Synthesis of phenazine 5,10-dioxides from benzofuroxan catalyzed by molecular sieves

Article abstract of DOI:10.3987/com-00-8957

The synthesis of substituted phenazines was carded out. Phenazine 5,10-dioxides (3) were obtained from benzofuroxan (1) with dihydroxybenzene derivatives (2) catalyzed by molecular sieves at room temperature.

Full text of DOI:10.3987/com-00-8957

HETEROCYCLES, Vol. 53, No.10, 2000, pp. 2151-2162, Received, 29th May, 2000
SYNTHESIS OF PHENAZINE 5,10-DIOXIDES FROM
BENZOFUROXAN CATALYZED BY MOLECULAR SIEVES
Tohru Takabatake, Tomoyuki Miyazawa, Mahiro Kojo,
*
and Minoru Hasegawa
College of Pharmacy, Nihon University, 7-7-1 Narashinodai,
Funabashi-shi, Chiba 274-8555, Japan
Abstract - The synthesis of substituted phenazines was carried out.
Phenazine 5,10-dioxides (3) were obtained from benzofuroxan (1)
with dihydroxybenzene derivatives (2) catalyzed by molecular sieves
at room temperature.
INTRODUCTION
Benzofuroxan (1) has been shown to have numerous pharmacological and industrial
applications.1a-c Reactions of benzofuroxan with phenolic compounds in basic medium
provide the corresponding phenazine 5,10-dioxide derivatives.2 Certain phenazine
derivatives are known to have antibacterial activity and two of which, iodinin and myxin,
4
are microbial metabolites.3,
As a part of benzofurazan chemistry, reactions of
benzofuroxans with active methylene compounds lead to the corresponding quinoxaline
1,4-dioxides catalyzed by silica gel5 or molecular sieves6, 7 and the antibacterial activity of
quinoxaline 1,4-dioxides has been reported.8 Pyrido[2,3-b]pyrazine 1,4-dioxides and
pyrido[2,3-b]pyrazine 1-oxides have been obtained from pyrido[2,3-c]furoxan catalyzed

by silica gel, alumina, or molecular sieves9 and the antibacterial activity of pyrido[2,3-
b]pyrazine 1,4-dioxides and pyrido[2,3-b]pyrazine 1-oxides has been reported.10 In this
study, phenazine 5,10-dioxide derivatives were obtained from benzofuroxan and
dihydroxybenzene derivatives catalyzed by molecular sieves or silica gel or alumina at
room temperature.
RESULTS AND DISCUSSION
Phenazine 5,10-dioxide derivatives were synthesized as follows.
compound (1) and 1,4-dihydroxybenzene derivatives (2) in methanol was evaporated in
the presence of molecular sieves 4A, aluminum oxide, or silica gel. Both starting
A solution of
materials were adsorbed on the molecular sieves or other catalysts followed by standing at
room temperature, 40 oC or 90 oC. The reaction mixture was chromatographed on silica
gel to give the corresponding phenazine 5,10-dioxide derivatives (3).
Table 1
O
OH
N
O
N
N
N
O
OH
O
OH
1
2a
3a
11
Catalysts
3a (%)
1 (%, recovery)
Reaction condition
rt, 2 h
Molecular sieves 4A
87
0
o
37
56
0
8
Aluminum oxide, basic
90 C,1 h
o
40 C, 2 h
o
40 C, 2 h
acidic
21
29
7
0
o
40 C, 2 h
neutral
o
Silica gel C-200
None
16
0
39
97
90 C, 2 h
rt, 2 h

Various catalysts and temperature in the reaction of compound (1) with 1,4-
dihydroxybenzene (2a) were examined (Table 1). In using catalysts, reaction efficacy
varied considerably with the catalyst used.
Phenazine 5,10-dioxide derivatives were
obtained in good yield using molecular sieves 4A as catalyst at room temperature. The
most suitable catalyst was molecular sieves 4A.
Table 2
OH
+
Molecular Sieves
O
OH
rt, 2 h
N
N
OH
2a
OH
N
o
(90 C,1 h)
O
O
+
3a
N
O
OH
OH
4
X
1
O
N
OH
OH
+
X
N
O
5
6
Yield (%) of
Phenazine
Compound
No.
(3a)
2a
4
87
(3a, 6)
(3a)
0
1.1*
0
(6)
5
0* (6)
o
* 90 C,1 h

1,4-Dihydroxybenzene reacted with compound (1) to give 2-hydroxyphenazine 5,10-
dioxide (3a) in good yield but 1,2-dihydroxybenzene (5) did not and the reactivity of 1,3-
dihydroxybenzene (4) was less. No 1-hydroxyphenazine 5,10-dioxide (6) was obtained
(Table 2).
Various 1,4-dihydroxybenzene derivatives (2a~2g) in reactions with compound (1) were
examined. The influence of electron-withdrawing and electron-donating groups in the
reactions was examined using dihydroxybenzene derivatives.
Table 3
R1 = electron-donating group
O
OH
N
R
1
N
R
1
+
O
Molecular Sieves
rt, 2 h
N
O
N
O
OH
OH
1
2
3
Compound
No.
R
Yield (%)
1 (Recovery)
1
H
87
80
3a
3b
0
0
0
CH
3
OCH
91
3c
3
As evident from Table 3, the electron-donating group on 1,4-dihydroxybenzene made
possible phenazine synthesis in good yield but comparison of yields of various phenazines
as products indicated the electron-withdrawing group on 1,4-dihydroxybenzene not to lead

to good yield (See Table 4). Phenazines (3a~3f), the assignments were made based on
1
1
the following; When H-NMR signals of phenazines were compared, H-NMR spectrum
of compound (3d) showed two doublet signals (δ 7.45 and 8.91 ppm) and the coupling
constant was 10.27 Hz. These signals may possible consist of protons 3 and 4.
Phenazines including the electron-donating group have two singlet signals consisting of
protons 1 and 4.
Table 4
R2 = electron-withdrawing group
O
R
2
OH
N
OH
N
R
2
+
O
Molecular Sieves
rt, 2 h
N
O
N
O
OH
1
2
3
Compound
No.
R
Yield (%)
2
1 (Recovery)
CHO
52
29
44
3d
COCH
26
3e
3f
3
COCH CH
2
34
O
3
47
90
3g
COOH
1
The ethyl 2-hydroxyphenazine-1-yl ketone 5,10-dioxide (3f) has interesting H-NMR
spectrum which showed two quartets at δ 2.63 and 2.99 ppm with each 1H integration for
o
protons at the methylene of 3f at 25 C. The methylene group may thus rotate slowly
enough to show different chemical shifts of two kinds of protons. The temperature-

1
dependent H-NMR spectra for compound (3f) are shown in Figure 1. The two quartet
signals broadened slightly at 80 oC and then changed to one signal (δ 2.82 ppm) at 140 oC.
Scheme 1 shows the positions of protons at the methylene of 3f to be close to oxygen at N-
oxide, and consequently oxygen affects the rotation of the two protons at methylene. The
oxygen may possibly function as a barrier against conformation of methylene and so
methylene group rotation is slow enough that different chemical shifts are apparent.
Molecular sieves 4A or other catalysts would thus appear to affect dehydration in the
reaction mechanism and the reaction proceed not in but on molecular sieves in that the

CH3
Hb
O
Ha
O
N
OH
N
O
3f
Scheme 1
pore diameter of molecular sieves 4A is approximately 0.4 nm. Windows to the cages are
too small to allow the organic molecules access to cages.
The enol form of carbonyl compounds was previously shown necessary for the formation
of quinoxalines or pyridopyrazines, whose yields depends on enol content in 1,3-
diketones.7, 9 Molecular sieves or other catalysts may serve to enhance the stability of the
enol form of carbonyl compound and the dehydration capacity of catalysts may determine
significantly the possibility of synthesis.
Molecular sieves may have similar effect as electron-withdrawing groups on
dihydroxybenzenes (see Scheme 2). Electron-withdrawing groups and molecular sieves
surface force dihydroxybenzenes to couple at the ortho position followed by cyclization
and elimination of water to yield phenazines. The different attacking positions in the
reaction on molecular sieves may lead to different structures of phenazines as products. In
the case of reaction with 2,5-dihydroxybenzoic acid, no product was obtained, possibly
owing to steric hindrance.
The present method is simple and efficient for the preparation of phenazine 5,10-dioxide
derivatives under mild conditions.

Electron-withdrawing group
Ex.-COCH
3
Molecular Sieves
CH3
C
R1
C
O
H
O
O
C
OH
N
O
N
N
O
N
H
R2
HO
O
O
CH3
CH3
C
CH3
C
O
O
N
O
N
H
H C
O
O
OH
OH
OH
N
N
O
N
O
N
O
HO
OH
H2O
O
Electron-donating group
Ex.-OCH
3
O
N
HO
H
HO
N
O
N
OCH3
OH
O
OCH3
OH
N
O
O
O
OH
OCH3
OH
OCH3
OH
N
N
N
O
N
O
H
H2O
Scheme 2
EXPERIMENTAL
Melting points were determined with a Yanagimoto micromelting point apparatus and are
uncorrected. The IR spectra were recorded on a JASCO IR-810 spectrophotometer. The
1H-NMR spectra were recorded on a JNM-GSX 400 FT NMR System with TMS as the
internal standard. The MS spectra were recorded on a Hitachi M-2000 and JEOL JMS-
GCmateꢀspectrometers with an electron beam energy of 70 eV. Microanalysis was

performed at the microanalytical laboratory of the Center for Instrumental Analysis in
College of Science & Technology, Nihon University.
General Procedure (Table 1 ).
To a solution of 1 (34.5 mg, 0.25 mmol) and dihydroxybenzene (2a) (30.3 mg, 0.275
mmol) in methanol (5 mL) was added silica gel [Wako Pure Chemical Industries,
Wakogel C-200, 1 g] or aluminium oxide [Merck, Aluminium oxide 90 active basic for
column chromatography (Art. 1076), Aluminium oxide 90 active neutral for column
chromatography (Art. 1077), Aluminium oxide 90 active acidic for column
chromatography (Art. 1078), 1 g] or molecular sieves [4A powder, Union Showa, 1 g].
o
The mixture was evaporated in an evaporator at 30 C. The adsorbent containing the
adsorbed reagents was allowed to stand for 2 h at rt and then introduced onto the silica gel
column (Wako Pure Chemical Industries, Wakogel C-200).
The product 2-
Hydroxyphenazine 5,10-dioxide (3a) was eluted with dichloromethane/methanol (95:5)
and purified by preparative TLC (Merck, Silica gel plate 60 F254 Art. 5717) with
dichloromethane/methanol (95:5). Yield 49.8 mg (87 %).
2-Hydroxyphenazine 5,10-dioxide (3a)
o
o
Deep red powder, mp 243-245 C(decomp) (lit.,11 mp 234 C(decomp)). IR (KBr) cm-1:
1615, 1595, 1353, 1238, 1078, 837, 762. 1H- NMR (DMSO-d6) δ : 7.49 (dd, 1H, J1, 3 =
2.2 Hz, J3, 4 = 9.5 Hz, C3-H), 7.77 (d, 1H, J1, 3 = 2.2 Hz, C1-H), 7.84-7.93 (m, 2H, C7-H,
C8-H), 8.48 (d, 1H, J3, 4 = 9.5 Hz, C4-H), 8.52-8.56 (m, 2H, C6-H, C9-H), 11.33 (br s,
1H, OH, deuterium oxide-exchangeable). EI-MS m/z: 228.0502 (Calcd for C12H8N2O3:
228.0534). 3a was characterized by comparison of IR spectra with an authentic sample. 11
2-Hydroxy-3-methylphenazine 5,10-dioxide (3b)
Deep red powder, mp 223-225 oC. IR (KBr) cm-1: 1620, 1457, 1346, 1254,1076, 830, 760.
1H-NMR (DMSO-d6) δ : 2.41 (s, 3H, CH3), 7.78 (s, 1H, C1-H), 7.78-7.90 (m, 2H, C7-H,
C8-H), 8.33 (s, 1H, C4-H), 8.46-8.55 (m, 2H, C6-H, C9-H), 11.28 (br s, 1H, OH,
deuterium oxide-exchangeable).
EI-MS m/z: 242.0672 (Calcd for C13H10N2O3 :

242.0690). Anal. Calcd for C13H10N2O3: C, 64.46; H, 4.16; N, 11.56. Found: C, 64.46; H,
4.19; N, 11.57.
2-Hydroxy-3-methoxyphenazine 5,10-dioxide (3c)
o
Deep red powder, mp 248-250 C. IR (KBr) cm-1: 1620, 1524, 1470, 1347, 1223, 1185,
1082, 852, 763. 1H-NMR (DMSO-d6) δ : 4.06 (s, 3H, OCH3), 7.80 (s, 1H, C1-H), 7.81 (s,
1H, C4-H), 7.84-7.89 (m, 2H, C7-H, C8-H), 8.52-8.57 (m, 2H, C6-H, C9-H), 11.47 (br s,
1H, OH, deuterium oxide-exchangeable).
EI-MS m/z: 258.0639 (Calcd for
C13H10N2O4 : 258.0639). Anal. Calcd for C13H10N2O4: C, 60.47; H, 3.90; N, 10.85.
Found: C, 60.42; H, 4.01; N, 10.80.
2-Hydroxy-1-phenazinecarboxaldehyde 5,10-dioxide (3d)
o
Orange powder, mp 221-224 C. IR (KBr) cm-1: 1630, 1583, 1472, 1355, 1290, 1170,
1104, 832, 776. 1H-NMR (DMSO-d6) δ : 7.45 (d, 1H, J3, 4 = 10.2 Hz, C3-H), 7.85-7.96
(m, 2H, C7-H, C8-H), 8.68-8.77 (m, 2H, C6-H, C9-H), 8.91 (d, 1H, J3, 4 = 10.2 Hz, C4-H),
11.99 (s, 1H, CHO), 15.23 (s, 1H, OH, deuterium oxide-exchangeable). EI-MS m/z:
256.0489 (Calcd for C13H8N2O4 : 256.0483). Anal. Calcd for C13H8N2O4: C, 60.94; H,
3.15; N, 10.93. Found: C, 60.85; H, 3.29; N, 10.73.
2-Hydroxyphenazine-1-yl methyl ketone 5,10-dioxide (3e)
o
o
Deep red powder, mp 182-183 C (mp. 180-181 C). 11 IR (KBr) cm-1: 1706, 1555, 1415,
1337, 1278, 1173, 816, 768. 1H-NMR (DMSO-d6) δ : 2.56 (s, 3H, CH3), 7.61 (d, 1H,
J3, 4 = 9.5 Hz, C3-H), 7.83-7.88 (m, 2H, C7-H, C8-H), 8.40 (d, 1H, J3, 4 = 9.5 Hz, C4-H),
8.45-8.51 (m, 2H, C6-H, C9-H), 11.45 (s, 1H, OH, deuterium oxide-exchangeable). EI-
MS m/z: 270.0686 (Calcd for C14H10N2O4 : 270.0640). 3e was characterized by
comparison of IR spectra with an authentic sample. 11
Ethyl 2-hydroxyphenazine-1-yl ketone 5,10-dioxide (3f)

o
Deep red powder, mp 180-182 C. IR (KBr) cm-1: 1675, 1590, 1555, 1420, 1348, 1285,
1180, 1113, 831, 763. 1H-NMR (DMSO-d6) δ : 1.17 (t, 3H, J = 6.8 Hz, CH3-CH2),
2.63 (q, 1H, J = 6.8 Hz, CH3-CHaHb), 2.99 (q, 1H, J = 6.8 Hz, CH3-CHaHb), 7.56 (d,
1H, J3, 4 = 9.7 Hz, C3-H), 7.87 (m, 1H, C7-H, C8-H), 8.40 (m, 1H, C9-H), 8.50 (d, 1H,
J3, 4 = 9.7 Hz, C4-H), 8.52 (m, 1H, C6-H, C9-H), 11.36 (s, 1H, OH, deuterium oxide-
exchangeable). EI-MS m/z: 284.0804 (Calcd for C15H12N2O4 : 284.0796). Anal. Calcd
for C15H12N2O4: C, 63.38; H,4.25 ; N, 9.85. Found: C, 63.22; H, 4.38; N, 9.86.
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