Influence of the reaction conditions in the N-alkylation of acridone-2-Carboxylic acids

Article abstract of DOI:10.1081/SCC-100104467

The synthesis and a study about the influence of the solvent in the alkylation reaction of 2-Carboxy-6-chloro-9(10H) acridone (3b) and 2-Carboxy-6-chloro-7-nitro-9(10H) acridone (3a) was done, obtaining the N-ethyl ester derivative of the alkylated produc

Full text of DOI:10.1081/SCC-100104467

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INFLUENCE OF THE REACTION CONDITIONS IN THE N-
ALKYLATION OF ACRIDONE-2-CARBOXYLIC ACIDS
Lisbet Xuárez Marill , Rolando F. Pellón Comdom & Miriam Mesa Hernández
Published online: 09 Nov 2006.
To cite this article: Lisbet Xuárez Marill , Rolando F. Pellón Comdom & Miriam Mesa Hernández (2001) INFLUENCE OF
THE REACTION CONDITIONS IN THE N-ALKYLATION OF ACRIDONE-2-CARBOXYLIC ACIDS, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:14, 2159-2167, DOI: 10.1081/
SCC-100104467
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SYNTHETIC COMMUNICATIONS, 31(14), 2159–2167 (2001)
INFLUENCE OF THE REACTION
CONDITIONS IN THE N-ALKYLATION OF
ACRIDONE-2-CARBOXYLIC ACIDS
Lisbet Xuarez Marill, Rolando F. Pellon Comdom,*
and Miriam Mesa Hernandez
Centre of Pharmaceutical Chemistry, P.O. Box 16042
Havana, Cuba
ABSTRACT
The synthesis and a study about the influence of the solvent in
the alkylation reaction of 2-Carboxy-6-chloro-9(10H) acri-
done (3b) and 2-Carboxy-6-chloro-7-nitro-9(10H) acridone
(3a) was done, obtaining the N-ethyl ester derivative of the
alkylated products. Using the liquid-liquid phase transfer cat-
alysis only the N-alkylated derivative was obtained in both
cases with an improved yield.
Various N-alkylated derivatives of acridone have been described as
antiallergic,1–3 antiviral4–8 and anticancer9–12 compounds. As a part of
our investigations in acridone derivatives we were interested in the synthesis
of a new 2-Carboxy-6-chloro-7-nitro-9(10H) acridone (3a) and the corre-
sponding N-ethyl alkylated derivative.
The alkylation of acridones has been reported in several studies,13–15
alkylation of acridones-2-carboxylic acids using organic solvents was
reported by Gorving,2 but the alkylation of these derivatives using phase
* Corresponding author. Fax: (537) 336471; E-mail: cqf@infomed.sld.cu
2159
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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XUAREZ MARILL, PELLON COMDOM, AND MESA HERNANDEZ
transfer catalysis conditions has not been reported. The purpose of this
paper is to present the influence of the reaction conditions in the alkylation
of 2-Carboxy-6-chloro-9(10H) acridone and 2-Carboxy-6-chloro-7-nitro-
9(10H) acridone.
RESULTS AND DISCUSSION
The synthetic route to the obtention of 2-carboxy-6-chloro-7-nitro-
9(10H) acridone is outlined in Scheme I.
Scheme I.
2,4-Dichloro-5-nitrobenzoic acid (1a) was prepared by the procedure
described in literature16 from 2,4-Dichlorobenzoic acid. The 2,4-Dichloro-5-
nitro-benzoic acid (1a) obtained was condensed with p-aminobenzoic acid
under conditions previously reported17 using DMF as solvent to give the
2[(4-Carboxyphenyl)amino] 5-chloro-4-nitro benzoic acid (2a) which was
cyclized to the required 2-Carboxy-6-chloro-7-nitro-9(10-H) acridone (3a)
with sulphuric acid in one hour reaction time. 2-Carboxy-6-chloro-9(10-H)
acridone (3b) and 2-Methyl-6-chloro-9(10-H) acridone (3c) were prepared
similarly from the corresponding acids (2b) and (2c). The methyl derivative

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2161
(3c) was oxidised with KMNO4 using solid-liquid phase transfer catalysis in
presence of 18-crown-6 as catalyst, yielding the corresponding acridone (3b).
The nitration of 2-Carboxy-6-chloro-9(10-H) acridone (3b) using conc.
HNO3 at 40–50ꢀC yielded (3a).
In order to obtain the alkylated compounds (Scheme II), first we used
ethanol as protic solvent for the alkylation of 3b with ethyl bromide in
presence of potassium carbonate at 50ꢀC during three hours no reaction
occurred and only 10% yield was obtained after seven hours reaction time of
the corresponding 2-Carboxy-6-chloro-9(10ethyl) acridone ethyl ester (4b).
Scheme II.
To avoid the solvating of a protic solvent, we performed the reaction
using DMF as solvent in presence of potassium carbonate during three
hours at 50ꢀC to obtain the N-alkylated ethyl ester (4b) as the only reaction
product in 67% yield.
When the alkylation reaction was done employing the 7-NO2 (3a)
derivative using condition previously reported in DMF, the corresponding
2-Carboxy-6-chloro-7-nitro-10-(ethyl) acridone ethyl ester (4a) was obtained
in 79% yield.
The presence of protic solvents reduces the acridones reactivity
because of the formation of intramolecular hydrogen bonding. This does
not occurs using DMF as solvent, in this case the compound is free to react
with the electrophylic reagent.
The resultant ethyl ester (4a) and (4b) were base hydrolysed using 2N
potassium hydroxide solution to give N-ethyl acridone-2-carboxylic acids
(5a) and (5b).

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XUAREZ MARILL, PELLON COMDOM, AND MESA HERNANDEZ
The alkylation reaction of 3a and 3b used liquid-liquid phase transfer
catalysis, triethylbenzylammonium chloride (TEBAC) as PTC catalyst, the
liquid phase was sodium hydroxide solution (50%) and butanone, the alkyl
derivative employed was ethyl bromide and the reaction time 2 hours
obtaining the 10-ethyl acridiones 5a and 5b in 86% and 88% respectively
as the only reaction product.
EXPERIMENTAL
All solvents were destilled prior to use from an appropriate drying
agent. Melting point were determined with a hot stage apparatus and are
uncorrected. Elemental analysis were performed within the department.
Infrared spectra were recorded as KBr pellets on a Philips PU 9512 spectro-
meter and expressed in cmꢁ1. Mass spectra were recorded on a Quadrupolar
1
Mass Fisions Instrument TRIO 1000 spectrometer. The H and 13C NMR
spectra were recorder using DMSO-d6 as solvent with tetramethylsilane
(TMS) as an internal standard on a Bruker A 250 Z NMR spectrometer.
The chemical shifts are reported in parts per million (d ppm). Compound 2b
and 3b were reported by Gorving2 and compound 2c and 3c were reported
by Madgison and Grigooruski18 but no spectral data have been reported.
Verification and purity of these compounds were established by combustion
analysis and spectral data, using the instrumentation described above.
N-Phenylanthranilic Acid Derivatives, General Procedure
A mixture of benzoic acid (0.02 mol), amine (0.04 mol), potassium
carbonate (0.3 mol), copper powder (0.03 g) and DMF (60 mL) was heated
and stirred at reflux temperature for 2.5 hours. The reaction mixture was
added slowly to a 1:1 (H2O:HCl) solution (240 mL), the solid obtained was
filtered, washed with water and dissolved in a 1% sodium hydroxide sol-
ution (260 mL). The acid was precipitated with a (1:3) diluted acetic acid
(16 mL), filtered and crystallised to give the corresponding N-phenylanthra-
nilic acid.
2[(4-Carboxyphenyl) amino] 5-chloro-4-nitro benzoic acid (2a) was
recrystallyzed from acetic acid/water (1:3) to yield the pure acid as a
yellow solid (3g; 45%), mp 288–290ꢀC; IR(cmꢁ1): 3455.6(NH); 3087.2(OH
acid); 1685.7(C ¼ O); 1533.5(as NO2); 1324.0(sy NO2) and 767.2(C-Cl);
NMR-1H d: 6.95 (2H, dd, C6’-H and C2’-H); 7.40 (1H, m, C6-H), 8.0 (2H,
d, C3’-H and C5’-H); 8.65 (1H, s, C3-H), 10.5 (s, carboxylic acids); NMR-13C
d: 166.47 (C acid); 167.55 (C acid) ; 149.35 (C1); 142.19 (C1); 136.02 (C5);

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132.29 (C4); 130.94 (C6); 126.99 (C3); 121.92 (C3’y C5’); 119.11 (C4’); 115.62
(C2); 112.01 (C6’ and C2’); ME (m/z): 336 (Mþ). Analysis: C14H9ClN2O6
requires: C, 50.00; H, 2.68; N, 8.33; Cl, 10.56. Found: C, 49.85; H, 2.61;
N, 8.26; Cl, 10.47.
2[(4-Carboxyphenyl) amino] 5-chloro benzoic acid (2b) was recrystal-
lyzed from ethanol/water as a yellow product (4.08 g; 70%), mp:
284.0–284.2ꢀC. IR (cmꢁ1): 3400.5(NH); 3033(OH acid); 1677.8(C ¼ O);
766.6(C-Cl), NMR-1H d: 7.94 (2H, m, C6’-H and C2’-H); 7.35 (2H, m,
C4-H and C6-H); 6.73 (2H, dd, C3’-H, C5’-H); 10.0 (2H, s, carboxylic
acids). NMR-13C d: 166.66 (C acid); 168.81 (C acid); 146.02 (C1); 144.26
(C1’); 138.62 (C5); 133.52 (C3); 130.99 (C3’ and C5’); 124.55 (C6), 119.12
(C4’); 118,80 (C4); 114.37 (C2); 113.29 (C6’ and C2’). ME (m/z): 291(Mþ).
Analysis: C14H10ClNO4 requires: C, 57.70; H, 3.44; N, 4.81; Cl, 12.20.
Found: C, 57.35; H, 3.46; N, 4.70; Cl, 12.16.
2[(4-Methylphenyl) amino] 5-chloro benzoic acid (2c) was recrystallyzed
from acetic acid/water (1:3) to yield the pure acid as a yellow solid (2.6 g;
50%), mp: 226–228ꢀC. IR (cmꢁ1): 3336(NH); 3033(OH acid); 1677,8(C ¼ O);
748(C-Cl). NMR-1H d: 2.3 (3H, s, CH3), 6.74 (2H, dd, C6’-H and C2’-H),
6.95 (2H, d, C4-H and C6-H), 7.2 (2H, m, C3’-H and C5’-H), 7.88 (1H, d,
C3-H) and 13.2 (s, carboxylic acids). NMR-13C d: 169.24 (C acid); 149.05
(C1); 138.86 (C4,); 136.63 (C1’); 133.75 (C6); 133.58 (C3’ y C5’); 130.09 (C5);
123.25 (C3); 116.44 (C4); 111.92 (C2); 110.43 (C6’ and C2’) y 39.45 (C
methyl). EM (m/z): 261(Mþ). Analysis: C14H12ClNO2 requires: C, 64.20;
H, 4.58; N, 5.35; Cl, 13.57. Found: C, 64.17; H, 4.50; N, 5.38; Cl, 13.41.
Acridones, GeneralProcedure
A Mixture of the appropriate N-phenylanthranilic acid derivatives
obtained (2g) was heated in conc. sulphuric acid (10 mL) at 100ꢀC for one
hour to produce a fluorescent solution which was diluted with 100 mL of ice-
cold water. Solid product that separated was isolated by Buchner filtration
and suspended in boiling water (100 mL), filtered hot and dried in a vacuum
oven at 100ꢀC for one hour and purified by recrystallization.
2-Carboxy-6-chloro-7-nitro-9(10H) acridone (3a) was obtained as a
green solid (1.9 g; 94.6%), mp:> 350ꢀC. IR (cmꢁ1): 3672(NH), 3080 (OH
acid), 1728 (C ¼ O), 728 (C-Cl), 1532 (as NO2), 1332 (sy NO2). NMR-1H
d: 8.8 (1H, d, C8-H), 8.2 (1H, m C1-H), 7.6 (1H, d, C3-H), 7.4 (1H, s, C5-H),
7.3 (1H, dd, C4-H), NMR-13C d: 166.38 (C acid); 143.25 (C5a); 141.34 (C4a);
138.27 (C2); 133.38 (C3); 132.53 (C8); 128.31 (C6); 128.14 (C8a); 123.44 (C1a);
121.95 (C1); 119.72 (C7); 117.48 (C5); 116.42 (C4). ME (m/z): 318 (Mþ).

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XUAREZ MARILL, PELLON COMDOM, AND MESA HERNANDEZ
Analysis: C14H7CIN2O5: requries: C, 52.83; H, 2.20; N, 1.80; Cl, 11.16.
Found: C, 52.78; H, 1.98; N, 1.83; Cl, 11.24.
2-Carboxy-6-chloro-9(10H) acridone (3b) was obtained as a grey solid
(1.79 g; 95.6%), mp:> 350ꢀC. IR (cmꢁ1): 3628(NH), 3184(OH acid), 1776
(C ¼ O), 708 (C-Cl). NMR-1H d: 8.1 (1H, m, C1-H); 7.8 (s, 1H, C8-H), 7.6 (d,
1H, C3-H), 7.5 (d, 1H, C7-H), 6.8 (d, 1H, C5-H) and 6.7 (dd, 1H, C4-H).
NMR-13C d: 167.80 (C acid); 150.0 (C5a); 146.2 (C4a); 139.4 (C3); 134.7 (C6);
132.0 (C1); 131.6 (C8); 127.1 (C8a); 125.3 (C1a); 119.8 (C7); 118.0 (C4); 117.5
(C5) y 108.1 (C2). ME (m/z): 273 (Mþ) Analysis: C14H8ClNO3: requires: C,
61.64; H, 2.93; N, 5.10; Cl, 13.00. Found: C, 61.60; H, 2.98; N, 4.89; Cl,
12.90.
2-Methyl-6-chloro-9(10H) acridone (3c) was obtained as a yellow solid
(1.76 g; 95.0%), mp:> 350ꢀC. IR (cmꢁ1): 3264(NH),1652(C ¼ O), 2920(as
CH3), 2820(sy CH3). NMR-1H d: 8.2 (1H, d, C1-H), 8.0 (1H, s, C8-H), 7.4
(1H, m, C7-H), 7.3 (1H, d, C3-H), 7.2 (1H, d, C4-H), 7.0 (1H, s, C5-H) y 2.4
(3H, s, CH3). NMR-13C d: 171.20 (C ¼ O); 138.71 (C5a); 134.92 (C4a); 137.56
(C6); 130.50 (C1); 128.10 (C8); 123.70 (C7); 124.85 (C8a); 120.78 (C2); 118.80
(C1a); 117.11 (C4); 115.95 (C5) and 20.26 (C methyl). ME (m/z): 243 (Mþ).
Analysis C14H10ClNO: requires C, 68.90; H, 4.10; N, 5.75; Cl, 14.58. Found:
C, 68.71; H, 4.09; N, 5.75; Cl, 14.52.
2-Carboxy-6-chloro-9(10H) Acridone (3b) Obtained Oxidising (3c)
A mixture of potassium permanganate 3.16 g (0.02 mol), 6-chloro-
2methyl-9 (10H) acridone (3c, 2.43 g, 0.01 mol), benzene (20 mL) and de
18-crown-6 (0.073 g) was stirred and heated to reflux for three hours and
then cooled to room temperature. A 1% sodium hydroxide solution (20 mL)
was added and the mixture heated and stirred for one hour. The aqueous
layer is acidified using diluted HCl:H2O (1:1) and the precipitated product
filtered and identified as 2-carboxy-6-chloro-9(10-H) acridone (3b) (2.05;
75%).
2-Carboxy-6-chloro-7-nitro-9(10H) Acridone. Nitration of (3b)
A mixture of 2-carboxy-6-chloro-9(10H) acridone (3b, 2.0 g) and 70% nitric
acid (10 mL) was heated in a water bath to 40–50ꢀC stirred for two hours at
room temperature. The reaction mixture was then poured into water
(120 mL), the resulting precipitated was recovered in a 5% Na2CO3 sol-
ution. Concentration of the solution gave a solid which was filtered and

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2165
redisolved in water (70 mL). The solution was acidified and dried to yield
40% of 2-carboxy-6-chloro-7-NO2-9 (10-H) acridone.
Acridone Alkylation (using solvent)
A mixture of acridone (0.01 mol), potassium carbonate (0.03 mol),
ethyl bromide (0.8 mL) in appropriated solvent (20 mL) was stirred with
heating for three hours at 50ꢀC. The reaction mixture was added slowly
to a diluted HCl solution, the solid obtained was filtered and washed with
water, crystallised from ethanol and dried in a vacuum oven at 100ꢀC.
Acridone Alkylation (using PTC)
A mixture of acridone (0.01 mol), 50% sodium hydroxide solution,
triethylbenzylammonium chloride 0.08 g, ethyl bromide 0.8 mL and buta-
none 20 mL was heated and stirred to reflux two hours. The organic layer
was separated and dried with anhydrous sodium sulphate. The organic layer
is rotoevaporated, the solid obtained is dissolved in water and precipitated
with a 1:1 hydrochloric acid:water solution obtaining the corresponding 2-
carboxy-N-ethyl acridones.
2-Carboxy-6-chloro-9(10ethyl) acridone ethyl ester (4b) was obtained as
a beige solid (2.20 g; 67,0%), mp: 202–204ꢀC. IR (cmꢁ1): 1460(C-H),
1712(C ¼ O), 1608, 1500(C ¼ C), 1225-950(C-H), 828(C-H), 728(C-Cl).
ME (m/z): 329 (Mþ). NMR-1H d: 8.2 (1H, d, C1-H); 8.3 (1H, d, C3-H);
7.8 (1H, s, C8-H); 6.9 (1H, d, C4-H); 6.7 (1H, s, C5-H). NMR-13C d: 149.8
(C5a); 146.25 (C4a); 135.4 (C6); 134.8 (C3); 132.4 (C8); 130.8 (C1); 129.5 (C7);
127.62 (C8a); 125.3 (C1a); 120.3 (C2); 118.0 (C5) y 117.8 (C4). Analysis:
C18H16NO3Cl: requires: C, 65.65; H, 4.86; N, 4.25; Cl, 10.79. Found: C,
65.40; H, 4.29; N, 4.74; Cl, 10.60.
2-Carboxy-6-chloro-7-nitro-9(10ethyl) acridone ethyl ester (4a) was
obtained as a brown solid (2.95 g; 79%), mp: 199–200ꢀC, IR (cmꢁ1):
1734(C ¼ O), 1652(C ¼ O), 1596(as NO2), 1352(sy NO2), 2920 and 2818
(CH3). NMR-1H d: 8.45 (C8-H); 8.23 (C1-H); 8.0 (C3-H); 7,0 (C5-H); 6.65
(C4-H). NMR-13C d: 152.0 (C7); 149.2 (C5a); 149.14 (C4a); 134.0 (C3); 132.1
(C1); 130.2 (C6); 127.9 (C8a); 127.5 (C8); 126.2 (C1a); 120.5 (C2); 119.0 (C5) y
117.2 (C4). ME (m/z): 374(Mþ). Analysis: C18H15N2O5Cl: requires C, 57.67;
H, 4.01; N, 7.49; Cl, 9.49. Found: C, 54.41; H, 4.12; N, 7.52; Cl, 9.54.
2-Carboxy-6-chloro-9(10ethyl) acridone (5b) was obtained as a cream
solid (2.63 g; 87.5%), mp: 201–203ꢀC. IR (cmꢁ1): 2936 (OH acid), 1460
(C ¼ C), 1732(C ¼ O), 1668(C ¼ O), 728(C-Cl). NMR-1H d: 11.0 (1H, d, H

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XUAREZ MARILL, PELLON COMDOM, AND MESA HERNANDEZ
acid); 8.3 (1H, d, C1-H); 8.0 (1H, s, C3-H); 7.5 (1H, s, C5-H); 7.3 (1H, d, C5-
H); 7.0 (1H, d, C7-H); 6.7 (1H, s, C5-H). NMR-13C d: 150.0 (C5a); 146.0
(C4a); 135.32 (C6); 134.65 (C3); 132.62 (C1); 132.3 (C8); 129.7 (C7); 127.9
(C8a); 125.1 (C1a); 120.1 (C2); 118.2 (C5) and 117.4 (C4). ME (m/z): 301 (Mþ)
Analysis: C16H12NO3Cl: C, 63.79; H, 3.99; N, 4.65; Cl, 11.79. Found: C,
63.41; H, 4.10; N, 4.74; Cl, 12.04.
2-Carboxy-6-chloro-7-nitro-9-(10ethyl) acridone (5a) was obtained as a
green solid (2.79 g; 85.9%), mp: >350ꢀC. IR (cmꢁ1): 2928 (OH acid),
1460(C ¼ C), 1688(C ¼ O), 1652 (C ¼ O), 1546 and 1352 NO2, 728(C-Cl).
NMN-1H d: 12.0 (H acid); 8.5 (1H, d, C1-H); 8.3 (1H, d, C3-H); 8.0 (1H,
d, C7-H); 7.1 (1H, s, C5-H); 7.0 (1H, d, C4-H). NMR-13C d: 152.2 (C5a);
151.5 (C4a); 148.0 (C7); 134.7 (C3); 132.50 (C1); 130.6 (C6); 127.8 (C8a); 127.1
(C8); 126.0 (C1a); 119.7 (C2); 119.3 (C5) y 117.4 (C4). ME (m/z): 346 (Mþ).
Analysis: C15H11N2O5Cl: C, 52.02; H, 3.18; N, 8.09; Cl, 10.26. Found: C,
52.21; H, 3.30; N, 8.24; Cl, 10.30.
CONCLUSIONS
In the synthesis of N-alkyl derivatives of acridones 2-carboxylic acids
the best results were obtained using PTC conditions.
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Received in the USA October 19, 2000

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