The synthesis of benzo[a]phenazine-5,6-dione 7-oxides

Full text of DOI:10.1007/s10593-014-1436-0

Chemistry of Heterocyclic Compounds, Vol. 49, No. 12, March, 2014 (Russian Original Vol. 49, No. 12, December, 2013)
LETTERS TO THE EDITOR
THE SYNTHESIS OF BENZO[а]PHENAZINE-5,6-DIONE 7-OXIDES
1
2
1
*
L. M. Gornostaev , T. A. Lyashchenko , and E. V. Arnold
Keywords: 4-arylamino-1,2-naphthoquinones, benzo[а]phenazine-5,6-dione 7-oxides, heterocyclization.
Tetracyclic nitrogen-containing quinone derivatives exhibit various types of biological activity and
show promise for practical applications [1, 2]. Linear and angular quinoid derivatives of benzophenazines are of
particular interest. Thus, it was recently discovered that benzo[а]phenazine-5,6-dione derivatives, diimines in
particular, may function as ligands for rhodium and ruthenium, and also possess selective anticancer activity [3].
We found that the 4-arylamino-1,2-naphthoquinones 1а-d were converted to the benzo[а]phenazine-
5,6-dione N-oxides 2а-d by treatment with nitrosylsulfuric acid that was prepared in situ from sodium nitrite
and sulfuric acid [4], and using acetic acid as the solvent.
O
2
O
1
3
4
11
8
N
11a
7a
12a
10
9
NOHSO4
12b
4a
AcOH
15–20°C
N+
O
O
HN
R
O
R
1a–d
2a–d
1, 2 a R = H, b R = Me, c R = Cl, d R = F
The arylaminonaphthoquinones 1а-d were apparently cyclized to the phenazine N-oxides 2а-d by a
radical cation mechanism that could involve the formation of 4-arylamino-3-nitroso-1,2-naphthoquinones [5]. It
is known that 2-nitrosodiarylamines cyclized to the corresponding phenazine N-oxides by the action of sodium
nitrite in hydrochloric acid [6-7].
_______
*To whom correspondence should be addressed, e-mail: gornostaev@kspu.ru.
1Krasnoyarsk State Pedagogical University named after V. P. Astaf'ev, 89 Ady Lebedevoi St., Krasnoyarsk
660049, Russia.
2Krasnoyarsk State Medical University named after Prof. Voyno-Yasenetsky, 1 Partizana Zheleznyaka St.,
Krasnoyarsk 660021, Russia; e-mail: tatyana_xim@mail.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1972-1975, December, 2013.
Original article submitted July 7, 2013; revision submitted November 19, 2013.
0009-3122/14/4912-1827©2014 Springer Science+Business Media New York
1827

It should be noted that our discovered cyclization reaction gave high yields of the phenazine N-oxides
2а-d only when a large excess of nitrosylsulfuric acid was used. This observation may indicate a multistage
mechanism for the cyclization of nitrosonium cation. An additional evidence for a radical mechanism in the
heterocyclization of compounds 1а-d and 2а-d was found in the approximately equal duration of these
reactions.
It should be noted that only traces of compounds 2а-d were found by TLC after maintaining the starting
arylaminonaphthoquinones 1а-d for many hours in 95% sulfuric acid with an excess of nitrosylsulfuric acid.
Obviously, the arylaminonaphthoquinones 1а-d were completely protonated under these conditions. Compounds
O
O
O
O
.
+
NO
N=O
1a–d
.
H
+
.
– H+
.
N
– NO
N
R
R
O
N
O
O
N
H
O
+
O
N=O
N=O
2a–d
– H+
HN
R
R
1а-d are known to be protonated at the carbonyl group [8], forming the immonium cations 3а-d, which are
incapable of reacting with nitrosonium cation by the radical mechanism.
O
OH
H+
1a–d
+
HN
R
3a–d
The obtained benzo[а]phenazine-5,6-dione N-oxides 2а-d were structurally characterized by
physicochemical methods. There were intense IR absorption bands at 1356-1404 cm-1, corresponding to the
stretching vibrations of the N-oxide group, and the absorption bands were shifted to higher frequencies by
the presence of electron-withdrawing groups in the molecule [9]. Characteristically, compounds 2а-d showed
intense mass spectral peaks at [М-44]+. Apparently, these peaks could be explained by the elimination of
1
nitrous oxide from the molecular ions. The Н and 13С NMR spectral data for compounds 2а-d (given in
Experimental) were similar to the spectral data of polycyclic o-quinoid heterocycles [10].
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Thus, we have developed a new, convenient synthetic approach to a new type of tetracyclic azine
heterocycles incorporating quinoid structures. Presumably, the obtained series of benzo[а]phenazine-5,6-dione
7-oxides may be used for further chemical modification.
IR spectra were recorded on a Shimadzu IRAffinity-1 instrument in KВr pellets. UV spectra were
1
recorded on a Thermo Scientific Evolution 300 instrument (10 mm cuvettes) in DMSO. Н and 13С NMR
spectra were acquired on a Bruker DRX spectrometer (500 and 125 MHz) in DMSO-d6, with TMS as internal
standard. Mass spectra were obtained on a Finnigan MAT 8200 instrument (EI, 70 eV). Elemental analysis was
performed on a EURO EA 3000 instrument. Melting points were determined on a Boetius micro hot stage. The
reaction progress and the purity of the synthesized compounds were monitored by TLC on Silufol UV-254
plates (eluent 10:1 toluene–acetone).
The starting 4-arylamino-1,2-naphthoquinones 1а-d were obtained by a published method [11].
Benzo[а]phenazine-5,6-dione 7-Oxide (2а). Nitrosylsulfuric acid was prepared from sodium nitrite
(1.25 g, 18 mmol) and concentrated sulfuric acid (8 ml) and added over the course of 5 min to a solution of
4-phenylamino-1,2-naphthoquinone (1a) (1.25 g, 5 mmol) in glacial acetic acid (30 ml). The reaction mixture
was stirred for 1 h at 15-20°С, then poured with stirring into ice–water mixture (200 ml). The precipitate was
filtered off, washed with water until neutral pH, and dried. Yield 1.16 g (84%). Orange crystals. Mp 284-285°С
(о-dichlorobenzene). IR spectrum, ν, cm-1: 1363 (N–O), 1676 (С=О). UV spectrum, λmax, nm (log ε): 324 (4.55).
1H NMR spectrum, δ, ppm (J, Hz): 7.78 (1Н, t, J =7.6, H-3); 7.90 (1H, t, J = 7.0, H-10); 7.96 (1Н, t, J = 7.6, H-2);
8.05 (1Н, t, J = 7.0, H-9); 8.12 (1Н, dd, J = 7.0, J = 1.0, H-11); 8.24 (1Н, dd, J = 7.6, J = 1.3, H-1); 8.50 (1Н, dd,
J = 7.6, J = 1.3, H-4) 8.82 (1Н, dd, J = 7.0, J = 0.9, H-8). 13C NMR spectrum, δ, ppm: 119.8 (С-10); 126.9 (С-8);
128.6 (С-3); 130.7 (С-2); 131.8 (С-9); 132.3 (С-11а); 132.5 (С-11); 134.2 (С-12b); 134.6 (С-1); 134.9 (С-4а); 135.7
(С-4); 138.1 (С-7а); 143.8 (С-12а); 150.9 (С-6а); 171.6 (С-5); 177.8 (С-6). Mass spectrum, m/z (Irel,%): 276 [М]+
(5), 262 (99), 232 (65), 76 (100). Found, %: С 69.72; Н 2.83; N 10.06. C16H8N2O3. Calculated, %: С 69.57; Н 2.92;
N 10.14.
9-Methylbenzo[а]phenazine-5,6-dione 7-Oxide (2b). Nitrosylsulfuric acid was prepared from sodium
nitrite (2.50 g, 36 mmol) and concentrated sulfuric acid (15 ml) and added over the course of 5 min to a solution
of 4-p-tolylamino-1,2-naphthoquinone (1b) (2.63 g, 10 mmol) in glacial acetic acid (60 ml). The reaction
mixture was stirred for 1 h at 15-20°С, then poured with stirring into ice–water mixture (200 ml). The precipitate
was filtered off, washed with water until neutral pH, and dried. Yield 2.65 g (91%). Red crystals. Mp 248-250°С
(о-dichlorobenzene). IR spectrum, ν, cm-1: 1356 (N–O), 1672 (С=О). UV spectrum, λmax, nm (log ε): 316 (4.62). 1H
NMR spectrum, δ, ppm (J, Hz): 2.62 (3Н, s, СН3); 7.75 (1Н, t, J = 7.6, H-3); 7.87 (1Н, dd, J = 8.5, J = 2.0, H-10);
7.93 (1Н, t, J = 7.6, H-2); 8.10 (1Н, dd, J = 7.6, J = 1.0, H-1); 8.11 (1Н, d, J = 8.5, H-11); 8.28 (1Н, s, Н-8); 8.78
13
(1Н, dd, J = 7.6, J = 1.0, H-4). C NMR spectrum, δ, ppm: 22.1 (СН3); 118.6 (С-10); 126.7 (С-8); 128.6 (С-3);
130.4 (С-2); 132.1 (С-11а); 132.2 (С-11); 133.9 (С-12b); 135.0 (С-4а); 135.7 (С-1); 136.5 (С-4); 137.9 (С-7а);
142.3 (С-12а); 142.8 (С-9); 150.1 (С-6а); 171.1 (С-5); 177.8 (С-6). Mass spectrum, m/z (Irel,%): 290 [М]+ (16), 246
(100), 89 (56), 76 (37). Found, %: С 69.85; Н 3.35; N 9.54. C17H10N2O3. Calculated, %: С 70.34; Н 3.45; N 9.66.
9-Chlorobenzo[а]phenazine-5,6-dione 7-Oxide (2с). Nitrosylsulfuric acid was prepared from sodium
nitrite (2.50 g, 36 mmol) and concentrated sulfuric acid (16 ml), and added over the course of 5 min to a
solution of 4-(p-chlorophenylamino)-1,2-naphthoquinone (1c) (2.83 g, 10 mmol) in glacial acetic acid (60 ml).
The reaction mixture was stirred for 6 h at 15-20°С, then poured with stirring into ice–water mixture (200 ml).
The precipitate was filtered off, washed with water until neutral pH, and dried. Yield 2.65 g (95%). Orange
crystals. Mp 305-307°С (о-dichlorobenzene). IR spectrum, ν, cm-1: 1396 (N–O), 1674 (С=О). UV spectrum,
λmax, nm (log ε): 314 (4.63). 1H NMR spectrum, δ, ppm (J, Hz): 7.79 (1Н, t, J = 7.7, H-3); 7.96 (1Н, t, J = 7.7,
H-2); 8.09 (1Н, dd, J = 8.9, J = 2.4, H-10); 8.13 (1Н, dd, J = 7.7, J = 1.2, H-1); 8.27 (1Н, d, J = 8.9, H-11); 8.50
(1Н, d, J = 2.4, H-8); 8.81 (1Н, d, J = 7.7, H-4). 13C NMR spectrum, δ, ppm: 119.1 (С-10); 126.9 (С-8); 128.7
(С-3); 132.3 (С-11а); 132.6 (С-11); 132.7 (С-2); 134.5 (С-9); 134.6 (С-4а); 135.0 (С-1); 135.8 (С-4); 136.4
(С-12b); 138.4 (С-7а); 142.6 (С-12а); 151.3 (С-6а); 171.4 (С-5); 177.5 (С-6). Mass spectrum, m/z (Irel,%): 310
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[М]+ (3), 266 (67), 238 (55), 76 (51), 75 (100), 50 (61), 32 (64). Found, %: С 61.71; Н 2.22; N 8.98.
C16H7ClN2O3. Calculated, %: С 61.84; Н 2.25; N 9.02.
9-Fluorobenzo[а]phenazine-5,6-dione 7-Oxide (2d). Nitrosylsulfuric acid was prepared from sodium
nitrite (1.25 g, 18 mmol) and concentrated sulfuric acid (8 ml) and added over the course of 5 min to a solution
of 4-p-fluorophenylamino-1,2-naphthoquinone (1d) (1.35 g, 5 mmol) in glacial acetic acid (15 ml). The reaction
mixture was stirred for 1 h at 15-20°С, then poured with stirring into ice–water mixture (200 ml). The precipitate
was filtered off, washed with water until neutral pH, and dried. Yield 0.93 g (63%). Brick-colored crystals. Mp
276-277°С (о-dichlorobenzene). IR spectrum, ν, cm-1: 1404 (N–O), 1676 (С=О). UV spectrum, λmax, nm (log ε):
316 (4.61). 1H NMR spectrum, δ, ppm (J, Hz): 7.77 (1Н, t, J = 7.6, H-3); 7.96 (1Н, t, J = 7.6, H-2); 8.00 (1Н, m,
H-10); 8.13 (1Н, d, J = 7.6, H-1); 8.25 (1Н, dd, J = 9.1, J = 2.4, H-11); 8.34 (1Н, dd, J = 9.1, J = 2.4, H-8); 8.80
13
(1Н, d, J = 7.6, H-4). C NMR spectrum, δ, ppm: 105.0 (С-10); 105.2 (С-8); 126.8 (С-3); 128.7 (С-2); 132.3
(С-11а); 132.5 (С-11); 133.7 (С-1); 134.3 (С-12b); 134.7 (С-4а); 135.8 (С-4); 138.8 (С-7а); 141.1 (С-12а);
150.5 (С-6а); 162.5 (С-9); 171.5 (С-5); 177.6 (С-6). Mass spectrum, m/z (Irel,%): 294 [М]+ (5), 250 (85), 222
(100), 94 (54), 75 (48). Found, %: С 65.48; Н 2.41; N 9.49. C16H7FN2O3. Calculated, %: С 65.31; Н 2.38; N
9.52.
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