Reactions of 1-acylamino- and 1-methylsulfonylamino-2-aryloxy-4-hydroxy-9, 10-anthraquinones with secondary amines

Article abstract of DOI:10.1134/S107042800810014X

Reactions of 1-acylamino-4-hydroxy-2-phenoxy-9,10-anthraquinones with piperidine resulted in replacement of the phenoxy group by piperidino, while 1-methylsulfonyl-2-aryloxy-4-hydroxy-9,10-anthraquinones reacted with secondary amines to give products of n

Full text of DOI:10.1134/S107042800810014X

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 10, pp. 1490–1493. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © V.A. Beresnev, M.S. Sokolova, N.P. Gritsan, L.M. Gornostaev, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44,
No. 10, pp. 1514–1517.
Reactions of 1-Acylamino- and 1-Methylsulfonylamino-
2-aryloxy-4-hydroxy-9,10-anthraquinones
with Secondary Amines
V. A. Beresneva, M. S. Sokolovaa, N. P. Gritsanb, and L. M. Gornostaeva
a Astaf’ev Krasnoyarsk State Pedagogical University, ul. A. Lebedevoi 89, Krasnoyarsk, 660049 Russia
e-mail: gornostaev@kspu.ru
b Institute of Chemical Kinetics and Combustion, Siberian Division, Russian Academy of Sciences,
Institutskaya 3, Novosibirsk, 630090 Russia
Received December 18, 2007
Abstract—Reactions of 1-acylamino-4-hydroxy-2-phenoxy-9,10-anthraquinones with piperidine resulted in
replacement of the phenoxy group by piperidino, while 1-methylsulfonyl-2-aryloxy-4-hydroxy-9,10-anthra-
quinones reacted with secondary amines to give products of nucleophilic substitution of hydrogen in position 3.
DOI: 10.1134/S107042800810014X
It is known that 1,4-dihydroxy-9,10-anthraquinone
reacts with aliphatic amines at room temperature to
give the corresponding 2-amino-1,4-dihydroxy-9,10-
anthraquinones [1]. 1-Amino-4-hydroxy-9,10-anthra-
quinone reacts with strongly nucleophilic amines (such
as piperidine and morpholine) only on prolonged heat-
ing at 80°C in excess reagent [2]; the reaction is not
selective, and products of hydrogen substitution in
positions 2 and 3 are formed. 1-Acetylamino-4-
hydroxy-9,10-anthraquinone reacts with piperidine in
a more selective fashion, yielding 1-acetylamino-3-
piperidino-4-hydroxy-9,10-anthraquinone [2]. It was
interesting to examine analogous amination reactions
of 1-amino-4-hydroxy-9,10-anthraquinone derivatives
having various acyl groups on the nitrogen atom and
nucleofugal substituents in the 2-position.
In the present work we studied the behavior of
1-acylamino-2-aryloxy-4-hydroxy-9,10-anthraquinones
Ia and Ib and 2-aryloxy-4-hydroxy-1-methylsulfonyl-
amino-9,10-anthraquinones IIa and IIb in reaction
Scheme 1.
COR
COR
O
HN
O
O
HN
NH
OPh
N
O
OH
OH
IIIa, IIIb
Ia, Ib
SO2Me
O
SO2Me
O
O
O
HN
O
HN
R2R3NH
R1
R1
N
R3
R2
OH
IIa, IIb
O
OH
IVa–IVe
I, III, R = Me (a), Ph (b); II, IV, R1 = H (a, c–e), t-Bu (b); IV, R2R3N = piperidino (a, b), pyrrolidin-1-yl (c),
morpholino (d); R2 = Me, R3 = HO(CH2)2 (e).
1490

REACTIONS OF 1-ACYLAMINO- AND 1-METHYLSULFONYLAMINO-2-ARYLOXY-...
1491
with secondary amines. The amination of amides Ia,
Ib, IIa, and IIb was carried out in DMF at 55–95°C.
When the reaction was complete, the mixture was
treated with a small amount of water, and the products
(compounds IIIa, IIIb, and IVa–IVe; Scheme 1) were
isolated by fractional crystallization and were then
purified by recrystallization.
a bulky tetrahedral methylsulfonyl group. Therefore,
the difference in the directions of amination of anthra-
quinones I and II may be explained as follows. The
substitution of aryloxy group by amino is most likely
to follow SNAr mechanism. In the case of conformers
Ia′ and IIa′, nucleophile approach to the reaction
center (carbon atom linked to the phenoxy group) is
considerably hindered. Compounds I can undergo
amination at the 2-position through conformer Ia″,
whereas amination of II can occur only with con-
former IIa′ in which nucleophilic attack at the 2-posi-
tion is strongly hindered for steric reasons. As a result,
nucleophile attacks spatially more accessible carbon
atom in position 3.
1
Analysis of the H NMR and mass spectra of com-
pounds III and IV indicates that the amination of acyl-
amines Ia and Ib involves replacement of the phenoxy
group in position 2 and that sulfonamides IIa–IIe react
via replacement of hydrogen on C3. The observed
difference in the directions of nucleophilic attack on
substrates I and II is difficult to explain taking into
consideration only different electron-withdrawing
properties of the acetyl (benzoyl) and methylsulfonyl
groups. In fact, anthraquinones Ia and IIa are charac-
terized by the same position of the long-wave absorp-
tion maximum in the electronic spectra (λmax 436 nm).
Similar blue shifts (Δλ = 115 nm) in going from
1-amino-4-hydroxy-2-phenoxy-9,10-anthraquinone to
compounds Ia and IIa suggest similar electronic ef-
fects of the acetyl and methylsulfonyl groups. Also, the
chemical shifts of the 3-H proton in Ia and IIa differ
only slightly (δ 6.50 and 6.55 ppm, respectively).
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
DRX spectrometer (500 MHz) using DMSO-d6 as
solvent as tetramethylsilane as internal reference. The
melting points were measured on a Boetius melting
point apparatus. The molecular weights were deter-
mined from the mass spectra which were obtained on
a Finnigan MAT-8200 spectrometer. The progress of
reactions and the purity of products were monitored by
TLC on Silufol plates using toluene–acetone (10:1) as
eluent.
Quantum-chemical calculations performed at the
B3LYP/6-31G(d) level of theory [3, 4] using Gaussian-
98 software package [5] confirmed the above stated.
The calculated charges on C2 and C3, as well as on the
oxygen atom in the phenoxy group, in molecules Ia
and IIa almost coincide in pairs (see figure). Figure
shows the structures of two most thermodynamically
favorable conformers of compound Ia (Ia′ and Ia″),
differing by orientation of the phenyl group. The cal-
culated (B3LYP) Gibbs energy of conformer Ia″ is
higher by only 12.55 kJ/mol than that of Ia′. The
phenyl group in molecule IIa cannot adopt orientation
analogous to structure Ia″ because of the presence of
N-(4-Hydroxy-9,10-dioxo-2-phenoxy-9,10-dihy-
droanthracen-1-yl)benzamide (Ib). A mixture of 1 g
(3.06 mmol) of 1-amino-4-hydroxy-2-phenoxy-9,10-
anthraquinone, 5 ml of toluene, and 0.5 ml of benzoyl
chloride was stirred for 60 min at 100°C. After cool-
ing, the precipitate was filtered off, washed with
ethanol, and recrystallized from toluene. Yield 1.18 g
1
(88%), mp 204–205°C. H NMR spectrum, δ, ppm
(hereinafter, primed locants refer to the benzoyl
group): 6.51 s (1H, 3-H), 7.2 d (2H, o-H, J = 2.6 Hz),
7.30 t (1H, p-H, J = 2.5 Hz), 7.49 t (2H, m-H, J =
3.1 Hz), 7.56 t (2H, m′-H, J = 3.1 Hz), 7.63 t (1H,
O
S
O
N
N
N
O
O
O
O
O
O, –0.57
O, –0.59
O, –0.57
0.38
–0.23
0.40
–0.23
0.39
–0.23
O
O
O
O
O
O
Ia′
Ia′′
IIa′
Structures of the most thermodynamically favorable conformers of N-(4-hydroxy-9,10-dioxo-2-phenoxy-9,10-dihydroanthracen-1-yl)-
acetamide (Ib) and N-(4-hydroxy-9,10-dioxo-2-phenoxy-9,10-dihydroanthracen-1-yl)methanesulfonamide (IIa), calculated by the
B3LYP/6-31G(d) method; given are Mulliken charges on the C2, C3, and 2-O atoms.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 10 2008

BERESNEV et al.
1492
p′-H, J = 2.5 Hz), 7.94 m (2H, 6-H, 7-H), 8.03 d (2H,
o′-H, J = 3.2 Hz), 8.13 m (1H, 5-H or 8-H), 8.24 m
(1H, 8-H or 5-H), 10.30 s (1H, NH), 13.30 s (1H, OH).
Found, %: C 74.28; H 3.89; N 3.22. C27H17N1O5. Cal-
culated, %: C 74.48; H 3.91; N 3.22.
spectrum: m/z 492 [M]+. Found, %: C 63.51; H 4.88;
N 5.52; S 6.14. C26H24N2O6S. Calculated, %: C 63.41;
H 4.88; N 5.69; S 6.50.
N-[2-(4-tert-Butylphenoxy)-4-hydroxy-9,10-di-
oxo-3-piperidino-9,10-dihydroanthracen-1-yl]meth-
anesulfonamide (IVb) was synthesized in a similar
way from 0.5 g (1.09 mmol) of compound IIb. Yield
N-(4-Hydroxy-9,10-dioxo-2-piperidino-9,10-di-
hydroanthracen-1-yl)acetamide (IIIa). A mixture of
0.50 g (1.36 mmol) of amide Ia, 5 ml of DMF, and
1 ml of piperidine was stirred for 7 h at 70°C, 1 ml of
water was added dropwise under stirring to the hot
solution, the mixture was cooled to 18°C, and the pre-
cipitate was filtered off, washed with aqueous ethanol
(1:1), water, and ethanol, dried, and recrystallized from
1
0.32 g (55%), mp 216–218°C. H NMR spectrum, δ,
ppm: 1.4 s (6H, CH2), 1.6 s [9H, C(CH3)3], 3.00 m
(5H, CH3, NCH2), 6.88 d (2H, o-H), 7.28 d (2H, m-H),
7.95 m (2H, 6-H, 7-H), 8.24 d (1H, 5-H or 8-H), 8.26 d
(1H, 8-H or 5-H), 11.10 s (1H, NH), 14.18 br.s
(1H, OH). Found, %: C 65.23; H 5.66; N 4.49.
C30H32N2O6S. Calculated, %: C 65.69; H 5.84; N 5.11.
1
toluene. Yield 0.31 g (62%), mp 95–97°C. H NMR
spectrum, δ, ppm: 1.60 s (6H, CH2), 2.10 s (3H, CH3),
3.01 m (4H, NCH2), 6.53 s (1H, 3-H), 7.89 m (2H,
6-H, 7-H), 8.09 m (1H, 8-H or 5-H), 8.17 m (1H, 5-H
or 8-H), 9.40 s (1H, NH). Found, %: C 69.33; H 5.51;
N 7.45. C21H20N2O4. Calculated, %: C 69.23; H 5.49;
N 7.69.
N-[4-Hydroxy-9,10-dioxo-2-phenoxy-3-(pyrroli-
din-1-yl)-9,10-dihydroanthracen-1-yl]methanesul-
fonamide (IVc). Compound IIa, 1.1 g (2.72 mmol),
was added to 4.5 ml of pyrrolidine, the mixture was
stirred for 3 h at 40–45°C, 2 ml of DMF was then
added, the mixture was heated to 60°C, 0.5 ml of water
was added dropwise under stirring, and the mixture
was cooled to 15°C. The precipitate was filtered off,
washed with alcohol, and recrystallized from DMF–
water (10:1). Yield 0.71 g (55%), mp 234–236°C.
1H NMR spectrum, δ, ppm: 1.6 s (4H, CH2), 3.50 m
(7H, CH3, NCH2), 6.88 d (2H, o-H), 7.08 t (1H, p-H),
7.28 t (2H, m-H), 7.95 m (2H, 6-H, 7-H), 8.24 d (1H,
5-H or 8-H), 8.26 d (1H, 8-H or 5-H), 11.30 br.s (1H,
NH), 14.60 br.s (1H, OH). Mass spectrum: m/z 478
[M]+. Found, %: C 62.47; H 4.67; N 5.93; S 6.31.
C25H22N2O6S. Calculated, %: C 62.76; H 4.60; N 5.86;
S 6.69.
N-(4-Hydroxy-9,10-dioxo-2-piperidino-9,10-di-
hydroanthracen-1-yl)benzamide (IIIb). A mixture of
1 g (2.33 mmol) of amide Ib, 6 ml of DMF, and 1 ml
of piperidine was stirred for 15 h at 110°C, 1 ml of
water was added dropwise under stirring to the hot
solution, the mixture was cooled to 18°C, and the pre-
cipitate was filtered off, washed with aqueous ethanol
(1:1), water, and ethanol, dried, and recrystallized from
toluene. Yield 0.73 g (75%), mp 100–102°C. 1H NMR
spectrum, δ, ppm: 1.50 s (6H, CH2), 3.30 m (4H,
NCH2), 6.82 s (1H, 3-H), 7.59 t (2H, m′-H), 7.61 t (1H,
p′-H), 7.89 t (1H, 7-H or 6-H), 7.92 t (1H, 6-H or 7-H),
8.05 m (3H, 5-H or 8-H, o′-H), 8.20 d (1H, 8-H or
5-H), 10.11 s (1H, NH), 13.50 s (1H, OH). Mass spec-
trum: m/z 426 [M]+. Found, %: C 73.24; H 5.39;
N 6.66. C26H23N2O4. Calculated, %: C 73.23; H 5.39;
N 6.57.
N-(4-Hydroxy-3-morpholino-9,10-dioxo-2-phen-
oxy-9,10-dihydroanthracen-1-yl)methanesulfon-
amide (IVd). A solution of 1 g (2.48 mmol) of sul-
fonamide IIa in 10 ml of DMF–morpholine (1:1) was
stirred for 20 h at 80°C, 1.5 ml of water was added
dropwise under stirring to the hot solution, and the
mixture was cooled to 18°C. The precipitate was fil-
tered off, washed with ethanol, dried, and recrystal-
lized twice from DMF–water (5:1). Yield 0.61 g
N-(4-Hydroxy-9,10-dioxo-2-phenoxy-3-piperi-
dino-9,10-dihydroanthracen-1-yl)methanesulfon-
amide (IVa). A solution of 1 g (2.48 mmol) of sulfon-
amide IIa in 7 ml of a 2:1 DMF–piperidine mixture
was stirred for 6 h at 60°C, 1.5 ml of water was added
dropwise under stirring to the hot solution, and the
mixture was cooled to 18°C. The precipitate was fil-
tered off, washed with ethanol, dried, and recrystal-
lized twice from DMF–water (5:1). Yield 0.66 g
1
(50%), mp 235–237°C. H NMR spectrum, δ, ppm:
3.10 t (4H, OCH2), 3.41 m (7H, CH3, NCH2), 6.92 d
(2H, o-H), 7.12 t (1H, p-H), 7.36 t (2H, m-H), 7.96 m
(2H, 6-H, 7-H), 8.24 d (1H, 5-H or 8-H), 8.26 d (1H,
8-H or 5-H), 11.00 br.s (1H, NH), 14.10 br.s (1H, OH).
Found, %: C 60.97; H 4.57; N 5.90. C25H22N2O7S. Cal-
culated, %: C 60.72; H 4.45; N 5.67.
1
(55%), mp 205–207°C. H NMR spectrum, δ, ppm:
1.4 s (6H, CH2), 3.00 m (7H, CH3, NCH2), 6.88 d (2H,
o-H), 7.08 t (1H, p-H), 7.28 t (2H, m-H), 7.95 m (2H,
6-H, 7-H), 8.24 d (1H, 5-H or 8-H), 8.26 d (1H, 5-H or
8-H), 11.10 s (1H, NH), 14.20 br.s (1H, OH). Mass
N-{4-Hydroxy-3-[(2-hydroxyethyl)(methyl)-
amino]-9,10-dioxo-2-phenoxy-9,10-dihydroanthra-
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REACTIONS OF 1-ACYLAMINO- AND 1-METHYLSULFONYLAMINO-2-ARYLOXY-...
1493
3. Becke, A.D., J. Chem. Phys., 1993, vol. 98, p. 5648.
cen-1-yl}methanesulfonamide (IVe) was synthesized
in a similar way from 0.86 g (2.13 mmol) of compound
IIa and 2-(methylamino)ethanol. Yield 0.63 g (64%),
4. Lee, C., Yang, W., and Parr, R.G., Phys. Rev. B, 1988,
vol. 37, p. 785.
1
mp 190–192°C. H NMR spectrum, δ, ppm: 3.41–
5. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E.,
Robb, M.A., Cheeseman, J.R., Zakrzewski, V.G., Mont-
gomery, J.A., Stratmann, R.E., Burant, J.C., Dapprich, S.,
Millam, J.M., Daniels, A.D., Kudin, K.N., Strain, M.C.,
Farkas, O., Tomasi, J., Barone, V., Cossi, M., Cammi, R.,
Mennucci, B., Pomelli, C., Adamo, C., Clifford, S.,
Ochterski, J., Petersson, G.A., Ayala, P.Y., Cui, Q., Moro-
kuma, K., Malick, D.K., Rabuck, A.D., Raghavachari, K.,
Foresman, J.B., Cioslowski, J., Ortiz, J.V., Stefa-
nov, B.B., Liu, G., Liashenko, A., Piskorz, P., Koma-
romi, I., Gomperts, R., Martin, R.L., Fox, D.J., Keith, T.,
Al-Laham, M.A., Peng, C.Y., Nanayakkara, A., Gonza-
lez, C., Challacombe, M., Gill, P.M.W., Johnson, B.,
Chen, W., Wong, M.W., Andres, J.L., Gonzalez, C.,
Head-Gordon, M., Replogle, E.S., and Pople, J.A., Gaus-
sian 98, Revision A.6, Pittsburgh, PA: Gaussian, 1998.
3.11 m (10H, CH3, CH2), 4.45 s (1H, OH), 6.90 d (2H,
o-H), 7.10 t (1H, p-H), 7.34 t (2H, m-H), 7.96 m (2H,
6-H, 7-H), 8.24 d (1H, 5-H or 8-H), 8.26 d (1H, 8-H or
5-H), 11.10 br.s (1H, NH), 14.20 br.s (1H, 4-OH).
Mass spectrum: m/z 482 [M]+. Found, %: C 60.20;
H 4.70; N 5.74; S 6.31. C24H22N2O7S. Calculated, %:
C 59.75; H 4.76; N 5.81; S 6.64.
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Mazur, V.G., Zh. Prikl. Khim., 1971, vol. 44, p. 2271.
2. Russkikh, S.A., Loskutov, V.A., and Russkikh, V.V.,
Zh. Obshch. Khim., 1974, vol. 44, p. 642.
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