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Table 1
the evaluation of antioxidant activity of tricyclic oxazino-fused-
tetrahydroquinolines/benzoxazines. In continuation of our re-
search work aimed towards the development of new strategies
for the synthesis of organic compounds,36 we were encouraged
to design a convenient and efficient route to synthesize novel tricy-
clic oxazino-fused-tetrahydroquinoline/benzoxazine compounds,
which are having promising antioxidant activity.
Effect of pressure on the reductive cyclization of 1-phenyl-2-(quinolin-8-yloxy)eth-
anone (5a)
Entry
Pressure (psi)
Conversion of 5a (%)
Yield of 4a (%)
1
2
3
4
100
150
200
250
75.4
99.7
98.9
82.8
63.5
63.7
79.3
85.2
Phenacylbromides 6a–m were prepared by our method re-
ported earlier.36a Further O-alkylation of 8-hydroxyquinoline with
phenacyl bromide using K2CO3 in DMF had resulted in 1-phenyl-2-
(quinolin-8-yloxy)ethanone (5a).37 Analogously, the O-alkylated
derivatives 5b–m were prepared in 80–90% yield (see Supplemen-
tary data). Compound 5a was subjected to hydrogenative
cyclization over 20% Pd/C to get the desired 3-phenyl-2,3,6,7-tetra-
hydro-5H-pyrido[1,2,3-de]-1,4-benzoxazine (4a, Scheme 1). The
plausible rationale for formation of product is shown in Scheme 2.
We optimized the reaction conditions (reaction time, pressure
and catalyst loading) to achieve maximum conversions (Tables 1
and 2). The time required for reaction completion was 3 h. Using
methanol as solvent and 20 wt % catalyst loading at room temper-
ature, we performed different reactions systematically varying
pressure of reaction viz 100, 150, 200, 250 psi and results are given
in Table 1. In all cases good to excellent conversions were obtained.
However, conversion increases with pressure up to 200 psi and
then decreases. Maximum conversions 99.7% and 98.9% were
achieved at 150 and 200 psi pressure, respectively (Table 1, entries
2 and 3). However, yield of the desired product 4a increased with
pressure, and was 85.2% at 250 psi (Table 1). Based on these re-
sults, the reaction pressure was fixed at 200 psi for further studies.
We optimized the conversion of 5a by varying the catalyst loading
while keeping other parameters such as temperature, time and
pressure constant, and results are shown in Table 2. Maximum
conversion (98.9%) was achieved at 20 wt % catalyst loading. How-
ever the yield was increased with catalyst loading up to 20 wt % of
catalyst.
Reaction conditions: substrate 5a: 50 mg (0.19 mmol), catalyst: 20% Pd/C, rt, time:
3 h.
Table 2
Effect of catalyst wt % on the reductive cyclization of 1-phenyl-2-(quinolin-8-
yloxy)ethanone (5a)
Entry
Catalyst (wt %)
Conversion of 5a (%)
Yield of 4a (%)
1
2
3
10
20
30
96.7
98.9
96.2
60.8
79.3
75.8
Reactions conditions: substrate 5a: 50 mg (0.19 mmol), rt, time: 3 h, pressure:
200 psi.
6–10 for R1 = alkoxylated phenyl). It is noteworthy, however, that
for R1 = 3-(4)-aminophenyl or 2-thienyl slightly lower yields
were obtained, which may be due to a decrease in activity of the
catalyst through coordination with N and S lone pairs (entries
11–13).
Antioxidant activities of the synthesized THQs were measured
against 2,2-diphenyl-1-picrylhydrazyl (DPPH),38 and 2,20-azin-
obis-(3-ethylbenzthiazoline-6-sulfonate) cation (ABTS+)39 radicals
as described earlier. DPPH and ABTS radical scavenging activity
are the most commonly used methods for screening the antioxi-
dant activities of the various natural as well as synthetic antioxi-
dants. The IC50 values, that are the concentration required to
scavenge 50% of the radicals, were calculated to evaluate the po-
tential antioxidant activities. The IC50 of butylated hydroxytoluene
(BHT) and ascorbic acid were also determined for comparison. The
results were summarized in Table 4.
Maximum yield 79.3% for 4a was observed at 20 wt % of
catalyst. In order to investigate the general applicability of this
methodology, we employed various substituted 1-aryl-2-(quino-
lin-8-yloxy)ethanone (5a–m) and performed reactions at opti-
mized reaction conditions, results are given in Table 3. In all
cases the tricyclic compounds 4a–m were isolated in good to
excellent yields (see Table 3, entries 1–5 for R1 = aryl, entries
It can be seen from Table 4 that compounds 4g, 4h, and 4l
showed better radical scavenging activities than the synthetic
O
a
b
+
N
N
N
Br
O
O
OH
6a
5a
4a
7
O
Scheme 1. Synthesis of tricyclic oxazino-fused-tetrahydroquinoline/benzoxazine (4a). Reagents and conditions: (a) K2CO3, DMF, rt, 4 h, 90%; (b) H2, Pd/C (20%), MeOH,
200 psi, rt, 3 h, 70%.
H2,
N
N
N
N
H
Pd/C
O
O
O
O
O
O
5a
4a
Scheme 2. Plausible rationale for reductive cyclization.