Synthesis of functionalised 2,3-dihydroquinolin-4(1: H)-ones vs. quinoline or N -alkenylindole derivatives through sequential reactions of 2-alkynylanilines with ketones

Article abstract of DOI:10.1039/d0ob02106g

This study describes diversity-oriented synthesis of 2,2,3-substituted-2,3-dihydroquinolin-4(1H)-ones vs. functionalised quinoline or N-alkenylindole derivatives through Br?nsted acid mediated or Lewis acid catalyzed sequential reactions of 2-alkynylanilines with ketones. In particular, a series of challenging quinolin-4-one derivatives are prepared with good functional group tolerance in an atom-economical fashion by using p-toluenesulfonic acid monohydrate as a promoter of the reaction of ketones with 2-alkynylanilines in EtOH at reflux, while the same starting materials give the corresponding 4-substituted quinolines in toluene at 110 °C both in the presence of p-toluenesulfonic acid monohydrate as the promoter and FeCl3 as the catalyst. The divergent formation of N-alkenylindole derivatives occurs by switching to the use of ZnBr2 as the catalyst under the same reaction conditions. Conversely, only 4-methylsubstituted quinoline derivatives were isolated by reacting 2-ethynylanilines and/or 2-trimethylsylilanilines with ketones in all examined cases. This journal is

Full text of DOI:10.1039/d0ob02106g

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Synthesis of functionalised 2,3-dihydroquinolin-
4(1H)-ones vs. quinoline or N-alkenylindole
derivatives through sequential reactions of
2-alkynylanilines with ketones†‡
Cite this: DOI: 10.1039/d0ob02106g
Vincenzo Marsicano,a Antonio Arcadi, *a Marco Chiarini, b Giancarlo Fabrizi,c
c
Antonella Goggiamani c and Antonia Iazzetti
This study describes diversity-oriented synthesis of 2,2,3-substituted-2,3-dihydroquinolin-4(1H)-ones vs.
functionalised quinoline or N-alkenylindole derivatives through Brønsted acid mediated or Lewis acid
catalyzed sequential reactions of 2-alkynylanilines with ketones. In particular, a series of challenging qui-
nolin-4-one derivatives are prepared with good functional group tolerance in an atom-economical
fashion by using p-toluenesulfonic acid monohydrate as a promoter of the reaction of ketones with
2-alkynylanilines in EtOH at reflux, while the same starting materials give the corresponding 4-substituted
quinolines in toluene at 110 °C both in the presence of p-toluenesulfonic acid monohydrate as the pro-
moter and FeCl3 as the catalyst. The divergent formation of N-alkenylindole derivatives occurs by switch-
ing to the use of ZnBr2 as the catalyst under the same reaction conditions. Conversely, only 4-methyl-
substituted quinoline derivatives were isolated by reacting 2-ethynylanilines and/or 2-trimethylsylilanilines
with ketones in all examined cases.
Received 18th October 2020,
Accepted 4th December 2020
DOI: 10.1039/d0ob02106g
rsc.li/obc
have also been explored. Moreover, the in situ generation of
un-activated N-arylenamines from 2-alkynylanilines followed
Introduction
The divergent formation of different products from the same by 7-endo-dig annulation has also been documented in the lit-
starting materials by controlling the reaction selectivity is still erature for the regioselective synthesis of 1-benzoazepine car-
an attractive goal in organic chemistry.1 The access only to
target scaffolds through readily available raw materials by
means of efficient synthetic routes could help in addressing
this goal.
In the previous reports on the sequential reaction of 2-alky-
nylanilines 1 with activated carbonyl derivatives, it was shown
that the process can be selectively directed towards the for-
mation of N-alkenyl indoles,2 3-alkenyl indoles3 or polyfunctio-
nalised quinolines4 by a suitable choice of the catalytic system
(Scheme 1). A base promoted method generating quinolines5
and
a copper-catalysed intramolecular aerobic oxidative
method generating quinolines6 from activated N-arylenamines
aDipartimento di Scienze Fisiche e Chimiche, Università di L’Aquila,
Via Vetoio- 67010 Coppito (AQ), Italy
bFacoltà di Bioscienze e Tecnologie Agro-alimentari e Ambientali,
Università di Teramo, Via R. Balzarini 1, 64100 - Teramo (Te), Italy
cDipartimento di Chimica e Tecnologie del Farmaco, Sapienza, Università di Roma,
P.le A. Moro 5, 00185 Rome, Italy. E-mail: antonia.iazzetti@uniroma1.it
†Dedicated to the memory of Prof. Sandro Cacchi.
Scheme 1 Product selectivity control in the annulation reaction of the
in situ generated N-aryl enamines from 2-alkynylanilines 1 and activated
ketones.
‡Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0ob02106g
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Scheme 2 Selective 7-endo cyclization/cyanation of the in situ formed unactivated N-arylenamines.
bonitriles (Scheme 2).7 The imination reaction of 2-alkynylani-
line derivatives with aldehydes has been suggested to generate
an iminium ion intermediate.8 Very likely, the intramolecular
attack of the alkyne moiety on the iminium intermediate gen-
erated by the sequential reaction of 2-((2-trimethylsilyl)
ethynyl)anilines with aryl aldehydes gave a cyclic cation which
afforded 4-alkoxyquinoline by methanol quenching, desilyla-
tion and air oxidation. The reaction of 2-alkynylaniline deriva-
tives bearing a hydroxyl or amine functionality with aldehydes
afforded quinolones and 1,2-dihydroquinoline derivatives
having an extra fused ring derived by a bicyclization sub-
sequent to the synergistic effect of Pd(II) and acid catalysis9 or
Sc(OTf)3 catalysis (Scheme 3).10
Following our interest in developing divergent sequential
reactions by switching from metal catalyzed vs. Brønsted acid
mediated processes,11 we considered the possibility to selec-
Scheme 4 Product selectivity control of the reaction of 2-alkynylani-
tively direct the reaction of 2-alkynylanilines 1 with ketones 2 lines 1 with ketones 2.
towards the synthesis of 2,2,3-functionalised-2,3-dihydroqui-
nolin-4(1H)-ones 3 by a suitable choice of the reaction con-
ditions (Scheme 4a).12 In particular, we envisaged to achieve
the construction of spirocyclic quinolones which are not
easily available through traditional organic reactions.13 More
in general, the hydroquinoline skeleton is of relevant signifi-
cance from the standpoint of medicinal chemistry because of
its wide use as a pharmacophore in drug discovery and a
structural essential element in biologically active natural pro-
ducts.14 The 4-oxoquinoline moiety has been a suitable core
from which potentially important anticancer,15 antibacter-
ials,16 and antimalarial agents can be designed.17 Accordingly,
there is a continuing search of structurally unique skeletal
types and practical synthetic methods for dehydroquinolines
that have potential pharmacological profiles.18 Furthermore,
we thought that, by the simple change of the reaction con-
ditions, the same starting reagents could selectively afford the
functionalized quinolines 5 (Scheme 4b) or N-alkenyl indoles
6 (Scheme 4c).
Diversity-oriented synthesis (DOS) of N-heterocycles by
reacting 2-alkynylanilines with ketones is still an important
Scheme 3 Cyclization and bicyclization reactions of the alkynylimminium intermediate.
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challenge in organic synthesis from the viewpoints of oper- annulation of 2-alkynylanilines with activated ketones in
ational simplicity and assembly efficiency.19
ethanol at reflux,4 we isolated the desired 4-(tert-butyl)-3′-
phenyl-1′H-spiro[cyclohexane-1,2′-quinolin]-4′(3′H)-one 3aa in
good yield (Table 1, entry 1). Poorer results were observed by
reducing the amount of p-TsOH·H2O to 0.2 equiv. (Table 1,
entry 2) and the reaction temperature (Table 1, entries 3 and 4)
and by using different Brønsted acids (Table 1, entries 5–9).
Hereafter we report the results of our investigation.
Results and discussion
We began our investigation with the use of 2-(phenylethynyl) The solvent played a key role in the reaction outcome. CH3CN
aniline 1a and 4-t-butylcyclohexanone 2a as model substrates proved to be unsuitable to direct the reaction toward the selec-
under different reaction conditions. Our results are summar- tive formation of the spirocyclic quinolinone both in the pres-
ized in Table 1.
ence of 1 equiv. of p-TsOH·H2O (Table 1, entry 10) and 1 equiv.
Instead of the reported formation of polyfunctionalized qui- of HCl (Table 1, entry 11). Conversely, the formation of quino-
nolines by means of the p-toluenesulfonic acid promoted line derivative 5aa prevailed over the formation of 3aa when
Table 1 Study of the influence of the reaction conditions on the outcome of the reaction of the 2-(phenylethynyl) aniline 1a with the 4-t-butylcy-
clohexanone 2a a
Entry
Promoter (%)
Solvent
Time (h)
T (°C)
Productb (% yield)
1
2
3
4
5
6
7
6
p-TSA·H2O (100)
p-TSA·H2O (20)
p-TSA·H2O (100)
p-TSA·H2O (100)
TFA (100)
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
8
80
80
40
rt
80
80
80
80
80
80
80
110
80
80
80
110
110
110
110
110
110
3aa (70)
3aa (52)
3aa (41)c
4a (5)d
3aa (15)
3aa (38) f
3aa (65)
4a (4)h
3aa (52)
3aa (15)
4a (44)
5aa (54)
—
24
24
24
6
5
5
24
24
6
6
6
24
24
24
24
6
2
6
HCle (100)
HIg (100)
AcOH (100)
TfOH (100)
9
EtOH
10
11
12
13
14
15
16
17
18
19
20
21
p-TSA·H2O (100)
CH3CN
CH3CN
Toluene
EtOH
DCE
DCE
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
HClc (100)
p-TSA·H2O (100)
Yb(OTf)3 (5)
Yb(OTf)3 (5)
Y(OTf)3 (5)
FeCl3 (20)
ZnBr2 (20)
NaAuCl4·2H2O (5)
NaPdCl4 (5)
CuBr2 (10)
5aa (28)i
5aa (29) j
5aa (60)
6aa (62)
6aa (41)k
6aa (33)
6aa (33)l
6aa (5)m
9
7
AgOTf (10)
a Unless otherwise stated, reactions were carried out by reacting 0.5 mmol of 1a with 0.5 mmol of 2a in 2.0 mL of solvent. b Isolated yield. c The
starting alkyne 1a was recovered in 57% yield. d The starting alkyne 1a was recovered in 90% yield. e Hydrochloric acid, 36% w/w aq. soln.
f Compound 4a was isolated in 56% yield. g Hydriodic acid, 57% w/w aq. soln. h The starting alkyne 1a was recovered in 64% yield. i The starting
alkyne 1a was recovered in 97% yield. j The starting alkyne 1a was recovered in 58% yield. k Compound 7a was isolated in 45% yield. l Compound
7a was isolated in 20% yield. m The starting alkyne 1a was recovered in 60% yield.
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the reaction was carried out in toluene at 110 °C in the pres- Brønsted acids. Yb(OTf)3 proved to be an ineffective catalyst
ence of a stoichiometric amount of p-TsOH·H2O (Table 1, (0.05 equiv.) in EtOH at 80 °C and led only to the formation of
entry 12). We, also, explored the use of Lewis acids instead of the quinoline 5aa in poor yield in DCE at 80 °C (Table 1,
entries 13 and 14). Under the latter reaction conditions, a
similar result was observed by using Y(OTf)3 (0.05 equiv.)
(Table 1, entry 15). A better yield of 5aa was observed by
switching to FeCl3 (0.2 equiv.) as the promoter in toluene
(Table 1, entry 16), whereas a variety of other Lewis acids cata-
lyze to different extents sequential imination/5-endo dig annu-
lation and intramolecular hydroamination/5-endo-dig annula-
tion to obtain the corresponding indole derivatives 6aa and 7a,
respectively (Table 1, entries 17–21). Further studies showed
that the p-toluenesulfonic acid promoted sequential reaction
of the N-COCH3 2-alkynyline 1aAc with the ketone 2a worked
equally well leading to the selective formation of 3aa.
Conversely, the N-Ts substituted 2-alkynylanile 1aTs proved to
be unreactive under the same reaction conditions (Scheme 5).
Both 1aAc and 1aTs were recovered unchanged when the reac-
tion was carried out in toluene at 100 °C for 24 h instead of
that in EtOH at reflux.
Scheme 5 Reaction of N-substituted 2-alkynylanilines 1aAc and 1aTs
with ketones 2a.
Scheme 6 Synthesis of 2,2,3-functionalised-2,3-dihydroquinolin-4(1H)-ones 3aa–3an through the p-TsOH·H2O promoted reaction of 2-pheny-
lethynylaniline 1a with ketones 2a–n in EtOH. Unless otherwise stated, reactions were carried out on a 0.25–0.68 mmol scale using 1 equiv. of 1a, 1
equiv. of 2 and 1 equiv. of p-TsOH·H2O in 2.0 mL of EtOH. Isolated yields; a 2 equiv. of the corresponding ketone 2 were used. b The quinoline 5ag
was isolated in 51% yield. c The corresponding quinoline was isolated in 29% yield. d Yields refer to the mixture of the two isolated diastereoisomers.
e The two diastereoisomers were separated through column chromatography over silica gel.
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