Reactions of N,3-diarylpropiolamides with arenes under superelectrophilic activation: Synthesis of 4,4-diaryl-3,4-dihydroquinolin-2(1H)-ones and their derivatives

Article abstract of DOI:10.3762/bjoc.12.93

The reaction of 3-aryl-N-(aryl)propiolamides with arenes in TfOH at room temperature for 0.5 h led to 4,4-diaryl-3,4-dihydroquinolin-2-(1H)-ones in yields of 44-98%. The obtained dihydroquinolinones were further transformed into the corresponding N-acyl or N-formyl derivatives. For the latter, the superelectrophilic activation of the N-formyl group by TfOH in the reaction with benzene resulted in the formation of N-(diphenylmethyl)-substituted dihydroquinolinones.

Full text of DOI:10.3762/bjoc.12.93

Reactions of N,3-diarylpropiolamides with arenes under
superelectrophilic activation: synthesis of 4,4-diaryl-3,4-
dihydroquinolin-2(1H)-ones and their derivatives
Larisa Yu. Gurskaya1,2, Diana S. Belyanskaya1, Dmitry S. Ryabukhin1,3, Denis I. Nilov1,
Irina A. Boyarskaya1 and Aleksander V. Vasilyev*1,3,§
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2016, 12, 950–956.
1Department of Organic Chemistry, Institute of Chemistry, Saint
Petersburg State University, Universitetskaya nab., 7/9, Saint
Petersburg, 199034, Russia, 2N.N. Vorozhtsov Novosibirsk Institute of
Organic Chemistry, Siberian Branch of Russian Academy of Science,
ul. Lavrentieva 9, Novosibirsk, 630090, Russia and 3Department of
Chemistry, Saint Petersburg State Forest Technical University,
Institutsky per. 5, Saint Petersburg, 194021, Russia
doi:10.3762/bjoc.12.93
Received: 13 March 2016
Accepted: 24 April 2016
Published: 11 May 2016
Associate Editor: D. Y.-K. Chen
Email:
© 2016 Gurskaya et al; licensee Beilstein-Institut.
License and terms: see end of document.
Aleksander V. Vasilyev* - aleksvasil@mail.ru
* Corresponding author
§ Tel./fax: +07-812-670-93-90
Keywords:
alkynes; quinolinones; Friedel–Crafts reactions; superacids;
superelectrophilic activation
Abstract
The reaction of 3-aryl-N-(aryl)propiolamides with arenes in TfOH at room temperature for 0.5 h led to 4,4-diaryl-3,4-dihydro-
quinolin-2-(1H)-ones in yields of 44–98%. The obtained dihydroquinolinones were further transformed into the corresponding
N-acyl or N-formyl derivatives. For the latter, the superelectrophilic activation of the N-formyl group by TfOH in the reaction with
benzene resulted in the formation of N-(diphenylmethyl)-substituted dihydroquinolinones.
Introduction
Quinoline derivatives are a very important class of heterocycles, based on alkynes, which are widely used for the preparation of
which are used in chemistry, biology, medicine, and materials various carbo- and heterocycles [6-10].
science. For instance, see a series of recent reviews on anti-
malaria drugs containing a quinoline motif in the structure Based on our works on the synthesis of 4-arylquinolin-2(1H)-
[1-3]. The synthesis of quinolines is an important task of ones from acetylene compounds under superelectrophilic acti-
organic chemistry [4,5]. Many of these synthetical protocols are vation conditions [11-14], we continued to develop some
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Beilstein J. Org. Chem. 2016, 12, 950–956.
methods for the syntheses of quinoline derivatives. Previously Reactions of the series of 3-aryl-N-(aryl)propiolamides 1a–u,
we showed, just in a few examples, that some 3-aryl-N- bearing various donor–acceptor substituents on aryl rings, with
(aryl)propiolamides reacted with benzene under the action of benzene and other arenes in the presence of TfOH, TfOH–SbF5,
Brønsted or Lewis superacids affording 4-aryl-4-phenyl-3,4- AlCl3, or AlBr3 were studied. Initial amides 1a–u, reaction
dihydroquinolin-2(1H)-ones [12,13].
conditions, target 4,4-diaryl-3,4-dihydroquinolin-2-(1H)-ones
2a–x, and some byproducts 3a–c and intermediate compounds
The main goal of this work was a systematic study on 4a,b are given in Table 1. Structures of compounds 2a–x, 3a–c,
reactions of 3-aryl-N-(aryl)propiolamides with arenes under the and 4a,b were determined by means of 1H, 13C, 19F NMR,
action of the Brønsted superacid TfOH (CF3SO3H, triflic acid), HRMS methods (see Supporting Information File 1), and X-ray
strong Lewis acids AlX3 (X = Cl, Br), or the conjugate analysis in case of compound 2f (Figure 1).
Brønsted–Lewis superacid TfOH–SbF5.
Results and Discussion
The protonation of alkynamides 1 on both the oxygen atom of
the amide group and a carbon atom of the acetylene bond in
superacids or coordination of these basic centers with strong
Lewis acids leads to the formation of dications A that are
considered as superelectrophiles [15] (Scheme 1). These dicat-
ions can either undergo an intramolecular cyclization to
4-arylquinolin-2(1H)-ones 3 or, alternatively, react with arenes
as external π-nucleophiles. In this latter pathway, Friedel–Crafts
alkenylation of arenes by species A leads to structures 4, which
can then be diprotonated to the cations B and finally cyclized to
4,4-diaryl-3,4-dihydroquinolin-2(1H)-ones 2. It should be noted
that quinolinones 3 do not react with arenes with formation of
compounds 2 under superelectrophilic activation, and starting
materials 3 remain unreacted [12,13].
Figure 1: Molecular structure of 2f (ellipsoid contours of probability
levels are 50%).
Such 4,4-diaryl-3,4-dihydroquinolin-2-(1H)-ones 2 are very
rare objects, there is no general method for their synthesis
We found that the best conditions for the synthesis of dihydro-
[16,17]. Thus, developing of synthetic method to get these com-
pounds is an actual goal of organic chemistry.
quinolines 2 from amides 1 and arenes were as follows: TfOH,
Scheme 1: Transformations of 3-aryl-N-(aryl)propiolamides 1 into 4-arylquinolin-2(1H)-ones 3 or 4,4-diaryl-3,4-dihydroquinolin-2(1H)-ones 2 in the
presence of arenes through the formation of intermediate cations A, B under the superelectrophilic activation.
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Beilstein J. Org. Chem. 2016, 12, 950–956.
room temperature, 0.5 h. Some optimization of the reaction on yields of compounds 2 were usually lower as compared to
minimization of the usage of arenes and TfOH were performed. TfOH (H0 −14) (Table 1, entries 2, 6 and 10). For the Lewis
The amount of arene may be decreased to 5 equivalents. But, acid AlBr3, additional formation of compounds 3a,b,c was
concerning the use of a lower amount of TfOH, for instance, detected (Table 1, entries 4, 36 and 37), or exchange of aryl
running the reaction in CH2Cl2 solution led to a dramatic de- groups in 2 took place (Table 1, entry 32, formation of 2g from
crease of the yields of the target products. Thus, it is better to 2q, as a result of the exchange of the p-tolyl moiety by a phe-
conduct the reaction in neat TfOH, which is a good weak nyl group).
nucleophilic medium for the stabilization of the intermediate
cationic species.
Amides 1, bearing various donor (Me, MeO, benzo-) and
acceptor (F, Cl) substituents on both aryl rings at the acetylene
No concurrent formation of the corresponding 4-arylquinolin- bond and at the nitrogen atom may be involved in this reaction.
ones 3 was observed, and in most cases the yields of the target Substrates 1g, 1h, having electron withdrawing 4-F and 4-Cl
products 2 are 44–98% (see Table 1). Also this reaction may be substituents on the N-aryl ring, were hardly cyclized under the
carried out under the action of other acids, e.g., TfOH–SbF5 or formation of dihydroquinolinones 2g, 2h. Thus, at room tem-
AlX3 (X = Cl, Br). But in the stronger acidic system perature for 0.5 h, apart from target compounds 2g, 2h, the cor-
TfOH–SbF5 (Hammet acidity function H0 −19, see [18]) the responding amides of 3,3-diphenylpropenoic acid 4a, 4b were
Table 1: Reactions of amides 1a–u with benzene (and other arenes) under superelectrophilic activation, leading to dihydroquinolinones 2a–x.
Entry
Starting amide 1
Acid (reaction
conditions)
Reaction product, dihydroquinolinone 2
no.
R
R′
no.
R
R′
Yield, %
1
2
1a
1a
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1e
1f
H
H
TfOHa
TfOH-SbF5a
AlCl3b
2a
2a
2a
2a
2b
2b
2c
2c
2d
2d
2e
2e
2e
2f
H
H
90
85
91
52c
93
38
75
83
98
53
73
95
55
52
58
18d
84
95
72
23f
88
52
3
4
AlBr3b
5
2-Me
3-Me
4-Me
2-F
H
H
H
H
TfOHa
8-Me
7-Me
6-Me
8-F
H
H
H
H
6
TfOH-SbF5a
TfOHa
7
8
TfOH-SbF5a
TfOHa
9
10
11
12
13
14
15
16
17
18
19
20
21
22
TfOH-SbF5a
TfOHa
TfOH-SbF5a
AlBr3b
3-F
4-F
H
H
TfOHa
7-F
6-F
H
H
1f
AlBr3b
2f
1g
1g
1g
1g
1h
1h
1h
TfOHa
2g
2g
2g
2g
2h
2h
2h
TfOHe
TfOH-SbF5a
AlBr3b
4-Cl
H
TfOHa
6-Cl
H
TfOHe
AlBr3b
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Beilstein J. Org. Chem. 2016, 12, 950–956.
Table 1: Reactions of amides 1a–u with benzene (and other arenes) under superelectrophilic activation, leading to dihydroquinolinones 2a–x.
(continued)
23
24
25
26
27
28
29
30
31
32
1i
1j
2,3-Me2
2,4-Me2
3,4-Me2
2-MeO
3-MeO
4-MeO
3-F, 4-MeO
H
H
H
TfOHa
TfOHa
TfOHa
TfOHa
TfOHa
TfOHa
TfOHa
TfOHa
TfOHa
AlBr3b
2i
2j
7,8-Me2
6,8-Me2
6,7-Me2
8-MeO
7-MeO
6-MeO
7-F, 6-MeO
H
H
H
88
89
74
98
44
64
53
90
68
53
13
66
87
70
22g
17h
50
60
1k
1l
H
2k
2l
H
H
H
1m
1n
1o
1p
1q
1q
H
2m
2n
2o
2p
2q
2q
2g
2r
H
H
H
H
H
4-Me
4-Me
4-Me
4-Me
4-F
6-F
6-F
H
H
33
34
35
36
37
38
39
1r
1s
1s
1t
H
4-F
TfOHa
TfOHa
AlBr3b
AlBr3b
AlBr3b
TfOHa,i
TfOHa,j
4-F
4-Cl
4-F
4-Cl
2s
2s
2t
6-F
2,3-benzo
3,4-benzo
H
H
H
H
7,8-benzo
H
H
1u
1a
1a
2u
2v
2x
5,6-benzo
H
H
4-Cl
3,4-Cl2
aRoom temperature, 0.5 h. b80 °C, 1 h. c4-Phenylquinolin-2(1H)-one 3a was also obtained in a yield of 41%. dN-(4-Fluorophenyl)amide of 3,3-
diphenylpropenoic acid 4a [Ph2C=CHCONH(4-FC6H4)] was obtained as a major reaction product in a yield of 80%. eRoom temperature, 7 h. fN-(4-
Chlorophenyl)amide of 3,3-diphenylpropenoic acid 4b [Ph2C=CHCONH(4-ClC6H4)] was obtained as a major reaction product in a yield of 75%.
g4-Phenyl-7,8-benzoquinolin-2(1H)-one 3b was also obtained in a yield of 15%. h4-Phenyl-5,6-benzoquinolin-2(1H)-one 3c was also obtained in a
yield of 17%. iReaction with chlorobenzene. jReaction with 1,2-dichlorobenzene.
isolated (Table 1, entries 16 and 20). Increasing the reaction To show the synthetic potential of dihydroquinolinones 2 their
time to 7 h resulted in the solely formation of 2g and 2h N-formylation and N-acetylation reactions were carried out.
(Table 1, entries 17 and 21). That clearly proved the participa- Compounds 2a,d,e and h were N-formylated in the system
tion of compounds 4 in the reaction pathway leading to dihydro- POCl3–DMF–CHCl3 under the Vilsmeier–Haack reaction
quinoliones 2 (Scheme 1).
conditions with formation of compounds 5a–d (Scheme 2).
Apart from that, dihydroquinolinones 2a,e–h were acetylated
It should be noted, that substrates 1 with more than one possible into derivatives 6a–e (Scheme 2).
reaction site, namely 3-substituted amides 1c,f and 3,4-disubsti-
tuted amides 1k,o gave regioselectively only 7-substituted Then reactions of compounds 5 and 6 with arenes in TfOH were
quinolinones 2c,f (Table 1, entries 7, 8, 14 and 15) and 6,7- checked. Analogously to other heteroaromatic aldehydes of the
disubstituted quinolinones 2k,o (Table 1, entries 25 and 29), re- series of pyridine [19], quinolone [20], pyrazol [21], and imida-
spectively.
zole [22], the superelectrophilic activation of the formyl group
in 5 was expected. Indeed, compounds 5a,b and d reacted with
Concerning the arene component of this reaction, apart from benzene in a Friedel–Crafts process affording N-diphenyl-
benzene, chlorobenzene and 1,2-dichlorobenzene it may take methyl substituted derivatives 7a–c, respectively (Scheme 3).
part in this Friedel–Crafts process (Table 1, entries 38 and 39). Most probably, the reaction proceeds through the formation of
More donating aromatic substrates, such as toluene, isomeric O,O’-diprotanated intermediate C (Scheme 3), which are
xylenes, mesitylene, or pseudocumene, led to complex mix- considered as superlectrophiles [15]. The close structural prox-
tures of oligomeric reaction products. Such activated aryl imity of two positive charges in C substantially increases the
groups may undergo several electrophilic attack from interme- electrophilic properties of the carbon of the O-protonated
diate cationic species A and B (Scheme 1), that complicated this N-formyl group and explains its reactivity. The reactions of 5
reaction.
with other arenes, such as 1,2-dichlorobenzene, toluene, or
isomeric xylenes, gave deformylation products 2. In this case,
Thus, reaction of amides 1 with benzene and some other arenes probably, target compounds 7 were initially formed, but then
in TfOH is an effective way to 4,4-diaryl-3,4-dihydroquinolin- protolytic cleavage of the N–CH(Ar)2 bond occurred leading to
2(1H)-ones 2.
relatively stable diarylmethyl cations (+CH(Ar)2). That took
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Beilstein J. Org. Chem. 2016, 12, 950–956.
Scheme 2: N-Formylation and N-acylation of dihydroquinolinones 2.
Scheme 3: Superelectrophilic activation of the N-formyl group of compounds 5 and their reaction with benzene.
place to less extent also for the N-diphenylmethyl group in contribution of atomic orbital into LUMO and global electro-
7a–c. It should be mentioned, that this is the first example of philicity indices ω [23,24] were calculated (Table 2, and
such a superelectrophilic activation of a N-formyl group, and Figure 2). The calculations showed that the Cα carbon of the
this reaction did not take place for N-acyl derivatives 6.
protonated N-formyl and N-acyl groups in species C1 and D1,
respectively, have a rather large positive charge. Despite the
Additionally a DFT calculation of dications C1 and D1 derived large charge on C2 of the protonated carbonyl groups and its
from 5a and 6a, respectively, was carried out to estimate the substantial contribution into LUMO (Figure 2), this carbon is
electrophilic properties of these species. Charge distribution, not reactive, probably, due to steric reasons. A comparison of
Table 2: Selected electronic characteristics (DFT calculations) of dications C1 and D1 derived from protonation of 5a and 6a, respectively.
cation
EHOMO, eV ELUMO, eV ω,a eV
q(C2),b
q(Ca),b
q(CN),b
k(C2)LUMO,с % k(Ca)LUMO,с % k(CN)LUMO,с %
C1
D1
−7.11
−7.22
−4.56
−4.49
6.69
6.28
0.84
0.82
0.60
0.84
−0.44
−0.50
14.8
24.9
11.5
11.9
1.1
3.1
aGlobal electrophilicity index ω = (EHOMO + ELUMO) 2/8(ELUMO − EHOMO). bNatural charges. cContribution of atomic orbitals into the molecular orbital.
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Beilstein J. Org. Chem. 2016, 12, 950–956.
Figure 2: LUMO of species C1 and D1.
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