Synthesis of new tetracycle fused acridine analogues bearing oxazole ring

Article abstract of DOI:10.1081/SCC-120003145

New acridine derivatives have been prepared via Ullman condensation involving benzoxazole (5) and 2-bromo-benzoic acid. Linear products were obtained. The structure of oxazolo[4,5-b]acridine was determined by NMR spectroscopy.

Full text of DOI:10.1081/SCC-120003145

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SYNTHESIS OF NEW TETRACYCLE FUSED ACRIDINE
ANALOGUES BEARING OXAZOLE RING
Maxime Robin a , Robert Faure a , Alain Périchaud b & Jean-Pierre Galy a
a Laboratoire de Valorisation de la Chimie Fine , Faculté des Sciences et Techniques de Saint
Jérôme , Université d’Aix-Marseille III , Av. Escadrille Normandie-Niemen, Marseille Cedex 3,
Marseille, 13397, France
b Laboratoire de Chimie Macromoléculaire , 3 Place Victor Hugo, Marseille Cedex 3,
Marseille, 13331, France
Published online: 21 Aug 2006.
To cite this article: Maxime Robin , Robert Faure , Alain Périchaud & Jean-Pierre Galy (2002) SYNTHESIS OF NEW TETRACYCLE
FUSED ACRIDINE ANALOGUES BEARING OXAZOLE RING, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 32:7, 981-988, DOI: 10.1081/SCC-120003145
To link to this article: http://dx.doi.org/10.1081/SCC-120003145
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SYNTHETIC COMMUNICATIONS, 32(7), 981–988 (2002)
SYNTHESIS OF NEW TETRACYCLE
FUSED ACRIDINE ANALOGUES
BEARING OXAZOLE RING
Maxime Robin,1, Robert Faure,1 Alain Perichaud,2
*
and Jean-Pierre Galy1
1Laboratoire de Valorisation de la Chimie Fine,
Faculte des Sciences et Techniques de Saint Jerome,
Universite d’ Aix-Marseille III, Av. Escadrille
Normandie-Niemen, 13397 Marseille Cedex 3, France
2Laboratoire de Chimie Macromoleculaire, 3 Place
Victor Hugo, 13331 Marseille Cedex 3, France
ABSTRACT
New acridine derivatives have been prepared via Ullman con-
densation involving benzoxazole (5) and 2-bromo-benzoic
acid. Linear products were obtained. The structure of
oxazolo[4,5-b]acridine was determined by NMR spectroscopy.
In our effort to synthesize acridine derivatives with a wide range of
properties we investigated the opportunities to introduce the oxazole ring
on the acridine skeleton. Many heterocycle-fused acridines have been
synthesized bearing a five1 or six2-membered heterocycle. These compounds
*Corresponding author.
981
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

982
ROBIN ET AL.
Figure 1. Allyl-1-methyl-4-(2-benzoxazolyl)piperazinium iodide CP2289.
possess a variety of biological properties, such as antiviral, antimicrobial,
antitumor properties, enzyme inhibitors and DNA-intercalation.3
Benzoxazoles are important intermediates for the synthesis of fluorescent
whitening agents,4 o-sulfonamidophenol dye-releasers5 in instant color
photography, biological interests in polyethers antibiotics,6 and new
5-HT3 receptor ligand (Figure).7–10
Our synthesis of oxazoloacridine starts with 2-N-dimethylbenzoxazole
3 because the nitration of the commercial 2-chlorobenzoxazole 1 (Scheme 1)
resulted in the formation of 2-hydroxy-4-nitro- and 2-hydroxy-5-nitro-
formanilides (2a, 2b).
Scheme 1. Reagents: (a) HNO3/H2SO4, ꢀ15ꢁC, 1 h; (b) Dimethylamine in
aqueous solution 40% (10 eq.), rt, 2 h.
The 1H and 13C NMR spectra of 2a and 2b were consistent with
their structures and identical to those reported for these compounds.11
2-N-Dimethylbenzoxazole (3)12 instead was not hydrolyzed under Katz13
nitration conditions. We obtained 5- and 6-nitro compounds 4a and 4b in

TETRACYCLE FUSED ACRIDINE ANALOGUES
983
a ratio 2/8 respectively. The major 6-nitro-2-N,N-dimethylbenzoxazole (4b)
was obtain by crystallization from ethanol (52% yield). Hydrogenation of
4b using Pd/C as catalyst at rt14 afforded 5 (93%). The subsequent Ullman–
Goldberg condensation to anthranilic acid (Scheme 2) was usually done
using Copper catalyst for 12 h with poor yield (40–50%).15
Scheme 2. Reagents: (a) EtOH, Pd/C, H2, rt; (b) o-Bromo bezoic acid, 2-butanone,
Cu/Zn, Ultrasonic irradiation, 80ꢁC, 3 h; (c) H2SO4, 120ꢁC, 2 h; (d) POCl3, reflux,
1 h; (e) N-(4-amino-3-methoxy phenyl) methane sulfonamide, EtOH, rt, 12 h; (f )
Ammonium carbonate, Phenol, 80ꢁC, 2 h.
This N-substitution reaction could be improved using the ultra-
sound.16,17 When ultrasound was applied, the reaction of 5 with o-bromo
benzoic acid and Cu/Zn as catalyst18 yielded 6 in 90% (Scheme 2).
The cyclisation of anthranilic acid (6) to acridine derivatives can give
two isomers as described in the literature.1 In our case, we obtained
oxazolo[4,5-b]acridines, the linear compounds (7–8), using a PPA, H2SO4
and POCl3 in 60, 67 and 80% respectively as the sole product. The structure
of these compounds was established using a combination of 1D- and
2D-NMR techniques. The occurrence of ‘‘linear’’ skeleton follows from
the multiplet pattern analysis of 1H data (two singulets for H-4 and
H-11 resonances).19,21 Using compound 8 we synthesized an analogue
(9) of m-Amsacrine,22,23 which is now known to target the enzyme
topoisomerase II (Topo II).24–26 The reaction of 8 with carbonate
ammonium in hot phenol produced in excellent yield (65%) the imino
derivatives 10.27

984
ROBIN ET AL.
EXPERIMENTAL
2-Chlorobenzoxazole and o-bromo benzoic acid were obtained from
commercial suppliers. N-(4-amino-3-methoxy phenyl) methane sulfonamide
was synthesized according to the published procedure.28 All reagents
and solvents were used as received without further purification. Melting
points were determined with an Electrothermal 9300 apparatus and
were uncorrected. The NMR spectra were recorded on a Bruker AC 200
1
spectrometer operating at 200 MHz for H and 13C. Two-D NMR spectra,
both of homonuclear (COSY) and heteronuclear (HMBC, HMQC) cor-
relation, were obtained with a Bruker AMX 400. In all cases TMS was
used as an internal standard.
2-N,N-Dimethylaminobenzoxazole (3): 2-Chlorobenzoxazole (2 g,
13 mmol) and 10 ml of 40% aqueous dimethylamine solution were stirred
at rt for 1 h. The white precipitate formed was filtered and washed
with water to give 3 as pure product (1.88 g, 11.6 mmol, yield 90%,
m.p. 85ꢁC (lit.,9 m.p. 83–84ꢁC), mol. wt.: 162). H NMR (CDCl3, d): 3.12
1
(s, 6H, 2CH3), 6.94 (ddd, 1H, J ¼ 1.1, 6.6, 7.7 Hz, C-H5), 7.10 (ddd,
1H, J ¼ 1.1, 6.6, 7.7 Hz, C-H6), 7.20 (dd, 1H, J ¼ 1.1, 7.7 Hz, C-H7), 7.31
(dd, 1H, J ¼ 1.1, 7.7 Hz, C-H4). 13C NMR (CDCl3, d): 37.5 (C-a), 108.4
(C-7), 115.8 (C-6), 120.4 (C-4), 123.7 (C-5), 143.5 (C-3a), 149.0 (C-7a),
162.9 (C-2).
2-N,N-Dimethylamino-6-nitro-benzoxazole (4b): This compound was
prepared according to the method described by Katz,13 by nitration of 3
(1.5 g, 9.3 mmol) with 5 ml of HNO3 in 10 ml of H2SO4 at 0ꢁC. The yellow
reaction mixture was poured into ice water and neutralized with 16%
NH4OH; the yellow precipitate which formed was collected by filtration
to give 1.8 g of 5-, and 6-nitro compounds (4a and 4b) 20/80, yield 93%.
The mixture was crystallized from ethanol (10 ml) to give 4b (1 g, 4.8 mmol,
yield 52%, m.p. 182ꢁC, mol. wt.: 207). H NMR (Cd-Cl3, d): 3.21 (s, 6H,
1
2aCH3), 7.21 (d, 1H, J ¼ 8.25 Hz, C-H4), 8.03 (d, 1H, J ¼ 2.2 Hz, C-H7), 8.13
(dd, 1H, J ¼ 2.2, 8.8 Hz, H5). 13C NMR (Cd-Cl3, d): 37.6 (C-a), 104.8 (C-7),
114.5 (C-4), 121.3 (C-5), 140.9 (C-6), 148.0 (C-7a), 150.4 (C-3a), 165.5 (C-2).
Anal. calcd for C9H9N3O3: C, 52.17; H, 4.38; N, 20.28. Found: C, 52.18; H,
4.42; N, 20.35.
2,6-Bis(N,N-Dimethylamino)benzoxazole (5): (4b) (1 g, 4.8 mmol), 0.1 g
of Pd/C catalyst was placed in 85 ml of ethanol. The solution was placed
under hydrogen atmosphere and vigorously stirred for 2 h. The reaction was
monitored by TLC (CH2Cl2/MeOH 9/1). After complete consumption of
starting materials, the resulting solution was filtered and the filtrate was
concentrated under vacuum to give 5 as pure product (0.8 g, yield 93%,
m.p. 165ꢁC, mol. wt.: 177). H NMR (DMSO-d6, d): 3.01 (s, 6H, 2aCH3),
1

TETRACYCLE FUSED ACRIDINE ANALOGUES
985
4.84 (s, 2H, NH2), 6.40 (dd, 1H, J ¼ 2.2, 8.25 Hz, C-H5), 6.63 (d, 1H,
J ¼ 2.2 Hz, C-H7), 6.94 (d, 1H, J ¼ 8.25 Hz, C-H4). 13C NMR (DMSO-d6,
d): 37.6 (C-a), 95.6 (C-7), 110.5 (C-4), 115.7 (C-5), 133.7 (C-3a), 143.6 (C-6),
149.9 (C-7a), 161.3 (C-2). Anal. calcd for C9H11N3O: C, 61.00; H, 6.26; N,
23.71. Found: C, 59.87; H, 6.31; N, 23.56.
2-{[2-(Dimethylamino)-benzoxazole-6-yl]amino}-benzoic acid (6): (5)
(0.7 g, 6 mmol), o-bromobenzoic acid (1.41 g, 7 mmol), anhydrous potassium
carbonate (1.11 g, 8 mmol), powdered copper catalyst (0.05 g), and ethyl
methyl ketone (15 ml) were placed in a 250 ml round-bottomed flask. This
mixture was sonicated in a bath (80ꢁC) for 3 h. The solution was concen-
trated in vacuo, the brown residue stirred in hot water (80 ml), filtered, and
the filtrate acidified to pH 5 with 2N aqueous hydrochloric acid. The green
precipitate was filtered and washed with water to give pure (6) without
any further purification (1.6 g, yield 90%, m.p. 224ꢁC, mol. wt.: 297).
1H NMR (DMSO-d6, d): 3.09 (s, 6H, 2aCH3), 6.67 (ddd, 1H, J ¼ 1.1,
7.7 Hz, C-H11), 6.98 (m, 2H, C-H5, C-H10), 7.28 (m, 2H, C-H4, C-H9),
7.30 (s, 1H, C-H7), 7.86 (dd, 1H, J ¼ 7.7 Hz, C-H12), 9.54 (s, 1H, N-H8).
13C NMR (DMSO-d6, d): 37.5 (C-a), 105.3 (C-4), 111.6 (C-12a), 113.2 (C-9),
115.8 (C-5), 116.7 (C-11), 120.2 (C-7), 132.0 (C-12), 133.3 (C-6), 134.5
(C-10), 140.5 (C-3a), 149.0 (C-7a), 149.3 (C-8a), 163.1 (C-2), 170.4 (C-13).
Anal. calcd for C16H15N3O3: C, 64.64; H, 5.09; N, 14.13. Found: C, 64.51;
H, 5.10; N, 14.26.
2-(Dimethylamino)-oxazolo[4,5-b]acridin-10(5H)-one (7): Compound (6)
(0.22 g, 0.75 mmol) in H2SO4 (5 ml) was stirred at 120ꢁC for 2 h. The solu-
tion was poured onto ice water and neutralized with (10%) ammonia, the
resulting green precipitate was filtered off, washed with water, and
crystallized from ethanol to give (7) (0.15 g, yield 67%, m.p. >260ꢁC,
1
mol. wt.: 279). H NMR (DMSO-d6, d): 3.13 (s, 6H, 2aCH3), 7.19 (ddd,
1H, J ¼ 1.1, 7.25 Hz, C-H8), 7.41 (s, 1H, C-H11), 7.45 (dd, 1H, J ¼ 8.25 Hz,
C-H6), 7.65 (ddd, 1H, J ¼ 1.1, 7.3 Hz, C-H7), 7.90 (s, 1H, C-H4), 8.20
(dd, 1H, J ¼ 7.95 Hz, C-H9), 11.75 (s, 1H, N-H5). 13C NMR (DMSO-d6,
d): 37.6 (C-a), 96.7 (C-4), 109.5 (C-11), 117.1 (C-6), 118.4 (C-10a), 119.6
(C-9a), 120.8 (C-8), 126.0 (C-9), 133.0 (C-7), 136.3 (C-11a), 137.2 (C-4a),
140.7 (C-5a), 153.7 (C-3a), 161.9 (C-2), 176.2 (C-10). Anal. calcd
for C16H12N3O2: C, 69.06; H, 4.35; N, 15.10. Found: C, 69.24; H, 4.21;
N, 15.04.
10-Chloro-2-N,N-dimethylamino-oxazolo[4,5-b]acridine (8): Compound
(6) (0.6 g, 2 mmol) and POCl3 (20 ml, 220 mmol) were introduced into a
100 ml round-bottomed flask and heated at 80ꢁC for 15 min, and then the
solution was heated to 120ꢁC for 30 min. The solution was allowed to cool
to rt and the excess of POCl3 was eliminated with petroleum spirit (60–80ꢁC,
200 ml). The resulting orange syrupy oil was poured onto ice (100 g) and

986
ROBIN ET AL.
neutralized with 10% ammonia. The precipitate was collected by filtration,
dried, to give (8) as a red powder (0.5 g, yield 80%, m.p. 218ꢁC, mol. wt.;
298). 1H NMR (Cd-Cl3, d): 3.24 (s, 6H, 2aCH3), 7.53 (dt, 1H, J ¼ 7.5 Hz, C-
H8), 7.66 (dt, 1H, J ¼ 6.4 Hz, C-H7), 7.85 (s, 1H, C-H4), 8.04 (s, 1H, C-H11),
8.12 (d, 1H, J ¼ 7.85 Hz, C-H6), 8.33 (d, 1H, J ¼ 8.8 Hz, C-H9). 13C NMR
(Cd-Cl3, d): 37.9 (C-a), 105.1 (C-4), 106.1 (C-11), 123.6 (C-9a), 123.7 (C-
10a), 124.4 (C-9), 129.0 (C-6), 129.4 (C-7), 126.3 (C-8), 139.3 (C-10), 146.1
(C-11a), 146.5 (C-4a), 147.1 (C-5a), 153.6 (C-3a), 165.0 (C-2). Anal. calcd
for C16H12ClN3O: C, 64.54; H, 4.06; N, 14.11. Found: C, 64.62; H, 4.11; N,
14.08.
N-4-[(N,N-Dimethyl-2-amine-oxazolo[4,5-b]acridin-11(6H)-ylidene)
amino]-3-methoxy phenyl methane sulfonalide (9): (8) (1 g, 3.3 mmol) and N-
(4-amino-3-methoxyphenyl)methanesulfonamide (0.76 g, 3.5 mmol) were
mixed in ethanol (100 ml) overnight and stirred at rt. The orange precipitate
obtain was filtered to give (9) as an orange powder (1.2 g, yield 75%,
m.p. >260ꢁC, mol. wt.; 478). 1H NMR (DMSO-d6, d): 3.09 (s, 3H,
(CH3)20), 3.15 (s, 6H, 2(CH3)23), 3.48 (s, 3H, (CH3)21), 7.00 (d, 1H,
J ¼ 7.15 Hz, C-H17), 7.02 (s, 1H, C-H15), 7.37 (dt, 1H, J ¼ 6.6 Hz, C-H8),
7.45 (d, 1H, J ¼ 8.8 Hz, C-H6), 7.76 (s, 1H, C-H11), 7.84 (d, 1H, C-H18), 7.92
(dt, 1H, J ¼ 6.6 Hz, C-H7), 8.12 (d, 1H, J ¼ 8.8 Hz, C-H9), 10.10 (s, 1H,
N-H19), 10.71 (s, 1H, N-H5). 13C NMR (DMSO-d6 þ TFA, d): 37.6 (C-23),
39.4 (C-20), 55.8 (C-21), 96.9 (C-4), 104.2 (C-15), 106.9 (C-11), 111.7
(C-10a), 112.0 (C-17), 112.7 (C-9a), 118.9 (C-6), 123.6 (C-8), 124.5 (C-9),
124.8 (C-13), 127.9 (C-18), 134.3 (C-7), 136.7 (C-4a), 138.6 (C-5a), 139.6
(C-16), 142.8 (C-11a), 154.3 (C-14), 154.5 (C-10), 154.5 (C-3a), 164.2 (C-2).
Anal. calcd for C24H23N5O4S: C, 60.36; H, 4.85; N, 14.67. Found: C, 60.54;
H, 4.69; N, 14.31.
10-Imino-2-N,N-dimethylamino-5,10-dihydro-oxazolo[4,5-b]acridine (10):
To a stirred solution of 8 (0.6 g, 2 mmol) in phenol (2 g, 21 mmol) heated
at 80ꢁC was added ammonium carbonate (0.21 g, 2.2 mmol), and
then the solution was heated to 120ꢁC for 2 h. The reaction mixture
was allowed to cool rt, acetone (40 ml) was introduced and stirred for
2 h. The green precipitate formed was collected and washed in hot water,
filtered to afford (10) as green powder (0.36 g, yield 65%, m.p. >260ꢁC,
mol. wt.; 278). 1H NMR (DMSO-d6 þ TFA, d): 3.13 (s, 6H, 2(CH3)13), 7.45
(dt, 1H, J ¼ 6.5 Hz, C-H8), 7.69 (s, 1H, C-H4), 7.82 (m, 2H, C-H6,7), 8.23 (s,
1H, C-H11), 8.59 (d, 1H, J ¼ 8.1 Hz, C-H9), 9.65 (bs, 1H, N-H12), 13.99 (s, 1H,
N-H5). 13C NMR (DMSO-d6 þ TFA, d): 37.8 (C-13), 97.1 (C-4), 107.2 (C-
10a), 109.6 (C-11), 109.7 (C-9a), 118.6 (C-6), 123.7 (C-8), 124.8 (C-9), 134.7
(C-7), 136.3 (C-4a), 138.7 (C-5a), 141.7 (C-11a), 154.5 (C-3a), 154.8 (C-10),
163.7 (C-2). Anal. calcd for C16H14N4O: C, 69.05; H, 5.07; N, 20.13. Found:
C, 69.12; H, 5.14; N, 20.47.

TETRACYCLE FUSED ACRIDINE ANALOGUES
ACKNOWLEDGMENT
987
I thank the ‘‘Conseil Regional PACA’’ and ‘‘Catalyse’’ for a scholar-
ship (nꢁ: 9811/2200).
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Received in the USAApril 5, 2001