Structurally diversified products from the reactions of 2-aminobenzamides with 1,3-cyclohexanediones catalyzed by iodine

Article abstract of DOI:10.1016/j.tetlet.2012.11.042

Controlling the reaction temperature at 50 °C, 80 °C, and 110 °C, respectively, the iodine-catalyzed reaction of 2-aminobenzamides with 1,3-cyclohexanediones gave structurally diversified products. In the latter, it gave bis-quinazolin-4(3H)-ones unexpectedly, with 1,3-cyclohexanediones ring-opening.

Full text of DOI:10.1016/j.tetlet.2012.11.042

Tetrahedron Letters 54 (2013) 757–760
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Structurally diversified products from the reactions of 2-aminobenzamides
with 1,3-cyclohexanediones catalyzed by iodine
Lian Lu a, Mei-Mei Zhang b, Hong Jiang b, Xiang-Shan Wang a,
⇑
a School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Jiangsu Normal University,
Xuzhou Jiangsu 221116, PR China
b The Key Laboratory of Biotechnology on Medical Plant of Jiangsu Province, Jiangsu Normal University, Xuzhou Jiangsu 221116, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Controlling the reaction temperature at 50 °C, 80 °C, and 110 °C, respectively, the iodine-catalyzed reac-
tion of 2-aminobenzamides with 1,3-cyclohexanediones gave structurally diversified products. In the lat-
ter, it gave bis-quinazolin-4(3H)-ones unexpectedly, with 1,3-cyclohexanediones ring-opening.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 13 August 2012
Revised 5 November 2012
Accepted 9 November 2012
Available online 2 December 2012
Keywords:
Quinazolin-4(3H)-one
2-Aminobenzamide
1,3-Cyclohexanedione
Iodine
Introduction
ring-opening of 1,3-cyclohexanedione, novel bis-quinazolin-4(3H)-
one derivatives were obtained in moderate yields respectively.
Quinazoline and its derivatives are an important class of hetero-
cyclic compounds, which have attracted a considerable attention
for their anti-cancer activity,1 and have also been tested for their
potential biological and pharmacological activities, for example
anti-inflammatory,2 anti-hypertensive,3 anti-tumor,4 and anti-bac-
terial activity.5 Recently, they have also been evaluated as antago-
nists of various biological receptors, such as treating 5-HT5A
receptor related diseases,6 antagonists of calcitonin gene-related
peptide receptor,7 vasopressin V3 receptor antagonists.8 Hence,
the synthesis of quinazoline derivatives is currently of great inter-
est both in organic synthesis and medicinal chemistry.9
To our knowledge, only a few literature studies concern about
the synthesis of bis-quinazoline derivatives.10 As a novel member
of this family, it contains two quinazoline moieties, may afford
unique biological activities. In our previous study,10a we have
described that quinazolin-4(3H)-one or bis-quinazolin-4(3H)-one
derivatives were obtained in high yields, using 2-aminobenza-
mides and various kinds of aldehydes or ketones including 1,4-
cyclohexanedione as reactants in ionic liquids catalyzed by iodine.
As a continued study to the synthesis of the potential biological
active molecules and with iodine-catalyzed reactions, herein,
we would like to report the reaction of 2-aminobenzamide with
1,3-cyclohexanedione catalyzed by iodine. With the unexpected
Results and Discussions
Treatment of 2-aminobenzamide 1a with an equivalent of 5,5-
dimethyl-1,3-cyclohexanedione (dimedone) 2a in toluene at
100 °C catalyzed by 5 mol % iodine, gave 2-(3-(1,2,3,4-tetrahydro-
2-methyl-4-oxoquinazolin-2-yl)-2,2-dimethylpropyl)quinazolin-
4(3H)-one 3a in 42% yield unexpectedly (Scheme 1).
Subsequently, reaction conditions including reaction tempera-
ture, amount of iodine, and mole ratio, were optimized in our
lab. The yield of 3a was improved to 72% in toluene at reflux cata-
lyzed by 10 mol % iodine, with a molar ratio of 1a and 2a being
2.1:1. Under the optimized reaction conditions, various kinds of
2-aminobenzamides 1 and 1,3-cyclohexanediones 2 were sub-
jected to the reaction to give 3a–i in moderate yields (65–75%,
Scheme 2, Table 1). The structure of 3a was confirmed by X-ray dif-
fraction analysis, and its crystal structure is shown in Figure 1.
According to the structure of the product and the literature,12
we think that the dehydration, isomerization, cyclization, ring-
opening of dimedone, second dehydration, and cyclization reac-
tions may take place in a sequence. The proposed mechanism
was outlined in Scheme 3.
In order to get more insight into the above-mentioned reaction,
we lowered the reaction temperature to obtain the intermediates.
To our delight, intermediate 5a was isolated in 43% yield,13 when
the reaction temperature was controlled at 80 °C, with the molar
ratio of 1a and 2a being 1.1:1 (Scheme 4). The structure of 5a
⇑
Corresponding author.
E-mail address: xswang1974@yahoo.com (X.-S. Wang).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.042

758
L. Lu et al. / Tetrahedron Letters 54 (2013) 757–760
O
O
O
H
N
NH
NH2
I2
+
N
toluene
O
NH2
1a
HN
O
2a
3a
Scheme 1. The model reaction of 1a and 2a.
O
O
O
O
R1
H
N
NH
NH2
R
NH2
NH2
R1
R2
I2
R
R
+
O
+
N
R
R2
HN
NH2
O
2
1
3
1
Scheme 2. The reaction of 1 and 2 in toluene.
Table 1
O
O
O
a,11
Synthetic results of 3a–i in toluene
I2, 80 o
C
NH
NH2
R1
R2
Time (h)
Isolated yields (%)
R
R
Products
R
+
NH2
N
O
3a
3b
3c
3d
3e
3f
3g
3h
3i
H
CH3
CH3
CH3
CH3
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
12
15
16
10
15
12
11
14
13
72
68
70
75
65
73
67
70
65
O
4-Cl
5-Cl
5-CH3
H
5-CH3
5-Br
4-Cl
5-CH3
5
1
2
5a: R = H, 43 %; 5b: R = 5-CH3, 58 %; 5c: R = 5-Br, 62 %
Scheme 4. The synthetic route of products 5a–c.
a
Reaction condition: toluene (10.0 mL), 1 (2.1 mmol), 2 (1.0 mmol) and iodine
(0.026 g, 0.01 mmol), 110 °C.
was agreed with the one14 reported by Miyano and Lessel,
respectively.
In our continued study, intermediate products 5 were obtained
without further separation, then, they were treated with another
equivalent of different 2-aminobenzamide directly at 110 °C
(Scheme 5), giving structurally diversified bis-quinazolin-4(3H)-
one derivatives 6a–g in moderate yields (Table 2) as we expected.
Figure 1. Crystal structure of product 3a.
I2
O
O
O
NH2
NH2
isomerization
dehydration
+
NH2
N
O
2
1
I2
O
O
O
I2
NH2
O
NH
NH
ring-opening
NH
N
cyclization
O
N
H
O
I2
O
I2
5
4
O
O
H2N
N
O
H
N
NH
NH
-I2
dehydration
cyclization
N
1
N
HN
I2
O
3
Scheme 3. The possible mechanism for the formation of product 3.

L. Lu et al. / Tetrahedron Letters 54 (2013) 757–760
759
O
N
O
H
N
NH
I2
80 o
NH
I2
1
+
2
R
R
C
110 o
C
R1
N
HN
O
O
5
6
without separation
Scheme 5. The crisscross reaction of 2 with two different equivalents of 1.
Table 2
Synthetic results of 6a–g in toluene
a,15
Entry
R
R1
Products
Isolated yields (%)
1
2
3
4
5
6
7
H
H
H
H
H
5-CH3
5-CH3
5-Br
3-CH3
4-Cl
5-Cl
5-CH3
4-Cl
6a
6b
6c
6d
6e
6f
63
65
70
74
65
76
70
5-Cl
6g
a
Reaction condition: toluene (10.0 mL),
1
(1.1 mmol), dimedone (0.140 g,
1.0 mmol), and iodine (0.026 g, 0.01 mmol), 80 °C; then 1 (1.0 mmol), 110 °C.
Figure 2. Crystal structure of product 6d.
Figure 3. Crystal structure of intermediate 4f.
Table 3
One of the products 6d was also confirmed by X-ray diffraction
analysis and its crystal structure is shown in Figure 2.
a,16
Synthetic results of 4a–l in toluene
Entry
R
R1
Products Time (h) Isolated yields (%)
It is very interesting that intermediates 4a–l were obtained in
high yields (Table 3), when the reaction temperature was further
lowered to 50 °C catalyzed by 5 mol % iodine. In addition, it was
found that 4 with substituent on the nitrogen atom of amide could
not be further converted into 5. Perhaps, a high steric effect hin-
dered the subsequent cyclization and ring-opening reactions.
Therefore, the reaction was held at the stage of enamine (Scheme 6).
The structure of 4f was additionally confirmed by X-ray diffraction
analysis and its crystal structure is shown in Figure 3.
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
Ph
4a
4b
6
8
90
92
87
84
88
90
93
91
87
90
86
86
4-MeOC6H4CH2 4c
8
3-Cl-4-FC6H3
4-FC6H4
4-MeC6H4
2-Furylmethyl
4-i-PrC6H4
4-n-BuC6H4
H
4d
4e
4f
10
10
8
4g
4h
4i
8
8
6
9
H
10
11
12
5-Me
5-Cl
5-Br
4j
6
H
H
4k
4l
10
10
Conclusion
a
Reaction condition: toluene (10 mL),
1
(2.1 mmol), dimedone (0.280 g,
In summary, the interesting and iodine-catalyzed reaction of 2-
aminobenzamides with 1,3-cyclohexanediones is described in this
Letter. Controlling the reaction temperature, it gives structurally
diversified products, respectively, and produces novel and unex-
pected bis-quinazolinone derivatives at 110 °C finally.
2.0 mmol), and iodine (0.026 g, 0.01 mmol), 50 °C.
O
O
I2, 80 oC
R1
NHR1
I2
50 o
N
R
1
2
+
R
C
Acknowledgements
NH
N
R1
O
H
We are grateful to the National Natural Science foundation of
China (20802061), a Project Funded by the Priority Academic Pro-
gram Development of Jiangsu Higher Education Institutions, Qing
Lan Project (10QLD008) and College Industrialization Project
(JHB2012-31) of Jiangsu Province for the financial support.
O
4
5
Scheme 6. The reaction of 1 and 2 at 50 °C.

760
L. Lu et al. / Tetrahedron Letters 54 (2013) 757–760
373855.; (c) El-Sharief, A. M. S.; Ammar, Y. A.; Zahran, M. A.; Kh. Sabet, H.
Supplementary data
Phosphorus, Sulfur Silicon Related Elements 2004, 179, 267–275; (d) Yang, X.;
Wu, M.; Ding, M. Youji Huaxue 2010, 30, 1032–1038; (e) Yang, X.-H.; Wu, M.-
H.; Sun, S.-F.; Ding, M.-W.; Xie, J.-L.; Xia, Q.-H. J. Heterocycl. Chem. 2008, 45,
1365–1369; (f) Helmholz, F.; Schroeder, R.; Langer, P. Synthesis 2006, 15, 2507–
2514.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
11.042.
11. General procedure for the synthesis of 3: A dry 50 mL flask was charged with 2-
aminobenzamides 1 (2.1 mmol), 1,3-cyclohexanedione 2 (1.0 mmol), iodine
(0.026 g, 0.01 mmol) and toluene (10.0 mL). The mixture was stirred at reflux
until the reactant was consumed. After the completion of the reaction
monitored by TLC, toluene was recovered by distillation under reduced
pressure, and the residue was purified by silica column chromatography
using ethyl acetate and petroleum ether (1:3) as the eluent to give 3. 2-(2,2-
Dimethyl-3-(2-methyl-4-oxo-1,2,3,4-tetrahydroquinazolin-2-
References and notes
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Jackman, A. L. Bioorg. Med. Chem. 2006, 14, 5020–5042.
yl)propyl)quinazolin-4(3H)-one (3a): mp 250–252 °C; 1H NMR (DMSO-d6,
400 MHz): dH 1.10 (s, 3H, CH3), 1.12 (s, 3H, CH3), 1.41 (s, 3H, CH3), 1.74–1.84
(m, 2H, CH2), 2.67–2.77 (m, 2H, CH2), 6.59–6.65 (m, 2H, ArH), 6.89 (s, 1H, NH),
7.19–7.23 (m, 1H, ArH), 7.47–7.51 (m, 1H, ArH), 7.57–7.63 (m, 2H, ArH), 7.79–
7.83 (m, 1H, ArH), 8.11 (d, J = 8.0 Hz, 1H, ArH), 8.26 (s, 1H, NH), 12.20 (s, 1H,
NH). 13C NMR (DMSO-d6, 100 MHz): dC 28.9, 31.2, 35.0, 45.6, 48.6, 69.7, 113.2,
114.0, 116.0, 120.6, 125.7, 126.1, 126.6, 127.1, 133.3, 134.4, 146.7, 148.2, 156.0,
161.6, 162.6. IR (KBr): 3374, 3139, 3036, 2969, 2928, 2780, 1600, 1567, 1518,
1501, 1470, 1436, 1387, 1275, 1248, 1224, 1196, 1145, 1132, 1072, 894, 788,
765 cmÀ1. HRMS (ESI, m/z): calcd for C22H24N4O2Na [M+Na]+ 399.1797, found
399.1846.
12. Maloshitskaya, O. A.; Sinkkonen, J.; Alekseyev, V. V.; Zelenin, K. N.; Pihlaja, K.
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13. General procedure for the synthesis of 5: A dry 50 mL flask was charged with 2-
aminobenzamides
1 (1.1 mmol), dimedone (0.140 g, 1.0 mmol), iodine
(0.026 g, 0.01 mmol) and toluene (10.0 mL). The mixture was stirred at 50 °C
until the reactant was consumed. After the completion of the reaction
monitored by TLC, toluene was recovered by distillation under reduced
pressure, and the residue was purified by silica column chromatography
using ethyl acetate and petroleum ether (1:3) as the eluent to give products 5.
2-(2,2-Dimethyl-4-oxopentyl) quinazolin-4(3H)-one (5a): mp 157–158 °C
(Lit.14b: 158–160 °C); 1H NMR (DMSO-d6, 400 MHz): dH 1.06 (s, 6H, 2CH3),
2.11 (s, 3H, CH3), 2.04 (s, 2H, CH2), 2.64 (s, 2H, CH2), 7.45–7.49 (m, 1H, ArH),
7.59 (d, J = 8.0 Hz, 1H, ArH), 7.76–7.80 (m, 1H, ArH), 8.09 (d, J = 7.6 Hz, 1H,
ArH), 12.08 (s, 1H, NH). IR (KBr): 3166, 3038, 3003, 2950, 2919, 2881, 1714,
1684, 1617, 1470, 1419, 1399, 1366, 1337, 1262, 1252, 1162, 964, 908,
772 cmÀ1. HRMS (ESI, m/z): calcd for C15H17N2O2 [MÀH]À 257.1282, found
257.1288.
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N.; Takeda, K.; Sumoto, K. Synthesis 1983, 5, 401–402.
15. General procedure for the synthesis of 6: A dry 50 mL flask was charged with 2-
aminobenzamide 1 (1.1 mmol), dimedone (0.140 g, 1.0 mmol), iodine (0.026 g,
0.01 mmol) and toluene (10.0 mL). The mixture was stirred at 80 °C until the
reactant was consumed. Then, another equivalent of 2-aminobenzamide was
added to the mixture, and refluxed for a few hours. After the completion of the
reaction monitored by TLC, toluene was recovered by distillation under
reduced pressure, and the residue was purified by silica column chromatog-
raphy using ethyl acetate and petroleum ether (1:2) as the eluent to give
products 6. 2-(3-(6-Chloro-2-methyl-4-oxo-1,2,3,4-tetrahydroquinazolin-2-
yl)-2,2-dimethylpropyl)quinazolin-4(3H)-one (6d): mp 258–262 °C; 1H NMR
(DMSO-d6, 400 MHz): dH 1.09 (s, 3H, CH3), 1.11 (s, 3H, CH3), 1.42 (s, 3H, CH3),
1.76–1.86 (m, 2H, CH2), 2.74–2.79 (m, 2H, CH2), 6.67 (d, J = 8.4 Hz, 1H, ArH),
7.10 (s, 1H, NH), 7.24 (d, J = 8.0 Hz, 1H, ArH), 7.47–7.50 (m, 2H, ArH), 7.59–7.61
(m, 1H, ArH), 7.79–7.82 (m, 1H, ArH), 8.10 (d, J = 7.6 Hz, 1H, ArH), 8.45 (s, 1H,
NH), 12.18 (s, 1H, NH). IR (KBr): 3286, 3209, 3128, 3043, 2974, 2927, 1687,
1651, 1613, 1516, 1487, 1472, 1452, 1425, 1359, 1336, 1251, 1219, 1196, 1148,
1136, 1125, 1074, 1012, 971, 919, 901, 824, 787, 771 cmÀ1. HRMS (ESI, m/z):
calcd for C22H23ClN4NaO2 [M+H]+ 411.1588, found 411.1602.
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16. General procedure for the synthesis of 4: A dry 50 mL flask was charged with 2-
aminobenzamides
1 (2.1 mmol), dimedone (0.280 g, 2.0 mmol), iodine
(0.026 g, 0.01 mmol) and toluene (10.0 mL). The mixture was stirred at 50 °C
until the reactant was consumed. After the completion of the reaction
monitored by TLC, toluene was recovered by distillation under reduced
pressure, and the residue was purified by recrystallization in EtOH to give
products 4. 2-((5,5-Dimethyl-3-oxocyclohex-1-en-1-yl)amino)-N-(p-tolyl)-
benzamide (4f): mp 212–214 °C; 1H NMR (DMSO-d6, 400 MHz): dH 0.96 (s,
6H, 2CH3), 1.99 (s, 2H, CH2), 2.27 (s, 3H, CH3), 2.33 (s, 2H, CH2), 5.15 (s, 1H, CH),
7.14 (d, J = 8.4 Hz, 2H, ArH), 7.31–7.39 (m, 2H, ArH), 7.53–7.57 (m, 3H, ArH),
7.69 (d, J = 7.6 Hz, 1H, ArH), 8.89 (s, 1H, NH), 10.26 (s, 1H, NH). IR (KBr): 3275,
3187, 3133, 2951, 2888, 1651, 1623, 1597, 1487, 1442, 1403, 1369, 1319, 1232,
1210, 1167, 1147, 1119, 1083, 952, 894, 818, 759 cmÀ1. HRMS (ESI, m/z): calcd
for C22H24N2O2Na [M+Na]+ 371.1735, found 371.1761.
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quinazoline compounds for the treatment of bacterial infections and their
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