Synthesis and base-catalyzed cleavage of 1-aryl-4,9-dioxo-1H-naphtho[2,3-d] [1,2,3]triazole 2-oxides

Article abstract of DOI:10.1007/s11172-011-0023-0

A method was developed for the synthesis of 1H-1-arylnaphtho[2,3-d][1,2,3] triazole-4,9-dione 2-oxides based on 2-arylamino-3-chloro-1,4-naphthoquinones. The reaction of 1H-1-arylnaphtho[2,3-d][1,2,3]triazole-4,9-dione 2-oxides with an ethanolic alkali so

Full text of DOI:10.1007/s11172-011-0023-0

Russian Chemical Bulletin, International Edition, Vol. 60, No. 1, pp. 157—159, January, 2011
157
Synthesis and baseꢀcatalyzed cleavage of
1ꢀarylꢀ4,9ꢀdioxoꢀ1Hꢀnaphtho[2,3ꢀd][1,2,3]triazole 2ꢀoxides
L. M. Gornostaev,a L. V. Dolgushina,a Yu. G. Khalyavina,a G. A. Stashina,b and S. I. Firgangb
aV. P. Astafiev Krasnoyarsk State Pedagogical University,
89 ul. A. Lebedevoi, 660049 Krasnoyarsk, Russian Federation.
Eꢀmail: gornostaev@kspu.ru
bN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Eꢀmail: galina_stashina@chemicalꢀblock.com
A method was developed for the synthesis of 1Hꢀ1ꢀarylnaphtho[2,3ꢀd][1,2,3]triazoleꢀ4,9ꢀ
dione 2ꢀoxides based on 2ꢀarylaminoꢀ3ꢀchloroꢀ1,4ꢀnaphthoquinones. The reaction of 1Hꢀ1ꢀ
arylnaphtho[2,3ꢀd][1,2,3]triazoleꢀ4,9ꢀdione 2ꢀoxides with an ethanolic alkali solution affords
2ꢀ{[1ꢀ(aryl)ꢀ2ꢀoxidoꢀ1Hꢀ1,2,3ꢀtriazolꢀ4ꢀyl]carbonyl}benzoic acids.
Key words: 1,2,3ꢀtriazole 2ꢀoxides, quiones, cleavage, fused heterocycles.
Fused 1,2,3ꢀtriazole 2ꢀoxides are rather difficult to preꢀ
pare, and their chemical properties are poorly known.1
Recently, it has been found2 that 1Hꢀ1ꢀalkylnaphtho[2,3ꢀd]ꢀ
[1,2,3]triazoleꢀ4,9ꢀdione 2ꢀoxides 1 exhibit antitumor acꢀ
tivity, due to which these compounds are of additional
interest.
Previously, we have developed3 a simple but multistep
approach to the synthesis of compounds 1 (R = Alk) deꢀ
scribed by Scheme 1.
starting from available4 2ꢀarylaminoꢀ3ꢀchloroꢀ1,4ꢀnaphꢀ
thoquinones 2a—c by excluding the isolation and puriꢀ
fication of intermediate 2ꢀ(NꢀarylaminoꢀNꢀnitroso)ꢀ3ꢀ
chloroꢀ1,4ꢀnaphthoquinones (Scheme 2).
Scheme 2
Scheme 1
Ar = Ph (a), 3ꢀMe—C6H4 (b), 4ꢀF—C6H4 (c)
i. HNO2, NaN3, heating.
We chose this method for the synthesis of triazole oxꢀ
ides 3a—c because these compounds are relatively poorly
soluble due to which they can easily be isolated in high
total yield (50—60%).
R = Alk
i. Heating.
In the present study, we simplified the method for the
synthesis of Nꢀarylꢀsubstituted triazole oxides (3a—c)
The structures of compounds 3a—c were confirmed by
1H NMR spectroscopy and mass spectrometry. It should
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 1, pp. 150—152, January, 2011.
1066ꢀ5285/11/6001ꢀ157 © 2011 Springer Science+Business Media, Inc.

158
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Gornostaev et al.
be noted that the molecular ions of triazole oxides 3a—c
and 1Hꢀ1ꢀphenylnaphtho[2,3ꢀd][1,2,3]triazoleꢀ4,9ꢀdione
(5) have different fragmentation patterns. The mass specꢀ
tra of triazole oxides 3a—c show the peak [M – 30] (NO)
and the intense peak M – NO – ArNC at m/z 158, whereꢀ
as the mass spectrum of triazole 5 exhibits a different fragꢀ
mentation pattern. Taking into account the structure
of triazole oxides 3a—c, it could be suggested that the
mass of the ion at m/z 158 corresponds to the mass of the
fragmentation products of the composition C10H6O2 or
C9H4NO2. For triazole oxide 3b, the highꢀresolution mass
spectrum was obtained. The exact mass of the ion at
m/z 158 was evaluated at 158.0238, which corresponds to
the composition C9H4NO2 (m/z = 158.0237) and differs
from the composition C10H6O2 (m/z = 158.0362). Apparꢀ
ently, the fragmentation [M]+ of compound 3b affords the
ion corresponding to the dehydrogenation of 2ꢀazaꢀ1,4ꢀ
naphthoquinone (Scheme 3).
by the proton chemical shifts of the heterocycles in comꢀ
pounds 4a and 6. The singlet for the proton of the triazole
oxide moiety of compound 4a is shifted downfield by apꢀ
proximately 0.6 ppm compared to the signal for the correꢀ
sponding proton of product 6.
The regioselectivity of the cleavage of triazole oxides
1
3a—c was confirmed by 2D H NOESY spectroscopy of
compound 4b (Scheme 5).
Scheme 5
Scheme 3
Compounds 3a—c appeared to be sensitive to an ethaꢀ
nolic alkali solution. These compounds were transformed
into 2ꢀ{[1ꢀ(aryl)ꢀ2ꢀoxidoꢀ1Hꢀ1,2,3ꢀtriazolꢀ4ꢀyl]carbꢀ
onyl}benzoic acids 4a—c already at 20—25 °C. These mild
conditions of the cleavage of triazole oxides compared to,
for example, 9,10ꢀanthraquinone4 are apparently associꢀ
ated with the electronꢀwithdrawing effect of the triazole
oxide ring on the quinoid moiety of the molecule. It should
be noted that the activating effect of the triazole oxide
moiety is substantially stronger than the effect of the triazꢀ
ole ring in the known cleavage reaction5 of 1Hꢀ1ꢀphenylꢀ
naphtho[2,3ꢀd][1,2,3]triazoleꢀ4,9ꢀdione 5 giving 2ꢀ[(1ꢀ
phenylꢀ1Hꢀ1,2,3ꢀtriazolꢀ4ꢀyl)carbonyl]benzoic acid 6.
This fact was confirmed by kinetic data (see the Experiꢀ
mental section) (Scheme 4).
The aboveꢀdescribed data provide evidence that there
is the throughꢀspace interaction between the protons H(2´)
and H(6´) of the tolyl moiety and the proton H(5) of the
heterocycle in molecule 4b. This interaction would not be
observed in the case of the cleavage reaction of triazole
oxide 3b giving alternative 2ꢀ{[1ꢀ(3ꢀmethylphenyl)ꢀ2ꢀoxꢀ
idoꢀ1Hꢀ1,2,3ꢀtriazolꢀ5ꢀyl]carbonyl}benzoic acid 7b.
To sum up, we developed an approach to the synthesis
of nonꢀfused diarylꢀ1,2,3ꢀtriazole 2ꢀoxides 4. The presꢀ
ence of the reactive groups in these compounds opens
a route to their further modifications.
Experimental
Scheme 4
The 1H NMR spectra were recorded on a Bruker DRX inꢀ
strument (500 MHz) in DMSOꢀd6 with Me4Si as the internal
standard. The progress of the reactions was monitored and the
purity of the reaction products was checked by TLC on Silufol
UVꢀ254 plates. The melting points were measured on a Boetius
hotꢀstage apparatus. The molecular weights of the reaction prodꢀ
ucts were confirmed by mass spectrometry on a Finnigan MAT
8200 instrument. The highꢀresolution mass spectrum was obꢀ
tained on a DFS highꢀresolution mass spectrometer.
The kinetics of the baseꢀcatalyzed cleavage was studied by
spectrophotometry on an Evolution 300 instrument equipped
with a temperatureꢀcontrolled cell holder at 25 °C in a 10%
The stronger electronꢀwithdrawing effect of the Nꢀoxꢀ
ide moiety on the quinoid part is also indirectly evidenced

Annulated dioxotriazole oxides
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 1, January, 2011
159
ethanolic solution of KОH in 1 cm quartz cells at the initial
2ꢀ{[1ꢀ(Aryl)ꢀ2ꢀoxidoꢀ1Hꢀ1,2,3ꢀtriazolꢀ4ꢀyl]carbonyl}benzoic
acids (4a—c). 1ꢀArylꢀ4,9ꢀdioxoꢀ1Hꢀnaphtho[2,3ꢀd][1,2,3]triꢀ
azole 2ꢀoxide 3a—c (4 mmol) was added to a solution of KOH
(1 g) in ethanol (12 mL). The reaction mixture was stirred at
20—25 °C for 5—10 h and then diluted with an equal volume of
water. The undissolved residue (0.1—0.2 g) was filtered off, and
the filtrate was acidified to pH = 2—3 with 10% hydrochloric
acid. The precipitate was filtered off, washed with water, and
recrystallized from ethanol.
concentration of the starting compounds of 0.5•10–4 mol L–1
.
The changes in the concentration of triazole oxide 3a and triꢀ
azole 5 were detected at longꢀwavelength absorption maxima of
284 and 318 nm, respectively. The firstꢀorder rate constants
were calculated according to the standard procedure based on
the results of two experiments for each sample and then averꢀ
aged. For compound 3a, keff = 40•10–4 s–1; for compound 5,
keff = 1.9•10–4 s–1
.
1ꢀArylꢀ4,9ꢀdioxoꢀ1Hꢀnaphtho[2,3ꢀd][1,2,3]triazole 2ꢀoxides
(3a—c). Sodium nitrite (0.5—0.8 g) was added portionwise with
stirring to a solution of 2ꢀarylaminoꢀ3ꢀchloroꢀ1,4ꢀnaphthoquinoꢀ
ne 2a—c (4 mmol) in acetic acid (100 mL) at 15—20 °C for
60 min. Then the reaction mixture was stirred for 20—40 min
(TLC, the absence of the starting chloroquinone) and poured
into ice water (400—500 mL). The yellow precipitate of the
corresponding Nꢀnitrosoamine that formed was filtered off and
washed with water. The reaction product was dissolved without
drying in a mixture of ethanol (30 mL) and DMF (30 mL) and
treated with a solution of NaN3 (6 mmol) in water (3 mL) for
20—30 min. The reaction mixture was diluted with cold water
(200 mL), and the precipitate of 2ꢀazidoꢀ3ꢀNꢀnitrosoꢀ1,4ꢀ
naphthoquinone was extracted with benzene (50 mL). The benꢀ
zene solution was dried with calcium chloride, brought to reflux
during 30 min, and refluxed for 30 min. Then the solution was
concentrated to 20—25 mL and cooled. 1ꢀArylꢀ4,9ꢀdioxoꢀ1Hꢀ
naphtho[2,3ꢀd][1,2,3]triazole 2ꢀoxide (3a—c) that precipitatꢀ
ed was washed with ethanol, dried, and crystallized from ethyl
cellosolve.
4,9ꢀDioxoꢀ1ꢀphenylꢀ1Hꢀnaphtho[2,3ꢀd][1,2,3]triazole
2ꢀoxide (3a). The yield was 60%, m.p. 249—252 °C. 1H NMR
(CDCl3), δ: 7.48—7.70 (m, 5 H, Ph); 7.78 (dt, 1 H, H(7), J = 7.4 Hz,
J = 1.6 Hz); 7.81 (dt, 1 H, H(6), J = 7.4 Hz, J = 1.6 Hz); 8.08
(dd, 1 H, H(8), J = 7.4 Hz, J = 1.6 Hz); 8.28 (dd, 1 H, H(5),
J = 7.4 Hz, J = 1.6 Hz). Found (%): C, 66.07; H, 2.99; N, 14.10.
C16H9N3O3. Calculated (%): C, 65.98; H, 3.09; N, 14.43. MS
(EI, 70 eV), m/z (Irel (%)): 261 [M – NO]+ (8.21), 158 [M – NO –
– C7H5N or PhNC]+ (56.16), 102 [C7H4N]+ (42.64).
1ꢀ(3ꢀMethylphenyl)ꢀ4,9ꢀdioxoꢀ1Hꢀnaphtho[2,3ꢀd][1,2,3]ꢀ
triazole 2ꢀoxide (3b). The yield was 70%, m.p. 277—279 °C.
1H NMR (DMSOꢀd6), δ: 2.43 (s, 3 H, MePh); 7.48 (d, 1 H,
H(4´), J = 7.6 Hz); 7.51 (s, 1 H, H(2´)); 7.53 (d, 1 H, H(6´),
J = 7.6 Hz); 7.57 (d, 1 H, H(5´), J = 7.6 Hz); 7.91 (dt, 1 H, H(7),
J = 7.4 Hz, J = 1.6 Hz); 7.94 (dt, 1 H, H(6) J = 7.4 Hz, J = 1.6 Hz);
8.02 (dd, 1 H, H(8), J = 7.4 Hz, J = 1.6 Hz); 8.18 (dd, 1 H, H(5),
J = 7.4 Hz, J = 1.6 Hz). Found (%): C, 66.91; H, 3.64; N, 13.76.
C17H11N3O3. Calculated (%): C, 66.89; H, 3.61; N, 13.77. MS
(EI, 70 eV), m/z (Irel (%)): 305 [M]+ (3.70), 275 [M – NO]+
(53.65), 158 [M – NO – C8H7N or MePhNC]+ (100), 102
[C7H4N]+ (48.85), 91 [C7H7]+ (16.42).
1ꢀ(4ꢀFluorophenyl)ꢀ4,9ꢀdioxoꢀ1Hꢀnaphtho[2,3ꢀd][1,2,3]ꢀ
triazole 2ꢀoxide (3c). The yield was 73%, m.p. 312—314 °C.
1H NMR (DMSOꢀd6), δ: 7.55 (t, 2 H, H(3´), H(5´), J = 8.8 Hz);
7.79 (dd, 2 H, H(2´), H(6´), J = 8.8 Hz, JH,F = 4.9 Hz); 7.92
(dt, 1 H, H(7), J = 7.4 Hz, J = 1.6 Hz); 7.95 (dt, 1 H, H(6),
J = 7.4 Hz, J = 1.6 Hz); 8.03 (dd, 1 H, H(8), J = 7.4 Hz, J = 1.6 Hz);
8.19 (dd, 1 H, H(5), J = 7.4 Hz, J = 1.6 Hz). Found (%):
C, 62.01; H, 2.48; N, 13.61. C16H8FN3O3. Calculated (%):
C, 61.94; H, 2.58; N, 13.55. MS (EI, 70 eV), m/z (Irel (%)): 309
[M]+ (3.60), 279 [M – NO]+ (10.11), 158 [M – NO – C7H4FN]+
(100), 102 [C7H4N]+ (51.65), 95 [C6H4F]+ (50.85).
2ꢀ[(2ꢀOxidoꢀ1ꢀphenylꢀ1Hꢀ1,2,3ꢀtriazolꢀ4ꢀyl)carbonyl]benzoic
acid (4a). The yield was 89%, m.p. 165—166 °C. 1H NMR
(DMSOꢀd6), δ: 7.15 (t, 1 H, pꢀPh, J = 7.4 Hz); 7.38 (t, 2 H,
mꢀPh, J = 7.4 Hz); 7.66 (d, 2 H, oꢀPh, J = 7.4 Hz); 7.70 (dt, 1 H,
H(3), J = 7.5 Hz, J = 1.2 Hz); 7.71 (dd, 1 H, H(5), J = 7.5 Hz,
J = 1.2 Hz); 7.77 (dd, 1 H, H(4), J = 7.5 Hz, J = 1.26 Hz); 8.01
(dd, 1 H, H(2), J = 7.5 Hz, J = 1.2 Hz); 10.18 (s, 1 H, H(5´));
13.64 (br.s, 1 H, COOH). Found (%): C, 62.14; H, 3.64; N, 13.66.
C16H11N3O4. Calculated (%): C, 62.14; H, 3.56; N, 13.59. MS
(EI, 70 eV), m/z (Irel (%)): 309 [M]+ (77.38), 281 [M – CO]+
(13.81), 264 [M – COOH]+ (10.11), 263 [M – CO2H – H]
(22.02), 219 (36.24), 161 (61.66), 149 (92.89), 133 (56.86), 105
(100), 77 (96.10).
2ꢀ{[1ꢀ(3ꢀMethylphenyl)ꢀ2ꢀoxidoꢀ1Hꢀ1,2,3ꢀtriazolꢀ4ꢀyl]ꢀ
carbonyl}benzoic acid (4b). The yield was 92%, m.p. 147—148 °C.
1H NMR (DMSOꢀd60), δ: 2.32 (s, 3 H, MePh); 6.17 (d, 1 H,
H(4″), J = 8.65 Hz); 7.35 (t, 1 H, H(5″), J = 8.65 Hz); 7.46
(s, 1 H, H(2″)); 7.46 (d, 1 H, H(6″), J = 8.65 Hz); 7.69 (t, 1 H,
H(3), J = 7.75 Hz); 7.70 (d, 1 H, H(5), J = 7.75 Hz); 7.77
(t, 1 H, H(4), J = 7.75 Hz); 8.01 (d, 1 H, H(2), J = 7.75 Hz);
10.12 (s, 1 H, H(5´)); 13.10 (br.s, 1 H, COOH). Found (%):
C, 61.90; H, 3.46; N, 13.49. C17H13N3O4. Calculated (%):
C, 63.16; H, 4.02; N, 13.00. MS (EI, 70 eV), m/z (Irel (%)): 323
[M]+ (7.21), 295 [M – CO]+ (2.0), 277 [M – CO2H – H] (1.30),
233 (1.31), 161 (13.01), 149 (13.91), 133 (11.61), 107 (77.78),
105 (28.93), 91 (100), 77 (36.34).
2ꢀ{[2ꢀOxidoꢀ1ꢀ(4ꢀfluorophenyl)ꢀ1Hꢀ1,2,3ꢀtriazolꢀ4ꢀyl]carbꢀ
onyl}benzoic acid (4c). The yield was 90%, m.p. 145—146 °C.
1H NMR (DMSOꢀd6), δ: 7.22 (t, 2 H, H(3″), H(5″), J = 8.8 Hz,
JH,F = 8.8 Hz); 7.67—7.72 (m, 4 H, H(3), H(5), H(2″), H(6″));
7.77 (t, 1 H, H(4), J = 7.5 Hz); 8.01 (d, 1 H, H(2), J = 7.5 Hz);
10.16 (s, 1 H, H(5´)); 13.60 (br.s, 1 H, COOH). Found (%):
C, 58.45; H, 3.05; N, 12.91. C16H10FN3O4. Calculated (%):
C, 58.72; H, 3.06; N, 12.84. MS (EI, 70 eV), m/z (Irel (%)): 327
[M]+ (4.30), 299 [M – CO]+ (1.70), 281 [M – CO2H – H]
(0.90), 161 (47.35), 133 (22.42), 122 (23,52), 111 (100), 105
(62.86), 95 (23.32), 77 (43.84).
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Received August 20, 2010;
in revised form November 25, 2010