Synthesis of new 9-(N-substituted)-acridinamines bearing a pendant polymerizable side chain

Article abstract of DOI:10.1081/SCC-200050363

Five new 9-(N-substituted)-acridinamines (7-11), have been synthesized from allyl 4-(9-chloro-7-methoxy-2-acridinyl)-butanoate (6). The structure of these new acridine derivatives was determined using and ¹H, ¹³C, and 2D nuclear magn

Full text of DOI:10.1081/SCC-200050363

This article was downloaded by: [Florida Atlantic University]
On: 28 August 2013, At: 03:25
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of New
9‐(N‐Substituted)‐Acridinamines Bearing a
Pendant Polymerizable Side Chain
Gabriel Roubaud a , Sebastien Billeau a , Robert Faure a , Maxime Robin a &
Jean‐Pierre Galy a
a UMR CNRS 6178 Symbio, Laboratoire de Valorisation de la Chimie Fine,
Faculté des Sciences et Techniques de Saint Jérôme, Université Paul
Cézanne, Marseille, Cedex 3, France
Published online: 20 Aug 2006.
To cite this article: Gabriel Roubaud , Sebastien Billeau , Robert Faure , Maxime Robin & JeanPierre Galy
(2005) Synthesis of New 9‐(N‐Substituted)‐Acridinamines Bearing a Pendant Polymerizable Side Chain,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
35:5, 683-692, DOI: 10.1081/SCC-200050363
To link to this article: http://dx.doi.org/10.1081/SCC-200050363
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 35: 683–692, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200050363
Synthesis of New 9-(N-Substituted)-
Acridinamines Bearing a Pendant
Polymerizable Side Chain
Gabriel Roubaud, Sebastien Billeau, Robert Faure,
Maxime Robin, and Jean-Pierre Galy
UMR CNRS 6178 Symbio, Laboratoire de Valorisation de la Chimie Fine,
´ ´ ˆ ´
Faculte des Sciences et Techniques de Saint Jerome, Universite Paul
´
Cezanne, Marseille Cedex 3, France
Abstract: Five new 9-(N-substituted)-acridinamines (7–11), have been synthesized
from allyl 4-(9-chloro-7-methoxy-2-acridinyl)-butanoate (6). The structure of these
new acridine derivatives was determined using and 1H, 13C, and 2D nuclear
magnetic resonance (NMR) spectroscopy.
Keywords: Acridine, N-alkylation, 2D NMR spectroscopy, polymer
INTRODUCTION
N-substitued-9-acridinamine derivatives, which have been extensively studied
in clinical medicine as potential anti-tumor agents,[1] also show an array of bio-
logical activities such as anti-inflammatory, anti-Alzheimer’s, anti-HIV, and
cystostatic activity.[2–6] Recently, these compounds were also used as fluor-
escent agents[7] for synthetic fibers and DNA-hybridization labeling.[8]
Acridones are poor water soluble compounds and don’t have a good biodispon-
ibility. It is known that more than 95% of all new potential therapeutics have
poor pharmacokinetics and biopharmaceuticals properties.[9] The emergence
Received in Poland 25 October 2004
Address correspondence to Maxime Robin, Universite Paul Cezanne, Av.
Escadrille Normandie-Niemen, Marseille, Cedex 3 13397, France. E-mail: maxime.
robin@univ.u-3mrs.fr

684
G. Roubaud et al.
of new techniques in drug delivery in the development of pharmaceutical
compounds[10] had led us to prepare new acridine derivatives ready to be intro-
duced in a biocompatible and nontoxic polymer (i.e., lactic-co-glycolic).
In the course of preparing novel acridinamines as candidates for pharmaco-
logical evaluation, we have recently published the preparation and NMR spectral
data of such compounds.[11–14] In this paper, we present the synthesis of new
N-substituted-9-acridinamine derivatives with a pendant polymerizable side
chain for further studies on polymers with biological activities (Figure 1).
Condensation of 2-bromo-5-methoxybenzoic acid (1) with methyl 4-(4-
aminophenyl)butanoate (2) using Ullmann conditions[15] gives 5-methoxy-
2-[4-(4-methoxy-4-oxobutyl)anilino]benzoic acid (3). Compound (3) was
then cyclized with phosphorus oxide chloride[16] to afford methyl 4-(9-
chloro-7-methoxy-2-acridinyl)butanoate (4). The acid compound (5) was
obtained by deprotection of the ester function[17] in a mixture of NaOH/
EtOH and was then converted to (6) using phase transfer catalyst and allyl
bromide (Scheme 1).
Compound (6) was used as starting material for the synthesis of the
desired N-9-acridinamine derivatives (7–11). Using the same experimental
conditions by solubilizing (6) in phenol at 808C under nitrogen atmosphere
and the introduction of a solution of the desired amino compound in triethyl-
amine, we obtained 7–11 with good yields (54%, 62%, 62%, 52%, 53%
respectively) as described in Scheme 2.
All these compounds were characterized using nuclear magnetic
resonance (NMR) spectroscopy. The 1H and 13C chemical shifts were unequi-
vocally assigned from the concerted use of one- and two-dimensional NMR
techniques including gs-COSY,[18] gs-HMQC[19], and gs-HMBC.[20] N-Alky-
laminoacridine derivatives can exist in at least three tautomeric forms owing
to the intramolecular transfer of the amino proton Ha as shown in Scheme 3.
At room temperature the shielding of the C-4, C-4a, C-5, and C-5a reson-
ances[21] was indicative of an amino-imino tautomerism shifted towards the
imino tautomers, with the exception of (8) in which tautomerism is shifted
towards the amino form as a consequence of intramolecular bond formation
(Figure 2).
This pseudo supplementary 6-member ring at position 9 could confer to
this product a potent antitumor activity as 9-anilinoacridine. Polymerization
of these compounds are under investigation by ultraviolet (UV) flash
Figure 1.

Synthesis of New 9-(N-Substituted)-Acridinamines
685
Scheme 1. Reagents: (a) K2CO3, Cu, DME, Ultrasonic irradiations, 808C, 2 h; (b)
POCl3, reflux 2 h; (c) EtOH/NaOH, 1208C, 2 h; (d) TBAHS, NaOH, Allylbromide,
Toluene, reflux 2 h.
polymerization (data not presented) in order to compare the biological activi-
ties of biopolymers and native compounds.
EXPERIMENTAL
4-(4-Amino-phenyl)-butyric acid and 2-bromo-5-methoxybenzoic acid were
obtained from commercial suppliers. Methyl 4-(4-amino-phenyl)-butanoate
was prepared according to reported procedure.[22] All reagents and solvents
were used as supplied. The NMR spectra were measured on a Bru¨ker
Avance DRX 500 spectrometer equipped with a Bru¨ker CryoPlatform and a
5 mm cryo TXI probe. For two-dimensional experiments, Bru¨ker micropro-
grams using gradient selection (gs) were applied. In all cases tetramethylsilane
(TMS) was used as an internal standard. Separations by chromatography were
performed on silica gel (Merck, 70–230 mesh). Melting points were deter-
mined on an Electrothermal 9300 apparatus and were uncorrected.
5-Methoxy-2-[4-(4-methoxy-4-oxobutyl)anilino]-benzoic Acid (3)
Methyl 4-(4-amino-phenyl)-butanoate (5 g, 2.6 mmol) (2), 2-bromo-5-
methoxy-benzoic acid (5 g, 2.3 mmol) (1), anhydrous potassium carbonate

686
G. Roubaud et al.
Scheme 2. Reagents: (a) Phenol, 808C, 1 h, N2; then b-alanine ethylester, Et3N; (b)
Phenol, 808C, 1 h, N2; then b-alanine, Et3N; (c) Et3N, phenol, 2-aminoethanethiol
hydrochloride, 808C, 3 h, N2; (d) Et3N, phenol, S-benzyl-cysteamine hydrochloride,
808C, 3 h, N2; (e) Phenol, 808C, 1 h, N2; then 4,4-diethoxy-1-butanamine, Et3N.
(5 g, 36.5 mmol), powdered copper catalyst (0.2 g) and DME (80 mL) were
placed in a 250 mL round-bottomed flask. This mixture was stirred and
heated at 808C for 4 h. The solution was concentrated in vacuo, the green
residue stirred in hot water (200 mL), filtered, and the filtrate acidified to
pH 6 with 2N aqueous hydrochloric acid. The green precipitate was filtered
and washed with water to give a pure compound (3) without any further puri-
1
fication (4.1 g, yield 46%, mp 1328C, Mol. Wt.; 343). H NMR (DMSO-d6)
d: 1.77 (quint, 2H, J ¼ 7.2 Hz, H-12), 2.27 (t, 2H, J ¼ 7.2 Hz, H-13), 2.53
(t, 2H, J ¼ 7.2 Hz, H-13), 3.56 (s, 3H, H-15), 3.70 (s, 3H, OCH3), 7.07 (dd,
1H, J ¼ 8.1; 2.0 Hz, H-30), 7.08 (d, 1H, J ¼ 8.1 Hz, H-20), 7.09 (m, 2H, H-2

Synthesis of New 9-(N-Substituted)-Acridinamines
687
Scheme 3.
and H-6), 7.17 (m, 2H, H-3 and H-5), 7.39 (d, 1H, J ¼ 2.0 Hz, H-50). 13C NMR
(DMSO-d6) d: 26.46 (C-12), 32.84 (C-13), 33.83 (C-11), 51.25 (C-15), 55.50
(OCH3), 113.80 (C-60), 114.75 (C-20), 116.60 (C-50), 120.38 (C-2 and C-6),
121.95 (C-30), 129.41 (C-5 and C-3), 135.37 (C-4), 139.68 (C-1), 141.34
(C-10), 151.08 (C-40), 169.54 (C-70), 173.31 (C-14). Anal. Calcd. for
C19H21NO5: C, 66.46; H, 6.16; N, 4.08. Found: C, 66.12; H, 5.87; N, 3.81.
Methyl 4-(9-chloro-7-methoxy-2-acridinyl)butanoate (4)
Compound (3) (3g, 8.7 mmol) and POCl3 (30 mL, 330 mmol) were heated at
1208C for 2 h. The solution was allowed to cool to room temperature (rt).
The resulting red oil was poured onto ice (200g) and neutralized with 25%
aqueous NH4OH. The solid obtained was chromatographied over silica
gel. Elution of the column with a mixture (1:1) of ethyl acetate and CH2Cl2
gave (4) as a yellow powder (2.3g, yield 76%, mp 1158C, Mol. Wt.: 343).
1H NMR (CDCl3) d: 2.09 (quint, 2H, J ¼ 7.2 Hz, H-12), 2.40 (t, 2H,
J ¼ 7.2 Hz, H-13), 2.90 (t, 2H, J ¼ 7.2 Hz, H-11), 3.66 (s, 3H, H-15), 3.99
Figure 2.

688
G. Roubaud et al.
(s, 3H, OCH3), 7.44 (dd, 1H, J ¼ 8.9; 2.0 Hz, H-6), 7.46 (d, 1H, J ¼ 2.0 Hz, H-
8), 7.60 (dd, 1H, J ¼ 8.5; 1.2 Hz, H-3), 8.09 (brs, 1H, H-1), 8.11 (d, 1H,
J ¼ 8.5 Hz, H-4), 8.14 (d, 1H, J ¼ 8.9 Hz, H-5). 13C NMR (CDCl3) d: 25.92
(C-12), 33.34 (C-13), 35.50 (C-11), 51.53 (C-15), 55.67 (OCH3), 99.86 (C-8),
122.12 (C-1), 124.35 (C-9a), 125.36 (C-8a), 125.86 (C-6), 129.16 (C-4),
130.73 (C-3), 131.57 (C-5), 138.05 (C-9), 140.69 (C-2), 144.92 (C-10a),
145.65 (C-4a), 158.33 (C-7), 173.64 (C-14). Anal. Calcd. for C19H18ClNO3:
C, 66.38; H, 5.28; N, 4.07. Found: C, 66.07; H, 4.96; N, 3.81.
4-(9-Chloro-7-methoxy-2-acridinyl)butanoic Acid (5)
The ester (4) (1 g, 3.1 mmol) was dissolved in C2H5OH (70 mL) and 1 N
NaOH (30 mL). The mixture was heated at 1208C for 2 h. The reaction
mixture was quenched with 1 N HCl, diluted with water and extracted with
CH2Cl2 (100 mL) to give (5) as a yellow powder (0.65 g, yield 76%, mp
1
1708C, Mol. Wt.: 329). H NMR (CDCl3) d: 1.93 (quint, 2H, J ¼ 7.2 Hz,
H-12), 2.30 (t, 2H, J ¼ 7.2 Hz, H-13), 2.84 (t, 2H, J ¼ 7.2 Hz, H-11), 3.95
(s, 3H, OCH3), 7.37 (dd, 1H, J ¼ 8.8; 2.2 Hz, H-6), 7.48 (d, 1H, J ¼ 2.0 Hz,
H-8), 7.66 (dd, 1H, J ¼ 8.5; 1.2 Hz, H-3), 7.98 (d, 1H, J ¼ 1.2 Hz, H-1)
8.01 (d, 1H, J ¼ 8.5 Hz, H-4), 8.02 (d, 1H, J ¼ 8.8 Hz, H-5). 13C NMR
(CDCl3) d: 25.89 (C-12), 33.25 (C-13), 34.95 (C-11), 55.84 (OCH3), 99.59
(C-8), 121.34 (C-1), 123.66 (C-9a), 124.71 (C-8a), 125.53 (C-6), 129.75
(C-4), 131.58 (C-3), 131.58 (C-5), 136.00 (C-9), 141.62 (C-2), 145.12
(C-10a), 145.91 (C-4a), 158.14 (C-7), 174.43 (C-14). Anal. Calcd. for
C18H16ClNO3: C, 65.56; H, 4.89; N, 4.25. Found: C, 65.33; H, 4.59; N, 3.99.
Allyl 4-(9-chloro-7-methoxy-2-acridinyl)butanoate (6)
A mixture of (5) (1.5g, 4.6 mmol), allylbromide (2.3g, 19mmol), 0.85g of
TBAHS (tetrabutylammonium hydrogenosulfate), 38mL of sodium hydro-
xide 25% and 75mL of toluene were refluxed for 8 h with stirring. The
solution was extracted with toluene, the organic layer concentrated and the
residue was chromatographied on silica gel with CH2Cl2-AcOEt 4:1 to yield 6
1
as an orange solid (1.49g, yield 88%, mp 618C, Mol. Wt.: 369). H NMR
(CDCl3) d: 2.12 (quint, 2H, J ¼ 7.2 Hz, H-12), 2.44 (t, 2H, J ¼ 7.2 Hz, H-13),
2.91 (t, 2H, J ¼ 7.2 Hz, H-11), 4.00 (s, 3H, OCH3), 4.58 (dt, 2H, J ¼ 5.7;
1.5 Hz, H-15), 5.22 (dq, 1H, J ¼ 10.5; 1.5 Hz, H-17a), 5.30 (dq, 1H, J ¼ 17.2;
1.5 Hz, H-17b), 5.91 (ddt, 1H, J ¼ 17.2; 10.5; 5.7 Hz, H-16), 7.43 (dd, 1H,
J ¼ 8.9; 2.0 Hz, H-6), 7.47 (d, 1H, J ¼ 2.0 Hz, H-8), 7.58 (dd, 1H, J ¼ 8.5;
1.2 Hz, H-3), 8.09 (d, 1H, J ¼ 8.5 Hz, H-4), 8.10 (d, 1H, J ¼ 1.2 Hz, H-1),
8.10 (d, 1H, J ¼ 8.9 Hz, H-5). 13C NMR (CDCl3) d: 25.96 (C-12), 33.51
(C-13), 35.51 (C-11), 55.65 (OCH3), 65.11 (C-15), 99.80 (C-8), 118.31 (C-
17), 122.16 (C-1), 124.35 (C-9a), 125.32 (C-8a), 125.44 (C-6), 129.87 (C-4),

Synthesis of New 9-(N-Substituted)-Acridinamines
689
131.10 (C-3), 131.46 (C-5), 132.16 (C-16), 137.32 (C-9), 140.43 (C-2), 145.67
(C-10a), 146.39 (C-4a), 158.14 (C-7), 172.91 (C-14). Anal. Calcd. for
C21H20ClNO3: C, 68.20; H, 5.45; N, 3.79. Found: C, 67.95; H, 5.13; N, 3.56.
Allyl 4-f9-[(3-ethoxy-3-oxopropyl)amino]-7-methoxy-2-acridinylg
butanoate (7)
A mixture of compound (6) (0.5g, 1.1 mmol) and phenol (4g, 42mmol) was
heated at 808C under nitrogen for 1h. Then a solution of b-alanine ethyl ester
hydrochloride (0.5g, 3.3 mmol) in triethylamine (1.5mL) was added and the
reaction mixture stirred under nitrogen for 3 h at 808C. The oil was cooled to
room temperature and poured into diethyl ether (300 mL). The precipitate was
filtered, washed with water, dried, and chromatographied on silica gel with
CH2Cl2-C2H5OH 4:1 to yield 7 as an yellow powder (0.33 g, yield 54%, mp
1
1118C, Mol. Wt.: 450). H NMR (DMSO-d6) d: 1.05 (t, 3H, J ¼ 7.0 Hz, H-
22), 1.97 (quint, 2H, J ¼ 7.2 Hz, H-12), 2.42 (t, 2H, J ¼ 7.2 Hz, H-13), 2.84
(t, 2H, J ¼ 7.2 Hz, H-11), 3.03 (t, 2H, J ¼ 7.1 Hz, H-19), 3.98 (s, 3H, OCH3),
4.00 (q, 2H, J ¼ 7.0 Hz, H-21), 4.39 (q, 2H, J ¼ 7.0 Hz, H-18), 4.54 (dt, 2H,
J ¼ 5.7; 1.5 Hz, H-15), 5.21 (dq, 1H, J ¼ 10.5; 1.4 Hz, H-17a), 5.29 (dq, 1H,
J ¼ 17.2; 1.5 Hz, H-17b), 5.91 (ddt, 1H, J ¼ 17.3; 10.5; 5.8 Hz, H-16), 7.70
(dd, 1H, J ¼ 9.0; 2.1 Hz, H-6), 7.85 (brd, 1H, J ¼ 8.6 Hz, H-3), 7.93 (d, 1H,
J ¼ 8.6 Hz, H-4), 7.95 (d, 1H, J ¼ 9.0 Hz, H-5), 7.96 (d, 1H, J ¼ 2.0 Hz, H-8),
8.30 (brs, 1H, H-1), 9.48 (brs, 1H, NH).13C NMR (DMSO-d6) d: 14.03 (C-22),
26.12 (C-12), 32.96 (C-13), 34.03 (C-19), 34.35 (C-11), 44.88 (C-18), 56.36
(OCH3), 60.41 (C-21), 64.52 (C-15), 103.89 (C-8), 112.03 (C-9a), 113.91 (C-
8a), 117.93 (C-17), 119.16 (C-4), 120.79 (C-5), 124.25 (C-1), 127.13 (C-6),
132.91 (C-16), 134.85 (C-10a),135.83 (C-3), 136.79 (C-2), 138.19 (C-4a),
155.61 (C-7), 170.79 (C-20), 172.45 (C-14). Anal. Calcd. for C26H30N2O5: C,
69.31; H, 6.71; N, 6.22. Found: C, 69.02; H, 6.52; N, 6.96.
N-f2-[4-(Allyloxy)-4-oxobutyl]-7-methoxy-9-acridinylg-b-alanine (8)
Following the procedure described for (7), compound (6) (0.5g, 1.1 mmol),
phenol (2g, 21mmol), and b-alanine (0.5g, 5.6 mmol) afforded a yellow solid
1
(8) (0.37 g, yield 62%, mp 1328C, Mol. Wt.: 450). H NMR (DMSO-d6) d:
1.95 (quint, 2H, J ¼ 7.2 Hz, H-12), 2.39 (t, 2H, J ¼ 7.2 Hz, H-13), 2.65 (t, 2H,
J ¼ 7.1 Hz, H-19), 2.78 (t, 2H, J ¼ 7.2 Hz, H- 11), 3.92 (s, 3H, OCH3), 3.94
(q, 2H, J ¼ 7.0 Hz, H-18), 4.52 (dt, 2H, J ¼ 5.7; 1.5 Hz, H-15), 5.18 (dq, 1H,
J ¼ 10.5; 1.4 Hz, H-17a), 5.27 (dq, 1H, J ¼ 17.2; 1.5 Hz, H-17b), 5.89 (ddt,
1H, J ¼ 17.3; 10.5; 5.8 Hz, H-16), 7.40 (dd, 1H, J ¼ 9.0; 2.1 Hz, H-6), 7.55
(brd, 1H, J ¼ 8.6 Hz, H-3), 7.65 (d, 1H, J ¼ 2.0 Hz, H-8), 7.82 (d, 1H,
J ¼ 8.6 Hz, H-4), 7.83 (d, 1H, J ¼ 9.0 Hz, H-5), 8.12 (brs, 1H, H-1). 13C NMR
(DMSO-d6) d: 26.15 (C-12), 33.05 (C- 13), 34.75 (C-19), 35.37 (C-11), 45.80

690
G. Roubaud et al.
(C-18), 55.78 (OCH3), 64.50 (C-15), 101.42(C-8), 116.54(C-9a), 117.55 (C-8a),
117.91 (C-17), 122.52 (C-6), 124.34 (C-1), 126.79 (C-4), 128.36 (C-5), 131.69
(C-3), 132.95 (C-16), 135.83 (C-3), 136.28 (C-2), 142.78 (C-10a), 144.71 (C-
4a), 155.29 (C-7), 172.53 (C-14), 173.54 (C-20). Anal. Calcd. for
C24H26N2O5: C, 68.23; H, 6.20; N, 6.63. Found: C, 67.96; H, 5.98; N, 6.31.
Allyl 4-f7-methoxy-9-[(2-sulfanylethyl)amino]-2-acridinylg
butanoate (9)
A mixture of compound (6) (0.5 g, 1.1 mmol), triethylamine (1.5 mL), 2-amino-
ethanethiol hydrochloride (0.5 g, 4.4 mmol), and phenol (4 g, 42 mmol) was
heated at 808C for 3 h under nitrogen. The oil was cooled to room temperature
and poured into diethyl ether (200 mL). The precipitate was filtered and washed
with aceton to provide a red powder (9) (0.29 g, yield 62%, mp 1888C, Mol.
1
Wt.: 410). H NMR (DMSO-d6) d: 1.89 (quint, 2H, J ¼ 7.2 Hz, H-12), 2.34
(t, 2H, J ¼ 7.2 Hz, H-13), 2.72 (t, 2H, J ¼ 7.2 Hz, H-11), 3.29 (t, 2H,
J ¼ 7.1 Hz, H-19), 3.88 (s, 3H, OCH3), 4.31 (t, 2H, J ¼ 7.0 Hz, H-18), 4.48 (dt,
2H, J ¼ 5.7; 1.5 Hz, H-15),), 5.15 (dq, 1H, J ¼ 10.5; 1.4 Hz, H-17a), 5.23 (dq,
1H, J ¼ 17.2; 1.5 Hz, H-17b), 5.85 (ddt, 1H, J ¼ 17.3; 10.5; 5.8 Hz, H-16), 7.56
(dd, 1H, J ¼ 9.0; 2.1 Hz, H-6), 7.72 (brd, 1H, J ¼ 8.6 Hz, H-3), 7.83 (d, 1H,
J ¼ 8.6 Hz, H-4), 7.88 (d, 1H, J ¼ 9.0 Hz, H-5), 7.89 (d, 1H, J ¼ 2.0 Hz, H-5),
8.18 (brs, 1H, H-1). 13C NMR (DMSO-d6) d: 26.08 (C-12), 32.96 (C-13), 34.33
(C-11), 37.06 (C-19), 47.91 (C-18), 56.46 (OCH3), 64.48 (C-15), 103.25 (C-8),
111.92 (C-9a), 114.11 (C-8a), 117.87 (C-17), 119.76 (C-4), 121.27 (C-5),
123.83 (C-1), 126.67 (C-6), 132.83 (C-16), 135.15 (C-3), 135.15 (C-10a),
136.54 (C-2), 138.60 (C-4a), 155.53 (C-7), 172.37 (C-14). Anal. Calcd. for
C23H26N2O3S: C, 67.29; H, 6.38; N, 6.82. Found: C, 67.01; H, 6.07; N, 6.55.
Allyl 4-(9-f[2-(benzylsulfanyl)ethyl]aminog-7-methoxy-2-acridinyl)-
butanoate (10)
Following the procedure described for (9), compound (6) (1 g, 2.2 mmol),
phenol (8 g, 84 mmol), triethylamine (3 mL) and S-benzyl-cysteamine hydro-
chloride (1 g, 4.9 mmol) afforded a yellow solid (10) (0.7 g, yield 52 %, mp
1
1068C, Mol. Wt.; 500). H NMR (DMSO-d6) d: 1.95 (quint, 2H, J ¼ 7.4 Hz,
H-12), 2.40 (t, 2H, J ¼ 7.4 Hz, H-13), 2.80 (t, 2H, J ¼ 7.4 Hz, H-11), 2.94
(t, 2H, J ¼ 6.7 Hz, H-19), 3.70 (s, 2H, H-20), 3.93 (s, 3H, OCH3), 4.12
(t, 2H, J ¼ 6.7 Hz, H-18), 4.52 (dt, 2H, J ¼ 5.5; 1.3 Hz, H-15), 5.18 (dq, 1H,
J ¼ 10.5; 1.3 Hz, H-17a), 5.26 (dq, 1H, J ¼ 17.3; 1.3 Hz, H-17b), 5.88 (ddt,
1H, J ¼ 17.3; 10.5; 5.5 Hz, H-16), 7.12 (m, 5H, H-22, H-23 and H-24) 7.61
(dd, 1H, J ¼ 9.3; 2.2 Hz, H-6), 7.76 (dd, 1H, J ¼ 8.8; 1.3 Hz, H-3), 7.83 (d, 1H,
J ¼ 2.2Hz, H-8), 7.87 (d, 1H, J ¼ 8.8Hz, H-4), 7.91 (d, 1H, J ¼ 9.3Hz, H-5),
8.17 (brs, 1H, H-1). 13C NMR (DMSO-d6) d 25.78 (C-12), 31.08 (C-20), 32.78

Synthesis of New 9-(N-Substituted)-Acridinamines
691
(C-13), 34.19 (C-19), 35.20 (C-11), 48.16 (C-18), 56.05 (OCH3), 64.15 (C-15),
103.21 (C-8), 112.94 (C-9a), 114.65 (C-8a), 117.53 (C-17), 120.81 (C-4),
122.41 (C-5), 123.31 (C-1), 125.98 (C-6), 126.56 (C-24), 128.00 (C-22), 128.39
(C-23), 132.61 (C-16), 134.33 (C-3), 136.61 (C-10a), 136.38 (C-2), 138.27
(C-21), 139.59 (C-4a), 154.35 (C-9), 155.33 (C-7), 172.07 (C-14). Anal. Calcd.
for C30H32N2O3S: C, 71.97; H, 6.44; N, 5.60. Found: C, 72.20; H, 6.21; N, 5.32.
Allyl 4-f9-[(4,4-diethoxybutyl)amino]-7-methoxy-2-acridinylg
butanoate (11)
Compound (6) (0.5 g, 1.35 mmol) and 2 g of phenol (21 mmol) were intro-
duced into a 100 mL round-bottomed flask. This mixture was stirred at
808C under nitrogen for 1 h 4,4-diethoxy-1-butanamine (0.3 mL) was then
introduced into the reaction mixture. The whole structure was stirred at
808C for 3 h, cooled to rt, and poured into 300 mL of ethyl ether. The
orange precipitate was then filtered and washed with ether. (0.35 g, yield
1
53%, mp 1028C). H NMR (CDCl3, d): 1.17 (t, 6H, J ¼ 7.0 Hz, H-23), 1.82
(td, 2H, J ¼ 7.3; 5.3 Hz, H-20), 2.00 (quint, 2H, H-12), 2.16 (quint, 2H,
J ¼ 7.7 Hz, H-19), 2.40 (t, 2H, J ¼ 7.3 Hz, H-13), 2.74 (t, 2H, J ¼ 7.9 Hz,
H-11), 3.51 (dq, 1H, J ¼ 9.3; 7.1 Hz, H-22a), 3.67 (dq, 1H, J ¼ 9.3; 7.1 Hz,
H-22b),3.93(s, 3H, OCH3), 4.15 (td, 2H, J ¼ 7.2; 5.7 Hz, H-18), 4.58 (dt, 2H,
J ¼ 5.7; 1.4 Hz, H-15), 4.60 (t, 1H, J ¼ 5.2 Hz, H-21), 5.23 (dq, 1H, J ¼ 10.5;
1.4 Hz, H-17a), 5.30 (dq, 1H, J ¼ 17.2; 1.5 Hz, H-17b), 5.90 (ddt, 1H, J ¼ 17.3;
10.5; 5.8 Hz, H-16), 6.86 (dd, 1H, J ¼ 9.2; 2.1 Hz, H-6), 7.43 (brd, 1H,
J ¼ 8.7 Hz, H-3), 7.51 (d, 1H, J ¼ 2.2 Hz, H-8), 7.80 (d, 1H, J ¼ 9.2 Hz, H-5),
7.90 (brs, 1H, H-1), 8.03 (d, 1H, J ¼ 8.7 Hz, H-4), 9.14 (t, 1H, J ¼ 5.7 Hz, NH).
13C NMR (CDCl3, d). 15.42 (C-23), 25.62 (C-19), 26.35 (C-12), 31.19 (C-20),
33.37 (C-13), 35.10 (C-11), 48.41 (C-18), 56.26 (OCH3), 61.99 (C-22), 65.29
(C-15), 102.47 (C-21), 102.56 (C-8), 111.60 (C-9a), 113.63 (C-8a), 118.53
(C-17), 119.83 (C-4), 120.55 (C-5), 123.68 (C-1), 125.98 (C-6), 132.18 (C-16),
133.96 (C-3), 134.61 (C-10a), 136.44 (C-2), 138.06 (C-4a), 154.75 (C-9),
155.62 (C-7), 172.82 (C-14). Anal. Calcd. for C29H38N2O5: C, 70.42; H, 7.74;
N, 5.66. Found: C, 70.11; H, 7.56; N, 5.32.
REFERENCES
1. Neidle, S.; Waring, M. Molecular Aspects of Anticancer Drugs-DNA Interactions;
MacMillan: London; 1994.
2. Shutske, G. M.; Pierrat, F. A.; Kapples, K. J.; Cornfeldt, M. L.; Szewczak, M. R.;
Hugar, F. P.; Boves, G. M.; Haroutunian, V.; Davis, K. L. 9-Amino-1,2,3,4-tetra-
hydroacridin-1-ols. Synthesis and evaluation as potential Alzheimer’s disease
therapeutics. J. Med. Chem. 1989, 32, 1805.

692
G. Roubaud et al.
3. Kimura, M.; Okabayashi, I.; Kato, A. Acridine derivatives. III. Preparation and
antitumor activity of the novel acridinyl-substituted uracils. Chem Pharm. Bull.
1989, 37, 697.
4. Demonchaux, P.; Laayoun, A.; Demeunynck, M.; Lhomme, J. Synthesis of
N-acridinyl and N-quinolinyl derivatives of radioprotective amino-thiols. Tetrahe-
dron 1989, 45, 6455.
5. Wilson, W. R.; Thompson, L. H.; Anderson, R. F.; Denny, W. A. Hypoxia-
selective antitumor agents. 2. Electronic effects of 4-substituents on the mechan-
isms of cytotoxicity and metabolic stability of nitracrine derivatives. J. Med.
Chem. 1989, 32, 31.
6. Galy, A. M.; Galy, J.-P.; Barbe, J.; Sharples, D. Preparation of a series of 9 alky-
laminoacridines and 9-imino-10 alkylacridines and their binding to desoxyribonu-
cleic acid. Arzneim.-Forsch (Drug Res.) 1987, 37, 1095.
7. Brayden, D. J. Controlled release technologies for drug delivery. Drug Discovery
Today 2003, 8, 976.
8. Wang, B.; Bouffier, L.; Demeunynck, M.; Mailley, P.; Roget, A.; Livache, T.;
Dumy, P. New acridone derivatives for the electrochemical DNA-hybridization
labelling. Bioelectrochemistry 2004, 63, 233.
´
´
´
9. Orive, G.; Gascon, A. R.; Hernandez, R. M.; Domınguez-Gil, A.; Pedraz, J. L.
Techniques: New approaches to the delivery of biopharmaceuticals. Trends in
Pharmacological Sciences 2004, 25, 382.
10. Yang, X.; Shen, G.; Yu, R. Q. A fiber optode for p-nitrophenol based on covalently
bound 9-allylaminoacridine. Mikro. Acta 2001, 136, 73.
´
11. Robin, M.; Faure, R.; Perichaud, A.; Galy, J.-P. Synthesis of new thiazolo[5,4-
a]acridine derivatives. Heterocycles 2000, 53, 387.
12. Robin, M.; Galy, J.-P.; Faure, R. 1H and 13C NMR chemical shifts for tetracycle-
fused acridine analogues of amsacrine. Magn. Reson. Chem. 2001, 39, 225.
13. Avellaneda, A.; Robin, M.; Faure, R.; Perichaud, A.; Galy, J.-P. 1H and
´
13C chemical shifts for acridines. Part XVII. (1,3-benzothiazol-2-yl) amino-9-
(10H)-acridinone derivatives. Magn. Reson. Chem. 2002, 40, 545.
14. Roubaud, G.; Faure, R.; Galy, J.-P. 1H and 13C chemical shifts for acridines. Part
XVIII. 9-Chloroacridine and 9-(N-allyl)- and 9-(N-propargyl)acridinamine deriva-
tives. Magn.Reson. Chem. 2003, 41, 549.
15. Ullmann, F. A. new path for preparing diphenylamine derivatives. Chem. Ber.
1903, 36, 2383.
16. Lesnianski, W. Acridone compounds. Bull. Acad. Pol. Chem. 1929, 81, 120.
17. Denny, A.; Rewcastle, G. The synthesis of substituted 9-oxoacridan-4-carboxylic
acids; Part 3. The reaction of methyl anthranilates with diphenyliodonium-2-car-
boxylates. Synthesis 1985, 21, 220.
18. Hurd, R. E. Gradient-enhanced spectroscopy. J. Magn. Reson. 1990, 87, 422.
19. Hurd, R. E.; John, B. K. Gradient-enhanced proton-detected heteronuclear
multiple-quantum coherence spectroscopy, J. Magn. Reson. 1991, 91, 648.
20. Wilker, W.; Leibfritz, D.; Kerssebaum, R.; Bermel, W. Gradient selection in inverse
heteronuclear correlation spectroscopy. Magn. Reson. Chem. 1993, 31, 287.
21. Galy, J.-P.; Faure, R.; Barbe, J.; Elguero. A carbon-13 NMR study of some 9-aminoa-
cridines and their cations in relation with tautomeric problems. J. Spectrosc. Lett. 1988,
21, 809.
22. Kaila, N.; Chen, L.; Thomas, B. E.; Tsao, D.; Tam, S.; Bedard, P. W.;
Camphausen, R. T.; Alvarez, J. C.; Ullas, G. b-C-Mannosides as selectin inhibi-
tors. J. Med. Chem. 2002, 45, 1563.