Chemoselective Synthesis of N -Arylenaminones and 3-Aroylquinolines by Synergistic Control of Temperature and Amount of Catalyst

Article abstract of DOI:10.1055/s-0036-1590950

An efficient and practical method has been developed for the divergent synthesis of N -arylenaminones and 3-aroylquinolines from 2-aminoaryl ketones and N, N -dimethylenaminones in the presence of 4-toluenesulfonic acid through synergistic control of the

Full text of DOI:10.1055/s-0036-1590950

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–F
letter
A
en
P. Zhou et al.
Letter
Synlett
Chemoselective Synthesis of N-Arylenaminones and 3-Aroylquino-
lines by Synergistic Control of Temperature and Amount of
Catalyst
Pan Zhoua
Biao Hua
Kairui Raoa
Lingdan Lia
Jiao Yanga
Chuanzhu Gaoa
Fengping Wangb
Fuchao Yu*a
a Faculty of Life Science and Technology, Kunming University of Science and
Technology, Kunming, 650504, P. R. of China
b Research Center of Food Engineering, Kunming University of Science and
Technology, Kunming, 650504, P. R. of China
yufuchao05@126.com
yufc@kmust.edu.cn
Received: 31.07.2017
Accepted after revision: 11.10.2017
Published online: 23.11.2017
through synergistic control is highly desirable, and would
benefit further research on the diversity of reactions and
molecules.
DOI: 10.1055/s-0036-1590950; Art ID: st-2017-w0599-l
Quinoline is one of the most privileged azaheterocyclic
scaffolds, and is found in many natural products, pharma-
ceuticals, and biologically active molecules.9 Several classi-
cal methods have been developed for the construction of
quinolone derivatives, including the Friedländer,10 Skraup–
Doebner–von Miller,11 Pfitzinger,12 and Combes reactions.13
Among these, the Friedländer reaction is one of the sim-
plest protocols and involves condensation of an aromatic 2-
amino-substituted carbonyl compound with a carbonyl
compound possessing a reactive α-methylene group.10
Recently, several modified Friedländer reactions have been
developed involving the reactions of aromatic 2-amino-
substituted carbonyl compounds with various other sub-
strates, such as, alkenes,14 alkenyl iodides,15 alkynes,16 α-
oxoketene dithioacetals,17 or N,N-dimethylenaminones.18
Although, these methods are effective, some require the use
of expensive reagents, harmful organic solvents, metal cat-
alyst, or large excess amount of metal salts, or they have
other disadvantages, such as environmental concerns, that
could limit their usefulness in large-scale production.
Enaminones serve as a class of available and powerful
synthons because of their versatile reactivity, and they have
been widely used in syntheses of a variety of heterocyclic 19
and fused heterocyclic compounds.20 In addition, enami-
none groups are present in a wide range of biologically
active molecules.21 Therefore, there is still a demand for the
development of convenient and efficient methods for the
synthesis of enaminones.
Abstract An efficient and practical method has been developed for
the divergent synthesis of N-arylenaminones and 3-aroylquinolines
from 2-aminoaryl ketones and N,N-dimethylenaminones in the pres-
ence of 4-toluenesulfonic acid through synergistic control of the tem-
perature and amount of catalyst. Furthermore, gram-scale synthesis
and synthetic applications have been evaluated. Features of this proto-
col include controllable results, mild conditions, good functional-group
tolerance, operational simplicity, and excellent yields.
Key words divergent synthesis, arylenaminones, aroylquinolines, di-
methylenaminones
Divergent synthesis provides high efficiency and selec-
tive access to structurally diverse architectures from a sin-
gle substrate, and is a powerful tool for the discovery of bio-
active molecules and functional materials. Furthermore, it
represents a significant synthetic challenge,1 and over the
past few years it has attracted substantial attention from
many researchers.2 Most of them actualized divergent syn-
theses through controlled reaction pathways, including
substrate-,2a,e,g,3 solvent-,2f,4 ligand-,5 and catalyst-con-
trolled6 approaches. For example, in our previous work, we
developed a Brønsted acid-controlled cascade cyclization of
enaminones and isatins for the divergent synthesis of pyr-
rolo[3,4-c]quinolin-1-ones and spirooxindoles.7 The success
of divergent synthesis through control of the temperature
or the amount of catalyst has received much less attention,8
and examples of synergistically controlled divergent syn-
thesis are still very unusual. Therefore, the development of
efficient divergent synthesis of valuable compounds
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
P. Zhou et al.
Letter
Synlett
As part of our ongoing program for the construction of
quinoline systems7,20f,22 and the development of environ-
mentally benign synthetic methods based on enami-
nones,23 we report a concise and ecofriendly method for the
divergent synthesis of functionalized N-arylenaminones
and 3-aroylquinolines through synergistic control of the
temperature and the amount of catalyst. Nucleophilic sub-
stitution of 2-aminoaryl ketones with N,N-dimethylenami-
nones in water with ultrasound assistance in the presence
of 1.0 equivalents of toluene-p-sulfonic acid (p-TSA) at
room temperature gave the corresponding N-arylenami-
nones, which were isolated by filtration. Remarkably, the
improved Friedländer reaction in 1:4 ethanol–water solu-
tion in the presence of 2.0 equivalents of p-TSA at 100 °C,
gave 3-aroylquinolines exclusively. To the best of our
knowledge, no previous reports of this divergent synthesis
have appeared in the literature.
To start our investigation, we chose 1-(2-amino-
phenyl)ethanone (1a) and N,N-dimethylenaminone 2a as
model substrates to optimize the reaction conditions
(Table 1). When the reaction was carried out in AcOH at
room temperature for six hours, N-arylenaminone 3a was
isolated exclusively in 57% yield (Table 1, entry 1). To our
delight, the reaction in the presence of 0.1 mL of AcOH or
1.0 equiv of a strong organic acid such as p-TSA, TFA, or
TfOH at room temperature for six hours with water as the
solvent gave 3a with a significantly improved yield (96–
95%; entries 2–5), whereas K2CO3 failed to give 3a (entry 6).
Interestingly, ultrasound assistance had an appreciable ef-
fect on the reaction (entries 7–8) markedly reducing the re-
action time from one hour to 20 minutes, while the desired
product 3a was still obtained exclusively in excellent yield
(97%; reaction conditions A).24
Table 1 Optimization of the Reaction Conditionsa
OMe
O
O
O
Me
Me
Me
MeO
N
NH2
1a
MeO
N
O
H
Me
2a
3a
4a
Me
O
N
Entry
Catalyst
Temp (°C)
Time
Yieldb (%) of 3a
Yieldb (%) of 4a
1c
2
AcOH (5.0 mL)
r.t.
6.0 h
57
96
95
95
96
NRe
97
97
49
97
92
65
44
34
27
trace
0
NDd
0
AcOH (0.1 mL)
r.t.
6.0 h
6.0 h
6.0 h
6.0 h
6.0 h
1.0 h
20 min
20 min
1.0 h
6.0 h
6.0 h
6.0 h
6.0 h
12.0 h
18.0 h
6.0 h
6.0 h
3
p-TSA (1.0 equiv)
TFA (1.0 equiv)
r.t.
0
4
r.t.
0
5
TfOH (1.0 equiv)
K2CO3(2.0 equiv)
AcOH (0.1 ml)
r.t.
0
6
r.t.
NR
0
7f
r.t.
8f
p-TSA (1.0 equiv)
p-TSA (0.5 equiv)
p-TSA (1.0 equiv)
p-TSA (2.0 equiv)
p-TSA (2.0 equiv)
p-TSA (2.0 equiv)
p-TSA (2.0 equiv)
p-TSA (2.0 equiv)
p-TSA (2.0 equiv)
p-TSA (2.0 equiv)
p-TSA (1.0 equiv)
r.t.
r.t.
0
9f
0
10f
11
12
13
14
15
16
17g
18g
r.t.
0
40
trace
23
43
52
68
83
93
48
60
80.
100
100
100
100
100
0
aReaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), H2O (5.0 mL).
b Isolated yield based on enaminone 2a.
c No solvent.
d ND = not detected.
e NR = no reaction;
f Ultrasound-assisted.
g Solvent 4:1 (v/v/) H2O–EtOH.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
P. Zhou et al.
Letter
Synlett
Table 2 Reactant Scope for N-Arylenaminones 3a,b
With the optimal reaction conditions in hand, we inves-
tigated the scope and limitations of the synthesis of N-
arylenaminones 3 under reaction conditions A (Table 2). A
wide range of N,N-dimethylenaminones 2 with methoxy-,
methyl-, or halo-substituted aromatic groups underwent
the desired reactions with 1-(2-aminophenyl)ethanone
(1a) to afford the desired products 3a–e in excellent yields
(91–98%; Table 2, entries 1–5). Even enaminones with ni-
tro- or trifluoromethyl groups on the aromatic ring or with
4-biphenyl or 2-naphthyl groups gave excellent yields (en-
tries 6–9; 89–96%). Furthermore, 2-thienyl-, 4-pyridyl-, and
styryl-substituted N,N-dimethylenaminones were suitable
reactants, giving products 3j–l in 75–94% yield (entries 10–
O
O
O
R2
R2
R1
O
R3
R1
ultrasound-assisted
Me
N
H
R3
H2O, p-TSA
r.t., 20 min
N
NH2
Me
3
2
1
Entry R1
R2
R3
Product Yieldb
(%)
1
2
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
H
4-MeOC6H4 (2a)
3a
3b
3c
3d
3e
3f
97
96
98
94
91
89
90
96
93
87
94
75
93
91
92
93
89
89
94
84
91
92
91
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
4-Tol (2b)
3
Ph (2c)
4
4-ClC6H4 (2d)
4-FC6H4 (2e)
4-F3CC6H4 (2f)
4-O2NC6H4 (2g)
4-biphenyl (2h)
2-naphthyl (2i)
2-thienyl (2j)
4-pyridyl (2k)
styryl (2l)
5
Table 3 Reactant Scope for 3-Aroylquinolines 4a,b
6
7
3g
3h
3i
O
R1
N
O
O
H2O/EtOH
(v/v = 4:1)
R2
R2
8
R3
R1
NH2
R3
9
Me
p-TSA
100 °C, 6 h
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
3j
Me
1
2
4
3k
3l
Entry
R1
R2
R3
3
Yieldb
(%)b
4-MeOC6H4 (2a)
4-Tol (2b)
3m
3n
3o
3p
3q
3r
1
2
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Me (1a)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
4-FC4H6 (1c)
H
4-MeOC6H4 (2a)
4-Tol (2b)
4a
4b
4c
4d
4e
4f
93
90
92
89
86
73
81
90
90
92
85
56
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
Ph (2c)
3
Ph (2c)
4-ClC6H4 (2d)
2-ClC6H4 (2m)
4-O2NC6H4 (2g)
4-biphenyl (2h)
2-thienyl (2j)
4-pyridyl (2j)
Ph (2c)
4
4-ClC6H4 (2d)
4-FC6H4 (2e)
4-F3CC6H4 (2f)
4-O2NC6H4 (2g)
4-biphenyl (2h)
2-naphthyl (2i)
2-thienyl (2j)
4-pyridyl (2k)
styryl (2l)
5
6
3s
3t
7
4g
4h
4i
8
3u
3v
3w
9
4-FC4H6 (1c)
2-ClC4H6 (1d) Cl
10
11
12
13
14
15
16
17
18
19
20
21
22
23
4j
Ph (2c)
4k
4l
a Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), p-TSA (1 equiv), H2O
(5.0 mL), ultrasound, r.t., 20 min.
b Isolated yield based on enaminones 2.
4-MeOC6H4 (2a)
4-Tol (2b)
4m 77
4n
4o
4p
4q
4r
91
87
87
82
74
82
80
81
84
Ph (2c)
However, conversion into 3a was incomplete when the
amount of p-TSA was reduced (Table 1, entry 9). Product 3a
was not transformed into the 3-aroylquinoline 4a when the
reaction time was prolonged (entry 10). However, the yield
of 4a increased and that of 3a decreased on increasing the
temperature and time (entry 7 versus entries 11–16). Grat-
ifyingly, when 4:1 (v/v) water–ethanol was used as the sol-
vent under the same reaction conditions, the yield of 4a in-
creased somewhat, and no 3a was formed in the presence
of 2.0 equivalents of p-TSA at 100 °C when the reaction time
was reduced to 6.0 hours (entry 17; 93% of 4a, reaction con-
ditions B).25 However, conversion into 4a was incomplete
when the amount of p-TSA was reduced (entry 18).
4-ClC6H4 (2d)
2-ClC6H4 (2m)
4-O2NC6H4 (2g)
4-biphenyl (2i)
2-thienyl (2j)
4-pyridyl (2j)
Ph (2c)
4s
4t
4u
4v
2-ClC4H6 (1d)
Ph (2c)
4w 87
a Reaction conditions: 1 (0.5 mmol), enaminone 2 (0.5 mmol), p-TSA (2
equiv), 4:1 (v/v/) H2O–EtOH (5.0 mL), 100 °C, 6 h.
b Isolated yield based on enaminones 2.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
P. Zhou et al.
Letter
Synlett
11). Similarly, replacement of 1a with other amino ketones
1b, 1c, and 1d had little effect on the result, and products
3m–w were obtained in 84–94% yield (entries 12–23).
The substrate scope for the synthesis of 3-aroylquino-
lines 4 under reaction conditions B was also investigated
(Table 3). The electronic properties of the N,N-dimethylen-
aminones did not have an effect, as substrates with electron-
rich (4-MeO), electron-neutral (4-H, 4-Me), or electron-
deficient (4-Cl, 2-Cl, 4-F, 4-F3C, 4-O2N) aromatic groups
gave quinolines 4a–g in yields of 73–93% (Table 3, entries 1-
7). When the substituent on the N,N-dimethylenaminone
was changed to a polycyclic aromatic (4-biphenyl or 2-
naphthyl) or heterocyclic (2-thienyl or 4-pyridyl) group, the
desired products 4h–k were also obtained in excellent
yields of 85–90% (entries 8–11); however, the styryl-substi-
tuted N,N-dimethylenaminone 2l gave a moderate yield of
the corresponding product 4l (56%; entry 12). Amino ke-
tones 1b, 1c, and 1d also reacted smoothly and gave the
corresponding the products 4m–w in yields of 74–91% (en-
tries 13–23).
In relation to the practicality and efficiency of this im-
proved Friedländer reaction, we demonstrated a gram-scale
(5 mmol-scale) reaction of 1b with 2m under reaction con-
ditions B to give 1.37 g of 3-aroyl quinoline 4q (80% yield;
Scheme 1a).
Encouraged by the above results, we next sought to
broaden the range of potential applications of this method
in organic synthesis. N-Oxidation of the 3-aroylquinoline
4q readily gave the corresponding quinoline N-oxide 5 in
60% yield (Scheme 1b).26 Analogues of 5 have found a wide
range of applications in chemistry and biology.27 Direct
benzylation of 5 by direct oxidative cross-dehydrogenative
coupling with inexpensive toluene as the benzyl source
gave the benzylated N-oxide 6 in 34% yield,26 together with
the reduced product 4q in 19% yield (Scheme 1c). This ex-
tension significantly broadens the range of applications of
our improved Friedländer reaction.
To gain insight into the mechanistic details, we treated
N-arylenaminone 3q with 1.0 equivalents of p-TSA under
reaction conditions B for four hours and obtained the target
product 4q in 92% yield (Scheme 2a). However, when the
reaction was carried out in the absence of p-TSA or at room
temperature, it failed to give the desired product 4q
(Schemes 2b and 2c). These results clearly indicate that the
N-arylenaminone is the key intermediate of the Friedländer
reaction to form 3-aroylquinolines, and that a combination
of the appropriate reaction temperature and amount of cat-
alyst has a significant synergistic effect on the reaction.
On the basis of the above results and previous re-
ports,14–18 we propose a plausible mechanism for the for-
mation of N-arylenaminones 3 and 3-aroylquinolines 4
shown in Scheme 3. First, condensation of 2-aminoaryl
ketone 1 with N,N-dimethylenaminone 2 affords the N-
arylenaminone 3 through a Michael addition/elimination
process19e,28 with loss of a molecule of dimethylamine. The
O
O
Ph
O
Cl
H2O/EtOH
(v/v = 4:1)
Ph
NH2
(a)
Me
p-TSA
100 °C, 6 h
Cl
N
N
Me
1b
2m
5 mmol
4q
80%, 1.37 g
5 mmol
O
O
m-CPBA (1.1 equiv)
DCM, r.t., 2 h
(b)
60%
N
Cl
N
4q
Cl
O
5
O
Cl
Me
5
(c)
4q, 19%
DTBP (2 equiv), N2
1,4-dioxane, 110 °C
N
O
Ph
6, 34%
Scheme 1 Gram-scale synthesis of 3-aroylquinoline 4q and its applica-
tion.
O
O
H2O–EtOH (v/v = 4:1)
p-TSA (1.0 equiv), 100 °C, 4 h
Ph
O
Cl
(a)
N
92%
H
N
Cl
3q
4q
H2O–EtOH (v/v = 4:1)
100 °C, 4 h
3q
4q
4q
(b)
(c)
n.r.
H2O–EtOH (v/v = 4:1)
p-TSA (1.0 equiv), r.t., 4 h
3q
n.r.
Scheme 2 Intramolecular cyclization of N-arylenaminone 3q to form 3-aroylquinoline 4q
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
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Letter
Synlett
3-aroyl quinoline 4 is then formed through a subsequent
intramolecular aldol reaction17,29 with elimination of a mol-
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O
HNMe2
R2
O
Ar
R2
NH2
NMe2
N
H
Ar
H+
3
R2
O
R2 OH
O
Ar
Ar
H+
H2O
N
N
4
4
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Scheme 3 Plausible reaction mechanism
In summary, an efficient divergent synthesis of N-
arylenaminones and 3-aroylquinolines from 2-aminoaryl
ketones and N,N-dimethylenaminones, promoted by p-TSA
in aqueous solution, with synergistic control by the tem-
perature and the amount of catalyst has been developed. N-
Arylenaminones were obtained in excellent yields by an
ultrasound-assisted reaction for 20 minutes at room tem-
perature in the presence of 1.0 equivalent of p-TSA When
the temperature was increased to 100 °C and the amount of
p-TSA was increased to 2.0 equivalents, 3-aroylquinolines
were obtained as the sole products. This protocol is particu-
larly attractive as it has the advantages of operational sim-
plicity, good functional-group tolerance, controllable re-
sults, mild conditions, and excellent yields, as well as being
environmentally benign. Further studies on the utilization
of the products are currently underway in our laboratory.
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Acknowledgment
We are grateful for financial support from the National Natural
Science Foundation of China (21402070), the Personnel Training
Foundation of Kunming University of Science and Technology
(KKSY201426017), and The Analytical and Testing Foundation of
Kunming University of Science and Technology (2017T20130137,
2017M20152118097, 2017M20162218006, and 2017B201511806126).
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1992, 57, 784. (b) Piechowska, J.; Gryko, D. T. J. Org. Chem. 2011,
76, 10220. (c) Xu, X.; Liu, W.; Wang, Z.; Feng, Y.; Yan, Y.; Zhang,
X. Tetrahedron Lett. 2016, 57, 226.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590950.
S
u
p
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ortiInfogrmoaitn
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p
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ortioInfgrmoaitn
(14) Senadi, G. C.; Hu, W.-P.; Garkhedkar, A. M.; Boominathan, S. S.
K.; Wang, J.-J. Chem. Commun. 2015, 51, 13795.
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mg, 0.5 mmol) were dissolved in H2O (5 mL), and the mixture
was stirred at r.t. with ultrasound irradiation for 20 min until 2a
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(KBr): 1632, 1597, 1543, 1452, 1400, 1297, 1236, 1163, 1024,
788, 755, 613 cm–1. 1H NMR (500 MHz, CDCl3): δ = 2.60 (s, 3 H,
CH3), 3.77 (s, 3 H, ArOCH3), 6.03 (d, J = 8.0 Hz, 1 H, C–CH), 6.85
(d, J = 9.0 Hz, 2 H, ArH), 6.94–6.97 (m, 1 H, ArH), 7.25 (d, J = 8.0
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13C NMR (125 MHz, CDCl3): δ = 28.2, 55.4, 96.6, 113.5, 113.5,
114.0, 121.0, 122.4, 129.9, 129.9, 132.1, 132.2, 134.3, 140.5,
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Typical Procedure
1-(2-Aminophenyl)ethanone (1a; 67.5 mg, 0.5 mmol), N,N-
dimethylenaminone 2a (102.5 mg, 0.5 mmol), and p-TSA (172
mg, 1.0 mmol) were dissolved in 4:1 (v/v) H2O–EtOH (5 mL),
and the mixture was stirred at 100 °C, for 6.0 h until 2a was
completely consumed. The mixture was cooled to r.t., neutral-
ized to pH 8–9 with sat. aq Na2CO3, and extracted with EtOAc (2
× 30 mL). The combined organic phase was washed with H2O
(20 mL), dried (Na2SO4), concentrated, and purified by flash
column chromatography to give a yellow solid; yield: 129 mg
(93%); mp 99–101 °C; IR (KBr): 1641, 1596, 1499, 1450, 1398,
1
1313, 1253, 1157, 926, 797, 705, 626 cm–1. H NMR (500 MHz,
CDCl3): δ = 2.58 (s, 3 H, ArCH3), 3.81 (s, 3 H, ArOCH3), 6.87–6.89
(m, 2 H, ArH), 7.57–7.59 (m, 1 H, ArH), 7.72–7.76 (m, 3 H, ArH),
8.04 (d, J = 8.0 Hz, 1 H, ArH), 8.09 (d, J = 8.0 Hz, 1 H, ArH), 8.73 (s,
1 H, ArH). 13C NMR (125 MHz, CDCl3): δ = 15.8, 55.6, 114.8,
114.8, 124.4, 127.3, 127.7, 130.2, 130.2, 130.5, 132.4, 132.6,
132.6, 143.0, 147.9, 148.5, 164.3, 195.5. HRMS (TOF ES+): m/z [M
+ H]+ calcd for C18H16NO2: 278.1176; found: 278.1179.
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2-en-1-one (3a); Typical Procedure
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1-(2-Aminophenyl)ethanone (1a; 67.5 mg, 0.5 mmol), N,N-
dimethylenaminone 2a (102.5 mg, 0.5 mmol), and p-TSA (86
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F