Quinolines formation by condensation of heteroaromatic ketones and 2-aminobenzophenones under MW irradiation

Article abstract of DOI:10.1002/bkcs.10557

Microwave (MW) irradiation facilitated synthesis provides fast, safe, simple, and green reaction conditions. MW irradiation of 2-aminobenzophenones with heteroaromatic ketones afforded quinolines via Friedlander condensation in high yields with intact hal

Full text of DOI:10.1002/bkcs.10557

Article
DOI: 10.1002/bkcs.10557
BULLETIN OF THE
S. K. Cho et al.
KOREAN CHEMICAL SOCIETY
Quinolines Formation by Condensation of Heteroaromatic Ketones
and 2-Aminobenzophenones under MW Irradiation
Soo Kyung Cho,† Ju Hyun Song,† Eon Jin Lee,† Do-Hun Lee,† Jung-Tai Hahn,‡ and Dai-Il Jung†,
*
†Department of Chemistry, Dong-A University, Busan 604-714, South Korea. *E-mail: dijung@dau.ac.kr
‡Department of Beautycare, Youngdong University, Youngdong 370-701, South Korea
Received January 19, 2015, Accepted July 31, 2015, Published online October 9, 2015
Microwave (MW) irradiation facilitated synthesis provides fast, safe, simple, and green reaction
conditions. MW irradiation of 2-aminobenzophenones with heteroaromatic ketones afforded quinolines
via Friedlander condensation in high yields with intact halogen substituents for further modifications.
Dibenzo[b,f][1,5]diazocines were found as minor products and in some instances as the only products
as the result of self-condensation of 2-aminobenzophenones. Different acid catalysts were found to affect
these cyclization processes. Mini library of quinolines and dibenzo[b,f][1,5]diazocines were created in
order to understand the substituents effect on the reaction. Resultant quinolines and dibenzo[b,f][1,5]diazo-
cines are anticipated to serve as an interesting library for high throughput screening of various biological
applications.
Keywords: Quinolines, Friedlander condensation, MW irradiation, Dibenzo[b,f][1,5]diazocines,
Self-condensation
Introduction
self-condensation, the effects of various acid catalysts were
investigated.
Quinoline and its derivatives are prevalent in a variety of bio-
logical natural and synthetic compounds. Reported biological
activities of quinoline derivatives include anticancer, antimy-
cobacterial, antimicrobial, anticonvulsant, antiinflamatory,
and cardiovascular properties.1–3 For example, chloroquine,
the most representative drug containing quinoline moiety,
has been used to treat malaria for decades.4 In addition to phar-
macological activities, quinoline and its derivatives are widely
used in industrial applications such as alkaloids, dyes, rubber
chemicals, flavoring agents, corrosion inhibitors, and preser-
vatives.5 This wide variety of applications prompted the syn-
thesis of quinoline derivatives.
Various synthetic routes have already been proposed along
with new methods being extensively investigated.6–8 Con-
ventionally, quinolines are usually synthesized using large
amounts of acid catalysts and highly toxic solvents
under harsh conditions (reaction temperature above 180 ꢀC
for 24 h or longer). In addition, microwave (MW) irradiation
is a promising alternative as it dramatically reduces the reac-
tion time (down to minutes), reduces solvents (or no solvent at
all), reduces side reactions, and hence increases yields in con-
trast to the conventional methods.9
Experimental
General Procedure for the Synthesis of Quinoline Com-
pounds 3–7. 2-Aminobenzophenone 1 (1 mmol), heteroaro-
matic ketone 2 (1 mmol), and diphenylphosphate (DPP)
(0.5 mmol) were mixed without any organic solvent and
the reaction mixture was irradiated in the microwave oven
(RE-555 TCW, Samsung, Busan, Korea) for 3 min. Resulting
reaction mixture was diluted with 50 mL of ethyl acetate,
neutralized with aqueous 10% NaOH and extracted with ethyl
acetate three times, washed with water, and dried using
MgSO4. Products were purified by column chromatography
(ethyl acetate/n-hexane = 1/20–1/40 v/v) to give the corre-
sponding quinoline compounds 3–7. (Analytical data pro-
vided in Supporting Information).
General Procedure for the Synthesis of Dibenzo[b,f][1,5]
diazocine Compounds 8–12. 2-Aminobenzophenone 1
(1 mmol) was self-condensed in the presence of catalysts
(DPP, hydrogen chloride [HCl], phosphoric acid [H3PO4],
acetic acid [CH3COOH], or acetic anhydride [(CH3CO)2O])
(0.5 mmol) without any organic solvent and the reaction mix-
ture was irradiated in the microwave oven for 3 min. Resulting
reaction mixture was diluted with 50 mL of ethyl acetate, neu-
tralized with aqueous 10 % NaOH and extracted with ethyl
acetate three times, washed with water, and dried using
MgSO4. Products were purified by column chromatography
(ethyl acetate/n-hexane = 1/20–1/40 v/v) to give the corre-
sponding dibenzo[b,f][1,5]diazocine compounds 8–12.
(Analytical data provided in Supporting Information).
In this paper, we report the synthesis of quinoline deri-
vatives via MW irradiation. MW irradiation allowed fast
and efficient quinoline formation without the need for
any organic solvent or high reaction temperature. During
the course of the study, dibenzo[b,f][1,5]diazocines were
found to be minor products and in some instances, to
be the only product as the result of self-condensation of
2-aminobenzophenones. In order to better understand the
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Results and Discussion
1c, 2-amino-20,5-dichlorobenzophenone 1d, and 2-amino-5-
chloro-20-fluorobenzophenone 1e) were tested. These substi-
tuents at various positions allow further modification of pro-
ducts for different applications such as conjugation of
pharmaceutically relevant moieties. In fact, present reaction
conditions using MW irradiation did not affect the halogen
substituents at various positions (evidenced by analytical data
provided in Supporting Information), which can serve as
important platforms for further modifications.
Friedlander condensation of 2-aminobenzophenones 1 with
various heteroaromatic ketones 2 via MW irradiation was car-
ried out in the absence of any organic solvent. To create a mini
library, 2-aminobenzophenones were condensed with acetyl
pyridines 2a–c, 2-acetylfuran 2d, 2-acetylthiophene 2e, and
4-methylacetophenone 2f (structural details provided in Sup-
porting Information). To further broaden the scope of the pro-
posed reaction, various 2-aminobenzophenones with different
substituents (e.g., 2-aminobenzophenone 1a, 2-amino-4-
bromobenzophenone 1b, 2-amino-5-chlorobenzophenone
Generally, quinolines were obtained as the major products
with good yields in the range of 60–75% (Table 1). There
were no noticeable trends in the reaction yields except for
Table 1. Condensation of 2-aminobenzophenones with various heteroaromatic ketones under MW irradiation.
Y
X
Z
N
Z
Z
N
Y
X
Y
X
Z
O
MW
+
+
-H2O
O
R
NH2
N
R
X
Y
1a-e
2a-f
3-7
Minor
2-Aminobenzophenones
Heteroaromatic ketones
Product
1
X
Y
Z
2
R
Major product 3–7 yield (%)a
Minor product yield (%)a
3a
3b
3c
3d
3e
4a
4b
4c
4d
4e
4f
5a
5b
5c
6a
6b
6c
6d
6e
6f
1a
H
H
H
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2f
2a
2b
2c
2a
2b
2c
2d
2e
2f
Pyridin-2-yl
Pyridin-3-yl
Pyridin-4-yl
Furan-2-yl
Thiophen-2-yl
Pyridin-2-yl
Pyridin-3-yl
Pyridin-4-yl
Furan-2-yl
71.0
74.5
71.0
68.0
60.0
71.0
74.3
66.5
78.5
72.5
77.7
70.0
72.0
66.5
71.4
37.1
62.9
67.8
70.4
60.1
64.1
57.9
40.3
74.3
66.1
56.1
13.2
15.6
12.3
10.5
11.0
13.2
15.1
9.4
11.4
15.8
9.3
8.9
9.4
1b
Br
H
H
Thiophen-2-yl
2-p-tolyl
1c
H
H
Cl
Cl
H
Pyridin-2-yl
Pyridin-3-yl
Pyridin-4-yl
Pyridin-2-yl
Pyridin-3-yl
Pyridin-4-yl
Furan-2-yl
Thiophen-2-yl
2-p-tolyl
Pyridin-2-yl
Pyridin-3-yl
Pyridin-4-yl
Furan-2-yl
9.4
1d
Cl
10.2
12.0
9.4
10.0
9.1
11.0
13.0
10.8
9.8
10.3
10.7
10.7
7a
7b
7c
7d
7e
7f
1e
H
Cl
F
2a
2b
2c
2d
2e
2f
Thiophen-2-yl
2-p-tolyl
a Isolated yields.
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Quinolines Formation by MW Irradiation
KOREAN CHEMICAL SOCIETY
3-acetylpyridine reacted species (i.e., 3b, 4b, and 5b) showing
higher yields (74.5, 74.3, and 72.0%, respectively) than
2-acetylpyridine and 4-acetylpyridine reacted species proba-
bly due to meta position effect. However, when the
Z-substituted 2-aminobenzophenones (i.e., 1d and 1e) were
reacted with 3-acetylpyridine, resultant products showed
exceptionally low yield (37.1% for 6b) or lower yield
(57.9% for 7b). As a matter of fact, Z-substituted
2-aminobenzophenones (1d and 1e), in general, exhibited
lower yields than non-Z-substituted 2-aminobenzophenones
(1a, 1b, and 1c) possibly due to steric hindrance effect.
Dipole–dipole interaction along with the increase in the polar-
ity of the system during the progress of the reaction is consid-
ered to be the driving force in MW-mediated solvent-free
conditions (Scheme 1).10
In all cases, dibenzo[b,f][1,5]diazocines were obtained as
minor products with relatively low yields in the range of
9–16 % (Table 1). However, when 2-aminobenzophenone
1a was reacted with 4-acetylmorpholine 2g, 3-acetyl-2-
oxazolidinone 2h, and 4-acetylimidazole 2i, 6,12-diphenyldi-
benzo[b,f][1,5]diazocine 8a was obtained as the only product
with higher yields (34.0, 42.0, and 41.0%, respectively). Mor-
pholine (2g), oxazolidinone (2h), and imidazole (2i) moieties
were chosen for applications in biological activity as they are
often found in antibacterial drugs,11,12 but these results sug-
gest that they inhibit the formation of quinolines.
attention of organic chemists since the 1960s due to antiviral,
cholesterol-lowering and hormone-like activity.13,14 Moreo-
ver, their reversible conformational changes during electro-
chemical redox processes make them interesting building
blocks for molecular machines and artificial muscles.15 Con-
ventional synthesis methods preparing dibenzo[b,f][1,5]dia-
zocines required long reflux times,16,17 which in this paper
was dramatically changed to solvent-less, no-heat-required,
and 3 min reaction.
Generally, acid catalysts are known to be more effective
than base catalysts in Friedlander condensations.18 Therefore,
several acid catalysts of interest (DPP, HCl, H3PO4,
CH3COOH, and (CH3CO)2O) were investigated on the self-
condensation of 2-aminobenzophenones (Table 2). Anhy-
drous DPP afforded dibenzo[b,f][1,5]diazocine products
8 with highest yields (above 70%). For the rest of the acid cat-
alysts, yields of dibenzo[b,f][1,5]diazocine products
decreased with decreasing acidity of catalysts. The cyclization
reaction was effectively mediated by the presence of DPP. It
would be an interesting subject of subsequent study to see if
catalysts with lower dibenzo[b,f][1,5]diazocine yields (i.e.,
CH3COOH or (CH3CO)2O) would facilitate higher quinoline
yields.
Table 2. Self-condensation of 2-aminobenzophenones with various
catalysts under MW irradiation.
Dibenzo[b,f][1,5]diazocine products are understood to be
formed by the self-condensation of 2-aminobenzophenones
(Scheme 2). Dibenzo[b,f][1,5]diazocines have drawn the
Y
X
Z
N
Z
N
Y
X
Z
O
MW
+
Catalyst
-H2O
O
NH2
O
O
-H2O
+
X
Y
HO
R
NH2
N
R
N
R
H
1a-e
8-12
1a
2
2-Aminobenzophenones
Product Catalyst
1
X
Y
Z
Yield (%)a
O
-H2O
8a
8d
8e
9a
9d
9e
10a
10d
10e
11a
11d
11e
12a
12d
12e
DPP
1a
1d
1e
1a
1d
1e
1a
1d
1e
1a
1d
1e
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
F
H
Cl
F
H
Cl
F
H
Cl
F
89.4
76.2
77.5
61.6
56.3
51.7
45.7
40.2
41.8
18.9
16.7
14.4
23.7
15.7
16.5
N
H
R
N
R
Cl
Cl
H
Cl
Cl
H
Cl
Cl
H
Cl
Cl
H
3
HCl
Scheme1.Friedlandercondensationof2-aminobenzophenone1with
heteroaromatic ketone 2 to afford quinoline compound 3.
H3PO4
O
CH3COOH
N
H
N
O
H
O
MW
N
H
N H
NH2
(CH3CO)2O 1a
H
Cl
F
1d
1e
Cl
Cl
1a
8a
Scheme 2. Self-condensation of 2-aminobenzophenone 1 to yield
dibenzo[b,f][1,5]diazocine compound 8.
a Isolated yields.
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Quinolines Formation by MW Irradiation
KOREAN CHEMICAL SOCIETY
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Conclusion
In conclusion, MW irradiation of 2-aminobenzophenones
with heteroaromatic ketones resulted in the formation of qui-
nolines via Friedlander condensation in high yields. MW irra-
diation facilitated fast, safe, simple, and green reaction
conditions. Dibenzo[b,f][1,5]diazocines were found as minor
products as the result of self-condensation of 2-aminobenzo-
phenones. Careful selection of acid catalysts is anticipated to
affect the side self-condensation and hence increase overall
yield of quinolines formation. High throughput screening of
resulting quinolines and dibenzo[b,f][1,5]diazocines library
for applications in biological activity are underway.
Acknowledgment. This work was financially supported by
Dong-A University Research Fund in 2014.
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