Transformation of 1-(acyl)(2-haloethyl)amino-9,10-anthraquinones into 1-(2-acyloxyethylamino)-9,10-anthraquinones

Article abstract of DOI:10.1134/S1070428006100125

Acylation of 1-(2-haloethylamino)-9,10-anthraquinones gave 1-[(2-haloethyl)(aroyl, hetaroyl, or acetyl)amino]-9,10-anthraquinones which were converted into the corresponding 1-[2-(aroyloxy, hetaroyloxy, or acetoxy)ethylamino]-9,10-anthraquinone on keeping

Full text of DOI:10.1134/S1070428006100125

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2006, Vol. 42, No. 10, pp. 1473–1476. © Pleiades Publishing, Inc., 2006.
Original Russian Text © L.M. Gornostaev, M.S. Sokolova, 2006, published in Zhurnal Organicheskoi Khimii, 2006, Vol. 42, No. 10, pp. 1488–1491.
Transformation of 1-(Acyl)(2-haloethyl)amino-9,10-anthra-
quinones into 1-(2-Acyloxyethylamino)-9,10-anthraquinones
L. M. Gornostaev and M. S. Sokolova
Astaf’ev Krasnoyarsk State Pedagogical University, ul. A. Lebedevoi 89, Krasnoyarsk, 660049 Russia
e-mail: gornostaev@kspu.ru
Received August 12, 2005
Abstract—Acylation of 1-(2-haloethylamino)-9,10-anthraquinones gave 1-[(2-haloethyl)(aroyl, hetaroyl, or
acetyl)amino]-9,10-anthraquinones which were converted into the corresponding 1-[2-(aroyloxy, hetaroyloxy,
or acetoxy)ethylamino]-9,10-anthraquinone on keeping in dimethylformamide. According to the experimental
data (including those obtained by kinetic study), the transformation involves intramolecular migration of the
acyl group through aziridinium or oxazolidinium intermediates.
DOI: 10.1134/S1070428006100125
I→II occurs under mild conditions (20–50°C) even
in the absence of a base (e.g., the transformation
Ig→IIg). Moreover, according to the results of kinetic
studies, the rate of the transformation of benzoylamino
derivative Ia into 1-(2-benzoyloxyethylamino)anthra-
quinone IIa remains almost unchanged over a wide pH
range; these data indicate the absence of base catalysis.
1-Acylamino-9,10-anthraquinones are known to un-
dergo base-catalyzed cyclization to naphtho[1,2,3-de]-
quinolinones (Scheme 1); here, the R1 substituent may
be both hydrogen atom and alkyl or aryl group, i.e.,
this substituent is not involved in the cyclization [1].
We have found that 1-[(2-haloethyl)(aroyl, hetaroyl, or
acetyl)amino]-9,10-anthraquinones Ia–Ih obtained by
acylation of 1-(2-haloethylamino)-9,10-anthraquinones
are converted under analogous conditions into the
corresponding 1-[2-(acyloxy)ethylamino]-9,10-anthra-
quinones IIa–IIg (Scheme 2). The transformation
Formalistically, the transformation I→II can be
represented as a series of consecutive reactions, in-
cluding, e.g., hydrolysis of amide I to 1-(2-haloethyl-
amino)anthraquinone III and subsequent replacement
Scheme 1.
O
R1
COCH2R2
R2
R1
O
O
N
N
R3
O
R3
Scheme 2.
XCH2CH2
O
COR
O
R
N
O
O
HN
O
O
Ia–Ih
IIa–IIg
X = Cl, R = Ph (a), 4-ClC6H4 (b), 3-O2NC6H4 (c), 4-O2NC6H4 (d), 2-thienylcarbonyl (e), 2-furylcarbonyl (f), Me (g);
X = Br, R = Me (h).
1473

GORNOSTAEV, SOKOLOVA
1474
Scheme 3.
unimolecular and that electron-acceptor substituents
reduce the reaction rate: the rate constants for aroyl
derivatives Ia–Id conform to the Hammett equation
(see figure).
X
O
HN
H2O
–RCOOH
RCOOH
I
II
These results, as well as published data [2] on an-
chimeric assistance with formation of five-membered
cyclic intermediates, suggest a probable reaction path
shown in Scheme 5. Presumably, the cyclization of
amides I to intermediates VI is the rate-determining
stage. In this case, the reaction rate should depend on
the halogen nature. In fact, the kinetic data for
N-acetylamino derivatives I showed that the rate of
the transformation of 1-[acetyl(2-bromoethyl)amino]-
9,10-anthraquinone (Ih) into ester IIg was higher by
a factor of 22.3 than the rate of the transformation of
2-chloroethyl-substituted analog Ig. However, the ob-
tained data do not allow us to unambiguously choose
between the two possible paths, I→IV→V→II and
I→VI→VII→II.
O
IIIa, IIIb
X = Cl (a), Br (b).
of the halogen atom by the liberated carboxylate ion
(Scheme 3).
However, by special experiments we showed that
1-(2-chloroethylamino)-9,10-anthraquinone reacts with
aromatic carboxylic acids at a much lower rate and
only in the presence of bases. Another factor ensuring
easy transformation of I into II may be anchimeric as-
sistance [2] by the halogen atom and acylamino group
in the α,β-positions, which facilitates formation of
aziridinium intermediate IV and its subsequent trans-
formation (Scheme 4). We did not detect N-acyl-N-(2-
hydroxyethyl)amino derivatives V which should be
formed in this case. This result neither supports nor
rules out the possibility for formation of aziridinium
intermediate IV, for the subsequent transformation
V→II may be fast. In addition, we found that the
reaction I→II is intramolecular since amide Ia in
aqueous DMF is converted exclusively into ester IIa
even in the presence of a large excess of thiophene-2-
carboxylic acid. The kinetic study of the transforma-
tion I→II showed that the rate-determining stage is
Thus we have revealed a new transformation of
1-acylamino-9,10-anthraquinones. We have to eluci-
date whether the observed reaction is typical of other
N-(2-haloethyl) carboxamides and obtain unambiguous
experimental proofs for one or another mechanism of
such reactions.
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
DRX-500 spectrometer relative to tetramethylsilane as
internal reference. The progress of reactions and the
Scheme 4.
MeCO
O
OH
O
O
N
COMe
Cl–
N
OH–
I
II
O
IV
V
Scheme 5.
O
N
O
N
HO
Me
Me
O
O
O
H2O
I
X–
II
O
VI
VII
X = Cl (a), Br (b).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 10 2006

TRANSFORMATION OF 1-(ACYL)(2-HALOETHYL)AMINO-9,10-ANTHRAQUINONES
1475
–logkap
purity of products were monitored by TLC on Silufol
p-NO2
m-NO2
plates using tolune–acetone (10:1) as eluent. The
kinetics of the transformation of amides Ia–Id, Ig, and
Ih into esters IIa–IId and IIg were studied by spec-
trophotometry using a Specord UV-Vis instrument at
50°C for Ia–Id and 25°C for Ig and Ih. The concentra-
tion of esters IIa–IId and IIg was determined at their
long-wave absorption maxima (λ 510 nm). Kinetic
experiments were performed in 2-cm cells; the con-
centration of initial amides Ia–Id, Ig, and Ih was
0.5×10–4 M; 50% aqueous DMF, pH 4.8. The rate
constants were calculated by standard procedure [3];
average values from three parallel runs for each trans-
formation were determined. The apparent rate con-
stants kap are given below:
2.5
2.0
1.5
1.0
p-Cl
H
0.0
0.2
0.4
0.6
σ
Correlation between the –logkap values and Hammett con-
stants σ (ρ = –0.9260, r = 0.9891, s = 0.0225).
1-[Acyl(2-haloethyl)amino]-9,10-anthraquinones
Ia–If (general procedure). A mixture of 10 mmol of
1-(2-chloroethylamino)-9,10-anthraquinone and
17 mmol of the corresponding acyl chloride in 2 ml of
nitrobenzene was stirred for 30–40 h at 150°C. The
mixture was cooled, and the yellow precipitate was
filtered off, washed with anhydrous diethyl ether, and
recrystallized from toluene.
Compound no.
kap ×104, s–1
Ia
Ib
Ic
Id
Ig
Ih
6.22 4.23 1.21 1.38 1.30 29.0
The transformation Ia→IIa at different pH values
(4.0 to 11.6) was studied in a similar way using
aqueous DMF buffers prepared from a 0.2 M solution
of Na2HPO4 and a 0.1 M solution of citric acid [4]. The
following values of logkap were obtained (kap, s–1).
N-(2-Chloroethyl)-N-(9,10-dioxo-9,10-dihydro-
anthracen-1-yl)benzamide (Ia). Yield 2.57 g (63%),
mp 205–206°C. H NMR spectrum (CDCl3), δ, ppm:
3.76–3.89 m (2H, CH2Cl), 4.57–4.64 m and 4.09–
4.15 m (2H, CH2N), 6.97–8.28 (12H, Harom). Found,
%: C 71.10; H 4.21; N 3.56. C23H16ClNO3. Calculated,
%: C 70.86; H 4.10; N 3.59.
1
pH
4.0
4.8
7.6
10
11.6
3.25
–logkap
3.16
3.20
3.12
3.07
4-Chloro-N-(2-chloroethyl)-N-(9,10-dioxo-9,10-
dihydroanthracen-1-yl)benzamide (Ib). Yield 2.67 g
(60%), mp 202–203°C. 1H NMR spectrum (CDCl3), δ,
ppm: 3.80–3.82 m (2H, CH2Cl), 3.91–3.97 m and
4.40–4.49 m (2H, CH2N), 7.30–8.22 (11H, Harom).
Found, %: C 65.11; H 3.52; N 3.21. C23H15Cl2NO3.
Calculated, %: C 65.09; H 3.53; N 3.30.
We failed to isolate compounds Ig and Ih as
individual substances; therefore, their transformation
into ester IIg was studied as follows: compound IIIa
(5.286 mg) or IIIb (6.129 mg) was dissolved on
heating in 10 ml of acetic anhydride, the mixture was
kept until the optical density at λ 400 nm no longer
increased, a 0.270-ml portion of the mixture was trans-
ferred into 10 ml of 50% aqueous DMF to obtain
a solution with a concentration of 0.5×10–4 M, and the
optical density at λ 510 nm (compound IIg) was
measured.
N-(2-Chloroethyl)-N-(9,10-dioxo-9,10-dihydro-
anthracen-1-yl)-3-nitrobenzamide (Ic). Yield 2.73 g
(60%), mp 220–221°C. 1H NMR spectrum (DMSO-d6),
δ, ppm: 3.71–3.80 m (2H, CH2Cl), 4.90–3.99 m and
4.45–4.50 m (2H, CH2N), 7.36–8.20 (11H, Harom).
Found, %: C 63.45; H 3.46; N 6.14. C23H15ClN2O5.
Calculated, %: C 63.52; H 3.45; N 6.44.
1-(2-Bromoethylamino)-9,10-anthraquinone (IIIb)
was synthesized as described in [5].
1-(2-Chloroethylamino)-9,10-anthraquinone
(IIIa). 1-(2-Hydroxyethylamino)-9,10-anthraquinone,
5 g (18 mmol) was dissolved in 15 ml of pyridine, the
solution was cooled, and 5 ml of benzenesulfonyl
chloride was added. The mixture was stirred for
20 min at 70°C and cooled, and the red precipitate was
filtered off and washed with ethanol. Yield 5.07 g
(95%), mp 179–180°C [5]. 1H NMR spectrum (CDCl3),
δ, ppm: 3.65–3.80 m (4H, CH2CH2), 7.05–8.30 m (7H,
N-(2-Chloroethyl)-N-(9,10-dioxo-9,10-dihydro-
anthracen-1-yl)-4-nitrobenzamide (Id). Yield 2.82 g
(62%), mp 218–220°C. 1H NMR spectrum (DMSO-d6),
δ, ppm: 3.77–3.86 m (2H, CH2Cl), 3.90–3.95 m and
4.45–4.51 m (2H, CH2N), 7.43–8.22 (11H, Harom).
Found, %: C 63.75; H 3.46; N 6.19. C23H15ClN2O5.
Calculated, %: C 63.52; H 3.45; N 6.44.
N-(2-Chloroethyl)-N-(9,10-dioxo-9,10-dihydro-
anthracen-1-yl)thiophene-2-carboxamide (Ie). Yield
Harom), 9.98 br.s (1H, NH).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 10 2006

GORNOSTAEV, SOKOLOVA
1476
1
2.69 g (65%), mp 198–200°C. H NMR spectrum
(DMSO-d6), δ, ppm: 3.72–3.82 m (2H, CH2Cl), 3.90–
3.95 m (2H, CH2NH), 6.65–6.80 d (3H, thiophene, J =
5.0 Hz.), 7.50–8.37 (7H, Harom). Found, %: C 63.39;
H 3.46; N 3.68. C21H14ClNO3S. Calculated, %: C 63.71;
H 3.53; N 3.53.
2-(9,10-Dioxo-9,10-dihydroanthracen-1-ylamino)-
ethyl thiophene-2-carboxylate (IIe). Yield 0.68 g
(72%), mp 150–152°C. 1H NMR spectrum (DMSO-d6),
δ, ppm: 3.83 q (2H, CH2NH, J = 5.0 Hz), 4.53 t (2H,
CH2O, J = 5.0 Hz), 7.30–8.20 (10H, Harom), 9.91 br.t
(1H, NH, J = 5.0 Hz). Found, %: C 66.65; H 3.94;
N 3.80. C21H15NO4S. Calculated, %: C 69.80; H 4.15;
N 3.87.
N-(2-Chloroethyl)-N-(9,10-dioxo-9,10-dihydro-
anthracen-1-yl)furan-2-carboxamide (If). Yield
1
2.06 g (52%), mp 212–214°C. H NMR spectrum
2-(9,10-Dioxo-9,10-dihydroanthracen-1-ylamino)-
(DMSO-d6), δ, ppm: 3.72–3.82 m (2H, CH2Cl), 3.90–
3.95 m (2H, CH2NH), 6.60–6.70 d (3H, furan, J =
5.0 Hz), 7.50–8.37 (7H, Harom). Found, %: C 66.47;
H 3.73; N 3.97. C21H14ClNO4. Calculated, %: C 66.40;
H 3.68; N 3.68.
1-(2-Acyloxyethylamino)-9,10-anthraquinones
IIa–IIf (general procedure). Amide Ia–If, 1 g, was
added under stirring to a mixture of 20 ml of DMF and
0.4 g (2.8 mmol) of potassium carbonate, and the
mixture was stirred for 3–4 h at 50°C. The mixture was
diluted with 20–40 ml of water, and the red solid was
separated and recrystallized from toluene.
2-(9,10-Dioxo-9,10-dihydroanthracen-1-ylamino)-
ethyl benzoate (IIa). Yield 0.88 g (93%), mp 167–
168°C. 1H NMR spectrum (DMSO-d6), δ, ppm: 3.85 q
(2H, CH2NH, J = 5.0 Hz), 4.60 t (2H, CH2O, J =
5.0 Hz), 7.45–8.20 (12H, Harom), 9.91 br.t (1H, NH,
J = 5.0 Hz). Found, %: C 75.38; H 4.65; N 3.56.
C23H17NO4. Calculated, %: C 74.39; H 4.58; N 3.77.
ethyl furan-2-carboxylate (IIe). Yield 0.76 g (80%),
mp 157–158°C. H NMR spectrum (DMSO-d6), δ,
ppm: 3.80 q (2H, CH2NH), 4.50 t (2H, CH2O), 6.70–
8.20 (10H, Harom), 9.85 br.s (1H, NH). Found, %:
C 68.91; H 4.09; N 3.95. C21H15NO5. Calculated, %:
C 70.04; H 4.34; N 4.05.
1
2-(9,10-Dioxo-9,10-dihydroanthracen-1-ylamino)-
ethyl acetate (IIg). a. A solution of 2.85 g (10 mmol)
of compound IIIa in 6 ml of acetic anhydride was
heated to the boiling point over a period of 5 min. The
mixture was cooled and poured onto ice, and the red
precipitate was filtered off, washed with ethanol, and
purified by recrystallization from toluene.
b. Following an analogous procedure, compound
IIg was obtained from bromo derivative IIIb. Yield
1
2.62 g (85%), mp 160–161°C. H NMR spectrum
(DMSO-d6), δ, ppm: 2.10 s (3H, CH3); 3.63 q (2H,
CH2N, J = 6.0 Hz); 4.35 t (2H, CH2O, J = 6.0 Hz);
7.35–7.60 m, 7.54–7.77 m, and 8.19–8.3 m (7H, Harom);
9.87 br.s (1H, NH). Found, %: C 69.70; H 4.78; N 4.57.
C18H15NO4. Calculated, %: C 69.90; H 4.85; N 4.53.
2-(9,10-Dioxo-9,10-dihydroanthracen-1-ylamino)-
ethyl 4-chlorobenzoate (IIb). Yield 0.74 g (82%),
1
mp 189–192°C. H NMR spectrum (DMSO-d6), δ,
ppm: 3.85 q (2H, CH2NH), 4.60 t (2H, CH2O), 7.40–
8.30 (11H, Harom), 9.91 s (1H, NH). Found, %: C 67.91;
H 3.91; N 3.35. C23H16ClNO3. Calculated, %: C 68.06;
H 3.94; N 3.45.
This study was performed under financial support
by the Astaf’ev Krasnoyarsk State Pedagogical Uni-
versity (project no. 24-05-1 F/P).
REFERENCES
2-(9,10-Dioxo-9,10-dihydroanthracen-1-ylamino)-
ethyl 3-nitrobenzoate (IIc). Yield 0.81 g (85%),
mp 175–176°C. H NMR spectrum (DMSO-d6), δ,
1. Gorelik M.V., Khimiya antrakhinonov i ikh proizvodnykh.
(Chemistry of Anthraquinones and Their Derivatives),
Moscow: Khimiya, 1983, p. 155.
2. March, J., Advanced Organic Chemistry. Reactions,
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1
ppm: 3.88 q (2H, CH2NH, J = 5.5 Hz), 4.62 t (2H,
CH2O, J = 5.5 Hz), 7.50–8.40 (11H, Harom), 9.91 br.t
(1H, NH, J = 5.5 Hz). Found, %: C 66.90; H 3.90;
N 6.56. C23H16N2O6. Calculated, %: C 66.34; H 3.84;
N 6.61.
2-(9,10-Dioxo-9,10-dihydroanthracen-1-ylamino)-
3. Zhdanov, Yu.A. and Minkin, V.I., Korrelyatsionnyi analiz
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Chemistry), Rostov-on-Don: Rostov. Gos. Univ., 1966,
p. 470.
ethyl 4-nitrobenzoate (IId). Yield 0.78 g (83%),
1
mp 200–201°C. H NMR spectrum (DMSO-d6), δ,
ppm: 3.88 q (2H, CH2NH, J = 5.5 Hz), 4.62 t (2H,
CH2O, J = 5.5 Hz), 7.50–8.40 (11H, Harom), 9.90 br.t
(1H, NH, J = 5.5 Hz). Found, %: C 66.30; H 3.86;
N 6.52. C23H16N2O6. Calculated, %: C 66.34; H 3.84;
N 6.61.
4. Perel’man, V.I., Kratkii spravochnik khimika (Brief
Chemist’s Handbook), Moscow: Khimiya, 1964, p. 330.
5. Fokin, E.P., Russkikh, S.A., and Russkikh, V.V., Izv. Sib.
Otd. Akad. Nauk, Ser. Khim., 1965, no. 11, p. 121.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 10 2006