New synthesis of 5,10-dioxyphenazine-2-carboxylic acid

Article abstract of DOI:10.1081/SCC-100104833

Phenazine di-N-oxides substituted in the 2-position by a carboxylic function were prepared in few steps from 4-amino-3-nitrobenzoic acid via the formation of methyl 5,10-dioxy-6,7,8,9-tetrahydrophenazine-2-carboxylate without purification of the intermediates.

Full text of DOI:10.1081/SCC-100104833

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NEW SYNTHESIS OF 5,10-DIOXYPHENAZINE-2-
CARBOXYLIC ACID
Michelyne Haroun a , Philippe Helissey a & Sylviane Giorgi-Renault b
a Laboratoire de Chimie Thérapeutique associé au CNRS et à l'Université René Descartes
(UMR 8638) , Faculté des Sciences Pharmaceutiques et Biologiques, 4 avenue de
l'Observatoire, Paris, Cedex 06, 75270, France
b Laboratoire de Chimie Thérapeutique associé au CNRS et à l'Université René Descartes
(UMR 8638) , Faculté des Sciences Pharmaceutiques et Biologiques, 4 avenue de
l'Observatoire, Paris, Cedex 06, 75270, France
Published online: 09 Nov 2006.
To cite this article: Michelyne Haroun , Philippe Helissey & Sylviane Giorgi-Renault (2001) NEW SYNTHESIS OF 5,10-
DIOXYPHENAZINE-2-CARBOXYLIC ACID, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 31:15, 2329-2334, DOI: 10.1081/SCC-100104833
To link to this article: http://dx.doi.org/10.1081/SCC-100104833
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SYNTHETIC COMMUNICATIONS, 31(15), 2329–2334 (2001)
NEW SYNTHESIS OF 5,10-
DIOXYPHENAZINE-2-CARBOXYLIC ACID
Michelyne Haroun, Philippe Helissey,
and Sylviane Giorgi-Renault*
Laboratoire de Chimie Therapeutique associe au CNRS et a
l’Universite Rene Descartes (UMR 8638), Faculte des Sciences
Pharmaceutiques et Biologiques, 4 avenue de l’Observatoire,
75270 Paris Cedex 06, France
ABSTRACT
Phenazine di-N-oxides substituted in the 2-position
by a carboxylic function were prepared in few steps from
4-amino-3-nitrobenzoic acid via the formation of methyl
5,10-dioxy-6,7,8,9-tetrahydrophenazine-2-carboxylate with-
out purification of the intermediates.
During the course of our investigations, we were interested in the
preparation of substituted phenazine-5,10-dioxides and particularly 5,10-
dioxyphenazine-2-carboxylic acid.
The classical route for preparing phenazinedioxides involves the oxida-
tion of the corresponding phenazines. In most cases, this oxidation affords a
mixture of mono-N-oxide and di-N-oxide derivatives, the latter being
isolated in modest or even poor yield. The oxidation of phenazine-2-
carboxylic acid into 5,10-dioxyphenazine-2-carboxylic acid by peracetic acid
* Corresponding author.
2329
Copyright & 2001 by Marcel Dekker, Inc.
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HAROUN, HELISSEY, AND GIORGI-RENAULT
has been described by Maffei1 but the yield of the reaction was not specified.
In our hands, this oxidation failed whatever the experimental conditions.2
Consequently, we had to develop a somewhat different strategy.
In this paper, we report a new synthesis of the 5,10-dioxyphena-
zine-2-carboxylic acid 8 via aromatization of the methyl 5,10-dioxy-
6,7,8,9-tetrahydrophenazine-2-carboxylate 5 which was obtained from
benzofuroxan-5-carboxylic acid 2 (Scheme).
Benzofuroxans were prepared either by hypochlorite oxidation of the
appropriate o-nitroanilines or by pyrolysis of the corresponding nitrophenyl
azides. The latter method was used in the past for the synthesis of benzofuro-
xan-5-carboxylic acid 2 which was obtained from 4-amino-3-nitrobenzoic
acid in two steps and 47% overall yield or from 4-chloro-3-nitrobenzoic
acid in one step and 50% yield by Boulton.3 A one-pot synthesis
carried out under extremely strict control of the temperature (60 ꢀ 0.1ꢁC)
in the presence of phase-transfer catalyst gave a yield of 88%.4 Oxidation of
Scheme.

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5,10-DIOXYPHENAZINE-2-CARBOXYLIC ACID
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4-amino-3-nitrobenzoic acid 1 by an excess of commercial hypochlorite sol-
ution in alkaline medium at 0ꢁC provides an easier, efficient (94%) and
rapid method.
The 5,10-dioxy-6,7,8,9-tetrahydrophenazine-2-carboxylic acid could
not be obtained in satisfactory yield by condensation of 2 with the N-cyclo-
hex-1-enylmorpholine 4 following the procedure described for the unsubsti-
tuted analogue.5 Consequently, the acid 2 was esterified into 3 and the
phenazine 5 was isolated in 50% yield by reaction with 4 in DMF at rt.
Direct aromatization of 5 into 7 was impossible. Indeed, the classical
method of aromatization at high temperature could not be used due to the
well-known instability of di-N-oxides. There is no reaction and sometimes
only degradation under the following conditions: p-chloranil/benzene,6 tri-
phenylmethanol/trifluoroacetic acid,7 MnO2/chloroform8 or benzene. With
DDQ in refluxing 1,2-dichloroethane, only 10% of 7 could be isolated.
The aromatic derivative 7 was eventually obtained in a two step pro-
cedure: dibromination of the saturated ring of 5 by NBS in the presence of a
catalytic amount of benzoyl peroxide and subsequent dehydrobromination
of 6 by t-BuOK in methanol. Saponification of 7 afforded the desired final
product 8 in good yield.
In conclusion, we have elaborated a new method of synthesis of phe-
nazine di-N-oxides substituted in the 2-position by a carboxylic function.
The acid 8 was obtained from commercially available 4-amino-3-nitroben-
zoic acid in 6 steps without purification of the intermediates. The mild con-
ditions utilized in every step of the synthesis avoid the risk of formation of
mono-oxide derivatives.
EXPERIMENTAL
All melting points were determined on a Maquenne apparatus and are
uncorrected. IR spectra were recorded on Perkin-Elmer 1600 infrared spectro-
photometer. NMR spectra were recorded on Bruker AC-300 spectrometer;
chemical shift values are given in ppm (d). Flash column chromatography
was performed using SDS silica gel 60, 35–70 mesh.
[2,1,3]Benzoxadiazole-5-carboxylic acid N-oxide 2
To a solution of KOH (8.07 g, 144 mmol) in C2H5OH (500 mL) pre-
viously heated to 70ꢁC was added 4-amino-3-nitrobenzoic acid (12.49 g,
68.6 mmol). The suspension was triturated for 15 min and then cooled to
0ꢁC. A commercially available (ꢂ 2 M) solution of sodium hypochlorite

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HAROUN, HELISSEY, AND GIORGI-RENAULT
(103 mL) was added dropwise at 0ꢁC. The reaction was stirred at the same
temperature for 15 min, poured into ice and acidified with a 6 N HCl
solution until pH 1 was reached. The mixture was concentrated and the
resulting precipitate was filtered off, washed with H2O, and then dried to
yield 11.58 g (94%) of an orange solid. m.p. 128–129ꢁC [lit.3 m.p. 128–129ꢁC
(toluene)]. IR (KBr): 3095-2539 (br), 1682, 1610, 1589, 1490, 1430, 1314 cmꢃ1
1H-NMR (DMSO-d6): d 8.00 (m, 3H, ArH), 13.00 (s, 1H, COOH).
.
Methyl [2,1,3]benzoxadiazole-5-carboxylate N-oxide 3
A suspension of acid 2 (11.55 g, 64.2 mmol) in CH3OH (450 mL) was
refluxed in the presence of concentrated sulfuric acid (23 mL) for 1.5 h. After
cooling and concentrating, the precipitate was filtered off, washed with H2O
and with CH3OH to give 11.25 g (90%) of a yellow solid. A sample was
recrystallized from CH3OH for analysis, m.p. 89–90ꢁC. IR (KBr): 1722,
1
1614, 1589, 1532, 1279, 1243 cmꢃ1. H-NMR (CDCl3): d 3.90 (s, 3H, CH3),
7.52 (m, 1H, ArH), 7.80 (m, 1H, ArH), 8.17 (m, 1H, ArH). Anal. Calcd. for
C8H6N2O4: C, 49.49; H, 3.11; N, 14.43. Found: C, 49.61; H, 3.07; N, 14.44.
Methyl 5,10-dioxy-6,7,8,9-tetrahydrophenazine-2-carboxylate 5
To a solution of ester 3 (300 mg, 1.55 mmol) in DMF (1,2 mL) was
added N-cyclohex-1-enylmorpholine 4 (1.14 mL, 6.96 mmol). The resulting
precipitate was filtered off, washed with DMF then with Et2O to give 210 mg
(50%) of a yellow solid. An analytical sample was obtained by flash chromato-
graphy (2 : 98 CH3OH/CH2Cl2). m.p. 209ꢁC (dec.). IR (KBr): 1720, 1340,
1
1277, 1239 cmꢃ1. H-NMR (DMSO-d6): d 1.97 (m, 4H, 2ꢄH7 and 2ꢄH8),
3.13 (m, 4H, 2ꢄH6 and 2ꢄH9), 4.00 (s, 3H, CH3), 8.38 (dd, 1H, J3-4 ¼ 9 Hz,
J3–1 ¼ 2 Hz, H3), 8.66 (d, 1H, J4–3 ¼ 9 Hz, H4), 9.27 (d, 1H, J1-3 ¼ 2 Hz,
H1). MS (CI/NH3) m/z 292 [MþNH4]þ, 275 [MH]þ, 259 [MH-O]þ, 243
[MH-2O]þ. Anal. Calcd. for C14H14N2O4, 0.25 H2O: C, 60.32; H, 5.24; N,
10.05. Found: C, 60.62; H, 5.15; N, 10.05.
Methyl 6,9-dibromo-5,10-dioxy-6,7,8,9-tetrahydrophenazine-
2-carboxylate 6
A mixture of 5 (416 mg, 1.52 mmol), NBS (541 mg, 3.04 mmol), and
benzoyl peroxide (70% purity) (8 mg, 0.023 mmol) in CCl4 (20 mL) was
refluxed for 5 h. After cooling, the reaction mixture was diluted with

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5,10-DIOXYPHENAZINE-2-CARBOXYLIC ACID
2333
CH2Cl2, washed with a saturated solution of K2CO3 and then with H2O.
The organic layer was evaporated and the resulting precipitate was washed
with ligroin to yield 564 mg (86%) of 6 as an orange solid. The product was
pure enough to be used in the next step without further purification. An
analytical sample was obtained by flash chromatography (70 : 30 cyclohex-
ane/AcOEt). m.p.130ꢁC. IR (KBr): 1728, 1349, 1271, 1227 cmꢃ1. H-NMR
1
(CDCl3): d 2.50 (m, 2H, H7 and H8), 2.76 (m, 2H, H7 and H8), 3.96 (s, 3H,
CH3), 5.80 (m, 2H, H6 and H9), 8.37 (dd, 1H, J3-4 ¼ 9 Hz, J3-1 ¼ 2 Hz, H3),
8.63 (d, 1H, J4-3 ¼ 9 Hz, H4), 9.22 (d, 1H, J1-3 ¼ 2 Hz, H1). MS (CI/NH3) m/z
433 [MH]þ, 417 [MH-O]þ. Anal. Calcd. for C14H12Br2N2O4, 0.5 H2O: C,
38.12; H, 2.97; N, 6.35. Found: C, 38.37; H, 2.88; N, 6.18.
Methyl 5,10-dioxyphenazine-2-carboxylate 7
To a solution of 6 (250 mg, 0.579 mmol) in CH3OH (25 mL) was added
t-BuOK (1.06 g, 9.48 mmol) at 0ꢁC. The reaction mixture was maintained at
0ꢁC for 1 h. The mixture was acidified to pH 1 with a 1 N HCl solution,
diluted with H2O and extracted with AcOEt. The organic layer was washed
with H2O, dried over Na2SO4, filtered and evaporated. Addition of ligroin
followed by filtration afforded a crude product which was purified by flash
chromatography (70 : 30 ligroin/AcOEt) to give 125 mg (80%) of 7 as a red
solid. m.p. 177ꢁC (dec.). IR (KBr): 1724, 1354, 1284, 1094 cmꢃ1. H-NMR
1
(CDCl3): d 3.97 (s, 3H, CH3), 7.80 (m, 2H, H7 and H8), 8.31 (dd, 1H,
J3-4 ¼ 7 Hz, J3-1 ¼ 2 Hz, H3), 8.65 (m, 3H, H4, H6 and H9), 9.33 (d, 1H,
J1-3 ¼ 2 Hz, H1). MS (CI/NH3) m/z 288 [MþNH4]þ, 271 [MH]þ, 255
[MH-O]þ, 239 [MH-2O]þ. Anal. Calcd. for C14H10N2O4: C, 62.22; H,
3.73; N, 10.37. Found: C, 62.03; H, 3.85; N, 10.04.
5,10-Dioxyphenazine-2-carboxylic acid 8
To a suspension of ester 7 (350 mg, 1.30 mmol) in CH3OH (80 mL) was
added a solution of sodium hydroxide (520 mg, 13.0 mmol) in H2O (80 mL).
The resulting suspension was refluxed for 10 min. After cooling, the reaction
mixture was acidified to pH 2 with a 6 N HCl solution. The resulting pre-
cipitate was filtered off, washed with H2O, and then dried to give 309 mg
(93%) of 8 as an orange solid. m.p. 280ꢁC [lit.1 m.p. 280ꢁC (C2H5OH)]. IR
(KBr): 3105-2360 (br), 1705, 1348, 1278, 1070, 765 cmꢃ1. 1H-NMR (DMSO-
d6): d 8.00 (m, 2H, H7 and H8), 8.30 (dd, 1H, J3-4 ¼ 9 Hz, J3-1 ¼ 2 Hz, H3),
8.60 (m, 3H, H4, H6 and H9), 9.00 (d, 1H, J1-3 ¼ 2 Hz, H1), 13.8 (s, 1H,
COOH).

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HAROUN, HELISSEY, AND GIORGI-RENAULT
ACKNOWLEDGMENT
M.H. thanks the National Council for Scientific Research of Lebanon
for financial support.
REFERENCES
1. Maffei, S.; Pietra, S. and Rivolta, A.N. Ann. Chim. (Rome) 1952, 42,
519.
2. Helissey, P.; Giorgi-Renault, S.; Colson, P.; Houssier, C. and Bailly, C.
Bioconjugate Chem. 2000, 11, 219.
3. Boulton, A.J.; Ghosh, P.B. and Katritzky, A.R. J. Chem. Soc. C 1996,
971.
4. Ayyangar, N.R.; Madan Kumar, S. and Srinivasan, K.V. Synthesis
1987, 616.
5. Haddadin, M.J. and Issidorides, C.H. Tetrahedron Lett. 1965, 3253.
6. Braude, E.A.; Brook, A.G. and Linstead, R.P. J. Chem. Soc. 1954,
3569.
7. Fu, P.P. and Harvey, R.G. Tetrahedron Lett. 1974, 3217.
8. Fatiadi, A.J. Synthesis 1976, 133.
Received in the UK July 24, 2000

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