mLꢀ1 3n treatments led to potent angiogenic
defects in zebrafish embryos. The results of this study will be of great significance for promoting drug
research in cardiovascular and cerebrovascular diseases.
Received 15th August 2018
Accepted 5th September 2018
DOI: 10.1039/c8ra06826g
rsc.li/rsc-advances
The construction of quinoline motifs has received intensive commonly used base metals and has been widely applied in
attention owing to their potential application in photovoltaic various coupling reactions.10 Therefore, it is desirable to develop an
devices1 and pharmaceuticals,2 such as anticancer, antiviral, anti- iron-catalysed dehydrogenative cycloaddition for the synthesis of
fungal, antiplatelet aggregation, antimalarial, antibacterial, anti- quinoline under air.
leishmanial and anti-inammatory medicine.3 Because of their
Herein, we report the rst acid-promoted iron-catalysed
importance, many methods have been reported for the synthesis of dehydrogenative [4 + 2] cycloaddition of N-alkyl anilines with
quinolines.4 Among them, the most attractive strategy for the alkenes or alkynes using air as a terminal oxidant (Scheme 1b).
synthesis of these compounds is the dehydrogenative [4 + 2] Iron-catalysed cycloaddition reaction for the synthesis of quin-
cycloaddition through transition-metal catalysis and Lewis/ olines under air has always been a challenge because of metal
Bronsted acid catalysis. In its most general and classical form, deactivation aer the end of the catalytic cycle. We commenced
dehydrogenative [4 + 2] cycloaddition catalysed by transition our studies by treating N-benzylaniline (1a) and styrene (2a)
metals such as Fe,5 Cu,6 Pd,7 and others,8 has been used as a potent with 5 mol% iron as a catalyst. Initially, we tried to use a variety
tool for the synthesis of quinolone derivatives (Scheme 1a). of iron catalysts to catalyse the cycloaddition of N-alkyl anilines
However, these methods require the presence of excess peroxides, and olens under air (Table 1, entries 1–6). Trace amounts of
chloranil, potassium persulfate or other oxidants to promote the the desired product (3a) were obtained with FeCl2, Fe(OTf)2,
cycloaddition reaction and to obtain good product yields. Fe2(SO4)3 and Fe2O3, as detected by GC analysis, and a 28% or
Furthermore, in these processes, the formation of stoichiometric 33% yield was observed when FeCl3 or Fe(OTf)3 was used as
amounts of acid or tetrachlorohydroquinone waste as byproducts a catalyst. To improve the reaction efficiency, different solvents
is a substantial problem that has limited their use. To overcome
these drawbacks, several methods that utilise oxygen as a terminal
oxidant have been reported.9 However, in many cases, the indus-
trial use of these methods is problematic owing to operational
difficulty. Therefore, the development of more efficient and
economical synthetic methods is still necessary. Undoubtedly, the
use of air as a terminal oxidant is the best choice. In addition, in
the eld of transition-metal catalysis, iron is one of the most
Medical School, Institute of Reproductive Medicine, Nantong University, Nantong
226019, China. E-mail: jfyang@ntu.edu.cn; sunfei@ntu.edu.cn
† Electronic supplementary information (ESI) available. See DOI:
Scheme 1 Different strategies for [4 + 2] cycloaddition of N-alkyl
10.1039/c8ra06826g
anilines and alkenes or alkynes by transition-metal catalysis.
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Table 1 Solvent effect and acid effect. N-benzylaniline (0.2 mmol), styrene (0.4 mmol), Fe(OTf)3 (10 mmol), acid (0.3 mmol), toluene (1.0 mL), at
140 ꢁC under air for 24 h
Entry
Catalyst (5 mol%)
Acid (0.3 mmol)
Solvent
T (ꢁC)
Yielda (%)
1
2
3
4
5
6
7
8
Fe(OTf)2
FeCl2
FeCl3
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
No
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Ethanol
Mysitylene
Dioxane
Nitrobenzene
Acetonitrile
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
120
120
120
120
120
120
120
120
120
120
120
150
140
100
80
Trace
Trace
28
Trace
Trace
33
0
26
0
28
Fe2O3
Fe2(SO4)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
Fe(OTf)3
No
9
10
11
12
13
14
15
16
17
18
19
20
21
22b
23
24
25
26
27
28
29c
30
23
42
49
16
8
60
40
Trace
0
0
0
65
61
57
42
50
82
35
15
54
51
Trace
No
H2SO4
TfOH
TFA
140
140
140
140
140
140
140
140
140
140
140
140
140
PTSA
BNPA
HCOOH
BzOH
AcOH
PhB(OH)2
B(OH)3
Phenol
AMSA
AcOH
a
c
Isolated yields. b BNPA ¼ 1,10-binaphthyl-2,20-diylhydrogen-phosphate. AMSA ¼ aminomethanesulfonic acid.
such as ethanol, mesitylene, 1,4-dioxane, nitrobenzene, aceto- that promoted the Fe-catalysed [4 + 2] cycloaddition of N-alkyl
nitrile and toluene were tested (Table 1, entries 6–11).
anilines and alkenes to deliver 2,4-diphenylquinoline in 65%
The optimal solvent for the reaction was toluene (Table 1, yield (Table 1, entries 18–20). If 1,10-binaphthyl-2,20-diylhy-
entry 6). Encouraged by this result, we examined a wide range of drogen phosphate or p-toluenesulfonic acid (PTSA) were used
reaction temperatures (Table 1, entries 12–17); the best yield instead of TFA, the yield was signicantly reduced (Scheme 3,
ꢁ
was obtained at 140 C, but it did not meet our expectations.
We reasoned that an unreactive catalytic species, FeL2
(Scheme 2), could be formed in the reaction from the interaction
of the imine intermediate and FeL3, which could not catalyse the
conversion of imines to quinoline. Critically, the FeL2 species was
difficult to oxidize to FeL3 under air conditions. Inspired by Birk's
work,11 we envisaged that the addition of an acid may promote
the oxidation of Fe(II) to Fe(III) under air. Based on this assump-
tion, we proposed that FeL3 can undergo ligand exchange with
HL0 to generate the active catalytic species L2FeL0. A subsequent
oxidation reaction provided LFeL0, which was easier oxidize to
L2FeL0 than FeL2 under air, enabling the next catalytic cycle.
Based on this hypothesis, we investigated some strong acids
and moderate acids. Triuoroacetic acid (TFA) was a cocatalyst
entries 21–22). For further improvement of the reaction, other
Scheme 2 Proposed strategy.
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transformations. Unfortunately, the current method could not be
applied to olens containing N heteroatoms, which was likely
because of the strong coordination of N atoms with iron.
Next, the scope of arylacetylenes was also investigated, and
the results are summarized in Scheme 4. Arylacetylenes could
be used instead of arylethylenes for the synthesis of 2,4-diary-
lquinoline under the optimized reaction conditions. Similar
good results were obtained, as shown in Scheme 4. Quinoline
derivatives 3a–3g, 3i, 3k–3m and 3o were obtained in satisfac-
tory to good yields (63–96%).
To test the synthetic utility of the current method, a gram
scale dehydrogenative [4 + 2] cycloaddition reaction of N-benzyl-
4-methoxyaniline with methyl-2-vinylbenzoate was conducted
under the optimal conditions, providing the target 3n in 45%
yield. To demonstrate the potential of our approach, we con-
ducted molecular docking studies of human phenylethanol-
amine N-methyltransferase (hPNMT) and the quinoline
derivatives. The studies were performed to help visualize
possible interactions between hPNMT and the quinoline
derivatives. The results showed that methyl-2-(6-methoxy-2-
phenylquinolin-4-yl)benzoate 3n may have p–p interactions
with ARG 90, and p–cation interactions with TYR 27 in hPNMT.
Based on this docking result, 3n is highly likely to be a potent
inhibitor of hPNMT. The results of the docked poses of hPNMT
and 3n are shown in the ESI.† The zebrash model has become
an important vertebrate model for evaluating drug effects. 12 To
demonstrate the drug effect of 3n on the vascular system in the
trunk of zebrash embryos, we tested the activity of 3n in
zebrash. The test results showed treatment of zebrash
embryos with 1 mg mLꢀ1 3n resulted in morphological malfor-
mation, and treatment with 0.01–0.1 mg mLꢀ1 3n led to potent
angiogenic defects (Scheme 5b). The results of this study will be
of great signicance for promoting drug research in cardio-
vascular and cerebrovascular diseases.
Scheme 3 Reaction conditions: substrate 1 (0.2 mmol), aryl olefin (0.4
mmol), Fe(OTf)3 (10 mmol), AcOH (0.3 mmol), toluene (1.0 mL), at
140 ꢁC under air for 24 h, and isolated yields of the products.
acid such as formic acid (HCOOH), benzoic acid (BzOH), acetic
acid (AcOH), phenylboronic acid, boric acid, phenol and car-
bamic acid were tested (Table 1, entries 23–29). The results
showed that the addition of 1.5 equivalents of acetic acid was
the best choice, furnishing the corresponding 2,4-diphe-
nylquinoline in 82% yield (Table 1, entry 25). Under the acidic
conditions, a strong acid was completely inefficient (Table 1,
entry 18), which suggested that the strength of the acid was
critical to the reaction. Other acids did not give better results.
Therefore, we performed the subsequent reactions between the
N-alkyl anilines with alkenes or alkynes in the presence of
ꢁ
Fe(OTf)3/AcOH at 140 C under air conditions for 24 h.
With the optimized reaction conditions in hand, a series of
aryl ethylenes were investigated for extending the substrate scope
(Scheme 3). This acid-promoted iron-catalysed dehydrogenative
[4 + 2] cycloaddition reaction displayed good functional group
tolerance. Aryl ethylenes with electron-neutral or electron-
donating groups on the aryl rings, such as alkyl, phenyl and
naphthyl, all gave the corresponding 2,4-diarylquinoline with
high selectivity in good yields. Aryls containing an electron-
withdrawing group such as uoro, chloro, bromo and ester
were also tolerated and afforded the corresponding 2,4-diary-
lquinolines 3e–3n in moderate to good yields. Moreover, the
reaction of N-benzylaniline 1b containing a substituent (MeO) at
the para-position of the aniline ring also produced the corre-
sponding quinoline products 3o in 79% yield. These results
indicated that different groups, such as methyl, phenyl, uoro,
chloro, bromo and methoxyl on benzene rings, were tolerated
under the optimized reaction conditions. Notably, the retention
of the F, Cl and Br atoms in the structures of the products should
make the products considerably useful in organic
Scheme 4 Reaction conditions: substrate 1 (0.2 mmol), aryl alkyne
(0.4 mmol), Fe(OTf)3 (10 mmol), AcOH (0.3 mmol), toluene (1.0 mL), at
140 ꢁC under air for 24 h, and isolated yields of the products.
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undergo a [4 + 2] cycloaddition with an alkyne or alkene,
forming the desired 2,4-diarylquinoline or dihydroquinoline. A
subsequent dehydrogenation reaction of dihydroquinoline
provided the target product. The intermediate LFeOAc under-
went an oxidation reaction in the presence of air to regenerate
the catalytic species L2FeOAc.
Conclusions
In summary, we successfully developed a highly efficient acid-
promoted iron-catalysed dehydrogenative [4 + 2] cycloaddition
for the synthesis of quinoline under air conditions. The new
method is compatible with alkenes and alkynes, and we per-
formed molecular docking experiments with 3n, which indi-
cated that this compound might be an inhibitor of hPNMT.
Moreover, we used the zebrash model as an important way to
demonstrate the drug effect of 3n treatment on the vascular
system in the trunk of zebrash embryos. The test results
showed that 3n had a signicant effect on angiogenesis. The
results of this study will be of great signicance for promoting
drug research in cardiovascular and cerebrovascular diseases.
Further investigation of cell experiments, animal experiments
and other reaction types are under way in our laboratory.
Scheme 5 Gram-scale synthesis and the drug effect of 3n treatment
on vascular in the trunk of Tg(kdrl:EGFP) zebrafish embryos at 48 hpf.
(A–D) control group and 1, 0.1, 0.01 mg mLꢀ1 3n treated groups. Scale
bar, 75 mm.
Ethics statement
All animal procedures were performed in accordance with the
Guidelines for Care and Use of Laboratory Animals of Nantong
University and Experiments were approved by the Animal Ethics
Committee of SYXK(SU) 2007–0021.
To gain a better understanding of the role of the acid, air and
iron in the current cycloaddition reaction, additional experi-
ments were conducted. First, control experiments showed that
the absence of any of the three components, air, AcOH and
Fe(OTf)3, signicantly reduced the reaction yield, implying that
each of the components was essential to this reaction. To clarify
that the reaction was undergoing the production of an imine
intermediate, we employed N-benzylideneaniline as a substrate
to test if 2,4-diphenylquinoline could be obtained (Scheme 6).
To our great surprise, 3a was obtained in 99% yield. The results
showed that a cycloaddition reaction occurred aer N-benzyla-
niline was oxidized to an imine. Based on these results, we
proposed the following catalytic cycle: FeL3 rst underwent
ligand exchange with AcOH to generate an active catalytic
species L2FeOAc, leading to subsequent oxidative dehydroge-
nation to provide the imine intermediate and intermediate
LFeOAc while releasing HL. The imine intermediate can then
Conflicts of interest
There are no conicts to declare.
Acknowledgements
We thank the National Natural Science Foundation of China
(81430027 and 81671510), the National Basic Research Program
(973 Program) (2014CB943100) for nancial support. This work
was also supported by the Fundamental Research Funds of
Nantong University (03081105 and 03083002).
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