Regioselective synthesis of 9,10-dihydro-6H-chromeno[4,3-d]imidazo-[1,2-a] pyridin-6-one derivatives

Article abstract of DOI:10.1039/c3ra46428h

A method for regioselective synthesis of 9,10-dihydro-6H-chromeno[4,3-d] imidazo[1,2-a]pyridin-6-one derivatives has been developed. The reaction was readily performed by reacting inexpensive materials, 4-chloro-3-formylcoumarin and HKAs, in EtOH catalyzed by Et₃N. This protocol has many advantages including convenient operation, short reaction times, green solvent, and simple purification by washing the crude products with 95% EtOH, defined as GAP (Group-Assistant-Purification) chemistry. The library of 9,10-dihydro-6H-chromeno[4,3-d]imidazo[1,2-a]pyridin-6-one derivatives has been constructed with excellent yields.

Full text of DOI:10.1039/c3ra46428h

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PAPER
Regioselective synthesis of 9,10-dihydro-6H-
chromeno[4,3-d]imidazo-[1,2-a]pyridin-6-one
derivatives†
Cite this: RSC Adv., 2014, 4, 6110
a
a
a
c
Fu-Chao Yu,ab Zhi-Qiong Chen, Xiao-Pan Hao, Sheng-Jiao Yan, Rong Huang
*
*
ac
*
and Jun Lin
A method for regioselective synthesis of 9,10-dihydro-6H-chromeno[4,3-d]imidazo[1,2-a]pyridin-6-one
derivatives has been developed. The reaction was readily performed by reacting inexpensive materials,
4-chloro-3-formylcoumarin and HKAs, in EtOH catalyzed by Et3N. This protocol has many advantages
including convenient operation, short reaction times, green solvent, and simple purification by washing
the crude products with 95% EtOH, defined as GAP (Group-Assistant-Purification) chemistry. The library
of 9,10-dihydro-6H-chromeno[4,3-d]imidazo[1,2-a]pyridin-6-one derivatives has been constructed with
excellent yields.
Received 6th November 2013
Accepted 10th December 2013
DOI: 10.1039/c3ra46428h
www.rsc.org/advances
Introduction
Modern chemistry has been inseparably linked with green
chemistry.1 With the increasing prevalence of green chemistry,
alternative technologies that use GAP chemistry, performed
without the use of traditional purication by chromatography
or recrystallization, is of interest in organic synthesis.2 The use
of GAP chemistry synthesis has increased rapidly in recent
years.3 We are pleased to nd that this concept can be extended
to other reactions, as shown in this paper.
Fig. 1 Coumarin derivatives with biological activities.
Coumarin is among the most important heterocyclic
systems, present as a structural framework in a large number of
bioactive natural products.4 Derivatives have also been found
that antitumor,5 antioxidant6 or anti-inammatory7 properties
and act as non-peptidic HIV protease inhibitors,8 top-
oisomerase II Inhibitors,9 tyrosine kinase inhibitors,10 diuretics
and analgesics,11 and so on.12 Heterocycles fused at the 3,4-
position of coumarin have also drawn special attention13 (Fig 1).
For example, Costa and co-workers reported the synthesis of
2H-chromeno[3,4-c]pyridin-5-one derivatives in unsatisfactory
yields.
However, some of the active compounds can be used as
adenosine receptors in the submicromolar range.14
In the past several years, our group has demonstrated that
HKAs are an emerging, more reactive class of functionalized
synthons15 through which a variety of biologically active
heterocyclic16 and fused heterocyclic compounds can be
obtained using easier and more efficient methodologies.17,18
aKey Laboratory of Medicinal Chemistry for Natural Resource (Yunnan University),
Ministry Education, School of Chemical Science and Technology, Yunnan University,
Kunming, 650091, P. R. China. E-mail: yansj@ynu.edu.cn; linjun@ynu.edu.cn; Fax:
+86 871 65033215
bFaculty of Life Science and Technology, Kunming University of Science and
Technology, Kunming, 650504, P. R. China
cAdvanced Analysis and Measurement Center, Yunnan University, Kunming, 650091,
P. R. China. E-mail: huangrong@ynu.edu.cn
† Electronic supplementary information (ESI) available. CCDC 959763. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ra46428h
Scheme 1 This work: Synthesis of 9,10-dihydro-6H-chromeno[4,3-d]-
imidazo[1,2-a]pyridin-6-one derivatives.
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Table 2 Preparation of 9,10-dihydro-6H-chromeno[4,3-d]imidazo-
[1,2-a]pyridin-6-one derivativesa
One concern of our group is green chemistry synthesis of
diverse libraries of compounds under mild reaction conditions.
The green synthesis can usually avoid tedious workup and
purications. Based on these, in this paper we report the
method for a one-pot synthesis of 9,10-dihydro-6H-chromeno-
[4,3-d]imidazo[1,2-a]pyridin-6-one derivatives (Scheme 1).
Results and discussion
Entry
R1
R2
n
4
Yieldb (%)
A initial attempt was made to react HKA 2a with 4-chloro-3-
formylcoumarin 3a using Et3N as the catalyst and acetone as the
solvent at ambient temperature. Aer 10 min, an orange solid
was obtained in about 73% yield aer separation by ltration
(Table 1, entry 1). To establish the optimal reaction conditions,
we screened other solvents by still using Et3N as the catalyst at
ambient temperature (Table 1, entries 2–4). As a result, we
found that EtOH afforded the highest yield (Table 1, entry 4).
Subsequently, we screened different catalysts such as HOAc
(Table 1, entry 6), Na2CO3 (Table 1, entry 5). Among the cata-
lysts, Et3N showed the highest efficiency (Table 1, entries 5–7).
Having demonstrated the viability of this cascade strategy,
different kinds of HKAs and 3-formylcoumarins were used as
substrates to synthesize the target compound library under
optimized condition. As shown in Table 2, most of the substrates
afforded products in good yields (80–96%). 4-chloro-3-for-
mylcoumarin 3a was used as the standard substrate initially.
Entries 1–6 in Table 2 demonstrate that the reaction tolerated
signicant functionalization of ve-member HKAs; substrates
with electron-donating groups (such as Me and OMe) on the
phenyl ring of the HKAs gave better yields than substrates
without substituents or electron-withdrawing groups (such as F
and Cl). The yields of substrates of six-member HKAs were
similar to those with ve-member HKAs (Table 2, entries 12–17).
Changing the hydrogen to a bromo group at the 6-position of
4-chloro-3-formylcoumarin resulted in products with relatively
high yields (Table 2, entries 7–11).
1
2
3
4
5
6
7
8
p-F (2a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
Br (3b)
Br (3b)
Br (3b)
Br (3b)
Br (3b)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
Br (3b)
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
80
83
87
91
93
95
88
90
94
95
96
84
88
91
92
94
90
p-Cl (2b)
o-Cl (2c)
H (2d)
p-Me (2e)
p-OMe (2f)
p-F (2a)
p-Cl (2b)
H (2d)
p-Me (2e)
p-OMe (2f)
p-F (2g)
p-Cl (2h)
H (2i)
p-Me (2j)
p-OMe (2k)
o-Cl (2l)
9
10
11
12
13
14
15
16
17
a
Reagents and conditions: HKA 2 (0.5 mmol), 4-chloro-3-formylcoumarin
b
3 (0.5 mmol), catalyst (10 mmol%), solvent (5.0 mL). Isolated yield
based on HKA 2.
A proposed mechanism for the synthesis of 9,10-dihydro-
6H-chromeno[4,3-d]imidazo[1,2-a]pyridin-6-one derivatives 4 is
shown in Scheme 2. Being the strong electron-withdrawing
keto-carbonyl groups at the a-position of the HKA and the
electron-donating diamino groups of HKA. HKA reacted with
4-chloro-3-formylcoumarin 3 via addition of an azaene,19
internal elimination of HCl to afford 5 catalyzed by Et3N. The
intermediate 5 is followed by imine–enamine tautomeriza-
tion20 and to yield product 6. Subsequently, intramolecular
attack of the NH group at the aldehyde group occurs via a
cyclization reaction to form 7. Finally, H2O was removed from 7
to give 9,10- dihydro-6H-chromeno[4,3-d]imidazo[1,2-a]pyr-
idin-6-onederivative 4.
Table 1 Optimization of reaction conditionsa
To verify the structure of the 9,10-dihydro-6H-chromeno[4,3-
d]imidazo[1,2-a]pyridin-6-one derivatives, 4d was selected as a
representative compound and characterized by X-ray crystal-
lography as shown in Fig. 2.
Entry
Solvent
Catalyst
t (ꢀC)
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
Acetone
H2O
Et3N
Et3N
Et3N
Et3N
Na2CO3
AcOH
—
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
10
10
10
10
10
10
10
73
30
65
80
37
43
24
Conclusions
MeOH
EtOH
EtOH
EtOH
EtOH
In conclusion, we have developed a novel, efficient and one-step
method for the regioselective synthesis of 9,10-dihydro-6H-
chromeno[4,3-d]imidazo[1,2-a]pyridin-6-ones between HKAs
and 4-chloro-3-formylcoumarin under simple and mild reaction
conditions. The advantages of this method include “Green
process” technology – mild reaction conditions, short-time,
excellent yields and simple operation.
a
Reagents and conditions: HKA 2a (0.5 mmol), 4-chloro-3-formyl-
coumarin 3a (0.5 mmol), catalyst (10 mmol%), solvent (5.0 mL).
b
Isolated yield based on HKA 2a.
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Scheme 2 Proposed mechanism for synthesis of 9,10-dihydro-6H-chromeno[4,3-d]imidazo[1,2-a]pyridin-6-one derivatives 4.
1
1004, 751 cmꢁ1; H NMR (500 MHz, CDCl3): d ¼ 4.10–4.12 (m,
2H, NCH2), 4.25–4.29 (m, 2H, NCH2), 6.97–7.00 (m, 1H, ArH),
7.20–7.24 (m, 3H, ArH), 7.41–7.46 (m, 2H, ArH), 8.15–8.18 (m,
2H, ArH), 8.50 (s, 1H, CH); 13C NMR (125 MHz, DMSO-d6
+
CDCl3): d ¼ 49.1, 53.5, 98.8, 115.6, 116.6, 116.8, 118.4, 124.5,
126.9, 132.4, 132.4, 132.4, 132.6, 134.9, 145.9, 152.4, 155.0,
159.3, 165.2, 167.2, 194.1; HRMS (TOF ES+): m/z calcd for
C
21H13FN2O3 [(M + H)+], 361.0983; found, 361.0989.
12-(4-Chlorobenzoyl)-9,10-dihydro-6H-chromeno[4,3-d]imi-
dazo[1,2-a]pyridin-6-one (4b). Orange solid; mp 301–304 ꢀC; IR
(KBr): 1719, 1674, 1622, 1523, 1454, 1274, 1213, 1094, 1000, 743
cmꢁ1; 1H NMR (500 MHz, CDCl3): d ¼ 4.10–4.12 (m, 2H, NCH2),
4.24–4.28 (m, 2H, NCH2), 6.98–7.00 (m, 1H, ArH), 7.23–7.25
(m, 1H, ArH), 7.42–7.45 (m, 2H, ArH), 7.52–7.53 (m, 2H, ArH),
8.07–8.09 (m, 2H, ArH), 8.50 (s, 1H, CH); 13C NMR (125 MHz,
DMSO-d6 + CDCl3): d ¼ 49.2, 53.5, 98.8, 115.4, 115.6, 118.5,
124.6, 126.9, 129.8, 131.2, 132.8, 134.5, 140.0, 146.0, 152.5,
155.0, 159.2, 194.5; HRMS (TOF ES+): m/z calcd for
Fig. 2 ORTEP diagram of 4d; ellipsoids are drawn at the 30% proba-
bility level.
Experimental section
All compounds were fully characterized by spectroscopic data.
The NMR spectra were recorded on a Bruker DRX500 (1H: 500
MHz, 13C: 125 MHz). Chemical shis (d) are expressed in ppm
and J values are given in Hz. Deuterated CDCl3 and DMSO-d6
were used as solvent. IR spectra were recorded on a FT-IR
Thermo Nicolet Avatar 360 using a KBr pellet. The reactions
were monitored by thin layer chromatography (TLC) using silica
gel GF254. The melting points were determined on a XT-4A
melting point apparatus and are uncorrected. HRMs were per-
formed on an Agilent LC/Msd TOF instrument. All chemicals
and solvents were used as received without further purication
unless otherwise stated. Compounds 2 were prepared according
to the literature.21 Materials 3 were synthesized according with
the literature.22
C
21H13ClN2O3 [(M + H)+], 377.0687; found, 377.0689.
12-(2-Chlorobenzoyl)-9,10-dihydro-6H-chromeno[4,3-d]imi-
ꢀ
dazo[1,2-a]pyridin-6-one (4c). Yellow solid; mp 256–258 C; IR
(KBr): 1695, 1592, 1504, 1422, 1375, 1282, 1196, 1046, 755 cmꢁ1
;
1H NMR (500 MHz, DMSO-d6 + CDCl3): d ¼ 4.03–4.07 (m, 2H,
CH2), 4.84–4.88 (m, 2H, CH2), 7.13–7.16 (m, 1H, ArH), 7.26–7.29
(m, 1H, ArH), 7.35 (d, J ¼ 8.15 Hz, 1H, ArH), 7.48 (d, J ¼ 8.05 Hz,
1H, ArH), 7.54–7.62 (m, 2H, ArH), 7.79 (d, J ¼ 7.75 Hz, 1H, ArH),
8.17 (s, 1H, CH); 13C NMR (125 MHz, DMSO-d6 + CDCl3): d ¼
44.7, 51.5, 97.8, 112.1, 114.2, 118.7, 124.6, 127.8, 128.9, 132.1,
133.9, 134.2, 135.4, 135.6, 146.2, 153.1, 155.1, 157.6, 162.7,
194.5; HRMS (TOF ES+): m/z calcd for C21H13ClN2O3 [(M + H)+],
377.0687; found, 377.0681.
General procedure
HKA derivatives 2 (0.5 mmol), 4-chloro-2-oxo-2H-chromene-3-
12-Benzoyl-9,10-dihydro-6H-chromeno[4,3-d]imidazo[1,2-a]-
carbaldehyde derivatives 3 (0.5 mmol) and ethanol (5 mL) were pyridin-6-one (4d). Orange solid; mp 272–275 ꢀC; IR (KBr): 1719,
placed into a 10 mL round-bottom ask and the mixture was 1669, 1617, 1521, 1450, 1327, 1273, 1216, 1145, 1104, 743 cmꢁ1
;
stirred at room temperature for 10 minutes. Upon completion, 1H NMR (500 MHz, DMSO-d6): d ¼ 3.77–3.79 (m, 2H, NCH2),
as monitored by TLC, trimethylamine (10 mmol%) was added 4.17–4.21 (m, 2H, NCH2), 7.00–7.02 (m, 1H, ArH), 7.23–7.25 (m,
and the mixture was stirred at room temperature for 5 minutes. 1H, ArH), 7.28–7.29 (m, 1H, ArH), 7.43–7.45 (m, 1H, ArH), 7.54–
Then the reaction mixture was cooled to room temperature and 7.57 (m, 2H, ArH), 7.68–7.69 (m, 1H, ArH), 8.02 (d, J ¼ 7.80 Hz,
ltered to give the pure crude product, which was further 2H, ArH), 8.68 (s, 1H, CH); 13C NMR (125 MHz, DMSO-d6): d ¼
washed with 95% EtOH to give pure product 4 with a yield of 82– 49.1, 53.4, 98.6, 115.6, 116.0, 118.6, 124.6, 126.9, 129.5, 129.5,
96%. The products were further identied by FTIR, NMR and 129.7, 129.7, 132.8, 134.7, 134.9, 135.7, 146.0, 152.4, 155.0,
HRMS, and were found to be in good agreement with the 159.4, 195.8; HRMS (TOF ES+): m/z calcd for C21H14N2O3 [(M +
assigned structures. (see ESI†).
H)+], 343.1077; found, 343.1080.
12-(4-Fluorobenzoyl)-9,10-dihydro-6H-chromeno[4,3-d]imi-
dazo[1,2-a]pyridin-6-one (4a). Orange solid; mp 291–294 C; IR dazo[1,2-a]pyridin-6-one (4e). Orange solid; mp 271–274 C; IR
12-(4-Methylbenzoyl)-9,10-dihydro-6H-chromeno[4,3-d]imi-
ꢀ
ꢀ
(KBr): 1719, 1669, 1622, 1511, 1327, 1273, 1224, 1147, 1086, (KBr): 1724, 1664, 1618, 1519, 1450, 1323, 1271, 1222, 1139,
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1
1094, 755 cmꢁ1; 1H NMR (500 MHz, DMSO-d6): d ¼ 2.37 (s, 3H, 1111, 967 cmꢁ1; H NMR (500 MHz, DMSO-d6): d ¼ 2.40 (s, 3H,
CH3), 3.76–3.78 (m, 2H, CH2), 4.17–4.21 (m, 2H, CH2), 6.99–7.02 CH3), 3.78–3.80 (m, 2H, CH2), 4.18–4.22 (m, 2H, CH2), 7.21 (d, J ¼
(m, 1H, ArH), 7.23 (d, J ¼ 8.10 Hz, 1H, ArH), 7.31 (d, J ¼ 8.20 Hz, 8.75 Hz, 1H, ArH), 7.38 (d, J ¼ 7.60 Hz, 2H, ArH), 7.43 (s, 1H, ArH),
1H, ArH), 7.35 (d, J ¼ 7.80 Hz, 2H, ArH), 7.42–7.45 (m, 1H, ArH), 7.62 (d, J ¼ 8.70 Hz, 1H, ArH), 7.92 (d, J ¼ 7.45 Hz, 2H, ArH), 8.68 (s,
7.90 (d, J ¼ 7.85 Hz, 2H, ArH), 8.66 (s, 1H, CH); 13C NMR (125 1H, CH); 13C NMR (125 MHz, DMSO-d6): d ¼ 21.7, 49.2, 53.5, 98.1,
MHz, DMSO-d6): d ¼ 21.7, 49.1, 53.4, 98.6, 115.7, 116.2, 118.5, 116.0, 116.9, 117.7, 120.8, 129.2, 129.5, 129.5, 130.4, 130.4, 133.1,
124.6, 126.9, 129.6, 129.6, 130.3, 130.3, 132.8, 133.4, 134.4, 133.2, 135.1, 146.0, 146.2, 151.6, 154.8, 158.9, 195.1; HRMS (TOF
145.7, 145.9, 152.4, 155.0, 159.4, 195.2; HRMS (TOF ES+): m/z ES+): m/z calcd for C22H15BrN2O3 [(M + H)+], 435.0339; found,
calcd for C22H16N2O3 [(M + H)+], 357.1234; found, 357.1233.
435.0335.
12-(4-Methoxybenzoyl)-9,10-dihydro-6H-chromeno[4,3-d]-
2-Bromo-12-(4-methoxybenzoyl)-9,10-dihydro-6H-chrom-eno-
imidazo[1,2-a]pyridin-6-one (4f). Orange solid; mp 224–227 ꢀC; [4,3-d]imidazo[1,2-a]pyridin-6-one (4k). Orange solid; mp 295–
IR (KBr): 1724, 1618, 1519, 1458, 1323, 1268, 1155, 1012, 763 298 ꢀC; IR (KBr): 1719, 1659, 1618, 1514, 1460, 1405, 1325, 1267,
cmꢁ1
;
1H NMR (500 MHz, DMSO-d6): d ¼ 3.76–3.80 (m, 2H, 1219, 1155, 1129, 1033, 955, 829 cmꢁ1
;
1H NMR (500 MHz,
CH2), 3.85 (s, 3H, OCH3), 4.19–4.20 (m, 2H, CH2), 7.01–7.07 (m, DMSO-d6): d ¼ 3.81–3.83 (m, 2H, CH2), 3.85 (s, 3H, OCH3), 4.19–
3H, ArH), 7.24 (d, J ¼ 8.45 Hz, 1H, ArH), 7.36 (d, J ¼ 8.25 Hz, 1H, 4.21 (m, 2H, CH2), 7.08 (d, J ¼ 7.65 Hz, 2H, ArH), 7.18 (d, J ¼ 8.40
ArH), 7.43–7.46 (m, 1H, ArH), 7.98 (d, J ¼ 7.00 Hz, 2H, ArH), 8.68 Hz, 1H, ArH), 7.48 (s, 1H, ArH), 7.59 (d, J ¼ 8.00 Hz, 1H, ArH),
(s, 1H, CH); 13C NMR (125 MHz, DMSO-d6): d ¼ 49.1, 53.4, 56.0, 8.00 (d, J ¼ 7.60 Hz, 2H, ArH), 8.66 (s, 1H, CH); 13C NMR (125
98.6, 115.0, 115.0, 115.8, 116.5, 118.5, 124.6, 127.0, 128.9, 131.9, MHz, DMSO-d6): d ¼ 49.2, 53.6, 56.1, 98.1, 115.1, 115.1, 116.0,
131.9, 132.7, 134.2, 145.8, 152.4, 155.0, 159.4, 164.6, 194.0; 117.1, 117.8, 120.7, 128.7, 129.3, 131.9, 131.9, 132.9, 135.0,
HRMS (TOF ES+): m/z calcd for C22H16N2O4 [(M + H)+], 373.1183; 146.0, 151.6, 154.9, 158.9, 164.8, 193.7; HRMS (TOF ES+): m/z
found, 373.1189.
calcd for C22H15BrN2O4 [(M + H)+], 451.0288; found, 451.0285.
2-Bromo-12-(4-uorobenzoyl)-9,10-dihydro-6H-chromeno [4,3-
10,11-Dihydro-13-(4-uorobenzoyl)-12-azachromeno[4,3-b]-
d]imidazo[1,2-a]pyridin-6-one (4g). Orange solid; mp 296–299 ꢀC; quinolizin-6(9H)-one (4l). Yellow solid; mp 284–287 ꢀC; IR (KBr):
IR (KBr): 1721, 1669, 1623, 1513, 1327, 1224, 1145, 959, 829 cmꢁ1
;
3422, 1720, 1677, 1617, 1550, 1485, 1301, 1232, 1149, 1099, 751
1H NMR (500 MHz, DMSO-d6 + CDCl3): d ¼ 3.79–3.83 (m, 2H, cmꢁ1
;
1H NMR (500 MHz, DMSO-d6): d ¼ 1.81–1.83 (m, 2H,
CH2), 4.19–4.23 (m, 2H, CH2), 7.19 (d, J ¼ 8.70 Hz, 2H, ArH), 7.35– CH2), 3.23 (m, 2H, CH2), 4.08–4.10 (m, 2H, CH2), 6.96–6.97 (m,
7.39 (m, 3H, ArH), 7.59 (d, J ¼ 8.60 Hz, 1H, ArH), 8.10–8.13 (m, 2H, 1H, ArH), 7.17 (d, J ¼ 7.70 Hz, 1H, ArH), 7.26–7.28 (m, 3H, ArH),
ArH), 8.67 (s, 1H, CH); 13C NMR (125 MHz, DMSO-d6 + CDCl3): d ¼ 7.37–7.38 (m, 1H, ArH), 8.04–8.06 (m, 2H, ArH), 8.35 (s, 1H, CH);
49.2, 53.6, 98.2, 116.1, 116.9, 117.1, 117.6, 120.8, 129.1, 132.4, 13C NMR (125 MHz, DMSO-d6): d ¼ 19.8, 44.4, 50.5, 98.4, 115.5,
132.5, 132.5, 133.5, 135.2, 146.3, 151.6, 154.8, 158.8, 165.5, 167.7, 116.6, 116.5, 118.4, 123.4, 124.5, 126.8, 130.7, 132.0, 132.0,
194.1; HRMS (TOF ES+): m/z calcd for C21H12BrFN2O3 [(M + H)+], 132.2, 133.2, 147.8, 148.3, 152.3, 159.5, 164.8–166.8(d, J ¼
439.0088; found, 439.0090.
251.30 Hz), 195.3; HRMS (TOF ES+): m/z calcd for C22H15FN2O3
2-Bromo-12-(4-chlorobenzoyl)-9,10-dihydro-6H-chromeno [4,3- [(M + H)+], 375.1139; found, 375.1147.
d]imidazo[1,2-a]pyridin-6-one (4h). Orange solid; mp 302–305 ꢀC;
10,11-Dihydro-13-(4-chlorobenzoyl)-12-azachromeno[4,3-b]-
IR (KBr): 1714, 1669, 1622, 1523, 1458, 1331, 1272, 1213, 1094, quinolizin-6(9H)-one (4m). Yellow solid; mp 293–296 ꢀC; IR
963, 653 cmꢁ1; 1H NMR (500 MHz, DMSO-d6): d ¼ 3.79–3.81 (m, (KBr): 3419, 1720, 1677, 1617, 1535, 1450, 1303, 1229, 1155, 1097,
2H, CH2), 4.20–4.22 (m, 2H, CH2), 7.23 (d, J ¼ 8.80 Hz, 1H, ArH), 747 cmꢁ1; 1H NMR (500 MHz, DMSO-d6): d ¼ 1.81–1.83 (m, 2H,
7.35–7.36 (m, 1H, ArH), 7.54–7.56 (m, 1H, ArH), 7.63–7.66 (m, 3H, CH2), 3.25–3.27 (m, 2H, CH2), 4.08–4.10 (m, 2H, CH2), 7.00–7.02
ArH), 8.05 (d, J ¼ 8.40 Hz, 1H, ArH), 8.71 (s, 1H, CH); 13C NMR (m, 1H, ArH), 7.22 (d, J ¼ 7.20 Hz, 1H, ArH), 7.26–7.27 (d, J ¼ 7.00
(125 MHz, DMSO-d6): d ¼ 49.2, 53.5, 98.4, 115.8, 116.0, 120.9, Hz, 1H, ArH), 7.42–7.44 (m, 1H, ArH), 7.58 (d, J ¼ 6.80 Hz, 2H,
128.5, 129.0, 130.1, 130.1, 130.4, 131.3, 131.3, 134.3, 135.3, 140.2, ArH), 8.00 (d, J ¼ 6.75 Hz, 2H, ArH), 8.35 (s, 1H, CH); 13C NMR
146.4, 151.7, 154.8, 158.8, 194.6; HRMS (TOF ES+): m/z calcd for (125 MHz, DMSO-d6): d ¼ 19.8, 44.4, 50.5, 98.3, 115.5, 118.6,
C21H12BrClN2O3 [(M + H)+], 454.9793; found, 454.9795.
123.1, 124.7, 126.7, 129.7, 129.7, 130.8, 130.8, 130.8, 132.4, 135.3,
12-Benzoyl-2-bromo-9,10-dihydro-6H-chromeno[4,3-d]imi- 139.2, 147.8, 148.4, 152.3, 159.5, 195.8; HRMS (TOF ES+): m/z
dazo[1,2-a]pyridin-6-one (4i). Orange solid; mp 302.5–305 ꢀC; IR calcd for C22H15ClN2O3 [(M + H)+], 391.0844; found, 391.0847.
(KBr): 1719, 1667, 1618, 1521, 1450, 1326, 1269, 1217, 1109, 963,
10,11-Dihydro-13-benzoyl-12-azachromeno[4,3-b]quinoliz-in-
751 cmꢁ1; 1H NMR (500 MHz, DMSO-d6): d ¼ 3.79–3.81 (m, 2H, 6(9H)-one (4n). Yellow solid; mp 261–264 ꢀC; IR (KBr): 3436,
CH2), 4.19–4.21 (m, 2H, CH2), 7.19–7.20 (m, 1H, ArH), 7.42 (s, 1695, 1593, 1501, 1374, 1279, 1184, 1052, 743 cmꢁ1; H NMR
1
1H, ArH), 7.57–7.59 (m, 3H, ArH), 7.71–7.73 (m, 1H, ArH), 8.03– (500 MHz, DMSO-d6): d ¼ 1.78–1.79 (m, 2H, CH2), 3.27–3.29 (m,
8.04 (m, 2H, ArH), 8.67 (s, 1H, CH); 13C NMR (125 MHz, DMSO- 1H, CH2), 4.07–4.13 (m, 3H, CH2), 6.95–6.97 (m, 1H, ArH), 7.19–
d6): d ¼ 49.2, 53.6, 98.2, 116.0, 116.6, 117.7, 120.8, 129.2, 129.4, 7.20 (d, J ¼ 8.25 Hz, 1H, ArH), 7.28 (d, J ¼ 8.05 Hz, 1H, ArH),
129.4, 129.8, 129.8, 133.4, 135.2, 135.2, 135.6, 146.3, 151.7, 7.38–7.40 (m, 1H, ArH), 7.49–7.52 (m, 2H, ArH), 7.62–7.64 (m,
154.8, 158.9, 195.6; HRMS (TOF ES+): m/z calcd for 1H, ArH), 7.98 (d, J ¼ 7.65 Hz, 2H, ArH), 8.35 (s, 1H, CH); 13C
C
21H13BrN2O3 [(M + H)+], 421.0182; found, 421.0186.
2-Bromo-12-(4-methylbenzoyl)-9,10-dihydro-6H-chromeno [4,3- 118.5, 123.7, 124.6, 126.8, 129.2, 129.2, 129.6, 129.6, 130.5, 132.3,
NMR (125 MHz, DMSO-d6): d ¼ 19.8, 44.4, 50.4, 98.2, 115.6,
d]imidazo[1,2-a]pyridin-6-one (4j). Orange solid; mp 308–311 C; 134.3, 136.5, 147.8, 148.3, 152.2, 159.6, 196.9; HRMS (TOF ES+):
ꢀ
IR (KBr): 1719, 1663, 1618, 1515, 1475, 1417, 1335, 1271, 1216, m/z calcd for C22H16N2O3 [(M + H)+], 357.1234; found, 357.1243.
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Paper
4 (a) V. Arango, S. Robledo, B. Son-Mniel, F. Bruno, C. Wilson,
S. Jairo and O. Felipe, J. Nat. Prod., 2010, 73, 1012; (b) G. Li,
D. Wang, M. Sun, G. Li, J. Hu, Y. Zhang, Y. Yuan, H. Ji,
N. Chen and G. Liu, J. Med. Chem., 2010, 53, 1741; (c)
F. Leonetti, A. Favia, A. Rao, R. Aliano, A. Paluszcak,
R. W. Hartmann and A. Carotti, J. Med. Chem., 2004, 47,
6792; (d) M. Catto, O. Nicolotti, F. Leonetti, A. Carotti,
10,11-Dihydro-13-(4-methylbenzoyl)-12-azachromeno[4,3-b]-
quinolizin-6(9H)-one (4o). Yellow solid; mp 279–282 ꢀC; IR
(KBr): 1720, 1677, 1535, 1450, 1303, 1229, 1155, 1097, 747 cmꢁ1
;
1H NMR (500 MHz, DMSO-d6): d ¼ 1.82–1.84 (m, 2H, CH2), 2.37
(s, 3H, CH3), 3.32–3.34 (m, 1H, CH2), 4.08–4.10 (m, 3H, CH2),
6.92–6.95 (m, 1H, ArH), 7.17 (d, J ¼ 8.20 Hz, 1H, ArH), 7.28–7.33
(m, 3H, ArH), 7.36–7.39 (m, 1H, ArH), 7.87 (d, J ¼ 7.95 Hz, 2H,
ArH), 8.32 (s, 1H, CH); 13C NMR (125 MHz, DMSO-d6): d ¼ 19.8,
21.6, 44.4, 50.5, 98.3, 115.6, 118.4, 124.0, 124.4, 127.0, 129.1,
129.1, 130.0, 130.0, 130.3, 132.1, 134.1, 144.7, 147.8, 148.1,
152.2, 159.6, 196.3; HRMS (TOF ES+): m/z calcd for C23H18N2O3
[(M + H)+], 371.1390; found, 371.1389.
´
´
A. D. Favia, R. Soto-Otero, E. Mendez-Alvarez and
A. Carotti, J. Med. Chem., 2006, 49, 4912; (e) J. Neyts, E. De
Clercq, R. Singha, Y. H. Chang, A. R. Das,
S. K. Chakraborty, S. C. Hong, S. C. Tsay, M. H. Hsu and
J. R. Hwu, J. Med. Chem., 2009, 52, 1486.
5 L. Santana, E. Uriarte, L. Dalla Via and O. Gia, Bioorg. Med.
Chem. Lett., 2000, 10, 135.
10,11-Dihydro-13-(4-methoxybenzoyl)-12-azachromeno[4,3-
b]quinolizin-6(9H)-one (4p). Yellow solid; mp 259–262 ꢀC; IR
(KBr): 1723, 1663, 1613, 1455, 1312, 1243, 1157, 1098, 1029, 747
´
6 A. Guiotto, A. Chilin, P. Manzini, F. DalıAcqua, F. Bordin and
cmꢁ1
;
1H NMR (500 MHz, DMSO-d6): d ¼ 1.79–1.80 (m, 2H,
P. Rodighiero, Farmaco, 1995, 50, 479.
7 P. Ploypradith, C. Mahidol, P. Sahakitpichan, S. Wongbundit
and S. Ruchirawat, Angew. Chem., Int. Ed., 2004, 43, 866.
8 M. N. Thaisrivongs, K. T. Janakiraman, P. K. Chong,
L. A. Tomich, S. R. Dolack, J. W. Turner, J. C. Strohbach,
M. M. Lynn, R. R. Horng and K. D. Hinshaw, J. Med.
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9 G. Rappa, K. Shyam, A. Lorico, O. Fodstad and
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CH2), 3.19–3.22 (m, 2H, CH2), 3.82 (s, 3H, OCH3), 4.07–4.09 (m,
2H, CH2), 6.96–7.03 (m, 3H, ArH), 7.20 (d, J ¼ 8.10 Hz, 1H, ArH),
7.35 (d, J ¼ 8.20 Hz, 1H, ArH), 7.38–7.41 (m, 1H, ArH), 7.94 (d, J
¼ 8.30 Hz, 1H, ArH), 8.34 (s, 1H, CH); 13C NMR (125 MHz,
DMSO-d6): d ¼ 19.8, 44.4, 50.5, 55.9, 98.1, 114.8, 114.8, 115.7,
118.5, 124.1, 124.6, 129.6, 129.6, 130.0, 131.4, 131.4, 132.2,
147.7, 148.2, 152.2, 159.6, 164.1, 195.2; HRMS (TOF ES+): m/z
calcd for C23H18N2O4 [(M + H)+], 387.1339; found, 387.1340.
10,11-Dihydro-2-bromo-13-(4-chlorobenzoyl)-12-azachro-meno-
ꢀ
[4,3-b]quinolizin-6(9H)-one (4q). Yellow solid; mp 305–308 C;
11 L. Bonsignore, F. Cottiglia, S. M. Lavagna, G. Loy and
D. Secci, Farmaco, 1998, 53, 693.
12 (a) D. A. Horton, G. T. Bourne and M. L. Smythe, Chem. Rev.,
IR (KBr): 1711, 1677, 1616, 1450, 1303, 1198, 1149, 1119, 1004,
820 cmꢁ1; 1H NMR (500 MHz, DMSO-d6): d ¼ 1.80–1.82 (m, 2H,
CH2), 3.21–3.23 (m, 2H, CH2), 4.08–4.10 (m, 2H, CH2), 7.21 (d,
J ¼ 8.20 Hz, 1H, ArH), 7.35 (s, 1H, ArH), 7.61–7.63 (m, 3H, ArH),
8.02 (d, J ¼ 7.05 Hz, 2H, ArH), 8.37 (s, 1H, CH); 13C NMR (125
MHz, DMSO-d6): d ¼ 19.7, 44.4, 50.5, 97.8, 116.1, 117.5, 120.9,
123.7, 128.9, 129.6, 129.9, 129.9, 130.8, 130.8, 134.8, 135.0,
139.5, 147.7, 148.7, 151.5, 159.1, 195.7; HRMS (TOF ES+): m/z
calcd for C22H14BrClN2O3 [(M + H)+], 468.9949; found, 468.9950.
´
2003, 103, 893; (b) M. E. Riveiro, D. Maes, R. Vazquez,
M. Vermeulen, S. Mangelinckx, J. Jacobs, S. Debenedetti,
C. Shayo, N. De Kimpe and C. Davio, Bioorg. Med. Chem.,
2009, 17, 6547; (c) M. E. Riveiro, N. De Kimpe, A. Moglioni,
´
R. Vazquez, F. Monczor, C. Shayo and C. Davio, Curr. Med.
Chem., 2010, 17, 1325.
13 (a) M. Darbarwar and V. Sundaramurthy, Synthesis, 1982,
337; (b) C. Bandyopadhyay, K. R. Sur, R. Patra and A. Sen,
Tetrahedron, 2000, 56, 3583; (c) N. Mulakayala,
D. Rambabu, M. R. Raja, M. Chaitanya, C. S. Kumar,
A. M. Kalle, G. R. Krishna, C. M. Reddy, M. V. B. Rao and
M. Pal, Bioorg. Med. Chem., 2012, 20, 759; (d)
V. O. Iaroshenko, F. Erben, S. Mkrtchyan, A. Hakobyan,
M. Vilches-Herrera, S. Dudkin, A. Bunescu, A. Villinger,
V. Y. Sosnovskikh and P. Langer, Tetrahedron, 2011, 67,
7946; (e) V. O. Iaroshenko, S. Ali, T. M. Babar, S. Dudkin,
S. Mkrtchyan, N. H. Rama, A. Villinger and P. Langer,
Tetrahedron Lett., 2011, 52, 373.
Acknowledgements
We gratefully acknowledge the nancial was support from the
National Natural Science Foundation of China (no. 81160384,
21162037, 21262042, U1202221 and 21362042) and the Talent
Found in Yunnan Province (2012HB001, 2011J021).
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