Reaction of 4-hydroxyacridin-9(10H)-one and 4-hydroxyacridine-9(10H)-thione with α,ω-alkyl dibromides

Article abstract of DOI:10.1007/PL00010131

Starting from 4-hydroxyacridin-9(10H)-one (1) and 4-hydroxyacridine-9(10H)-thione (2), a series of bis-derivatives was prepared, among them the bridged bis-acridin-(10H)-ones 9-14 and the bis-mercapto-(9H)-acridines 15-18. The reactivity of the 2-and 4-hydroxy series was compared; it was found that it is harder to demethylate 4-methoxy derivatives than their 2-methoxy analogues.

Full text of DOI:10.1007/PL00010131

Monatshefte fuÈr Chemie 129, 1199±1205 (1998)
Reaction of 4-Hydroxyacridin-9(10H)-one
and 4-Hydroxyacridine-9(10H)-thione with
ꢀ,!-Alkyl Dibromides
1
1
2
Jean-Pierre Galy1;Ã, Anne-Marie Galy , Alain Vichet , and Jose Elguero
Â
1
  Ã
URA-CNRS 1411, Faculte des Sciences et Techniques de Saint-Jerome, F-13397 Marseille
Â
Cedex 20, France
2
 Â
Instituto de Quõmica Medica, CSIC, E-28006 Madrid, Spain
Summary. Starting from 4-hydroxyacridin-9(10H)-one (1) and 4-hydroxyacridine-9(10H)-thione
(2), a series of bis-derivatives was prepared, among them the bridged bis-acridin-(10H)-ones 9±14
and the bis-mercapto-(9H)-acridines 15±18. The reactivity of the 2- and 4-hydroxy series was
compared; it was found that it is harder to demethylate 4-methoxy derivatives than their 2-methoxy
analogues.
Keywords. 4-Hydroxyacridinone; 4-Hydroxyacridine thione; 4-Methoxyacridinone; 4-Methoxy-
acridine thione; Alkylation.
Reaktion von 4-Hydroxyacridin-9(10H)-on und 4-Hydroxyacridin-9(10H)-thion mit
a,x-Alkyldibromiden
Zusammenfassung. Ausgehend von 4-Hydroxyacridin-9(10H)-on (1) und 4-Hydroxyacridin-
9(10H)-thion (2) wurde eine Serie von bis-Derivaten, unter ihnen die verbruÈckten bis-Acridin-
È
9(10H)-one 9±14 und die bis-Mercapto-(9H)-acridine 15±18, hergestellt. Die Reaktivitat der 2- und
4-Hydroxyderivate wurde verglichen; es wurde festgestellt, daû die 4-Methoxyderivate schwerer zu
demethylieren sind als die 2-Methoxyderivate.
Introduction
Compounds like 4-hydroxyacridin-9(10H)-one (1) [1] and 4-hydroxyacridine-
9(10H)-thione (2) present an interesting case of ambident reactivity since they can
be alkylated or acylated at the oxygen (or sulfur) and nitrogen atoms of the ring as
well as at the 4-hydroxy group [2±4]. Moreover, the resulting derivatives are
important from biological and supramolecular points of view, particularly in the
case of compounds containing several acridine units (Scheme 1) [5±8]. In this
paper we will report on the reactivity of compounds 1 and 2 and some of their N-
and O-methyl derivatives towards alkylating and acylating agents.
Ã
Corresponding author

1200
J.-P. Galy et al.
Scheme 1
Results and Discussion
When the acridinone is N-substituted, further substitution can only take place at the
4-hydroxy group. We studied the case of 4-hydroxy-10-methylacridin-9-one (7).
This compound was obtained by demethylation of 4-methoxy-10-methylacridin-9-
one (5) [9] by means of HBr (Scheme 2). 5 was prepared by N-methylation of 4-
methoxyacridin-9(10H)-one (3) [1] under phase transfer catalysis (PTC) condi-
tions.
Alkylation of 7 with alkyldihalides under PTC conditions afforded the bis-
acridinone diethers 10 and 11. An attempt to prepare the corresponding acridinone
diesters using thallium salts [10] and acylating agents failed; however, this reaction
gave good yields in the 2-hydroxy series [4] (Scheme 1). Compounds 9, 10, and 11
were characterized by their 13C NMR spectra (cf. Experimental).
A similar study with the corresponding thione 8 was not possible since it could
not be prepared. Two approaches were attempted: treatment of 7 with either
Lawesson reagent [11, 12] or P4S10 (note that 6 was obtained from 5 using P4S10)
[13, 14] and demethylation of 6 with HBr (only 7 was obtained) or with C2H5SH/
AlCl3 [15, 16] (no reaction was observed).
Alkylation of 1 with several dialkylhalides under PTC conditions afforded a
mixture of isomers from which the 4,40-bridged bis-acridines 12, 13, and 14 were
isolated by crystallization from ethanol. Proof for the 4,40-symmetrical acridinone
structure of 12, 13, and 14 was derived from their 13C NMR spectra which display
only one group of signals for the heterocycle together with a signal at 171 ppm
Scheme 2

Synthesis of Bis-acridine Derivatives
1201
Scheme 3
Scheme 4
(C-9) and one at 70±72 ppm for the two -O-CH2- groups. The other regioisomers,
if present, could not be identi®ed (Scheme 3).
The results obtained in the case of acridinethiones 2 and 4 are summarized in
Scheme 4. The only practical procedure to prepare 2 was treating 1 with P4S10
since demethylation of 4 by means of HBr led to complex mixtures. For instance,
treating 4 with HBr for 4 days led to a mixture of 1 (40%), 2 (40%), 3 (10%), and 4
(10%); after 8 days, only 1 was obtained. The reaction of 2 and 4 with alkyl-
dihalides afforded the 9,90-bridged bis-mercaptoacridines 15, 16, 17, and 18 (only,
1,6-dibromohexane was used). The demethylation of 18 to 15 failed, whereas 2-
methoxy dimers resulted in 2-hydroxy derivatives [4] (Scheme 4).
The S-substitution and the symmetry pattern of compounds 15, 16, 17, and
18 was established from their 13C NMR Spectra. The signal of C-9 is shifted
from 194±195 ppm in thiones to 134.5 ppm in thioethers; moreover, the terminal
methylene groups appear at 36 ppm which is characteristic for -S-CH2-moieties.
Conclusions
This study has established two facts:
i) 2-OCH3 and 4-OCH3 derivatives of the title compounds behave quite differently;
the former (48 h in all cases) [4] are much easier to demethylate than the latter
(5 days for 3, 8 days for 5).
ii) Concerning the regioselectivity, 4-hydroxy derivatives behave similarly to 2-
hydroxy derivatives [4], although the yields differ (Table 1).

1202
J.-P. Galy et al.
Table 1. Alkylation yields of hydroxy derivatives (%)
2-OH derivatives
4-OH derivatives [4]
9
86
95
90
64
41
28
86
49
46
60
60
70
50
33
20
80
90
70
10
11
12
13
14
15
16
17
Experimental
1
Melting points are uncorrected. H and 13C NMR spectra were recorded with a Bruker AMX-200
spectrometer. 1H and 13C chemical shifts (ꢁ, ppm) were measured relative to internal Me4Si.
Elemental analyses (C, H, N) agreed with the calculated values.
4-Hydroxyacridine-9(10H)-thione (2; C13H9NOS)
A mixture of 1.5 g 4-hydroxyacridin-9(10H)-one (1 [1]: 7 mmol), 2 g tetraphosphorus decasul®de
(4.5 mmol), and 20 ml hexamethylphosphorotriamide was re¯uxed for 48 h. After cooling, the
solution was poured into cold water. A red precipitate was obtained, ®ltered, and dried before
crystallization from methanol. Yield: 55%; m.p.: 213ꢀC; 1H NMR (200 MHz, ꢁ, DMSO-d6): 9.1±7.1
(m, 7H) ppm.
4-Hydroxy-10-methylacridin-9-one (7; C14H11NO2)
A mixture of 3.7 g 4-methoxy-10-methylacridin-9-one (5 [9]; 15 mmol) and 165 ml hydrobromic
acid (48%) was re¯uxed for 24 h. After cooling, the solution was poured into cold water. The
precipitate obtained by addition of diluted ammonia was ®ltered and crystallized from ethanol.
Yield: 80%; m.p.: >260ꢀC; 1H-NMR (200 MHz, ꢁ, DMSO-d6): 8.3±7.0 (m, 7H), 4.0 (s, 3H)
ppm).
General procedure for the preparation of 4,40-(ꢀ00,!00-dioxaalkyl)-bis-(10-methylacridin-9-ones)
9, 10, and 11
A mixture of 2.25 g 4-hydroxy-10-methylacridin-9-one (7, 10 mmol), 1.14 g triethylbenzylammo-
nium chloride (TEBAC) (5 mmol), 50 ml 50% aqueous potassium hydroxide, 100 ml toluene, and
6 mmol ꢀ,! dibromoalkane was re¯uxed for 4 h. The precipitate was separated, the organic layer
evaporated, and another crop was obtained. The solids (identical by 1H NMR) were mixed and
crystallized from ethanol.
4,40-(100,600-dioxahexyl)-bis-(10-methylacridin-9-one) (9; C32H28N2O4)
Yield: 60%; m.p.: >260ꢀC; 1H NMR (200 MHz, ꢁ, CF3CO2D): 8.9±7.6 (m, 14H), 4.8 (s, 6H), 4.5 (m,
4H), 2.5 (m, 4H) ppm; 13C NMR (50 MHz, ꢁ, CF3CO2D): 117.99 (C-1), 128.54 (C-2), 119.32

Synthesis of Bis-acridine Derivatives
1203
(C-3), 152.28 (C-4), 120.94 (C-5), 140.81 (C-6), 126.63 (C-7), 128.85 (C-8), 171.00 (C-9), 44.84
(C-10), 120.53 (C-9a), 138.58 (C-4a), 147.15 (C-10a), 117.99 (C-8a), 72.32 (CH2-ꢀ), 27.80 (CH2-ꢂ)
ppm.
4,40-(100,800-Dioxaoctyl)-bis-(10-methylacridin-9-one) (10; C34H32O2N4)
1
Yield: 60%; m.p.: >260ꢀC; H NMR (200 MHz, ꢁ, CF3CO2D): 8.9±7.6 (m, 14H), 4.8 (s, 6H), 4.45
(m, 4H), 2.5±1.7 (m, 8H) ppm; 13C NMR (50 MHz, ꢁ, CF3CO2D): 117.85 (C-1), 128.35 (C-2),
119.29 (C-3), 152.41 (C-4), 120.96 (C-5), 140.59 (C-6), 126.52 (C-7), 128.93 (C-8), 170.93 (C-9),
44.89 (C-10), 120.47 (C-9a), 138.66 (C-4a), 147.10 (C-10a), 117.93 (C-8a), 72.65 (CH2-ꢀ), 30.69
(CH2-ꢂ) ppm.
4,40-(100,1000-Dioxadecyl)-bis-(10-methylacridin-9-one) (11; C36H36N2O4)
Yield: 70%; m.p.: >260ꢀC; 1H NMR (200 MHz, ꢁ, CF3CO2D):P 8.9±7.6 (m, 14H), 4.8 (s, 6H), 4.35
(m, 4H), 2.5±1.5 (m, 12H) ppm; 13C NMR (50 MHz, ꢁ, CF3CO2D): 117.34 (C-1), 128.10 (C-2),
119.25 (C-3), 152.33 (C-4), 120.70 (C-5), 140.33 (C-6), 126.36 (C-7), 128.77 (C-8), 170.63 (C-9),
44.74 (C-10), 120.30 (C-9a), 138.48 (C-4a), 146.86 (C-10a), 117.75 (C-8a), 72.84 (CH2-ꢀ), 30.79
(CH2-ꢂ), 30.56 (CH2-ꢃ), 27.78 (CH2-ꢁ) ppm.
General procedure for the preparation of 4,40-(a00,!00-dioxaalkyl)-bis-(acridin-9(10H)-ones)
12, 13, and 14
A mixture of 2.11 g 4-hydroxyacridin-9(10H)-one (1, 10 mmol), 1.14 g TEBAC (5 mmol), 50 ml 50%
aqueous potassium hydroxide, 100 ml toluene, and 6 mmol ꢀ,!-dibromoalkane was re¯uxed for 4 h.
The resulting viscous product solidi®es when poured into water. The precipitate was ®ltered, dried,
and crystallized from ethanol.
4,40-(100,600-Dioxahexyl)-bis-(acridin-9(10H)-one) (12; C30H24N2O4)
1
Yield: 50%; m.p.: >260ꢀC; H NMR (200 MHz, ꢁ, CF3CO2D): 8.9±7.3 (m, 14H), 4.5 (m, 4H), 2.4
(m, 4H) ppm; 13C NMR (50 MHz, ꢁ, CF3CO2D): 116.54 (C-1), 129.06 (C-2), 117.00 (C-3), 149.31
(C-4), 120.93 (C-5), 140.05 (C-6), 125.88 (C-7), 128.60 (C-8), 171.31 (C-9), 117.83 (C-9a), 135.22
(C-4a), 142.41 (C-10a), 117.58 (C-8a), 71.72 (CH2-ꢀ), 27.12 (CH2-ꢂ) ppm.
4,40-(1,4,7-Trioxaheptyl)-bis-(acridin-9(10H)-one) (13; C30H24N2O5)
Yield: 33%; m.p.: >260ꢀC; 1H NMR (200 MHz, ꢁ, CF3CO2D): 8.9±7.3 (m, 14H), 4.6 (m, 8H) ppm;
13C NMR (50 MHz, ꢁ, CF3CO2D): 117.08 (C-1), 128.80 (C-2), 117.33 (C-3), 148.67 (C-4), 120.70
(C-5), 139.76 (C-6), 125.85 (C-7), 128.11 (C-8), 171.40 (C-9), 117.33 (C-9a), 134.75 (C-4a), 142.18
(C-10a), 117.33 (C-8a), 70.94 (CH2-ꢀ), 69.62 (CH2-ꢂ) ppm.
4,40-(1,4,7,10-Tetraoxadecyl)-bis-(acridin-9(10H)-one) (14; C32H28N2O6)
Yield: 20%; m.p.: 170ꢀC; 1H NMR (200 MHz, ꢁ, CF3CO2D): 9.0±7.5 (m, 14H), 4.6 (m, 12H) ppm;
13C NMR (50 MHz, ꢁ, CF3CO2D): 117.00 (C-1), 128.75 (C-2), 117.30 (C-3), 148.61 (C-4), 120.70
(C-5), 139.83 (C-6), 125.82 (C-7), 128.05 (C-8), 171.15 (C-9), 117.76 (C-9a), 134.70 (C-4a), 142.05
(C-10a), 117.30 (C-8a), 71.70 (CH2-ꢀ), 69.80 (CH2-ꢂ), 71.20 (CH2-ꢃ) ppm.

1204
J.-P. Galy et al.
General procedure for the preparation of 9,90-(ꢀ00,!00-dithiaalkyl)-bis-(4-hydroxyacridines)
15, 16, and 17
A mixture of 1.9 g 4-hydroxyacridine-9(10H)-thione (2, 8.3 mmol), 0.8 g TEBAC (3.5 mmol), 85 ml
50% aqueous potassium hydroxide, 165 ml toluene, and 5 mmol ꢀ,!-dibromoalkane was re¯uxed for
5 h. The resulting viscous product solidi®es when poured into water. The precipitate was ®ltered,
dried, and washed with hot methanol.
9,90-(100,600-Dithiahexyl)-bis-(4-hydroxyacridine) (15; C32H28N2O2S2)
1
Yield: 80%; m.p.: 167ꢀC; H NMR (200 MHz, ꢁ, CF3CO2D): 9.3±7.7 (m, 14H), 3.6±3.1 (m, 4H),
2.0±1.2 (m, 8H) ppm; 13C NMR (50 MHz, ꢁ, CF3CO2D): 120.73 (C-1), 130.85 (C-2), 122.13
(C-3), 147.65 (C-4), 121.53 (C-5), 140.12 (C-6), 130.15 (C-7), 130.85 (C-8), 167.19 (C-9), 132.75
(C-9a), 133.88 (C-4a), 139.77 (C-10a), 131.52 (C-8a), 42.13 (CH2-ꢀ), 32.17 (CH2-ꢂ), 29.69
(CH2-ꢃ) ppm.
9,90-(100,800-Dithiaoctyl)-bis-(4-hydroxyacridine) (16; C34H32N2O2S2)
1
Yield: 90%; m.p.: >300ꢀC; H NMR (200 MHz, ꢁ, CF3CO2D): 9.3±7.4 (m, 14H), 3.6±3.1 (m, 4H),
2.0±1.1 (m, 12H) ppm; 13C NMR (50 MHz, ꢁ, CF3CO2D): 120.38 (C-1), 130.51 (C-2), 121.80 (C-3),
147.44 (C-4), 120.94 (C-5), 139.75 (C-6), 130.00 (C-7), 130.51 (C-8), 166.83 (C-9), 131.75 (C-9a),
133.37 (C-4a), 140.50 (C-10a), 131.42 (C-8a), 42.21 (CH2-ꢀ), 31.76 (CH2-ꢂ), 29.98 (CH2-ꢃ), 29.65
(CH2-ꢁ) ppm.
9,90-(100,900-Dithianonyl)-bis-(4-hydroxyacridine) (17; C35H34N2O2S2)
1
Yield: 70%; m.p.: >300ꢀC; H NMR (200 MHz, ꢁ, CF3CO2D): 9.3±7.4 (m, 14H), 3.6±3.1 (m, 4H),
2.0±1.0 (m, 14H) ppm; 13C NMR (50 MHz, ꢁ, CF3CO2D): 120.53 (C-1), 130.58 (C-2), 121.82 (C-3),
147.39 (C-4), 121.47 (C-5), 139.98 (C-6), 130.15 (C-7), 130.58 (C-8), 167.75 (C-9), 132.01 (C-9a),
133.48 (C-4a), 139.48 (C-10a), 131.34 (C-8a), 42.47 (CH2-ꢀ), 32.17 (CH2-ꢂ), 30.62 (CH2-ꢃ), 30.31
(CH2-ꢁ), 29.94 (CH2-") ppm.
9,90-(100,600-dithiahexyl)-bis-(4-methoxyacridine) (18; C34H32N2O2S2)
A mixture of 1.14 g 4-methoxy-10-acridine-9(10H)-thione (4,5 mmol), 50 ml 50% aqueous
potassium hydroxide, 100 ml toluene, and 0.77 ml 1,6-dibromohexane (1.22 g, 6 mmol) was re¯uxed
for 3 h. The residual viscous product was separated, and the organic layer was evaporated in vacuo.
The residue from evaporation was poured into water. The precipitate thus obtained and the viscous
1
residue (identical by H NMR) were mixed, washed with warm ether, and dried.
1
Yield: 70%; m.p.: 138ꢀC; H NMR (200 MHz, ꢁ, CF3CO2D): 8.9±7.4 (m, 14H), 2.85 (s, 6H),
2.8 (m, 4H) 1.50 (m, 2H), 1.35 (m, 6H) ppm; 13C NMR (50 MHz, ꢁ, CF3CO2D): 119.86 (C-1),
130.93 (C-2), 120.44 (C-3), 152.08 (-C4), 121.25 (C-5), 140.23 (C-6), 130.09 (C-7), 130.77 (C-8),
166.88 (C-9), 132.04 (C-9a), 132.67 (C-4a), 139.56 (C-10a), 131.48 (C-8a), 42.15 (CH2-ꢀ), 32.18
(CH2-ꢂ), 29.70 (CH2-ꢃ), 57.58 (OCH3) ppm.
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Synthesis of Bis-acridine Derivatives
1205
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Received April 15, 1998. Accepted (revised) June 22, 1998