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Z.-W. Chen et al. / Chinese Chemical Letters 24 (2013) 199–201
O
O
O
R2
O
O
P2O5
O
R1
H
R2
+
+
OH
N
R1
EtOH, reflux
O
R3
OH
1
N
2
3
R3
4
O
O
O
R2
R1
POCl3
ClCH2CH2Cl, reflux
N
R3
5
Scheme 1. Synthesis of chromeno[30,40:5,6]pyrano[2,3-b]indole derivatives 5 via a two-step procedure.
under reflux for 3 h (reaction progression was monitored by TLC).
Then the reaction mixture was poured into ice–water (20 mL),
neutralized with saturated NaHCO3 aqueous solution and
extracted with dichloromethane (3ꢀ 15 mL). The combined
organic extracts were washed with water and brine, then dried
over anhydrous Na2SO4 and concentrated under vacuum to yield
the crude product, which was further purified by column
chromatography (silica gel, petroleum ether:EtOAc = 10:1, v/v)
to give 5a in 76% yield.
and indolin-2-one 3a was stirred in the presence of p-TSA
(10 mol%) in ethanol under reflux (Table 1, entry 1). Disappoint-
edly, the intermediate 4a was formed (one diastereomer) in 60%
yield without the appearance of the expected cyclized product 5a.
After screening numerous catalysts, such as Yb(OTf)3, ZnCl2,
NH2SO3H, PPA and P2O5, it was found that 100 mol% of P2O5 was
sufficient to promote the reaction efficiently (Table 1, entry 7), and
4a was obtained in 75% yield. Some of other solvents such as
CH3CN, DMF, toluene and ClCH2CH2Cl were also screened, but
merely 4a and others byproducts were formed.
It is well known that POCl3 is both an efficient cyclizing agent and
adehydrating agent [12–14]. POCl3 has been found wide applicabil-
ity in preparing oxy-heterocyclic compounds. Herein POCl3 was
employed to promote intramolecular cyclization of trimolecular
adducts. The cyclization of 4a was chosen as a model reaction to
optimize the conditions. The reaction temperature, reaction time
and the feed ratio of 4a: POCl3 were investigated. The cyclization
reaction of 4a in the presence of POCl3 was first attempted in
ClCH2CH2Cl at room temperature for 3 h, and no product 5a was
observed. Toour delight, increasing the reaction temperature clearly
improved the yield. When the reaction of 4a with 3.0 equiv of POCl3
was performed in ClCH2CH2Cl under reflux conditions for 4 h, the
yield of 5a reached to 75%. Subsequently, the effects of ratio of 4a:
POCl3 was also examined under the similar conditions. It was found
that the molar ratio of 1:3 of 4a: POCl3 was suitable. Other solvents
such as CHCl3 and toluene were also tested, but no appreciable
improvement in product yield was observed.
The structures of the isolated products 5a–m were corroborated
by IR, 1H NMR and 13C NMR spectroscopy, mass spectrometry and
high resolution mass spectrometry.
Selected data: 4a. Yellow solid; mp 183–185 8C; IR (KBr, cmꢁ1):
nmax 3209, 1691, 1620, 1472; 1H NMR (400 MHz, DMSO-d6):
d
11.46–10.38 (m, 1H), 9.01–7.94 (m, 1H), 7.61–7.55 (m, 2H), 7.41–
7.22 (m, 5H), 7.11–7.04 (m, 2H), 6.99 (d, 1H, J = 8.0 Hz), 6.89–6.79
(m, 1H), 6.61 (t, 1H, J = 8.0 Hz), 6.09 (d, 1H, J = 8.0 Hz), 5.03–4.91
(m, 1H), 4.66–4.43 (m, 1H); 13C NMR (100 MHz, DMSO-d6):
d 175.5,
175.0, 160.6, 157.8, 150.9, 142.6, 141.7, 137.0, 135.0, 130.7, 128.6,
128.0, 127.9, 127.7, 126.8, 126.6 (CH ꢀ 2), 126.4, 124.9, 123.9,
123.5 (CH ꢀ 2), 122.9, 122.5, 120.3 (CH ꢀ 2), 119.7, 115.5, 115.3,
108.4 (CH ꢀ 2), 106.7, 44.2, 42.5. MS (ESI): m/z (%) 381.9 (M+ꢁH).
HRMS-ESI: m/z (M+ꢁH) calcd. for C24H16NO4: 382.1079; found:
382.1082. 5a. Yellow solid; mp 268 ꢁ 270 8C; IR (KBr, cmꢁ1): nmax
3391, 1697, 1650, 1455; 1H NMR (400 MHz, DMSO-d6):
d 11.92 (s,
1H), 7.99–7.97 (m, 1H), 7.73–7.69 (m, 1H), 7.53–7.46 (m, 2H), 7.38
(d, 2H, J = 8.0 Hz), 7.29 (d, 1H, J = 8.0 Hz), 7.24–7.18 (m, 3H), 7.13–
7.10 (m, 1H), 7.02 (t, 1H, J = 8.0 Hz), 6.92–6.89 (m, 1H), 5.30 (s, 1H);
13C NMR (100 MHz, DMSO-d6):
d 199.2, 178.7, 164.8, 160.2, 154.7,
Table 1
Reactions of 4-hydroxycoumarin (1a), benzaldehyde (2a) and indolin-2-one (3a)
under different conditionsa.
151.9, 147.7, 141.7 (CH ꢀ 2), 132.4, 131.0, 127.9 (CH ꢀ 2), 124.6,
122.2, 119.5, 117.8, 116.4, 111.1, 104.5, 98.4, 75.2, 56.0, 45.1. MS
(ESI): m/z (%) 364.1 (M+ꢁH). HRMS–ESI: m/z (M+ꢁH) calcd. for
Entry
Solvent
Catalyst
Loading
(mol%)
Temperature
Yieldb
(%)
C
24H14NO3: 364.0974; found: 364.0984.
Characterization data of other compounds (5b–5m) are shown
in Supporting information.
1
2
EtOH
p-TSA
Yb(OTf)3
PPA
10
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
60
EtOH
10
Trace
63
3
EtOH
10
4
EtOH
ZnCl2
NH2SO3H
P2O5
10
65
3. Results and discussion
5
EtOH
10
56
6
EtOH
50
30
In the initial investigation, it was expected that the chrome-
no[30,40:5,6]pyrano[2,3-b]indole derivatives 5 could be directly
achieved via a one-pot, three-component condensation of 4-
hydroxycoumarin 1, arylaldehyde 2 and indolin-2-one 3. To
identify suitable conditions for the above transformation, 4-
hydroxycoumarin 1a, benzaldehyde 2a and indolin-2-one 3a were
chosen as model reagents for the screening of reaction conditions.
Initially, the reaction of 4-hydroxycoumarin 1a, benzaldehyde 2a
7
EtOH
P2O5
100
150
100
100
100
100
75
8
EtOH
P2O5
75
9
CH3CN
DMF
P2O5
30
10
11
12
P2O5
Trace
Trace
Trace
Toluene
ClCH2CH2Cl
P2O5
P2O5
a All reactions were run with the molar ratio of 1a:2a:3a = 1:1:1 for 3–5 h; reaction
progress was monitored by TLC.
b
Isolated yield of 4a based on 1a.