Caffeine catalyzed green synthesis of novel benzo[a][1,3]oxazino[6,5-c]phenazines via a one-pot multi-component sequential protocol in a basic ionic liquid

Article abstract of DOI:10.1016/j.cclet.2017.01.024

Caffeine was applied as a green and natural catalyst for the one-pot, four-component sequential condensation between 2-hydroxy-1,4-naphthoquinone, aromatic 1,2-diamines, ammonium thiocyanate and acid chlorides in the presence of a basic ionic liquid (1-butyl-3-methylimidazolium hydroxide) to afford the corresponding benzo[a][1,3]oxazino[6,5-c]phenazine derivatives. In this one-pot transformation, five bonds and two new rings are efficiently formed. This protocol has the advantages of operational simplicity, high yields, easy workup, avoidance of hazardous or toxic catalysts and organic solvents and high chemo- and regioselectivities.

Full text of DOI:10.1016/j.cclet.2017.01.024

Accepted Manuscript
Title: Caffeine catalyzed green synthesis of novel
benzo[a][1,3]oxazino[6,5-c]phenazines via a one-pot
multi-component sequential protocol in a basic ionic liquid
Authors: Razieh Mohebat, Afshin Yazdani-Elah-Abadi
PII:
S1001-8417(17)30047-5
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2017.01.024
CCLET 3973
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
25-11-2016
23-1-2017
30-1-2017
Please cite this article as: Razieh Mohebat, Afshin Yazdani-Elah-Abadi, Caffeine
catalyzed green synthesis of novel benzo[a][1,3]oxazino[6,5-c]phenazines via a one-pot
multi-component sequential protocol in a basic ionic liquid, Chinese Chemical Letters
http://dx.doi.org/10.1016/j.cclet.2017.01.024
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Original article
Caffeine catalyzed green synthesis of novel benzo[a][1,3]oxazino[6,5-
c]phenazines via a one-pot multi-component sequential protocol in a basic
ionic liquid
Razieh Mohebat a *, Afshin Yazdani-Elah-Abadi b
a
Young Researchers and Elite Club, Yazd Branch, Islamic Azad University, Yazd, Iran
Department of Biology, Science and Art University, Yazd, Iran
b
Graphical abstract
Caffeine was applied as a green and natural catalyst for the one-pot, four-component sequential condensation between 2-
hydroxy-1,4-naphthoquinone, aromatic 1,2-diamines, ammonium thiocyanate and acid chlorides in the presence of a basic ionic
liquid (1-butyl-3-methylimidazolium hydroxide) to afford the c orresponding benzo[a][1,3]oxazino[6,5-c]phenazine derivatives.
ABSTRACT
Caffeine was applied as a green and natural catalyst for the one-pot, four-component sequential condensation between 2-hydroxy-1,4-
naphthoquinone, aromatic 1,2-diamines, ammonium thiocyanate and acid chlorides in the presence of a basic ionic liquid (1-butyl-3-
methylimidazolium hydroxide) to afford the corresponding benzo[a][1,3]oxazino[6,5-c]phenazine derivatives. In this one-pot transformation, five
bonds and two new rings are efficiently formed. This protocol has the advantages of operational simplicity, high yields, easy workup, avoidance of
hazardous or toxic catalysts and organic solvents and high chemo- and regioselectivities.
Keywords:
Multi-component reactions (MCRs)
Green chemistry
Ionic liquid
Caffeine
Oxazine
Phenazine
Available online
ARTICLE INFO Article history:
Received 15 December 2016
Received in revised form 13 January 2017
Accepted 18 January 2017

1
. Introduction
In recent years, interest in green chemistry [1-3] has developed, and a major challenge to organic chemists is to identify facile,
efficient, and nonpolluting synthetic procedures that reduce the use of organic solvents and toxic reagents. In this area, use of natural
materials as promising catalysts in organic reactions has received a considerable amount of attention due to their green credentials [4,5]
and also ionic liquids (ILs) have become increasingly popular over the last few years in the field of green organic synthesis [6] owing
to several advantages such as their catalytic role, ability to dissolve a wide range of materials and mild reaction conditions, non-
inflammability, high isolation and purification yields, reusability and high thermal stability [7,8].
In order to achieve economic savings and pollution prevention, multi-component reactions [9-12] (MCRs) have considerable
ecological interest as a powerful strategy in the synthesis of complex heterocyclic molecules, drug design and drug discovery, arising
from minimization of time, waste, energy, and cost.
Functionalized nitrogen- and oxygen-containing heterocyclic molecules play key roles in medicinal chemistry [13]. Among them,
oxazines and their derivatives have been recognized as an important class of heterocyclic compounds due to a diversity of biological
functions [14-16]. Both natural and synthetic oxazine compounds exhibit a wide range of biological activities, including anticoagulant
[
17], fungicidal [18], AMPA receptors modulation [19], analgesic, antispasmodic [20], antidiabetic and hypolipidaemic activities [21].
Also, phenazine-based compounds are nitrogen-containing heterocycles that have been illustrated to possess numerous biological
functions including antimicrobial [22], antimycobacterial [23], antifungal [24] and antitumour [25] activities. For example,
pyridophenazinediones and pyridazinophenazinedione derivatives are antitumor agents [26,27].
Considering the significance of oxazine and phenazine derivatives and as part of our continuing interest in the development of new
synthetic methods for heterocyclic compounds [28-32] herein, we report a green and efficient method for the synthesis of novel
benzo[a][1,3]oxazino[6,5-c]phenazine derivatives through a sequential, one-pot, four-component condensation reaction between 2-
hydroxy-1,4-naphthoquinone 1, 1,2-diamines 2, ammonium thiocyanate 4 and acid chlorides 5 catalyzed by caffeine as a green and
natural catalyst in 1-butyl-3-methylimidazolium hydroxide (ionic liquid), which acts as reaction medium as well as a basic catalyst and
is easily prepared (Scheme 1).
2
. Results and discussion
Benzo[a][1,3]oxazino[6,5-c]phenazine derivatives can be synthesized via a three-step procedure: in the first step, 2-hydroxy-1,4-
naphthoquinone 1 (1 mmol) and 1,2-diamines 2 (1 mmol) were mixed at room temperature until benzo[a]phenazines 3 was formed (<
+

3
0 min) in [bmim] OH (ionic liquid). Then, ammonium thiocyanate 4 (1 mmol) and acid chlorides 5 (1 mmol) were mixed at 70 C
(
solvent-free) to produce a solid of aroyl isothiocyanate derivatives 6. The final step involves the reaction between the products of the
+

first step 3 with aroyl isothiocyanate derivatives 6 in the presence of caffeine in [bmim] OH to form the corresponding products 7.
To further appraise the activity of the catalyst, the one-pot four-component reaction of 2-hydroxy-1,4-naphthoquinone 1 (1 mmol),
benzene-1,2-diamine 2a (1 mmol), ammonium thiocyanate 4 (1 mmol) and benzoyl chloride 5a (1 mmol) in [bmim] OH (IL) was
selected as a model reaction and the yield and reaction time were monitored in different molar ratios of caffeine. The obtained results
have been summarized in Table 1. As shown in Table 1, higher yield and shorter reaction time were obtained when the reaction was
carried out in the presence of 20 mol% of the catalyst (Table 1, entry 4).
+

With the optimized conditions in hand, the scope and efficiency of the reaction were explored for the synthesis of
benzo[a][1,3]oxazino[6,5-c]phenazine derivatives. Thus, 2-hydroxy-1,4-naphthoquinone 1 was condensed with various aromatic 1,2-
diamines 2, ammonium thiocyanate 4, and different acid chlorides 5 in the presence of caffeine (20 mol %) in ionic liquids at room
temperature. The results are shown in Table 2.
In the first step of this one-pot sequential reaction, different aromatic 1,2-diamines containing benzene-1,2-diamine, 4,5-
dichlorobenzene-1,2-diamine and 4,5-dimethylbenzene-1,2-diamine were condensed with 2-hydroxy-1,4-naphthoquinone to form the
corresponding benzo[a]phenazines. Using benzene-1,2-diamine, higher yields of the products were obtained in shorter reaction times
in comparison with 4,5-dichlorobenzene-1,2-diamine and 4,5-dimethylbenzene-1,2-diamine (Table 2, entries 1, 6, and 9).
In the next step of this sequential protocol, various acid chlorides containing electron-withdrawing groups and electron-donating
groups were used. In all cases the products were obtained in good to high yields (Table 2, entries 1-10).
The structures of all the newly synthesized compounds were characterized by IR, H NMR, and 13C NMR spectroscopy and by
elemental analysis. The mass spectra of these compounds displayed molecular ion peaks with the appropriate m/z values.
We also studied the recycling of the ionic liquid using a selected model reaction of 2-hydroxy-1,4-naphthoquinone, benzene-1,2-
1
+

diamine, ammonium thiocyanate and benzoyl chloride in the presence of caffeine (20 mol%) in [bmim] OH (0.5 mL) at room
temperature (Table 2, entry 1). After the completion of the reaction, 5 mL of water was added and the precipitate was filtered off for
the separation of crude products. After washing the solid products with water completely, the water containing ionic liquid (ionic liquid
is soluble in water) was evaporated under reduced pressure and ionic liquid was recovered and reused. As shown in Fig. 1, the reaction
media could be successfully recycled for up to five runs with limited loss of activity (the yield decreased from 91% to 85% after 5 runs,
Fig. 1).

Although we have not established the mechanism of the reaction experimentally, an acceptable reaction scenario for the sequential
cyclocondensation is outlined in Scheme 2. Initially, 2-hydroxy-1,4-naphthoquinone 1 tautomerizes to intermediate 8. The
condensation of 4-hydroxy-1,2-naphthoquinone 8 with benzene-1,2-diamine 2 produces benzo[a]phenazin-5-ol 3. Then, the formation
of aroyl isothiocyanate 6, followed by formation of the 1:1 adduct 9 and its subsequent protonation by benzo[a]phenazin-5-ol 3
produces 10. The positively charged ion 10 is attacked by the anion of benzo[a]phenazin-5-ol 11. Finally, intermediate 12 undergoes a
cyclization reaction and elimination of water to produce 7 (Scheme 2).
3
. Conclusion
In summary, we have developed a green procedure for the facile synthesis of various potentially biologically active
polyfunctionalized benzo[a][1,3]oxazino[6,5-c]phenazines, using novel four-component sequential reactions in ionic liquid at room
temperature. This one-pot condensation reaction was carried out in the presence of caffeine as a natural, inexpensive, non-toxic and
solid catalyst. This protocol has the advantages of mild reaction conditions, cost effectiveness, environmental friendliness, simple
workup, high yields and usage in synthesis of complex molecules.
4
. Experimental
4
.1. General information
All melting points were determined on an Electrothermal 9100 apparatus and are uncorrected. IR spectra were recorded on a
1
13
Shimadzu IR-470 spectrometer. The H NMR and C NMR spectra were recorded on Bruker DRX-400 Avance instruments using
dimethyl sulfoxide (DMSO) as a solvent. Elemental analyses were performed using a Costech ECS 4010 CHNS-O analyser at
analytical laboratory of Islamic Azad University Yazd branch. Mass spectra were recorded on an Agilent Technology (HP)
spectrometer operating at an ionization potential of 70 eV. Thin-layer chromatography (TLC) was performed on silica-gel Polygram
SILG/UV 254 plates. All reagents were purchased from Merck and Aldrich and used without further purification. The weak basic ionic
liquid (1-butyl-3-methylimidazolium hydroxide) was prepared according to the reported procedure [33].
4
.2. General procedure for the synthesis of novel benzo[a][1,3]oxazino[6,5-c]phenazine derivatives (7a-j)
At first, 2-hydroxynaphthalene-1,4-dione 1 (1 mmol) and benzene-1,2-diamine 2 (1 mmol) were taken in a 10-mL round-bottomed
+

flask containing 0.5 mL of [bmim] OH . The mixture was stirred at room temperature in less than 30 minutes and benzo[a]phenazine 3
was formed. Then, ammonium thiocyanate 4 (1 mmol) and acid chlorides 5 (1 mmol) were mixed at 70 C (solvent-free) in less than 5
minutes to produce a solid of aroyl isothiocyanate derivatives 6. Finally, the obtained aroyl isothiocyanate 6 and caffeine (20 mol%)
were added into the initial reaction system and the reaction mixture was stirred at room temperature for the appropriate time (Table 2).
Upon the completion of the reaction, monitored by TLC analysis, 5 mL of water was added to the mixture. The ionic liquid was
dissolved in water and the crude product was collected by filtration. The separated product was washed twice with water (2×5 mL).
The solid crude product was recrystallized from hot EtOH to give the pure product 7. After isolation of the insoluble products, the IL
was recovered by evaporation of the water, washing the remaining viscous liquid with CH
pressure. The spectral and analytical data are presented below:
2 2
Cl (5 mL) and drying under reduced
3
-Phenyl-1H-benzo[a][1,3]oxazino[6,5-c]phenazine-1-thione (7a): Yellow solid; yield 0.356 g (91%); m.p. 291-294 C; IR (KBr,
-
1
1
cm ): νmax 1656, 1580, 1442, 1378, 1265, 1195, 760; H NMR (400 MHz, DMSO-d
6
): δ 7.07-7.11 (m, 1H, Ar-H), 7.36-7.41 (m, 4H,
Ar-H), 7.89–7.93 (m, 2H, Ar-H), 7.94-8.00 (m, 2H, Ar-H), 8.10-8.13 (m, 1H, Ar-H), 8.24-8.27 (m, 1H, Ar-H), 8.41 (d, 1H, J = 8.0 Hz,
1
3
Ar-H), 9.15 (d, 1H, J = 8.0 Hz, Ar-H); C NMR (100 MHz, DMSO-d
6
): δ 121.2, 122.4, 124.5, 125.8, 126.5, 127.8, 128.4, 128.9,
1
7
29.2, 129.6, 130.1, 130.4, 130.5, 130.7, 138.5, 140.3, 140.8, 141.5, 144.6, 145.8, 159.3, 198.1; Anal. Calcd. for C24 OS: C,
13 3
H N
+
3.64; H, 3.35; N, 10.73; S, 8.19 %. Found: C, 73.89; H, 3.47; N, 10.58; S, 8.41 %. MS (m/z, %): 391 (M , 5).
-(4-Nitrophenyl)-1H-benzo[a][1,3]oxazino[6,5-c]phenazine-1-thione (7b): Yellow solid; yield 0.401 g (92%); m.p. 280-282 C; IR
3
-
1
1
(
KBr, cm ): νmax 1659, 1591, 1508, 1386, 1351, 1226, 769; H NMR (400 MHz, DMSO-d
6
): δ 7.60 (d, 2H, J = 8.4 Hz, Ar-H), 7.68 (d,
2
8
1
H, J = 8.4 Hz, Ar-H), 7.92-7.96 (m, 2H, Ar-H), 8.10 (d, 2H, J = 8.4 Hz, Ar-H), 8.14-8.16 (m, 1H, Ar-H), 8.27-8.29 (m, 1H, Ar-H),
1
3
.48 (d, 1H, J = 8.0 Hz, Ar-H), 9.24 (d, 1H, J = 8.0 Hz, Ar-H); C NMR (100 MHz, DMSO-d
6
): δ 120.0, 122.3, 124.9, 125.4, 125.8,
28.4, 128.7, 129.4, 129.6, 130.0, 130.2, 130.5, 130.8, 130.9, 131.0, 139.5, 140.9, 144.3, 152.4, 159.7, 197.6; Anal. Calcd. for
+
C
24
H N
12 4
O
3
S: C, 66.05; H, 2.77; N, 12.84; S, 7.35 %. Found: C, 66.27; H, 2.89; N, 12.71; S, 7.57 %. MS (m/z, %): 436 (M , 8).
3
-(p-Tolyl)-1H-benzo[a][1,3]oxazino[6,5-c]phenazine-1-thione (7c): Yellow solid; yield 0.348 g (86%); m.p. 288-289 C; IR (KBr,
-
1
1
cm ) : νmax 1668, 1592, 1390, 1265, 1219, 1167, 761; H NMR (400 MHz, DMSO-d
6 3
): δ 2.36 (s, 3H, CH ), 7.39 (d, 2H, J = 8.0 Hz,
Ar-H), 7.42 (d, 2H, J = 8.0 Hz, Ar-H), 7.91-8.02 (m, 4H, Ar-H), 8.14-8.17 (m, 1H, Ar-H), 8.25-8.28 (m, 1H, Ar-H), 8.43-8.44 (m, 1H,
1
3
Ar-H), 9.21 (d, 1H, J = 8.0 Hz, Ar-H); C NMR (100 MHz, DMSO-d
6
): δ 21.2, 121.6, 122.1, 123.5, 125.8, 127.4, 128.5, 129.2, 129.5,
1
3
30.1, 130.5, 130.6, 131.0, 135.6, 140.2, 141.4, 146.7, 150.4, 159.8, 163.5, 167.9, 198.4; Anal. Calcd. for C25 OS: C, 74.05; H,
.73; N, 10.36; S, 7.91 %. Found: C, 73.84; H, 3.96; N, 10.51; S, 7.76 %. MS (m/z, %): 405 (M , 4).
15 3
H N
+

3
-(4-Bromophenyl)-1H-benzo[a][1,3]oxazino[6,5-c]phenazine-1-thione (7d): Yellow solid; yield 0.421 g (90%); m.p. 277-279 C;
-
1
1
6
IR (KBr, cm ): νmax 1662, 1575, 1391, 1246, 1193, 1150, 758; H NMR (400 MHz, DMSO-d ): δ 7.47-7.51 (m, 4H, Ar-H), 7.93-8.06
m, 4H, Ar-H), 8.17-8.22 (m, 1H, Ar-H), 8.29-8.32 (m, 1H, Ar-H), 8.45-8.47 (m, 1H, Ar-H), 9.24-9.28 (m, 1H, Ar-H); C NMR (100
1
3
(
MHz, DMSO-d
6
): δ 118.7, 119.5, 122.3, 124.6, 124.8, 125.6, 128.2, 128.5, 129.2, 129.3, 129.6, 129.7, 130.2, 130.3, 130.6, 130.8,
3
30.9, 140.2, 140.3, 141.4, 147.2, 161.2, 199.6; Anal. Calcd. for C24H12BrN OS: C, 61.29; H, 2.57; N, 8.93; S, 6.82 %. Found: C,
1
6
+
1.47; H, 2.66; N, 9.18; S, 7.03 %. MS (m/z, %): 468 (M , 6).
-(4-Chlorophenyl)-1H-benzo[a][1,3]oxazino[6,5-c]phenazine-1-thione (7e): Yellow solid; yield 0.374 g (88%); m.p. 286-289 C;
3
-
1
1
6
IR (KBr, cm ): νmax 1595, 1573, 1398, 1254, 1230, 1191, 759; H NMR (400 MHz, DMSO-d ): δ 7.43-7.45 (m, 4H, Ar-H), 7.89-8.01
1
3
(m, 4H, Ar-H), 8.07-8.10 (m, 1H, Ar-H), 8.24-8.27 (m, 1H, Ar-H), 8.41-8.43 (m, 1H, Ar-H), 9.19-9.22 (m, 1H, Ar-H); C NMR (100
MHz, DMSO-d
1
S, 7.68 %. MS (m/z, %): 425 (M , 3).
6
): δ 120.2, 122.5, 123.1, 124.7, 125.6, 128.4, 128.7 129.6, 129.7, 130.4, 130.5, 130.8, 130.9, 131.0, 138.5, 141.0,
3
44.5, 153.2, 159.5, 199.3; Anal. Calcd. for C24H12ClN OS: C, 67.68; H, 2.84; N, 9.87; S, 7.53 %. Found: C, 67.54; H, 2.61; N, 10.11;
+
1
1,12-Dichloro-3-phenyl-1H-benzo[a][1,3]oxazino[6,5-c]phenazine-1-thione (7f): Yellow solid; yield 0.404 g (88%); m.p. >300 C;
-
1
1
IR (KBr, cm ): νmax 1658, 1576, 1440, 1381, 1266, 1195, 763; H NMR (400 MHz, DMSO-d
6
): δ 7.11-7.16 (m, 1H, Ar-H), 7.40-7.47
(
m, 4H, Ar-H), 7.93-7.99 (m, 2H, Ar-H), 8.17-8.19 (m, 1H, Ar-H), 8.51 (s, 1H, Ar-H), 8.58 (s, 1H, Ar-H), 9.17 (d, 1H, J = 8.0 Hz, Ar-
1
3
H); C NMR (100 MHz, DMSO-d
2 3
38.5, 141.4, 142.1, 143.5, 146.7, 145.1, 158.4, 198.7; Anal. Calcd. for C24H11Cl N
6
): δ 120.3, 123.1, 124.7, 125.2, 125.1, 126.7, 128.6, 128.8, 129.4, 129.6, 130.2, 130.6, 130.9, 131.3,
1
OS: C, 62.62; H, 2.41; N, 9.13; S, 6.97 %. Found:
+
C, 62.80; H, 2.33; N, 9.37; S, 7.16 %. MS (m/z, %): 459 (M , 9).
1,12-Dichloro-3-(4-nitrophenyl)-1H-benzo[a][1,3]oxazino[6,5-c]phenazine-1-thione (7g): Yellow solid; yield 0.453 g (90%); m.p.
>
8
1
C
1
-
1
1
300 C; IR (KBr, cm ): νmax 1658, 1591, 1515, 1392, 1345, 1270, 751; H NMR (400 MHz, DMSO-d
6
): δ 7.62 (s, 1H, Ar-H), 7.95-
): δ 120.7, 121.4, 123.5, 125.6,
26.4, 128.6, 128.3, 129.6, 129.9, 130.4, 130.5, 130.7, 130.9, 131.2, 131.5, 138.2, 142.1, 144.0, 153.3, 160.1, 198.2; Anal. Calcd. for
1
3
.11 (m, 4H, Ar-H), 8.42-8.49 (m, 4H, Ar-H), 9.12-915 (m, 1H, Ar-H); C NMR (100 MHz, DMSO-d
6
+
24
H
10Cl
2
N
4
O
3
S: C, 57.04; H, 1.99; N, 11.09; S, 6.35 %. Found: C, 56.79; H, 2.16; N, 11.21; S, 6.59 %. MS (m/z, %): 503 (M , 6).
3
-(p-Tolyl)-1H-benzo[a][1,3]oxazino[6,5-c]phenazine-1-thione (7h): Yellow solid; yield 0.407 g (86%); m.p. 293-295 C; IR (KBr,
-
1
1
cm ): νmax 1664, 1597, 1396, 1292, 1222, 1171, 765; H NMR (400 MHz, DMSO-d
6
): δ 2.42 (s, 3H, CH
3
), 7.32-7.37 (m, 4H, Ar-H),
7
8
1
8
.93-7.97 (m, 1H, Ar-H), 8.00-8.04 (m, 1H, Ar-H), 8.35-8.37 (m, 1H, Ar-H), 8.50 (s, 1H, Ar-H), 8.55 (s, 1H, Ar-H), 9.18 (d, 1H, J =
.0 Hz, Ar-H); C NMR (100 MHz, DMSO-d ): δ 21.8, 122.0, 122.4, 123.1, 124.5, 126.2, 128.1, 128.5, 129.3, 129.4, 129.9, 130.2,
6
1
3
30.8, 131.4, 133.6, 141.3, 142.0, 146.1, 152.1, 156.9, 162.1, 165.6, 198.8; Anal. Calcd. for C25
.86; S, 6.76 %. Found: C, 63.12; H, 2.78; N, 9.01; S, 6.69 %. MS (m/z, %): 473 (M , 9).
H13Cl
2
N
3
OS: C, 63.30; H, 2.76; N,
+
1
1,12-Dimethyl-3-phenyl-1H-benzo[a][1,3]oxazino[6,5-c]phenazine-1-thione (7i): Yellow solid; yield 0.365 g (87%); m.p. 297-299
-
1
1

C; IR (KBr, cm ): νmax 1662, 1594, 1490, 1383, 1265, 1201, 766; H NMR (400 MHz, DMSO-d
6
): δ 2.44 (s, 6H, 2CH
3
), 7.09 (t, 1H, J
=
=
7.6 Hz, Ar-H), 7.34-7.38 (m, 4H, Ar-H), 7.63 (s, 1H, Ar-H), 7.84-7.96 (m, 3H, Ar-H), 8.40 (d, 1H, J = 8.0 Hz, Ar-H), 9.14 (d, 1H, J
8.0 Hz, Ar-H); C NMR (100 MHz, DMSO-d ): δ 20.3, 20.4, 122.1, 123.5, 126.1, 127.2, 127.5, 128.2, 129.1, 129.2, 129.5, 129.9,
6
1
3
1
1
30.2, 130.3, 130.8, 131.2, 135.5, 138.8, 140.5, 141.2, 145.1, 145.9, 157.3, 198.4; Anal. Calcd. for C26
0.02; S, 7.64 %. Found: C, 74.48; H, 4.19; N, 10.33; S, 7.50 %. MS (m/z, %): 419 (M , 5).
H
17
N
3
OS: C, 74.44; H, 4.08; N,
+
1
1,12-Dimethyl-3-(4-nitrophenyl)-1H-benzo[a][1,3]oxazino[6,5-c]phenazine-1-thione (7j): Yellow solid; yield 0.418 g (90%); m.p.
-
1
1
>
3
300 C; IR (KBr, cm ): νmax 1659, 1590, 1510, 1388, 1346, 1214, 762; H NMR (400 MHz, DMSO-d
H, CH
= 1.6 Hz, Ar-H), 9.12 (dd, 1H, J = 8.0 Hz, J = 1.2 Hz, Ar-H); C NMR (100 MHz, DMSO-d ): δ 20.3, 20.5, 121.2, 123.3, 124.2,
1 2 6
6
): δ 2.44 (s, 3H, CH ), 2.46 (s,
1
), 7.57-7.61 (m, 3H, Ar-H), 7.83 (s, 1H, Ar-H), 7.98–8.07 (m, 2H, Ar-H), 8.05-8.09 (m, 2H, Ar-H), 8.43 (dd, 1H, J = 8.0 Hz,
3
3
1
3
J
2
1
26.1, 126.5, 127.3, 127.9, 129.1, 129.5, 130.1, 130.2, 130.4, 130.6, 130.9, 133.2, 138.1, 141.5, 144.5, 151.8, 158.1, 197.9; Anal. Calcd.
+
16 4 3
for C26H N O S: C, 67.23; H, 3.47; N, 12.06; S, 6.90 %. Found: C, 67.01; H, 3.29; N, 12.28; S, 7.11 %. MS (m/z, %): 464 (M , 4).
Acknowledgment
We gratefully acknowledge financial support from the Research Council of Young Researchers and Elite Club, Yazd Branch,
Islamic Azad University, Yazd, Iran and University of Science and Arts of Yazd, Iran.

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+

Fig. 1. The recycling of [bmim] OH using a model reaction of 1, 2, 4 and 5 in the presence of caffeine at room temperature.
Scheme 1. One-pot, four-component synthesis of novel benzo[a][1,3]oxazino[6,5-c]phenazine derivatives in the presence of caffeine
as a natural and solid base catalyst.
Scheme 2. The proposed mechanism for the synthesis of novel benzo[a][1,3]oxazino[6,5-c]phenazine derivatives in the presence of
caffeine.

Table 1
Condensation reaction between 1 (1 mmol), 2a (1 mmol), 4 (1 mmol), and 5a (1 mmol) in the presence of different amounts of caffeine
+

in [bmim] OH (IL) at room temperature.
a
Entry
Catalyst (mol %)
Time (h)
Yield (%)
1
2
3
4
5
-
8
6
5
2
2
46
77
85
91
90
10
15
20
30
a
Isolated yield.

Table 2
Synthesis of novel benzo[a][1,3]oxazino[6,5-c]phenazine derivatives 7 from the reaction of 1, 2, 4 and 5 in the presence of caffeine (20
+

mol%) as catalyst in [bmim] OH (IL) at room temperature.
a
Entry
R
Ar
Product
7a
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
H
C
6
H
5
2
2
4
3
3
3
3
4
4
4
91
92
86
90
88
88
90
86
87
90
H
4-NO
4-Me-C
4-Br-C
4-Cl-C
2
-C
6
H
4
7b
7c
H
6 4
H
H
6
H
4
7d
7e
H
6 4
H
Cl
Cl
Cl
Me
Me
C
6
H
5
7f
4-NO
2
-C
H
6 4
7g
4-Me-C
6
H
4
7h
7i
6 5
C H
1
0
4-NO
2
-C
H
6 4
7j
a
Isolated yields.