Synthesis of quinolines and dibenzo[b,f][1,5]diazocines by mw-assisted solvent-free method

Article abstract of DOI:10.14233/ajchem.2014.15612

Acetylpyridines, 2-acetylfuran, 2-acetylthiophene, acetyimidazoles, acetone and 4-methyl-acetophenone were condensed with 2-amino- 4-bromobenzophenone (1) under the optimal reaction conditions. Condensation of 2a-j with 1 afforded quinolines in good yield

Full text of DOI:10.14233/ajchem.2014.15612

Asian Journal of Chemistry; Vol. 26, No. 7 (2014), 1991-1994
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.15612
Synthesis of Quinolines and Dibenzo[b,f][1,5]Diazocines by MW-Assisted Solvent-Free Method
1
1
1
2
SOON-KJU CHOI , JUNG-WOO YANG , DO-HUN LEE , DAI-IL JUNG1,* and JUNG-TAI HAHN
1Department of Chemistry, Dong-A University, Busan 604-714, Republic of Korea
2Department of Beautycare, Youngdong University, Youngdong 370-701, Republic of Korea
*Corresponding author: Fax: +82 51 2007259; Tel: +82 51 2007249; E-mail: dijung@dau.ac.kr
Received: 9 April 2013;
Accepted: 5 June 2013;
Published online: 22 March 2014;
AJC-14944
Acetylpyridines, 2-acetylfuran, 2-acetylthiophene, acetyimidazoles, acetone and 4-methyl-acetophenone were condensed with 2-amino-
4-bromobenzophenone (1) under the optimal reaction conditions. Condensation of 2a-j with 1 afforded quinolines in good yields (60-
74.5 %). In these reactions, (5z,11z)-3,9-dibromo-6,12-diphenyl-dibenzo[b,f][1,5]diazocine (4) was isolated as the minor product. The
self-condensation of 1 afforded 4 as the only product. In order to investigate the effect of DPP on product formation, the synthesis of 4 was
carried out under microwave irradiation using different amounts (in equivalents) of DPP. The obtained yield of 4 was higher when using
anhydrous DPP than when using HCl, H3PO4 and CH3COOH. The cyclization reaction proceeded very effectively in the presence of DPP,
as shown in the two reaction mechanisms for the formation of quinolines and dibenzo[b,f][1,5]diazocine.
Keywords: Quinolines, Dibenzo[b,f][1,5]diazocines, Microwave-assisted solvent-free method, Self condersation.
channel antagonist such as diltiazem, which has been success-
fully tested as a chemosensitizer against multiple drug resis-
tance (MDR)6.We first carried out Friedlander7,8 condensation of
various heteroaromatic ketones with 2-aminobenzophenones
under microwave irradiation. To explore the scope and limita-
tions of this condensation reaction under the above-mentioned
reaction conditions, we generated a mini-library of quinolines.
INTRODUCTION
Quinoline, 1-azanaphthalene, is an aromatic nitrogen
compound characterized by a solid-ring structure containing
a benzene fused to pyridine at two adjacent carbon atoms.
Quinoline-containing natural products have been investigated
extensively by synthetic and medicinal chemists over the last
several decades. The parent bicyclic structure is found in natural
products that exhibit a wide spectrum of biological activities;
a large number of medicinally important compounds are avai-
lable containing quinolone, di- and tetrahydroquinoline and
oxo-quinoline moieties1,2. Several synthetic routes have already
been proposed for quinolines and new methods are being
extensively investigated. Quinolines are usually synthesized
under harsh heating conditions (heating for 24 h or longer)
using large amounts of an acid catalyst and highly toxic
solvents3,4. Recently, considerable attention has been paid to
microwave-assisted organic reactions, which do not require
any solvent5. Thermal reactions are often carried out in solution
using large quantities of the reagents and may take several
hours for completion. However, these reactions proceed to
completion within minutes under microwave irradiation.
Herein, we report a new method involving microwave irradia-
tion for synthesizing quinolines and dibenzo[b,f][1,5]-
diazocines. Although dibenzo[b,f][1,5]diazocines are well
known, their biological activities have not been studied in detail
thus far. These compounds are structurally similar to calcium
EXPERIMENTAL
General procedure for the synthesis of 3a-j and 4: 2-
Amino-4-bromobenzophenone (1) (1 mmol), heteroaromatic
ketone (2) (1 mmol) and 0.5 equiv of DPP (0.5 mmol,
purchased from Aldrich) were mixed in the absence of any
organic solvent and then submitted for 3 min to microwave
irradiation inside a domestic microwave oven (Samsung, RE-
555 TCW). After the reaction was completed, the reaction
mixture was diluted with ethyl acetate and neutralized with
aqueous solution of NaOH (10 %). It was extracted with ethyl
acetate (three times), washed with water and dried (MgSO4).
After the reaction, products were purified by column chroma-
tography (EtOAc/n-hexane = 1:20-1:40, v/v) to give the
corresponding quinolines.
7-Bromo-4-phenyl-2-(pyridine-2-yl)quinolone (3a):
m.p.: 140-142 °C; 1H NMR (CDCl3, 200 MHz) δ7.9 (d, 2H),
7.9 (s, 1H), 7.8-7.9 (d, 1H), 7.6-7.7 (t, 2H), 7.1-7.5 (m, 6H),
6.9-7.0 (t, 1H); 13C NMR (CDCl3, 50MHz) δ155.3, 151.1,
150.3, 149.2, 145.3, 139.8, 137.2, 131.0, 130.6, 129.8, 129.2,

1992 Choi et al.
Asian J. Chem.
127.4, 124.0, 123.6, 121.4, 118.6, 102.6; MS (MOLDI-TOP),
m/z 361 (Anal. calcd. (%) for C, 66.50; H, 3.63; Br, 22.12; N,
7.75 Found (%); C, 66.53; H, 3.64; Br, 22.11; N, 7.72).
7-Bromo-4-phenyl-2-(pyridine-3-yl)quinolone (3b):
m.p.: 151-152 °C; 1H NMR (CDCl3, 200 MHz) δ7.9 (s, 1H),
7.8-7.9 (d, 1H), 7.6-7.7 (d, 1H), 7.5-7.6 (d, 1H), 7.4-7.5 (d,
1H), 7.3 (s, 1H), 7.0 (t, 1H), 6.9-7.0 (m, 6H); 13C NMR (CDCl3,
50MHz) δ154.5, 150.7, 149.5, 148.9, 144.4, 139.8, 134.6,
134.5, 131.0, 129.2,127.4, 121.2, 101.0; MS (MOLDI-TOP),
m/z 361 (Anal. calcd. (%) for C, 66.50; H, 3.63; Br, 22.12; N,
7.75 Found (%); C, 66.51; H, 3.62; Br, 30.10; N, 5.77).
7-Bromo-4-phenyl-2-(pyridine-4-yl)quinolone (3c):
m.p.: 139-140 °C; 1H NMR (CDCl3, 200 MHz) δ8.3 (d, 2H),
7.7 (d, 2H), 7.6-7.7 (d, 1H), 7.5 (d, 1H), 7.4 (s, 1H), 7.3-7.4 (t,
1H), 6.9-7.0 (m, 5H); 13C NMR (CDCl3, 50MHz) δ157.4,
150.3, 149.8, 145.7, 145.3, 139.8, 131.0, 130.6, 129.8, 129.2,
127.4, 124.0, 121.4, 118.6, 102.6; MS (MOLDI-TOP), m/z
361 (Anal. calcd. (%) for C, 66.50; H, 3.63; Br, 22.12; N, 7.75
Found (%); C, 66.46; H, 3.65; Br, 22.11; N, 7.78).
7-Bromo-4-phenyl-2-p-tolylquinolone (3i): m.p.: 144-
145 °C; 1H NMR (CDCl3, 200 MHz) δ8.1 (m, 3H), 7.6 (t, 1H),
7.5 (m, 3H), 7.4 (s, 1H), 7.3-7.4 (m, 2H), 6.6 (d, 2H), 2.4 (s,
3H); 13C NMR (CDCl3, 50 MHz) δ157.4, 150.3, 145.3, 139.8,
136.0, 131.0, 130.6, 130.3, 129.8, 129.5, 129.2, 127.4, 124.0,
1233, 118.6, 102.6, 21.3; MS (MOLDI-TOP), m/z 374.2 (Anal.
calcd. (%) for C, 70.60; H, 4.31; Br, 21.35; N, 3.74. Found
(%); C, 70.65; H, 4.29; Br, 21.34; N, 3.72).
7-Bromo-2-methylyl- 4-phenylquinolone (3j): m.p.:
122-123 °C; 1H NMR (CDCl3, 200 MHz) δ7.7 (d, 1H), 7.6 (d,
1H), 7.4-7.5 (m, 3H), 6.9-7.0 (t, 1H), 6.9 (s, 1H), 2.0 (s, 3H);
13C NMR (CDCl3, 50 MHz) δ160.0, 148.3, 145.0, 130.4, 129.5,
129.3, 127.4, 123.8, 120.9, 119.7; MS (MOLDI-TOP), m/z
298 (Anal. calcd. For C, 64.45; H, 4.06; Br, 26.80; N, 4.70
Found; C, 64.43; H, 4.08; Br, 26.80; N, 4.70).
General procedure for the preparation of dibenzo-
[b,f][1,5]diazocines (4): 2-Amino-4-bromobenzophenone (1.0
mmol) and 0.5 equivalents of DPP (0.5 mmol, purchased from
Aldrich) were mixed in the absence of any organic solvent
and then submitted for 3 min to microwave irradiation inside
a domestic microwave oven (Samsung, RE-555 TCW). The
work-up procedure is same as reported earlier10.After concen-
tration under reduced pressure, the residue was purified by
flash column chromatography on silica gel (EtOAc/n-hexane
= 1:20, v/v) to give the corresponding (5z,11z)-3,9-dibromo-
6,12-diphenyl-dibenzo[b,f][1,5]diazocine (4). m.p.: 190-192
°C; 1H NMR (CDCl3, 200 MHz) δ8.1-8.2 (d, 4H), 7.7 (d, 2H),
7.6-7.7 (t, 4H), 7.3-7.4 (d, 2H), 7.3 (t, 4H); 13C NMR (CDCl3,
50 MHz) δ131.8, 131.6, 131.2, 130.7, 129.2, 128.7, 128.2,
127.5, 123.1; MS (MOLDI-TOP), m/z 513.9 (Anal. calcd. (%)
for C, 66.49; H, 3.12; Br, 30.96; N, 5.43. Found (%); C, 66.48;
H, 3.10; Br, 30.99; N, 5.43).
7-Bromo-2-(furan-2-yl)-4-phenylquinolone (3d): m.p.:
122-125 °C; 1H NMR (CDCl3, 200 MHz) δ8.3 (s, 1H), 7.7 (d,
1H), 7.7 (d, 1H), 7.6-7.7 (m, 5H), 7.2-7.5 (m, 5H), 6.6 (t, 1H);
13C NMR (CDCl3, 50MHz) δ158.8, 157.7, 150.3, 145.3, 142.9,
139.8, 131.0, 130.6, 129.8, 129.2, 127.4, 124.0, 118.6, 112.0,
107.1, 102.6; MS (MOLDI-TOP), m/z 349 (Anal. calcd. (%)
for C, 65.16; H, 3.45; Br, 22.82; N, 4.00. Found (%); C, 65.11;
H, 3.47; Br, 22.83; N, 4.02).
7-Bromo-2-(furan-3-yl)-4-phenylquinolone (3e): m.p.:
1
126-127 °C; H NMR (CDCl3, 200 MHz) δ8.0 (s, 1H), 7.7-
7.9 (d, 2H), 7.5-7.9 (d, 2H), 7.5-7.6 (m, 4H), 7.2-7.5 (m, 4H),
6.2 (d, 1H); 13C NMR (CDCl3, 50MHz) δ157.4, 150.3, 145.3,
144.1, 139.8, 138.5, 131.0, 130.6, 129.8, 129.3, 129.2, 127.4,
124.0, 118.6, 108.8, 102.6; MS (MOLDI-TOP), m/z 349 (Anal.
calcd. (%) for C, 65.16; H, 3.45; Br, 22.82; N, 4.00. Found
(%); C, 65.16; H, 3.45; Br, 22.82; N, 4.00).
RESULTS AND DISCUSSION
Acetylpyridines, 2-acetylfuran, 2-acetylthiophene,
acetyimidazoles, acetone and 4-methyl-acetophenone were
condensed with 2-amino-4-bromobenzophenone (1) under the
above mentioned optimal reaction conditions. The results are
summarized in Table-1. Condensation of 2a-j with 1 afforded
quinolines in good yields (60.0-74.5 %); in these reactions,
(5z,11z)-3,9-dibromo-6,12-diphenyl-dibenzo[b,f][1,5]
diazocine (4) was isolated as the minor product. The effect of
microwave irradiation on quinoline formation can be explained
on the basis of microwave activation effects caused by dipole-
dipole interactions, mechanistic considerations and the increase
in the polarity of the system (P) during the progress of the
reaction9,10. 6,12-Diphenyl-dibenzo[b,f][1,5]diazocine (4) is
a minor product formed by the self-condensation (Q) of 1.
7-Bromo-4-phenyl-2-(thiophen-2-yl)quinolone (3f):
m.p.: 143-144 °C; 1H NMR (CDCl3, 200 MHz) δ8.6 (d, 1H),
7.7 (d, 1H), 7.6-7.7 (m, 6H), 7.6 (m, 3H), 7.3 (t, 1H); 13C
NMR (CDCl3, 50MHz) δ158.8, 150.3, 145.3, 142.4, 139.8,
131.0, 130.6, 129.8, 128.6, 128.0, 127.6, 124.0, 118.6, 102.6;
MS (MOLDI-TOP), m/z 366.3 (Anal. calcd. (%) for C, 62.30;
H, 3.30; Br, 21.82; N, 3.82; S, 8.75. Found (%); C, 62.30; H,
3.33; Br, 21.79; N, 3.81; S, 8.76).
7-Bromo-2(1H-imidazol-1-yl)-4-phenylquinoline (3g):
m.p.: 135-137 °C; 1H NMR (CDCl3, 200 MHz) δ7.7 (s, 1H),
7.6 (d, 1H), 7.5-7.6 (m, 3H), 7.3-7.5 (m, 5H), 6.9 (d, 2H); 13C
NMR (CDCl3, 50MHz) δ159.4, 150.0, 146.0, 143.5, 134.5,
131.0, 130.6, 129.8, 129.2, 127.8, 127.4, 124.0,121.2, 111.4;
MS (MOLDI-TOP), m/z 349 (Anal. calcd. (%) for C, 61.73;
H, 3.43; Br, 22.82; N, 12.00. Found (%); C, 61.72; H, 3.40;
Br, 22.83; N, 12.03).
7-Bromo-4-phenyl-2-(pyrazin-2-yl)quinolone (3h):
m.p.: 160-161 °C; 1H NMR (CDCl3, 200 MHz) δ8.2 (t, 3H),
7.9 (d, 1H), 7.7 (t, 1H), 7.5-7.7 (m, 4H), 7.1-7.3 (m, 3H); 13C
NMR (CDCl3, 50MHz) δ151.1, 150.3, 146.6, 145.3, 144.7,
144.4, 142.3, 139.8, 131.6, 129.8, 129.2, 127.4, 124.0, 118.6,
102.6; MS (MOLDI-TOP), m/z 361 (Anal. calcd. (%) for C,
63.00; H, 3.34; Br, 22.06; N, 11.6. Found (%); C, 62.98; H,
3.32; Br, 22.09; N, 11.61).
H
O
O
X
N
H
N
H
H
R
O
X
N
H
P
Q

Vol. 26, No. 7 (2014)
Synthesis of Quinolines and Dibenzo[b,f][1,5]Diazocines by MW-Assisted Solvent-Free Method 1993
TABLE-1
CONDENSATION OF 1 WITH VARIOUS HETEROAROMATIC KETONES 2a-j UNDER MW IRRADIATION
Product
2-Amino-4-bromo-
Heteroaromatic
Entry
Quinolines 3a-j
Dimer 4b
Yield (%)a
Benzophenone (1)
Ketone 2a-j
NH2
O
N
CH3
C
1
a
b
c
71
O
N
Br
N
Br
Br
Br
4
13.2
74.3
15.1
66.5
9.4
N
CH3
C
2
3
4
5
6
7
O
N
N
4
CH3
O
N
C
N
N
4
CH3
O
C
d
e
f
77.0
11.4
78.5
8.9
O
O
N
Br
Br
Br
Br
Br
4
CH3
C
O
O
N
O
4
CH3
S
C
72.5
15.8
78.1
10.4
O
S
N
4
CH3
C
N
g
N
O
N
N
N
4
N
CH3
O
C
8
h
75.1
10.2
N
N
N
N
4

1994 Choi et al.
Asian J. Chem.
CH3
H3C
C
9
i
77.7
O
N
Br
H3C
4
4
9.3
74.6
8.2
O
10
j
H3C
CH3
H3C
N
Br
a Isolated yield.
Br
N
N
b
Br
Product 4
TABLE-2
SYNTHESIS OF 4 USING VARIOUS CATALYSTS UNDER MICROWAVE IRRADIATION
Entry
Catalyst
1 (mol)
1.0
2a (mol)
Yield of 4a (%)
1
1.0
DPP
DPP
12.2
84.7
65.3
43.2
16.5
2
1.0
-
-
-
-
3
1.0
HCl
4
1.0
H3PO4
CH3COOH
5
1.0
aIsolated yields.
In order to broaden the scope of the proposed reaction,
we carried out reactions of 2-amino-4-bromobenzophenones
with acetylpyridines (2a-c). 7-Bromo-4-phenyl-2-(pyridine-
2-yl)quinoline (3a), 7-bromo-4-phenyl-2-(pyridine-3-
yl)quinolone (3b) and 7-bromo-4-phenyl-2-(pyridine-4-yl)
quinolone (3c) were isolated as the major products in good
yields from 2a, 2b and 2c, respectively. In this case, (5z,11z)-
3,9-dibromo-6,12-diphenyl-dibenzo[b,f][1,5]diazocine(4) was
obtained as the minor product in low yield (entry 4: 11.4 %;
entry 5: 8.9 %; and entry 6: 15.8 %). Therefore, it is important
to ensure that the bromo functionality is unaffected under the
present reaction conditions
ACKNOWLEDGEMENTS
This work was supported by the grant from Dong-A
University Fund in 2013.
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The self-condensation of 1 afforded 4 as the only product.
In order to investigate the effect of DPP on product formation,
the synthesis of 4 was carried out under microwave irradiation
using different amounts (in equivalents) of DPP. The obtained
yield of 4 was higher when using anhydrous DPP than when
using HCl, H3PO4 and CH3COOH (Table-2). The cyclization
reaction proceeded effectively in the presence of DPP, as shown
in the two reaction mechanisms for the formation of quinolines
and dibenzo[b,f][1,5]diazocine.
In summary, we have employed a microwave-assisted
solvent-free method ('green chemistry' conditions) to synthe-
size quinoline and dibenzo[b,f][1,5]diazocine derivatives. The
yields obtained with the proposed synthesis method are
markedly higher than those obtained in conventional thermal
reactions; further, this method does not require hazardous
solvents and excess amounts of expensive acidic catalysts. In
addition, this method is economical, environmentally benign
and affords the desired product within a short time.
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