Molecular sieves catalyzed synthesis of phenazine 5,10-dioxides under solvent-free conditions using microwave irradiation

Article abstract of DOI:10.3987/COM-10-12113

eport on the simple and quick synthesis of phenazine 5,10-dioxides in solvent-free conditions under microwave irradiation. Heating of benzofuroxan and dihydroxybenzene derivatives adsorbed on molecular sieves in a microwave oven for 30 seconds affords div

Full text of DOI:10.3987/COM-10-12113

HETEROCYCLES, Vol. 83, No. 3, 2011
531
HETEROCYCLES, Vol. 83, No. 3, 2011, pp. 531 - 534. © The Japan Institute of Heterocyclic Chemistry
Received, 26th November, 2010, Accepted, 31st January, 2011, Published online, 8th February, 2011
DOI: 10.3987/COM-10-12113
MOLECULAR SIEVES CATALYZED SYNTHESIS OF PHENAZINE
5,10-DIOXIDES UNDER SOLVENT-FREE CONDITIONS USING
MICROWAVE IRRADIATION
Saeka Takeuchi, Hiroaki Saito, Shinichi Miyairi, and Tohru Takabatake*
School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi-shi, Chiba
274-8555, Japan
takabatake.toru@nihon-u.ac.jp
Abstract – We report on the simple and quick synthesis of phenazine
5,10-dioxides in solvent-free conditions under microwave irradiation. Heating of
benzofuroxan and dihydroxybenzene derivatives adsorbed on molecular sieves in
a microwave oven for 30 seconds affords diverse biologically attractive phenazine
5,10-dioxides derivatives. Molecular sieves functions not only as support using
microwave but also as catalyst and dehydration reagent. Synthesis of phenazine
5,10-dioxides seems to proceed on molecular sieves, not in molecular sieves.
Benzofuroxan (benzofurazan N-oxide) 1 has been shown to have numerous pharmacological and
industrial applications.1a-d As a part of benzofurazan chemistry, reactions of various benzofuroxans with
active methylene compounds catalyzed by silica gel or molecular sieves yield the corresponding
quinoxaline 1,4-dioxides, the antibacterial activity of quinoxaline 1,4-dioxides, and synthesis of
quinoxaline 1,4-dioxides in solvent-free conditions under microwave irradiation has been reported.2a-e
Pyrido[2,3-b]pyrazine 1,4-dioxides have been obtained from a reaction of pyrido[2,3-c]furoxan with
active methylene compounds catalyzed by treatment with silica gel, alumina, or molecular sieves and the
antibacterial activity of pyrido[2,3-b]pyrazine 1,4-dioxides has been reported.3a-b Reactions of
benzofuroxan with various phenolic compounds catalyzed by silica gel, alumina, or molecular sieves
provide the corresponding phenazine 5,10-dioxide derivatives and the antibacterial activity of phenazine
5,10-dioxide derivatives has been reported.4a-b
Microwave-assisted organic synthesis is a new and rapidly developing area in synthetic organic chemistry
because it is an environmentally benign reaction.5 In order to overcome a serious risk of fire or explosion
due to sparking, several solvent-free procedures were developed.6 Herein, we report on the simple and
quick synthesis of phenazine 5,10-dioxides in solvent-free conditions under microwave irradiation.

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Reactions of various dihydroxybenzenes with compound 1 using various supports were examined. Table
1 shows the results of the reactions using microwave.
Table 1. Results using the microwave method (MW) of benzofuroxan with several dihydroxy
benzene
O
N
O
N
OH
R
MW
support
R
+
O
N
N
OH
O
OH
1
2a-c
3a-c
Substrate
R
Entry
Time (sec.)
Yield (%)
Support
1
2
3
30
30
30
72 (3a)
70 (3b)
73 (3c)
2a
2b
2c
H
molecular sieves 4A
molecular sieves 4A
molecular sieves 4A
Me
OMe
4
5
6
2a
2a
2a
H
H
H
30
60
60
molecular sieves 13X
silica gel
38 (3a)
8 (3a)
45 (3a)
aluminum oxide basic
And, effect of dehydration activity of molecular sieves was examined (Table 2). For example, Synthesis
of 3a in the presence of H2O yield is 21 %. Dryness of molecular sieves shown to be necessary for the
formation of phenazine 5,10-dioxide derivatives, whose yields decreased with an increase of H2O
adsorbed on molecular sieves. The dehydration capacity of molecular sieves must significantly determine
the possibility of synthesis of phenazine 5,10-dioxide derivatives. As shown in Table 1 entry 5, the low
dehydration activity is one of reasons for the poor yield using silica gel as support.
Table 2. Effect of adding H2O
O
N
OH
O
N
MW
+
O
molecular sieves 4A
N
N
OH
OH
O
3a
1
2a
Entry
Time (sec.)
Yield (%)
Condition
-
1
2
30
30
72
21
adding H2O

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In comparison with 2 kinds of molecular sieves, Table 1 showed the results of the reactions using
molecular sieves 4A as a support to give a better yield than those using molecular sieves 13X. Extraction
results of benzofuroxan were shown in Table 3. After benzofuroxan and dihydroxybenzene were
adsorbed by the molecular sieves 4A or 13X, the adsorbed benzofuroxan was washed with CH2Cl2 to
remove extra benzofuroxan from external surface of molecular sieves. Then, the molecular sieves were
collected by filtration. After dissolving the entire molecular sieves framework in H2SO4, the
benzofuroxan, which was adsorbed in the internal surface of molecular sieves, were able to be extracted
with CH2Cl2. In comparison with the amount of extracted benzofuroxan before dissolving the molecular
sieves in acid, benzofuroxan was obtained in perfect recovery in the case of molecular sieves 4A. The
results of the reactions using molecular sieves 4A to give better yields of phenazine than those using
molecular sieves 13X, is due to the difference in pore size. The benzofuroxan adsorbed in the internal
surface of molecular sieves 13X cannot react with dihydroxybenzenes. Synthesis of phenazines seems
to proceed on molecular sieves, not in molecular sieves.
Table 3. Comparison with molecular sieves 4A and 13X
Na+
13X
4A
Na+
O
N
O
N
O
O
X
N
N
Molecular sieves 13X
Molecular sieves 4A
on molecular sieves
(benzofuroxan %)
79
20
100
0
in molecular sieves
(benzofuroxan %)
After washed three times with CH2Cl2
In conclusion, we have developed a new procedure for the preparation of phenazine 5,10-dioxides under
microwave irradiation. Molecular sieves functions not only as support using microwave but also as
catalyst and dehydration reagent. Synthesis of phenazine 5,10-dioxides seems to proceed on molecular
sieves, not in molecular sieves. This method offers several advantages including an easier experimental
procedure than previously described methods, shorter reaction times.
ACKNOWLEDGEMENTS

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HETEROCYCLES, Vol. 83, No. 3, 2011
This research was supported by A Grant from “Academic Frontier” Project for Private Universities:
matching fund subsidy from MEXT (Ministry of Education, Culture, Sports, Science and Technology)
2002-2006.
REFERENCES AND NOTE
1. (a) A. J. Boulton and P. B. Ghosh, Adv. Heterocyclic Chem., 1969, 10, 1; (b) A. Gasco and A. J
Boulton, Adv. Heterocyclic Chem., 1981, 29, 251; (c) P. B. Ghosh, B. Ternai, and M. W. Whitehouse,
Med. Res. Rev., 1981, 1, 159; (d) A. R. Katritzky and M. F. Gordeev, Heterocycles, 1993, 35, 483.
2. (a) M. Hasegawa and T. Takabatake, Synthesis, 1985, 10, 938; (b) T. Takabatake and M. Hasegawa, J.
Heterocycl. Chem., 1987, 24, 529; (c) T. Takabatake, Y. Hasegawa, and M. Hasegawa, J. Heterocycl.
Chem., 1993, 30, 1477; (d) T. Takabatake, Y. Takabatake, T. Miyazawa, and M. Hasegawa, Yakugaku
Zasshi, 1996, 116, 491; (e) Y. Sumiyoshi, H. Saito, S. Miyairi, and T. Takabatake, Heterocycles, 2009,
78, 905.
3. (a) T. Takabatake, T. Miyazawa, and M. Hasegawa, Heterocycles, 1997, 45, 107; (b) T. Miyazawa, T.
Takabatake, and M. Hasegawa, Yakugaku Zasshi, 1997, 117, 126.
4. (a) T. Takabatake, T. Miyazawa, M. Kojo, and M. Hasegawa, Heterocycles, 2000, 53, 2151; (b) T.
Takabatake, T. Miyazawa, A. Takei, and M. Hasegawa, Medicine and Biology, 2001, 142, 5.
5. (a) S. Caddick, Tetrahedron, 1995, 51, 10403; (b) L. Perreux and A. Loupy, Tetrahedron, 2001, 57,
9199; (c) P. Lidström, J. Tierney, B. Wathey, and J. Westman, Tetrahedron, 2001, 57, 9225; (d) A. K.
Bose, M. S. Manhas, S. N. Ganguly, A. H. Sharma, and B. K. Banik, Synthesis, 2002, 1578.
6. (a) A. Loupy, A. Petit, J. Hamelin, F. Texier-Boullet, P. Jacquault, and D. Mathé, Synthesis, 1998,
1213; (b) S. Paul, P. Nanda, R. Gupta, and A. Loupy, Tetrahedron Lett., 2002, 43, 4261; (c) S. Kotha,
K. Mandal, A. C. Deb, and S. Banerjee, Tetrahedron Lett., 2004, 45, 9603.
7. All experiments were carried out by using a RE-T13 domestic oven manufactured by SHARP Inc.
Molecular sieves (powder, Union Showa) were dried by heating at 250 oC for 2 h. In the case of adding
H2O (Table 2, Entry 2), dried molecular sieves (4 g) were put into 9:1 MeOH / H2O (10 mL) and stand
overnight, and thereafter filtrated. The resulting molecular sieves were washed with MeOH and CH2Cl2,
and dried using air carefully at room temperature.
A typical experimental procedure for synthesizing phenazine 5,10-dioxides is as follows (Table 1): In a
round bottom flask, dried molecular sieves 4A (4 g) was impregnated with a solution of benzofuroxan
1 (68 mg, 0.5 mmol) and dihydroxybenzene 2a (60.5 mg, 0.55 mmol) in MeOH (10 mL). The solvent
was evaporated on a rotatory evaporator followed by standing under microwave irradiation (700 W) for
30 seconds without stirring. Then, It was purified by column chromatography (silica gel, 20:1 CH2Cl2 /
MeOH) to provide phenazine 5,10-dioxides in 72 % yield.