One-pot synthesis of 6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxazines via a copper-catalyzed process

Article abstract of DOI:10.1039/c3ra42108b

A convenient and efficient copper-catalyzed one-pot process for the construction of 6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxazines through reactions of 2-halophenols with 2-(chloromethyl)-1H-benzo[d]imidazoles under mild conditions is described. The reactions afforded a variety of products in good to excellent yields.

Full text of DOI:10.1039/c3ra42108b

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One-pot synthesis of
6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxazines via
a copper-catalyzed process3
Cite this: RSC Advances, 2013, 3,
13976
Aiping Huang, Huanhuan Liu and Chen Ma*
Received 29th April 2013,
Accepted 7th June 2013
A
convenient and efficient copper-catalyzed one-pot process for the construction of
6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxazines through reactions of 2-halophenols with 2-(chloro-
methyl)-1H-benzo[d]imidazoles under mild conditions is described. The reactions afforded a variety of
products in good to excellent yields.
DOI: 10.1039/c3ra42108b
www.rsc.org/advances
Introduction
Results and discussion
Benzimidazo[1,2-d][1,4]oxazine derivatives are an important
class of heterocyclic compounds that exhibit a wide range of
biological and medicinal activities.1 Benzoimidazo[1,2-
d][1,4]oxazines have attracted considerable interest due to
their remarkable activities, such as antiallergic A,1a antihel-
mintic,1c antidepressant and anxiolytic B1d properties. Some of
these heterocycles act as excellent 5-HT1A/B/D receptor antago-
nists B1d and inhibitors of the rice blast fungal enzyme C
(Fig. 1).1b
The methods for the preparation of benzimidazo[1,2-
d][1,4]oxazines remain rare. In the conventional methods
reported for the construction of benzimidazo[1,2-d][1,4]oxa-
zines, benzoxazines were used as the starting materials.2–6
However, these methods employ several steps, hazardous
reagents, harsh reaction conditions, and inconvenient opera-
tions. Therefore, it is desirable to develop a convenient and
efficient approach for the synthesis of these heterocycles.
Recently, copper-catalyzed cross-coupling reactions have
made considerable progress.7–18 Many N-heterocycles have been
constructed via the copper-catalyzed coupling strategy.19–27 Ma
and co-workers first applied CuI/amino acid catalyzed Ullmann
N-arylation, and made significant progress.7i,8 Many other groups
have also made remarkable progress in the copper-catalyzed
Ullmann N-arylation.9,13,19 Herein, we report a convenient and
efficient copper-catalyzed one-pot process for the construction
of 6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxazines through
the reaction of 2-halophenols and 2-(chloromethyl)-
1H-benzo[d]imidazoles under mild conditions.
As shown in Table 1, 2-iodophenol 1a and 2-(chloromethyl)-
1H-benzo[d]imidazole 2a were chosen as the model substrates
to optimize the reaction conditions including catalysts, ligands,
bases and solvents. Initially, bases (2.5 equiv.) were investigated
by using 0.1 equiv. of CuI, 0.2 equiv. of L-proline as the ligand,
and DMF as the solvent at 80 uC (entries 1–4). Cs2CO3 provided
the highest yield of 6H-benzo[b]benzo[4,5]imidazo[1,2-
d][1,4]oxazine 3a (entry 2), and K2CO3, KOH and K3PO4 provided
much lower yields of the product (entries 1, 3 and 4). We then
investigated the effect of the solvents (entries 6–10). THF and
CH3CN gave the products in moderate yields (entries 7 and 8).
The yield of the product in DMSO was much lower (entry 6). No
product was observed with the use of dioxane (entry 9). NMP
proved to be the most effective solvent (entry 10). The effect of
copper salts CuI, CuCl, CuCl2, CuBr, and Cu(OAc)2 were also
examined in NMP (entries 10–14). CuI proved to be the most
suitable catalyst for the reaction (entry 10). A copper catalyst was
absolutely required in this reaction, no target product was
observed in the absence of copper salt (entry 15). We attempted
to use different ligands, but 1,10-phenanthronine and
N,N9-dimethylethylenediamine (DMEDA) were not suitable for
this reaction, with only 43% and 19% isolated yields being
obtained (entries 17 and 18). trans-4-Hydro-L-proline gave the
product in good yield (entry 16). Consequently, the optimized
School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100,
P. R. China. E-mail: chenma@sdu.edu.cn
Electronic supplementary information (ESI) available: The copies of 1H NMR
3
and 13C NMR spectra of all compounds. See DOI: 10.1039/c3ra42108b
Fig. 1 Some important benzimidazo[1,2-d][1,4]oxazines.
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Table 1 Optimization of the reaction conditionsa
Entry
Cu salt
Ligand
Base
Temperature
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
K2CO3
Cs2CO3
KOH
80 uC
80 uC
80 uC
80 uC
80 uC
80 uC
Reflux
Reflux
80 uC
80 uC
80 uC
80 uC
80 uC
80 uC
80 uC
DMF
DMF
DMF
DMF
DMSO
DMSO
THF
CH3CN
Dioxane
NMP
34
48
37
12
28
36
65
59
0
70
37
31
42
35
0
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
L-proline
K3PO4
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
CuI
CuI
10
11
12
13
14
15
CuCl
CuCl2
Cu(OAc)2
CuBr
—
NMP
NMP
NMP
NMP
NMP
L-proline
16
17
18
CuI
CuI
CuI
4-Hydro-L-proline
1,10-Phenanthronine
DMEDA
Cs2CO3
Cs2CO3
Cs2CO3
80 uC
80 uC
80 uC
NMP
NMP
NMP
68
43
19
a
Reaction conditions: 1,2-iodophenol 1a (0.5 mmol), 2-(chloromethyl)-1H-benzo[d]imidazole 2a (0.5 mmmol), CuI (10 mol%), ligand (20%
b
mol), base (2.5 equiv.), solvent (3 mL). Isolated yield.
reaction conditions were CuI (10 mol%), L-proline (L, 20 mol%),
Cs2CO3 (2.5 equiv.) in NMP at 80 uC.
tional groups, such as the benzyloxy group (Table 2, entry 7), a
C–Cl bond (Table 2, entries 8 and 12), and a C–Br bond
(Table 2, entries 9 and 13).
The scope of the copper-catalyzed synthesis of
6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxazine derivatives 3
from the reactions of substituted 2-halophenols 128–32 with 2-
(chloromethyl)-1H-benzo[d]imidazole 2a was investigated
under the optimized conditions (Table 2). As shown in
Table 2, all the tested substrates worked well giving the
corresponding products in good to excellent yields. It is
noteworthy that substituted 2-iodophenols with electron-with-
drawing groups (Table 2, entries 8 and 9) had higher reactivity
than those with electron-donating groups (Table 2, entries 2–
7). 4-Chloro-2-iodophenol and 4-bromo-2-iodophenol led to
the target products in excellent yields (Table 2, entries 8 and
9). The substrates bearing a bromide group also afforded the
desired products in good yields. 2-Iodopyridin-3-ol and
To expand the applicability of this methodology, we then
investigated substituted 2-(chloromethyl)-1H-benzo[d]imidazoles 233
as shown in Table 3. Reactions of substituted benzimidazoles
with 2-iodophenol 1a, 4-chloro-2-iodophenol 1h, and 2-bromo-
pyridin-3-ol 1k provided the desired products in moderate to
good yields. However, benzimidazole with one methyl group
(Table 3, entries 1–3) displayed higher reactivity than those with
two methyl groups (Table 3, entries 4–6). Notably, reactions of 2-
(chloromethyl)-5-methyl-1H-benzo[d]imidazole 2b with 1a, 1h
and 1k provided two regioisomers. Benzimidazole with a strong
electron-withdrawing nitro group failed to give the target
product.
The
reaction
of
2-(1-chloroethyl)-1H-benzo
[d]imidazole 2d also provided the desired product in a good
2-bromopyridin-3-ol
afforded
the
target
product
yield (Table 3, entry 7).
6H-benzo[4,5]imidazo[1,2-d]pyrido[3,2-b][1,4]oxazine in 78%
and 75% yields (Table 2, entries 10 and 11). It is noteworthy
that not only the substrates bearing an iodine group reacted
smoothly under the reaction conditions (Table 2, entries 1–11),
but the substrates bearing two iodines were also compatible
with these conditions. 4-Chloro-2,6-diiodophenol and
4-bromo-2,6-diiodophenol worked well and gave the products
in good yields (Table 2, entries 12 and 13). In addition, the
copper-catalyzed reactions could tolerate some other func-
Conclusions
In summary, we have developed a convenient and efficient
copper-catalyzed methodology for the construction of
6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxazines from 2-halo-
phenols and 2-(chloromethyl)-1H-benzo[d]imidazoles in one-
pot
under
mild
conditions.
A
variety
of
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Table 2 Synthesis of 6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxazinesa
Table 2 (Continued)
Yield (%)b
78
Entry
1
Substrate 1
Product
Yield (%)b
70
Entry
10
Substrate 1
Product
1a
1j
3a
3b
3c
3d
3e
3f
3j
3j
2
3
4
5
6
7
8
9
78
74
68
83
86
76
90
85
11
12
75
92
1b
1c
1k
1l
3k
13
86
1d
1m
3l
a
Reaction conditions: 1,2-iodophenol 1 (0.5 mmol), 2-
(chloromethyl)-1H-benzo[d]imidazole 2a (0.5 mmmol), CuI (10
mol%), L-proline (20% mol), Cs2CO3 (2.5 equiv.), NMP (3 mL).
1e
1f
b
Isolated yield.
6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxazine
derivatives
were obtained in good to excellent yields. 2-Bromopyridin-3-
ol was compatible with this approach, giving the desired
products in high yields. This copper-catalyzed process has
potential applications in the synthesis of biologically and
medicinally relevant compounds.
1g
1h
1i
3g
3h
3i
Experimental section
General information
2-Halophenols28–32 and 2-(chloromethyl)-1H-benzo[d]imida-
zoles33 were prepared according to literature procedures. All
reactions were monitored by thin-layer chromatography (TLC).
1H NMR spectra were recorded on a Bruker Avance 400 or 300
spectrometer at 400 or 300 MHz, using CDCl3 as solvent and
tetramethylsilane (TMS) as an internal standard. 13C NMR
spectra were run on the same instrument at 100 or 75 MHz.
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Table 3 Synthesis of 6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxazinesa
Melting points were determined on an XD-4 digital micro
melting point apparatus. HRMS spectra were determined on a
Q-TOF6510 spectrograph (Agilent).
General experimental procedures for the synthesis of
6H-Benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxazines. A mixture
of
2-halophenol
1
(0.5
mmol),
2-(chloromethyl)-
1H-benzo[d]imidazole 2 (0.5 mmol), 10 mol% of CuI (0.05
mmol), 20 mol% of L-proline (0.1 mmol) and Cs2CO3 (2.5
mmol) in 3 mL DMSO, under nitrogen, was heated at 80 uC,
and the reaction was monitored by TLC. After that, the
reaction was cooled to room temperature, quenched with
water (10 mL), and diluted with 10 mL of ethyl acetate. The
layers were separated, and the aqueous layer was extracted
with ethyl acetate (2 6 10 mL). The combined organic layers
were dried with MgSO4 and the solvent was removed in vacuo
to afford a residue. The residue was purified by column
chromatography on silica gel to afford the desired product.
6H-Benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxazine (3a).
Purification by column chromatography on silica gel with
ethyl acetate : petroleum ether (1 : 8) as eluent afforded the
Entry Substrate 1
Substrate 2
Product
Yield (%)b
69
1
1a
2b
4a
2
86
79
61
73
57
78
1h
2b
2b
2c
2c
2c
1
product as a white solid (78 mg, 70%); mp 80–82 uC; H NMR
4b
(300 MHz, CDCl3) d 7.89–7.92 (m, 1H), 7.82–7.87 (m, 2H), 7.34–
7.43 (m, 2H), 7.19–7.23 (m, 3H), 5.38 (s, 2H); 13C NMR (100
MHz, CDCl3) d 146.5, 146.4, 143.6, 131.3, 126.3, 126.1, 124.0,
123.4, 123.2, 120.5, 118.4, 116.2, 111.4, 64.5; FT-HRMS (ESI)
calcd for C14H10N2O (M + H)+ 223.0876, found 223.0871.
2-Methyl-6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxazine
(3b). Purification by column chromatography on silica gel with
ethyl acetate : petroleum ether (1 : 8) as eluent afforded the
3
1k
4c
4
1
product as a yellow solid (92 mg, 78%); mp 98–99 C; H NMR
(300 MHz, CDCl3) d 7.92 (d, J = 7.5 Hz, 1H), 7.83 (dd, J = 6.9, 1.5
Hz, 1H), 7.64 (d, J = 1.5 Hz, 1H), 7.33–7.43 (m, 2H), 7.09 (d, J =
8.1 Hz, 1H), 6.95 (dd, J = 8.1, 1.2 Hz, 1H), 5.34 (s, 2H), 2.45 (s,
3H); 13C NMR (100 MHz, CDCl3) d 145.9, 144.9, 144.2, 132.9,
126.5, 126.1, 123.9, 123.3, 120.5, 118.0, 116.7, 111.5, 64.5, 21.2;
FT-HRMS (ESI) calcd for C15H12N2O (M + H)+ 237.1028, found
237.1039.
1a
4d
5
1h
2-Ethyl-6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxazine
(3c). Purification by column chromatography on silica gel with
ethyl acetate : petroleum ether (1 : 8) as eluent afforded the
4e
6
1
product as a brown liquid (93 mg, 74%); H NMR (300 MHz,
CDCl3) d 7.89 (dd, J = 2.7, 1.2 Hz, 1H), 7.80–7.83 (m, 1H), 7.63
(d, J = 1.5 Hz, 1H), 7.31–7.41 (m, 2H), 7.09 (d, J = 8.4 Hz, 1H),
7.00 (dd, J = 8.1, 1.8 Hz, 1H), 5.32 (s, 2H), 2.73 (q, J = 1.5 Hz,
2H), 1.31 (t, J = 7.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) d
146.8, 144.3, 143.6, 139.4, 131.3, 126.2, 125.3, 123.9, 123.3,
120.5, 118.1, 115.6, 111.4, 64.5, 28.5, 15.8; FT-HRMS (ESI) calcd
for C16H14N2O (M + H)+ 251.1184, found 251.1192.
1k
4f
7
1a
2-Isopropyl-6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxa-
zine (3d). Purification by column chromatography on silica gel
with ethyl acetate : petroleum ether (1 : 8) as eluent afforded
2d
4g
1
a
the product as a yellow solid (84 mg, 68%): mp 62–64 uC; H
Reaction conditions: 1,2-iodophenol 1 (0.5 mmol), 2-
(chloromethyl)-1H-benzo[d]imidazole 2 (0.5 mmmol), CuI (10 mol%),
L-proline (20% mol), Cs2CO3 (2.5 equiv.), NMP (3 mL). Isolated
NMR (300 MHz, CDCl3) d 7.89 (dd, J = 6.3, 1.2 Hz, 1H), 7.82–
7.85 (m, 1H), 7.69 (d, J = 1.8 Hz, 1H), 7.33–7.44 (m, 2H), 7.11 (d,
J = 8.4 Hz, 1H), 7.07 (dd, J = 1.2, 1.8 Hz, 1H), 5.34 (s, 2H), 3.00
(m, 1H), 1.34 (d, J = 7.2 Hz, 6H); 13C NMR (100 MHz, CDCl3) d
146.8, 144.4, 144.2, 143.5, 131.3, 127.4, 126.2, 123.9, 123.9,
b
yield.
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123.3, 120.5, 118.1, 114.3, 111.4; FT-HRMS (ESI) calcd for
C17H16N2O (M + H)+ 265.1341, found 265.1349.
product as a white solid (87 mg, 78%); or prepared according
to the procedure from 2-bromopyridin-3-ol (2k) and purified by
column chromatography on silica gel with ethyl acetate :
petroleum ether (1 : 5) as eluent to give the product as a white
solid (84 mg, 75%); mp 82–84 uC; 1H NMR (300 MHz, CDCl3) d
8.53 (d, J = 8.7 Hz, 1H), 8.19 (dd, J = 4.8, 1.2 Hz, 1H), 7.79 (d, J =
1.2 Hz, 1H), 7.34–7.44 (m, 3H), 7.11 (dd, J = 8.1, 4.8 Hz, 1H),
5.48 (s, 2H); 13C NMR (100 MHz, CDCl3) d 145.6, 143.3, 141.7,
141.4, 140.0, 131.2, 124.6, 124.5, 123.9, 121.2, 119.8, 114.6,
64.4; FT-HRMS (ESI) calcd for C13H9N3O (M + H)+ 224.0824,
found 224.0825.
2-Chloro-4-iodo-6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]
oxazine (3k). Purification by column chromatography on silica
gel with ethyl acetate : petroleum ether (1 : 5) as eluent
afforded the product as a white solid (175 mg, 92%); mp
188–190 uC; 1H NMR (400 M, CDCl3) d 7.86 (dd, J = 4.6, 1.4 Hz,
2H), 7.82 (d, J = 2.2 Hz, 1H), 7.66 (d, J = 2.2 Hz, 1H), 7.42–7.50
(m, 2H), 5.52 (s, 2H); 13C NMR (100 M, CDCl3) d 145.7, 144.9,
143.7, 136.8, 134.5, 130.8, 128.9, 126.2, 124.7, 124.1, 120.9,
116.4, 111.3, 65.1; FT-HRMS (ESI) calcd for C14H8ClIN2O (M +
H)+ 382.9443, found 382.9434.
2-Bromo-4-iodo-6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]
oxazine (3l). Purification by column chromatography on silica
gel with ethyl acetate : petroleum ether (1 : 5) as eluent
afforded the product as a white solid (183 mg, 86%); mp
208–210 uC; 1H NMR (400 M, CDCl3) d 7.92 (d, J = 2.1 Hz, 1H),
7.81–7.84 (m, 2H), 7.77 (d, J = 2.1 Hz, 1H), 7.37–7.46 (m, 2H),
5.46 (s, 2H); 13C NMR (100 M, CDCl3) d 145.7, 145.4, 143.6,
137.2, 130.8, 126.5, 124.7, 124.1, 120.9, 119.2, 115.8, 111.3,
65.1; FT-HRMS (ESI) calcd for C14H8BrIN2O (M + H)+ 426.8943,
found 426.8944.
9-Methyl or 10-methyl-6H-benzo[b]benzo[4,5]imidazo[1,2-
d][1,4]oxazine (4a). Purification by column chromatography
on silica gel with ethyl acetate : petroleum ether (1 : 8) as
eluent afforded the product as a white solid (81 mg, 69%); mp
83–84 uC; 1H NMR (400 MHz, CDCl3) d 7.59–7.81 (m, 3H), 7.17–
7.21 (m, 4H), 5.34 (d, J = 3.7 Hz, 2H), 2.53 (d, J = 18.8 Hz, 3H);
13C NMR (100 MHz, CDCl3) d 146.4, 146.3, 146.0, 143.9, 141.7,
134.1, 133.2, 131.5, 129.3, 126.5, 126.4, 125.9, 125.8, 125.3,
124.7, 123.1, 120.4, 119.9, 118.3, 118.2, 116.2, 116.1, 111.4,
110.8, 64.5, 64.5, 22.0, 21.5; FT-HRMS (ESI) calcd for
C15H12N2O (M + H)+ 237.1028, found 237.1046.
2-(tert-Butyl)-6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxa-
zine (3e). Purification by column chromatography on silica gel
with ethyl acetate : petroleum ether (1 : 8) as eluent afforded
the product as a white solid (115 mg, 83%); mp 132–133 uC; 1H
NMR (400 MHz, CDCl3) d 7.85–7.89 (m, 3H), 7.35–7.43 (m, 2H),
7.22 (dd, J = 8.5, 2.2 Hz, 1H), 7.13 (d, J = 8.5 Hz, 1H), 5.36 (s,
2H), 1.42 (s, 9H); 13C NMR (100 MHz, CDCl3) d 146.6, 144.1,
143.7, 131.3, 125.9, 124.0, 123.3, 122.9, 120.6, 117.7, 113.4,
111.3, 64.6, 34.7, 31.5; FT-HRMS (ESI) calcd for C18H18N2O (M
+ H)+ 279.1497, found 279.1506.
2-Phenyl-6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxazine
(3f). Purification by column chromatography on silica gel with
ethyl acetate : petroleum ether (1 : 8) as eluent afforded the
product as a white solid (128 mg, 86%); mp 116–118 C; 1H
NMR (300 MHz, CDCl3) d 8.03 (d, J = 1.8 Hz, 1H), 7.94 (dd, J =
7.8, 1.8 Hz, 1H), 7.85 (dd, J = 7.2, 1.8 Hz, 1H), 7.61–7.65 (m,
2H), 7.48–7.53 (m, 2H), 7.35–7.43 (m, 4H), 7.25 (d, J = 8.1 Hz,
1H), 5.41 (s, 2H); 13C NMR (100 MHz, CDCl3) d 146.5, 145.8,
143.5, 140.1, 136.9, 131.3, 129.1, 127.6, 127.0, 126.6, 124.8,
124.2, 123.6, 120.6, 118.6, 115.0, 111.5, 64.6; FT-HRMS (ESI)
calcd for C20H14N2O (M + H)+ 299.1179, found 299.1182.
2-(Benzyloxy)-6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxa-
zine (3g). Purification by column chromatography on silica gel
with ethyl acetate : petroleum ether (1 : 5) as eluent afforded
1
the product as a white solid (125 mg, 76%); mp 90–92 uC; H
NMR (300 MHz, CDCl3) d 7.79–7.85 (m, 1H), 7.68–7.73 (m, 1H),
7.42–7.51 (m, 5H), 7.35–7.41 (m, 3H), 7.11 (d, J = 8.7 Hz, 1H),
7.80 (dd, J = 8.7, 2.7 Hz, 1H), 5.31 (s, 2H), 5.15 (s, 2H); 13C NMR
(100 MHz, CDCl3) d 154.5, 146.9, 143.6, 140.5, 136.7, 131.2,
128.8, 128.3, 127.5, 126.7, 124.0, 123.4, 120.6, 118.6, 111.4,
111.3, 104.4, 71.0, 64.6; FT-HRMS (ESI) calcd for C21H16N2O2
(M + H)+ 329.1285, found 329.1281.
2-Chloro-6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxazine
(3h). Purification by column chromatography on silica gel with
ethyl acetate : petroleum ether (1 : 5) as eluent afforded the
product as a white solid (115 mg, 90%); mp 108–111 uC; 1H
NMR (300 MHz, CDCl3) d 7.82–7.90 (m, 3H), 7.38–7.48 (m, 2H),
7.17 (d, J = 2.7 Hz, 1H), 7.13 (d, J = 8.7 Hz, 1H), 5.40 (s, 2H); 13C
NMR (100 MHz, CDCl3) d 154.3, 144.9, 143.4, 137.4, 130.9,
125.8, 124.5, 123.9, 119.4, 116.8, 115.6, 111.3, 85.4, 64.5; FT-
HRMS (ESI) calcd for C14H9ClN2O (M + H)+ 257.0481, found
257.0488.
2-Bromo-6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxazine
(3i). Purification by column chromatography on silica gel with
ethyl acetate : petroleum ether (1 : 5) as eluent afforded the
product as a white solid (127 mg, 85%); mp 128–130 uC; 1H
NMR (300 MHz, CDCl3) d 8.03 (d, J = 2.1 Hz, 1H), 7.85 (m, 2H),
7.48 (m, 2H), 7.33 (dd, J = 8.4, 2.1 Hz, 1H), 7.09 (d, J = 8.7 Hz,
1H), 5.38 (s, 2H); 13C NMR (75 MHz, CDCl3) d 145.5, 134.9,
130.9, 128.8, 127.3, 126.5, 124.8, 123.8, 120.6, 119.8, 115.2,
111.2, 84.9, 64.5, FT-HRMS (ESI) calcd for C14H9BrN2O (M +
H)+ 300.9971, found 300.9961.
2-Chloro-9-methyl or 2-chloro-10-methyl-6H-benzo[b]ben-
zo[4,5]imidazo[1,2-d][1,4]oxazine (4b). Purification by column
chromatography on silica gel with ethyl acetate : petroleum
ether (1 : 8) as eluent afforded the product as a white solid
1
(116 mg, 86%); mp 110–114 uC; H NMR (400 MHz, CDCl3) d
7.78 (dd, J = 11.5, 2.1 Hz, 1H), 7.71 (dd, J = 10.6, 8.4 Hz, 1H),
7.20–7.25 (m, 1H), 7.10–7.15 (m, 2H), 5.34 (d, J = 4.4 Hz, 2H),
2.55 (d, J = 24.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) d 146.1,
145.6, 145.0, 144.8, 141.8, 134.6, 133.6, 131.3, 129.1, 128.1,
127.3, 127.2, 125.7, 125.6, 120.6, 120.2, 119.4, 119.3, 116.3,
116.2, 111.2, 110.7, 64.6, 64.6, 22.0, 21.5; FT-HRMS (ESI) calcd
for C15H11ClN2O (M + H)+ 271.0633, found 271.0625.
9-Methyl or 10-methyl-6H-benzo[4,5]imidazo[1,2-d]pyrido
[3,2-b][1,4]oxazine (4c). Purification by column chromatogra-
phy on silica gel with ethyl acetate : petroleum ether (1 : 6) as
eluent afforded the product as a white solid (94 mg, 79%); mp
6H-Benzo[4,5]imidazo[1,2-d]pyrido[3,2-b][1,4]oxazine (3j).
Prepared according to the procedure from 2-iodopyridin-3-ol
(2j) and purified by column chromatography on silica gel with
ethyl acetate : petroleum ether (1 : 5) as eluent to give the
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1
74–76 uC; H NMR (400 MHz, CDCl3) d 8.36 (t, J = 8.3 Hz, 1H),
Notes and references
8.19 (dd, J = 8.1, 5.0 Hz, 1H), 7.57–7.67 (m, 1H), 7.40 (dd, J =
7.7, 3.4 Hz, 1H), 7.21 (q, J = 8.4 Hz, 1H), 7.09–7.13 (m, 1H), 5.46
(d, J = 3.5 Hz, 2H), 2.53 (d, J = 17.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) d 145.5, 145.1, 143.6, 141.6, 141.6, 141.4, 140.1, 139.9,
134.7, 133.8, 131.4, 139.2, 125.9, 125.4, 124.6, 124.5, 121.0,
121.0, 119.7, 119.3, 114.4, 114.0, 64.4, 21.9, 21.6; FT-HRMS
(ESI) calcd for C14H11N3O (M + H)+ 238.0980, found 238.0980.
9,10-Dimethyl-6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxa-
zine (4d). Purification by column chromatography on silica gel
with ethyl acetate : petroleum ether (1 : 8) as eluent afforded
1 (a) I. R. Ager, A. C. Barnes, G. W. Danswan, P. W. Hairsine, D.
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1
the product as a white solid (76 mg, 61%); mp 94–96 uC; H
NMR (400 MHz, CDCl3) d 7.82 (dd, J = 10.4, 5.1 Hz, 1H), 7.67
(dd, J = 5.9, 4.5 Hz, 1H), 7.58 (s, 1H), 7.18–7.25 (m, 3H), 5.36 (s,
2H), 2.45 (s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) d
155.2, 146.4, 145.6, 138.4, 133.2, 130.1, 125.8, 123.2, 120.5,
118.3, 116.2, 111.7, 64.5, 20.7, 20.3; FT-HRMS (ESI) calcd for
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oxazine (4e). Purification by column chromatography on silica gel
with ethyl acetate : petroleum ether (1 : 8) as eluent afforded the
product as a white solid (104 mg, 73%); mp 144–146 uC; 1H NMR
(400 MHz, CDCl3) d 7.77 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 11.7 Hz, 2H),
7.10–7.16 (m, 2H), 5.34 (s, 2H), 2.47 (s, 3H), 2.40 (s, 3H); 13C NMR
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9,10-Dimethyl-6H-benzo[4,5]imidazo[1,2-d]pyrido[3,2-b][1,4]
oxazine (4f). Purification by column chromatography on silica gel
with ethyl acetate : petroleum ether (1 : 8) as eluent afforded the
product as a white solid (72 mg, 57%); mp 83–84 uC; 1H NMR (400
MHz, CDCl3) d 8.30 (s, 1H), 8.19 (dd, J = 4.7, 1.0 Hz, 2H), 7.55 (s,
2H), 7.39 (dd, J = 8.0, 1.1 Hz, 2H), 7.11 (dd, J = 8.0, 4.8 Hz, 1H), 5.46
(s, 2 H), 2.45 (s, 3H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) d
145.4, 143.8, 141.6, 141.5, 140.1, 133.9, 133.0, 124.6, 121.0, 119.8,
114.7, 64.4, 20.5, 20.4; FT-HRMS (ESI) calcd for C15H13N3O (M + H)+
252.1131, found 252.1127.
´
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6-Methyl-6H-benzo[b]benzo[4,5]imidazo[1,2-d][1,4]oxazine
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ethyl acetate : petroleum ether (1 : 10) as eluent afforded the
1
product as a white solid (92 mg, 78%); mp 84–86 uC; H NMR
(300 MHz, CDCl3) d 8.15 (dd, J = 5.7, 0.9 Hz, 1H), 8.06–8.11 (m,
1H), 7.79 (dd, J = 7.2, 1.5 Hz, 1H), 7.65 (dd, J = 9.1, 1.5 Hz, 1H),
7.34–7.45 (m, 2H), 7.16–7.19 (m, 1H), 6.88 (dd, J = 8.1, 1.5 Hz,
1H), 6.55–6.61 (m, 1H), 5.39 (q, J = 6.6 Hz, 1H), 1.93 (d, J = 6.6
Hz, 3H); 13C NMR (100 MHz, CDCl3) d 138.5, 130.1, 126.2,
124.2, 123.5, 123.1, 122.2, 120.5, 118.6, 116.2, 115.2, 111.5,
71.0, 17.7; FT-HRMS (ESI) calcd for C15H13N3O (M + H)+
237.0983, found 237.1097.
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We are grateful to the National Science Foundation of China
(No. 21172131) for the financial support of this research.
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13982 | RSC Adv., 2013, 3, 13976–13982
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