Aerobic, metal-free synthesis of 6: H -chromeno[4,3- b] quinolin-6-ones

Article abstract of DOI:10.1039/c9ra02267h

A Friedl?nder-based method for transition-metal free, aerobic synthesis of chromene-fused quinolinones is reported. The coupling of 4-hydrocoumarins and 2-aminobenzyl alcohols proceeds in the presence of acetic acid solvent and oxygen oxidant, affording 6

Full text of DOI:10.1039/c9ra02267h

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Aerobic, metal-free synthesis of 6H-chromeno[4,3-
b]quinolin-6-ones†
Cite this: RSC Adv., 2019, 9, 16215
*
Nhan N. H. Ton, Ha V. Dang, Nam T. S. Phan
and Tung T. Nguyen
A Friedlander-based method for transition-metal free, aerobic synthesis of chromene-fused quinolinones is
¨
reported. The coupling of 4-hydrocoumarins and 2-aminobenzyl alcohols proceeds in the presence of
acetic acid solvent and oxygen oxidant, affording 6H-chromeno[4,3-b]quinolin-6-ones in good to
excellent yields. The reactions are tolerant of functionalities such as alkyl, methoxy, bromo, chloro, and
N-heterocycle. Isosteric cyclic 1,3-diketones and 2-amino acetophenones also give fused quinolinones
under reaction conditions. The method herein offers a rapid and benign synthesis of hitherto challenging
N-heterocycles. To our best knowledge, such a convenient pathway to obtain chromene-fused
quinolinones have not been known in the literature.
Received 25th March 2019
Accepted 17th May 2019
DOI: 10.1039/c9ra02267h
rsc.li/rsc-advances
source dimethylsulfoxide (DMSO) (Scheme 1, pathway C).5c
These methods, however, suffer from undisputed problems
such as using excess amount of transition metal,5a the
requirement of prefunctionalized starting materials,5b and the
formation of toxic by-products,5c thus limiting the use in phar-
maceutical industry. Consequently, development of a simple
and benign method for synthesis of unsubstituted 6H-chro-
meno[4,3-b]quinolin-6-ones is pushed to the forefront of
synthetic demands.
1. Introduction
6H-Chromeno[4,3-b]quinolin-6-ones nd use as ourescent
sensors and bioactive molecules.1 Some derivatives are inherent
intermediates for synthesis of potent agents in biorelevant
studies.1b Conventional methods to prepare 6H-chromeno[4,3-
b]quinolin-6-ones rely on the Vilsmeier-Haack conditions to
build up bridge quinolines. Pioneering reports by Tabakovic
and Heber perhaps disclosed the earliest examples of
formylation/cyclization methodology.2 Following these reports,
a number of couplings have been developed to avoid the use of
toxic POCl3. Notably, most of the available methods require
In 2013, our group reported a method for synthesis of
6,7
¨
quinolines through the modied Friedlander mechanism.
The targeted compounds could be obtained from condensation
of 2-aminobenzaldehydes and acetophenones. The aldehydes,
prefunctionalized
2-halobenzaldehydes
or
4-halo-3-
formylcoumarin (halo ¼ bromo or chloro).3 Complementary to
atom economy, it would be much more benecial should
commercial, simple, and non-toxic reagents be used. Iodine-,
Lewis acid-, and ionic liquid-catalyzed coupling of 4-hydrox-
ycoumarins, anilines, and aldehydes to obtain 7-aryl 6H-chro-
meno[4,3-b]quinolin-6-ones are known.4 For synthesis of
unsubstituted, chromene-fused quinolines, the group of Yao
however, are commercially limited and commonly prone to
8
¨
some Friedlander conditions. Our conditions allowed for use of
2-aminobenzyl alcohols, which are more abundant and not
¨
decomposed during the course of Friedlander reactions. We
hypothesize that if 4-hydroxycoumarins oxidatively couple with
2-aminobenzyl alcohols, 6H-chromeno[4,3-b]quinolin-6-ones
would be obtained. Reported prominent examples of modied
¨
Friedlander for fused heterocycles' synthesis commonly require
reported
a seminal method for iron-mediated reductive
the use of transition metals.9 Herein we report a method for
a rapid, metal-free, aerobic synthesis of 6H-chromeno[4,3-b]
quinolin-6-ones and other isosteric fused quinolinones.
Importantly, oxygen is used as a sole oxidant for alcohol
oxidation.10 Until now there has not such an aerobic coupling of
4-hydroxycoumarins and 2-aminobenzyl alcohols reported in
the literature, to our best knowledge.
condensation of 2-nitrobenzaldehydes and 4-hydroxycoumarins
(Scheme 1, pathway A).5a Cyclic 1,3-diketones were also
competent substrates. Later, Su, Xie, and co-workers described
a
synthesis of 6H-chromeno[4,3-b]quinolin-6-ones from
specialized 4-(phenylamino)-2H-chromen-2-ones and N,N-
dimethylformamide (DMF) as a methine bridge (Scheme 1,
pathway B).5b Recently, Sakhuja et al. presented a similar
coupling of 4-hydroxycoumarins, phenylhydrazines, and a C1
2. Results and discussion
Faculty of Chemical Engineering, HCMC University of Technology, VNU-HCM, 268 Ly
Thuong Kiet, District 10, Ho Chi Minh City, Vietnam. E-mail: tungtn@hcmut.edu.vn
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra02267h
Reaction of 2-aminobenzyl alcohol and 4-hydroxycoumarin was
investigated with respect to solvent, oxidant, temperature, and
molar ratio of reactants (Table 1). Among acidic solvents, acetic
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Scheme 1 Synthesis of 6H-chromeno[4,3-b]quinolin-6-one.
Table 1 Optimization of reaction conditionsa
Entry
Solvent
Oxidant
Temp. (ꢀC)
Molar ratiob
Yield of 1c, %
1
2
TFA
AcOH
H2O
O2
O2
O2
O2
Air
DTBP
H2O2
Cumyl hydroperoxide
tert-Butyl perbenzoate
K2S2O8
O2
O2
O2
O2
O2
O2
120
120
120
120
120
120
120
120
120
120
100
80
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
2 : 1
1 : 2
1 : 3
1 : 4
1 : 4
78
86
23
31
47
76
47
28
18
63
69
39
57
77
88
95
3
4d
5
AcOH/glycerol
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
6
7
8
9
10
11
12
13
14
15
16e
120
120
120
120
a
b
c
2-Aminobenzyl alcohol (0.2 mmol), solvent (1 mL), 16 h. Molar ratio is of 2-aminobenzyl alcohol : 4-hydroxycoumarin. Yields are GC yields
d
e
using diphenyl ether internal standard. Acetic acid (0.2 mmol) in glycerol. 2 mL solvent. TFA ¼ triuoroacetic acid; AcOH ¼ acetic acid;
DTBP ¼ di-tert-butylperoxide.
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acid gave the best yield of product 1.11 The reaction can be run
in water, albeit at lower yield (entry 3). Using 1 equivalent of
acetic acid in glycerol resulted in incomplete conversion of
starting materials (entry 4). The reaction was cleanly progressed
under oxygen oxidant. A moderate yield of 1 was obtained if the
condensation was run under air atmosphere (entry 5). Although
organic peroxides are common oxidants for organic reactions,
using peroxides was not successful for the condensation. Di-
tert-butyl peroxide was inferior to oxygen as oxidant (entry 6),
while other peroxide-typed oxidants were much less reactive
(entries 7–9). Use of an inorganic oxidant K2S2O8 gave the
product in moderate yield (entry 10). Although we could not
rationalize the mechanism at this moment, low solubility of
K2S2O8 may help not oxidize the aldehyde intermediate, thus
avoid decomposition. Decreasing the reaction temperature
Scheme 2 Kinetic profile for the reaction of 2-aminobenzyl alcohol
with 4-hydroxycoumarin. Conditions: 2-aminobenzyl alcohol (0.2
mmol), 4-hydroxycoumarin (0.8 mmol), acetic acid (2 mL), in oxygen.
Yields are GC yields using diphenyl ether internal standard.
Table 2 Scope of 6H-chromeno[4,3-b]quinolin-6-ones synthesisa
Entry
Reactant 1
Reactant 2
Product
Yield, %
1
92, 85b, 90c, 88d
2
76
3
78
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Table 2 (Contd.)
Entry
Reactant 1
Reactant 2
Product
Yield, %
4
85e
5
84
6
86
7
75
8
89
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Table 2 (Contd.)
Entry
Reactant 1
Reactant 2
Product
Yield, %
9
81
10
90
11
86
a
2-Aminobenzyl alcohols (0.2 mmol), 4-hydroxycoumarins (0.8 mmol), acetic acid (2 mL), 120 ꢀC, 3 h. Yields are isolated yields. Please see the ESI
b
c
d
for details. 2-Aminobenzyl amine (0.2 mmol) instead 2-aminobenzyl alcohol. 2-Aminobenzyl alcohol (2 mmol), 120 ꢀC, 5 h. 2-Aminobenzyl
alcohol (50 mmol), 4-hydroxycoumarin (100 mmol), acetic acid (250 mL), 120 ꢀC, 24 h. The product was obtained aer recrystallization. e Purity:
93%.
plummeted the yield of product 1 (entries 11 and 12). Almost no amount of 2-aminobenzyl alcohol was used (entries 13–15).
conversion of starting material was observed if the reaction was Increasing the amount of solvent helped get better yield of the
run at room temperature. During the reaction course, self- reaction, since the product was somewhat insoluble (entry 16).
condensation of 2-aminobenzyl alcohol did not occur, Using more than 2 mL of acetic acid, however, did not affect the
presumably showing that reaction conditions are not extremely yield of 1. Kinetic of the reaction was also studied and presented
oxidative. Consequently, increasing the amount of 4-hydrox- in Scheme 2. Almost full conversion of 2-aminobenzyl alcohol
ycoumarin with regard to 2-aminobenzyl alcohol was then was observed aer only 2 hours. The method, thus, provides
considered because of the much cheaper reagent 4-hydrox- a rapid route to synthesize a complex heterocycles in a high
ycoumarin. As expected, the yield of 1 increased if excess yield.
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Scheme 3 Synthesis of other fused quinolinones.
Synthesis of 6H-chromeno[4,3-b]quinolin-6-ones is pre- [4,3-b]quinolin-6-ones. A dibenzonaphthyridinone 8 was ob-
sented in Table 2. Good to excellent yields were obtained in tained in good yield, showing that synthesis of N-heterocycles is
most cases. Reactions gave clean crude mixtures without affordable in the conditions. Unprotected 4-hydroxyquinolin-
forming byproducts from decomposition of 2-aminobenzyl 2(1H)-one failed to give the product. A few 2-aminobenzyl
alcohols. We rstly observe the compatibility of functionality on alcohols were also studied with regard to the coupling with 4-
4-hydroxycoumarins in the reaction. Isolation of 6H-chromeno hydroxycoumarin. 9-Chloro-6H-chromeno[4,3-b]quinolin-6-one
[4,3-b]quinolin-6-one from the coupling of 2-aminobenzyl 9 was obtained in 81% yield (entry 9). A hindered 2-amino-
alcohol gave 92% yield (entry 1). If 2-aminobenzyl amine was benzyl alcohol with respect to the nucleophilic amine site still
used, a same product was obtained, albeit at lower yield. To afforded the product in good yield (10). If 2-amino benzyhydrol
prove the practicability of the method, the reaction was run at was used, a 7-arylated 6H-chromeno[4,3-b]quinolin-6-one 11
larger scales and still afforded an excellent yield of compound 1. was obtained in 86% yield (entry 11). It should be noted that
Recrystallization could be used to obtain the product in good this compound is not synthetically possible if the conditions of
yield if 50 mmol scale reaction was run. Wide tolerance of Xie or Yao are applied.5a,5b
functional groups were observed in the method. Chloro (2),
The condensation became much more sluggish if 2-amino
bromo (3), methyl (4), ethyl (5), and methoxy (7) groups gave carbonyl compounds are used. A 7-substituted 6H-chromeno
products in good yields. Halogenated 6H-chromeno[4,3-b] [4,3-b]quinolin-6-one 12 was obtained in moderate yield when 4-
quinolin-6-ones are valuable, since further modications hydroxycoumarin reacted with 20-aminoacetophenone (Scheme
could be obtained through transition metal catalyzed carbon- 3). It should be noted that modied reaction conditions were
halogen activation. Especially, the bromo derivative is rstly required for this entry, since self-condensation of the 2-amino
synthesized using a simple method. In the report of Xie and keto compound was detected. A more hindered 2-amino-
Su,5b the use of high valent copper for selective C–H activation benzophenone failed to couple with 4-hydroxycoumarin.
would be competed with C–Br activation, resulting in the Synthesis of other fused quinolinones was also attempted.
¨
regioselective problem. Meanwhile, a metal-hydride condition, Friedlander reactions of 2-aminobenzyl alcohol and cyclic
as described by Yao and co-workers,5a could substitute a good ketones afforded products (13–15, Scheme 3) in moderate to
leaving group such as bromide by hydride. Thus, our method good yields. It should be noted that isosteric amides (barbituric
allows the synthesis of notorious halogenated 6H-chromeno acid) or esters (meldrum's acid) failed to give the products.
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Scheme 4 Plausible mechanism.
A possible mechanism is proposed as presented in Scheme 4. Signicant development from earlier methods include excellent
A tautomerism of 4-hydroxycoumarin would give a more active atom economy, ease in scale up, and general substrate scope.
form A, which then affords an imine intermediate with 2-ami- The reaction is tolerant of functionalities such as methyl,
nobenzyl alcohol. Oxidation of alcohol to aldehydes possibly methoxy, ethyl, chloro, bromo, and N-heterocycle. Other fused
happens aer condensation, since 2-amino carbonyls either quinolines could also be obtained in good yields without major
gave a complicated reaction mixture or failed to give product. modication of reaction conditions. The method provides
The following enamine-aldehyde condensation (B to D) would a rapid and convenient pathway to synthesize complex fused N-
complete the formation of quinoline ring. The presence of heterocycles that, to our best knowledge, have not been re-
hydroxy-form intermediate C was slightly detected by GC-MS ported in the literature.
and efforts to isolate the compound is on going. Alternatively,
formation of a benzyl cation from the intermediate B could
afford D by a nucleophilic addition. Aromatisation would give
Conflicts of interest
the desired product. Although oxidation of the C–C bond
commonly occurs in the presence of a transition metal,5b this
hypothesis could not be completely ruled out at this moment.
The authors declare no competing nancial interest.
Acknowledgements
This research is funded by Ho Chi Minh City University of
Technology – VNU-HCM under grant number T-KTHH-2018-99.
3. Conclusions
In conclusion, we have developed an operationally simple and We also want to thank Hanh T. H. Nguyen (University of
general method for aerobic, metal-free synthesis of 6H-chro- Houston) and Tuong A. To (Ho Chi Minh City University of
meno[4,3-b]quinolin-6-ones. The reaction employs acetic acid Technology
–
VNU-HCM) for giving us some valuable
as a Brønsted acid mediator and a solvent, and oxygen oxidant. substrates.
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G. Rahimzadeh, S. Bahadorikhalili, E. Kianmehr and
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