Isomerization of 4-arylamino-1,2-naphthoquinones to 2-arylamino-1,4-naphthoquinones

Article abstract of DOI:10.1007/s11172-017-1847-z

4-Arylamino-1,2-naphthoquinones isomerize into 2-arylamino-1,4-naphthoquinones upon refluxing in acetic acid. The isomerization follows two routes via intermediate 2-hydroxy-1,4-naphthoquinone and 2-arylamino-1,4-naphthoquinone 4-N-arylimines.

Full text of DOI:10.1007/s11172-017-1847-z

Russian Chemical Bulletin, International Edition, Vol. 66, No. 6, pp. 1007—1010, June, 2017
1007
Isomerization of 4-arylamino-1,2-naphthoquinones
to 2-arylamino-1,4-naphthoquinones
L. M. Gornostaev,a T. A. Rukovets,a,b T. I. Lavrikova,a Yu. G. Khalyavina,a and G. A. Stashinac
aKrasnoyarsk State Pedagogical University named after V. P. Astafyev,
89 ul. Ady Lebedevoi, 660049 Krasnoyarsk, Russian Federation.
E-mail: gornostaev@kspu.ru
bKrasnoyarsk State Medical University named after Prof. V. F. Voino-Yasenetsky,
1 ul. Partizana Zheleznyaka, 660021Krasnoyarsk, Russian Federation,
E-mail: tatyana_xim@mail.ru
cN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
E-mail: galina_stashina@chemical-block.com
4-Arylamino-1,2-naphthoquinones isomerize into 2-arylamino-1,4-naphthoquinones upon
refluxing in acetic acid. The isomerization follows two routes via intermediate 2-hydroxy-1,4-
naphthoquinone and 2-arylamino-1,4-naphthoquinone 4-N-arylimines.
Key words: naphthoquinones, 2-arylamino-1,4-naphthoquinones, 4-arylamino-1,2-
naphthoquinones, isomerization.
2-Arylamino-1,4-naphthoquinones 1 and 4-arylamino-
1,2-naphthoquinones 2 exhibit a variety of biological
activities.1,2 It has recently been shown3 that 2-arylamino-
1,4-naphthoquinones 1 underwent ring closure into
benzo[b]phenazine-6,11-dione 5-oxides 3 upon treat-
ment with nitrosylsulfuric acid in acetic acid. Under
the same reaction conditions, 4-arylamino-1,2-naphtho-
quinones 2 produce benzo[a]phenazine-5,6-dione
7-oxides 4.4 Compounds 3 and 4 (Scheme 1) are very
promising and apparently possess some biological ac-
tivity.5,6
It was interesting to study the possibility of interconver-
sion of arylaminonaphthoquinones 1 and 2. Isomerization of
4-arylamino-1,2-naphthoquinones 2 into 2-arylamino-1,4-
naphthoquinones 1 in acetic acid at 150 C has been
previously described by Elsbach.7 A confirmation of this re-
sult is given in the book,8 however without experimental details.
In the present work, we demonstrated that refluxing in
85% aqueous acetic acid enables isomerization of 4-aryl-
amino-1,2-naphthoquinones 2a—d into 2-arylamino-1,4-
naphthoquinones 1a—d in 58—65% yields (Scheme 2).
Thin‐layer chromatography (TLC) monitoring shows that
Scheme 1
R = H, Me, Cl, F
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 6, pp. 1007—1010, June, 2017.
1066-5285/17/6606-1007 © 2017 Springer Science+Business Media, Inc.

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Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
Gornostaev et al.
Scheme 2
1, 2, 6: Ar = 3-MeC6H4 (a), Ph (b), 4-MeC6H4 (c), 4-ClC6H4 (d)
isomerization 2  1 proceeds via intermediate 2-hydroxy-
1,4-naphthoquinone (5) and 2-arylamino-1,4-naphtho-
quinone 4-N-arylimines 6a—d. Chromatographic properties
of compounds 6a—d coincide with those of the authentic
samples synthesized analogously to the known procedures.9
Kinetic curves of isomerization 2a  1a were obtained
spectrophotometrically (Fig. 1). It is clear form Fig. 1 that
isomerization 2  1 follows two routes involving hydro-
lysis of the starting 4-arylamino-1,2-naphthoquinones 2
to 2-hydroxy-1,4-naphthoquinone (5) and arylamination
of compound 5 to 2-arylamino-1,4-naphthoquinones 1.
In addition, the starting quinones 2 undergo amination
with the released arylamine to give amino imines 6a—d,
which subsequently hydrolyze to 2-arylamino-1,4-naph-
thoquinones 1a—d (see Scheme 2).
naphthoquinone (1a) with excess m-toluidine under
prolonged reflux results in compound 6a in low yield (12%)
and some other products.
It is known10 that 4-arylamino-1,2-naphthoquinones
(2) exist in tautomeric equilibrium with 2-hydroxy-1,4-
naphthoquinone 4-arylimines. A comparison of UV
spectra of the studied 2-arylamino-1,4-naphthoquinone
4-arylimines 6 with those published by Biggs and Tedder11
indicates in favor of 1,4-quinonoid structure of compounds
6. The 1,4-quinonoid structure of 6 is also confirmed by
NMR spectroscopy (Figs 2 and 3).
1H—13C HMBC spectrum of compound 6a contains
a cross peak between the proton bonded to the nitrogen
It is of note that under selected conditions imines 6
transform into aminoquinones 1 nearly irreversibly. We
found that amination of 2-(3-methylphenylamino)-1,4-

С/mol L–1
150
0.10
{7.25, 151.20}
{8.43, 154.61}
1a
2a
0.08
160
170
180
0.06
0.04
5
0.02
6a
40 70 120
180 220
300
360 t/min
{8.435, 181.08}
{6.48, 181.08}
Fig. 1. Dependencies of molar concentrations (C) of the reaction
components on reaction time (t) for 2-(3-methylphenylamino)-
1,4-naphthoquinone (1a), 4-(3-methylphenylamino)-1,2-naph-
thoquinone (2a), 2-hydroxy-1,4-naphthoquinone (5), and
2-(3-methylphenylamino)-1,4-naphthoquinone 4-N-(3-me-
thylphenyl)imine (6a).
8.5
8.0
7.5
7.0
6.5

Fig. 2. 1H—13C HMBC spectrum of 2-(3-methylphenylamino)-
1,4-naphthoquinone 4-N-(3-methylphenyl)imine (6a) (fragment).

Isomerization of 4-arylamino-1,2-naphthoquinones Russ. Chem. Bull., Int. Ed., Vol. 66, No. 6, June, 2017
.
1009
6.5
{8.43, 7.01}
7.0
7.5
{7.01, 8.43}
8.0
8.5
8.5
8.0
7.5
7.0
6.5
6.0

Fig. 3. 1H—1H NOESY spectrum of 2-(3-methylphenylamino)-1,4-naphthoquinone 4-N-(3-methylphenyl)imine (6a) (fragment).
instrument using 70 eV electrons. Elemental analysis was carried
out with a EURO EA 3000 elemental analyzer. Melting points
were measured with a Boetius apparatus. The reaction course
and purity of the products were monitored by TLC on precoated
Silufol UV-254 plates (development in toluene—acetone, 10 : 1).
2-Arylamino-1,4-naphthoquinones 1a—d (general procedure).
A solution of 4-arylamino-1,2-naphthoquinone 2a—d (5 mmol)
in a mixture of AcOH (25 mL) and water (3 mL) was refluxed
for 8 h. The reaction mixture was cooled to 70 C and diluted with
water (30 mL). The precipitate formed was collected by filtration,
washed with aqueous EtOH, and recrystallized from propan-2-
ol—toluene (1 : 1). 1H NMR and mass spectra of the synthesized
compounds 1a—d agree with those published earlier.12
2-(3-Methylphenylamino)-1,4-naphthoquinone (1a). Red
crystals. Yield 0.82 g (62%), m.p. 174—175 C. Found (%): C,
77.61; H, 5.01; N, 5.52. C17H13NO2. Calculated (%): C, 77.57;
H, 4.94; N, 5.32. MS, m/z (Irel (%)): 263 [M]+, 248 (34), 234
(23), 76 (18). 1H NMR, : 2.34 (s, 3 H, CH3); 6.10 (s, 1 H, H(3));
7.04 (d, 1 H, H(4´), J = 7.5 Hz); 7.19 (d, 1 H, H(6´), J = 7.5 Hz);
7.20 (s, 1 H, H(2´)); 7.33 (t, 1 H, H(5´), J = 7.5 Hz); 7.77 (t, 1 H,
H(7), J = 7.5 Hz); 7.85 (t, 1 H, H(6), J = 7.5 Hz); 7.95 (d, 1 H,
H(5), J = 7.5 Hz); 8.05 (d, 1 H, H(8), J = 7.5 Hz); 9.16 (s, 1 H,
NH). 13C NMR, : 21.05 (CH3), 101.99 (C(3)); 120.85 (C(6´));
124.13 (C(2´)); 125.30 (C(8)); 126.04 (C(4´)); 126.13 (C(5));
129.14 (C(5´)); 130.12 (C(4a)); 132.60 (C(7)); 132.63 (C(8a));
134.89 (C(6)); 138.01 (C(3´)); 138.78 (C(1´)); 146.18 (C(2));
181.59 (C(1)); 182.55 (C(4)).
atom (H 8.35) and the carbonyl carbon atom (C 181.08).
The other HMBC cross peaks correspond to the couplings
of the H(3) naphthoquinone proton (H 6.48) with the
carbonyl carbon and the H(5) naphthoquinone proton
(H 8.43) with the imine carbon atom (C 154.61).
1H—1H NOESY spectrum of compound 6a shows cross
peak between the H(2) tolylimine proton (H 7.01) and
the H(5) naphthoquinone proton (H 8.43). These data
unambiguously indicate the (4Z)-arrangement of the
benzenoid ring of 1,4-naphthoquinone and the m-tolyl-
amine group of the imine.
In summary, we found that isomerization of 4-aryl-
amino-1,2-naphthoquinones follows two routes producing
2-hydroxy-1,4-naphthoquinone and 2-arylamino-1,4-
naphthoquinone 4-arylimines.
2-Phenylamino-1,4-naphthoquinone (1b). Red crystals. Yield
0.72 g (58%), m.p. 204—206 C.
2-(4-Methylphenylamino)-1,4-naphthoquinone (1c). Red
crystals. Yield 0.8 g (61%), m.p. 207—208 C.
Experimental
2-(4-Chlorophenylamino)-1,4-naphthoquinone (1d). Red
crystals. Yield 0.92 g (65%), m.p. 287—288 C.
1H and 13C NMR spectra were run on a Bruker DRX spec-
trometer (working frequencies of 500 and 125 MHz, respec-
tively) in DMSO-d6. Chemical shifts are given in the  scale
relative to Me4Si (an internal standard). UV spectra were obtained
on an Evolution 300 UV-VIS spectrophotometer in C6H6 (com-
pounds 1a, 2a, and 6a, C = 1•10–4 mol L–1) and CHCl3 (com-
pounds 5, C = 2•10–4 mol L–1) using 10 mm cuvettes. Electron
impact mass spectrometry was performed with a Finnigan MAT 8200
2-(3-Methylphenylamino)-1,4-naphthoquinone (1a) (indepen-
dent synthesis). A. A solution of 2-hydroxy-1,4-naphthoquinone
(5) (0.87 g, 5 mmol) and m-toluidine (1.07 g, 10 mmol) in
a mixture of AcOH (25 mL) and water (3 mL) was refluxed for
20 min. The reaction mixture was cooled to 70 C and diluted
with water (30 mL). The precipitate formed was collected by

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Gornostaev et al.
filtration and washed with aqueous EtOH and water. Yield 1.08 g
(82%), m.p. 174—175 C.
UV spectrum of compound 2a (C6H6), max/nm (lg): 291 (4.19),
342 (3.87), 452 (3.60). UV spectrum of compound 5 (CHCl3),
max/nm (lg): 249 (4.47), 276 (4.45), 335 (3.76). UV spectrum
of compound 6a (C6H6), max/nm (lg): 281 (4.37), 479 (3.81).
4-(3-Methylphenylamino)-1,2-naphthoquinone (2a) (0.87 g,
5 mmol) was introduced into a refluxing mixture of AcOH (25 mL)
and water (5 mL). At certain time intervals, the 2 mL samples
were taken and diluted with water (20 mL). The precipitate was
filtered off and the filtrate was treated with 6% aqueous HCl
(4 mL). The mixture was extracted with chloroform (2×20 mL)
and diluted with chloroform to 50.0 mL. Then a 1 mL aliquot
was taken, diluted to 5.0 mL, and the concentration of 2-hydroxy-
1,4-naphthoquinone (5) was measured by the absorption maxi-
mum of non-ionized form (max = 335 nm). The precipitate was
purified by silica gel (5—40 m) column chromatography under
reduced pressure13 (elution with benzene). The solid samples
obtained during the first three hours from the reaction onset were
not completely soluble in benzene; therefore, the weight of the
insoluble residue of the starting 4-(3-methylphenylamino)-1,2-
naphthoquinone (1a) was taken into account in plotting the
kinetic curves. Concentrations of the products in the benzene
solutions obtained by column chromatography were determined
spectrophotometrically at the following absorption maxima in
the visible range: for compound 1a, at max = 452 nm; for com-
pound 2a, at max = 470 nm; for compound 6a, at max = 479 nm.
The obtained results are plotted in Fig. 1.
B. A mixture of 2-hydroxy-1,4-naphthoquinone (3.25 g,
20 mmol) and m-toluidine (3.5 g, 33 mmol) in EtOH (25 mL)
was heated at 50—60 C. Then the reaction mixture was diluted
with water (15 mL). The precipitate formed was collected by
filtration and washed with EOH and water. Yield 3.24 g (62%).
C. A solution of 2-(3-methylphenylamino)-1,4-naphthoqui-
none 4-N-(3-methylphenyl)imine (0.27 g, 0.0008 mmol) in
a mixture of AcOH (45 mL) and water (5 mL) was refluxed for
8 h. The reaction mixture was cooled to 70  C and diluted with
water (30 mL). The precipitate formed was collected by filtration
and washed with EtOH and water. Yield 0.11 g (52%).
4-(3-Methylphenylamino)-1,2-naphthoquinone (2a). To
a mixture of sodium 1,2-naphthoquinone-4-sulfonate (26 g,
0.1 mol) in water (600 mL), a mixture of K2CO3 (10 g) and
m-toluidine (13 g) in EtOH (100 mL) was added. The reaction
mixture was stirred at 40 C for 30 min and cooled down. The
red precipitate formed was collected by filtration and succes-
sively washed with water, aqueous EtOH, and EtOH. Yield 20.91 g
(79%), m.p. 179—180 C (from DMSO—H2O, 1 : 1). MS, m/z
(Irel (%)): 263 [M]+, 248 (22), 234 (28), 220 (24), 217 (26).
Found (%): C, 77.31; H, 4.71; N, 5.29. Calculated (%): C, 77.57;
H, 4.94; N, 5.32.
2-(3-Methylphenylamino)-1,4-naphthoquinone 4-N-(3-me-
thylphenyl)imine (6a). A solution of 4-(3-methylphenylamino)-
1,2-naphthoquinone (5.28 g, 0.02 mmol) in 2-ethoxyethanol
(40 mL) was refluxed with m-toluidine (3.21g, 0.03 mol) for 3 h.
The precipitate formed was collected by filtration and washed
with EtOH and water. Yield 5.05 g (71%), m.p. 149—150 C (from
EtOH—dioxane, 1 : 1). 1H NMR, : 2.21, 2.32 (both s, 3 H each,
C(3´)Me, C(3)Me); 6.48 (s, 1 H, H(3)); 6.70 (d, 1 H, H(4´),
J = 7.9 Hz); 6.73 (s, 1 H, C(2´)); 6.84 (d, 1 H, H(6´), J = 7.5 Hz);
6.91 (d, 1 H, H(6), J = 7.6 Hz); 7.01 (s, 1 H, H(2)); 7.05
(d, 1 H, H(4), J = 7.6 Hz); 7.14 (t, 1 H, H(5´), J = 7.6 Hz); 7.25
(t, 1 H, H(5), J = 7.6 Hz); 7.72 (t, 1 H, H(6), J = 7.6 Hz); 7.81
(t, 1 H, H(7), J = 7.6 Hz); 8.14 (d, 1 H, H(8), J = 7.6 Hz); 8.35
(s, 1 H, NH); 8.43 (d, 1 H, H(5), J = 7.6 Hz). 13C NMR, :
20.93 (CH3); 20.99 (CH3); 97.17 (C(3)); 117.75 (C(4´)); 119.25
(C(6´)); 121.16 (C(2´); 122.20 (C(4)); 124.43 (C(2)); 124.54
(C(6)); 124.80 (C(5)); 125.90 (C(8)); 128.50 (C(5´)); 128.81
(C(5)); 130.35 (C(4a)); 130.75 (C(6)); 133.48 (C(7)); 135.13
(C(8a)); 138.13 (C(3´)); 138.39 (C(3)); 140.93 (CNH); 151.20
(C(1); 154.61 (C(4)=N); 181.08 (C=O). MS, m/z (Irel (%)): 352
[M]+, 261 (41), 91 (83), 77 (39), 65 (94), 39 (25). Found (%):
C, 81.69; H, 5.66, N, 8.05. C24H20N2O. Calculated (%): C, 81.79;
H, 5.72; N, 7.95.
2-(3-Methylphenylamino)-1,4-naphthoquinone 4-N-(3-me-
thylphenyl)imine (6a) (independent synthesis). A solution of
2-(4-methylphenylamino)-1,4-naphthoquinone (0.53 g,
0.002 mol) in m-toluidine (5 mL) was refluxed for 30 h. After this
time, the reaction mixture contained 2-(3-methylphenylamino)-
1,4-naphthoquinone 4-N-(3-methylphenyl)imine (6a) and
2-(3-methylphenylamino)-1,4-naphthoquinone (1a) (TLC
monitoring). The reaction mixture was cooled down and treated
with 5% aqueous HCl (40 mL). The precipitate formed was col-
lected by filtration, dried, and purified by chromatography (elu-
tion with benzene—ethyl acetate) to afford 0.08 g (12%) of
compound 6a.
This work was financially supported by the Ministry of
Education and Science of the Russian Federation (Project
No. 2854 for 2014—2016).
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Kinetic studies of the reaction 2  1a. First, the UV spectra of
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Received December 15, 2016;
in revised form February 14, 2017