Synthesis of new mono- and bi-bridged acridine dimers

Article abstract of DOI:10.1055/s-1999-2656

The preparation of new mono- and bi-bridged acridine derivatives by acylation of 4-amino-5-hydroxy-9(10H)-acridinone 6, 4-amino-5-hydroxyacridine 9 and 4-amino-5-propargyloxy-9(10H)-acridinone 7 is reported.

Full text of DOI:10.1055/s-1999-2656

LETTER
641
Synthesis of New Mono- and Bi-bridged Acridine Dimers
Saadia Issmaili, Gérard Boyer,* Jean-Pierre Galy
ESA 6009, Université d’Aix-Marseille III, case 552, Av. Escadrille Normandie-Niemen, 13392 Marseille Cedex 20, France
Fax +33 4.91.28.83.23; E-mail: gerard.boyer@mvcf.u-3mrs.fr
Received 11 January 1999
5'
6
1
2
Abstract : The preparation of new mono- and bi-bridged acridine
COOH
Br
HOOC
6'
4'
3'
5
4
a
derivatives by acylation of 4-amino-5-hydroxy-9(10H)-acridinone
6, 4-amino-5-hydroxyacridine 9 and 4-amino-5-propargyloxy-
9(10H)-acridinone 7 is reported.
NH2
N
H
1'
3
2'
OCH3
NO2
OCH3
NO2
Key words: acridines, bi-bridged compounds, DNA intercalands
3
1
2
O
9
8
1
9a
4a
8a
b
2
3
7
6
3
Acridine derivatives are well known therapeutic agents
due to their wide range of pharmacological and biological
activities, and many bisacridinic compounds have been
reported in the literature.1 We reported previously the
preparation of some mono and bi-bridged acridine
dimers2 and crown ethers3 obtained from amino or hy-
droxy acridines respectively.
10
N
4
10a
5
R1
H
R2
4 R1 = OMe; R2 = NO2 (93%)
5 R1 = OMe; R2 = NH2 (92%)
4 - 7
c
d
e
6 R1 = OH; R2 = NH2 (76%)
7 R1
=
; R2 = NH2 (61%)
OCH2C CH
Scheme 1. a) Na2CO3, Cu, C2H5OH, 3 h, ))), 80 °C; b) PPA, 3
h, 100 °C or H2SO4, 1/2 h, 90 °C; c) SnCl2, HCl, 4 h, reflux; d)
HBr 48 %, 48 h, reflux; e) CH2CCl ≡ CH, Cs2CO3, DMF, 4 h, 60
°C.
Hence we were interested in the preparation of new bisin-
tercalands bridged at positions 4 and 5 using the corre-
sponding amino hydroxy acridine derivatives. Our
approach towards this synthesis was based on the prepara-
tion of the 4-amino-5-hydroxy-9(10H)-acridinone 6 and
4-amino-5-hydroxyacridine 9 followed by N- or O-acyla-
tion with different acyl halides to obtain the desired acri-
din dimers.
a
c
5
The initially applied Ullmann condensation4 method be-
tween o-anisidine 1 and 2-bromo-3-nitrobenzoic acid 25
for the synthesis of 2’-methoxy-3-nitrophenylanthranilic
acid 3 suffered from tedious purification and poor yields;
in contrast, use of ultrasonic irradiation or reflux in
ethanol6 led to more than 60% yield. Cyclisation of an-
thranilic acid 3 with polyphosphoric acid yielded the cor-
responding 5-methoxy-4-nitro-9(10H)-acridinone 4.7
Reduction of 4 and demethylation gave the corresponding
aminohydroxy derivative 6,8 which could be propargylat-
ed to give the 4-amino-5-propargyloxy-9(10H)-acridin-
one 7.9
N
N
R1
NH2
OH
OH
NH
(CH2)n
NH
O
O
8 R1 = OMe (71%)
9 R1 = OH (71%)
b
O
γ
N
ß
NH
α
δ
10a n = 3 (65%)
10b n = 4 (66%)
10c n = 7 (62%)
N
O
NH
O
O
d
To synthesize the 4-amino-5-hydroxyacridine 9 we used
the intermediate methoxy acridinone 5, whose reduction
with sodium amalgam,10 followed by HBr demethylation,
led to 9 in good yield.
(CH2)m
O
(CH2)n
O
O
NH
11a n = 3, m = 4 (30%)
11b n = 3, m = 7 (22%)
11c n = 4, m = 4 (26%)
11d n = 7, m = 7 (16%)
N
We proceeded to the acylation of the 4-amino-5-hydroxy-
acridine 9, but in anhydrous acetone and at room temper-
ature, according to a procedure previously described in
our laboratory on monoamino-acridine dimerisation.2 The
first time, a series of mono bridged acridinic dimers was
obtained using the same acid halides, e.g. the 4.4’-(diami-
no-a",w’"-acyl)-bis-(5-hydroxyacridines) 10a-c.11
Scheme 2. a) i: Na/Hg, NaHCO3, C2H5OH, 3 h, reflux; ii: FeCl3, H2O,
0.5 h; b) HBr 48 %, 24 h, reflux; c) ClCO(CH2)nCOCl, CH3COCH3, 3
h, r.t.; d) i: CH3CH2OTl, C2H5OH, 2.5 h, r.t.; ii: ClCO(CH2)mCOCl,
pyridine, 18 h, r.t.
After acylation of the amino group, we studied the reac-
tivity of the hydroxy group in position 5; the goal was the
Synlett 1999, No. 5, 641–643 ISSN 0936-5214 © Thieme Stuttgart · New York

642
S. Issmaili et al.
LETTER
preparation of macrocylic bisintercalands able to have
new therapeutic properties. We tried first an O-alkylation
by phase transfer catalysis but all our attempts at purifica-
tion of the final products failed.12 According to good re-
sults previously described on mono- and dihydroxy
acridinones in our laboratory we tried alternatively to O-
acylate in pyridine the intermediate thallous salts of 10a-
c.13 Indeed, reaction of two acyl dihalides with the bis-(5-
hydroxyacridines) led to four bi-bridged compounds 11a-
d.14
References and Notes
(1) Johnson, D.S.; Boger D.L. in Comprehensive Supramolecular
Chemistry; Atwood, J.L., Ed.; Pergamon: Oxford, 1996; vol.
4, ch. 3; Wakelin, L.P.G.; Waring, M.J. in Comprehensive
Medicinal Chemistry; Sammes, P.G.; Taylor, J.B., Ed.;
Pergamon: Oxford, 1990; vol. 2, ch. 10.1.
(2) Boyer, G.; Galy J.P.; Barbe J. J. Heterocycl. Chem. 1991, 28,
913. Moisan, M.; Galy J.P.; Galy, A.M.; Barbe J. Monatsh.
Chem. 1993, 124, 23.
(3) Vichet, A.; Patellis A.M.; Galy J.P.; Galy, A.M.; Barbe J.;
Elguero J. J. Org. Chem. 1994, 59, 5156. Dhif D.; Galy J.P.;
Barbe J. Synth. Commun. 1991, 21, 969.
Acylation of compounds 6, 7 was next carried out by re-
action at the amino substituent at position 4. We chose
three acid dichlorides with a variable number of CH2
groups and performed the reaction on the derivatives 6
and 7 in pyridine under reflux,15 because of the best solu-
bility of these acridinones in this solvent. The acylated
mono-bridged bisacridines 12a-f were obtained in posi-
tions 4,4’.16
(4) Corsini, A.; Billo, E.J. J. Inorg. Chem. 1970, 32, 1241.
(5) 2-Bromo-3-nitrobenzoic acid was prepared according to the
literature: Culhane, P.J. Organic Synthese 1927, 1, 125.
(6) See: Hanoun, J.P.; Galy, J.P.; Tenaglia, A. Synth. Commun.
1995, 25, 2443. Compound 3:1H NMR (DMSO-d6) d:3.78 (s,
3H, OCH3), 6.75 (m, 2H, H-3’and H-6’), 7.01 (t, 1H, J = 8.01
Hz, H-5), 7.03 (m, 2H, J = 1.4 Hz, H-4’and H-5’), 8.06 (dd,
1H, J = 8.1 and 1.5 Hz, H-6), 8.21 (dd, 1H, J = 7.7 and 1.5 Hz,
H-4), 10.04 (s, 1H, NH), 11.34 (s, 1H, COOH). 13C NMR
(DMSO-d6) d:117.67 (C-3’), 116.31 (C-6’), 117.82 (C-5),
119.30 (C-1), 120.23 (C-5’), 123.82 (C-4’), 129.41 (C-1’),
130.67 (C-4), 138.58 (C-6), 139.08* (C-3), 139.17* (C-2),
150.10 (C-2’), 168.61 (COOH).
O
(7) See: Brockmann, H.; Muxfeldt, H.; Haese, G. Chem. Ber.
1957, 90, 44.
N
R1
H
NH
(CH2)n
NH
(8) Compound 5:1H NMR (DMSO-d6) d:4.05 (s, 3H, OCH3), 6.00
(s, 2 H, NH2), 7.11 (dd, 1H, J = 8.0 and 7.6 Hz, H-2), 7.21 (t,
1H, J = 8.0 Hz, H-7), 7.24 (dd, 1H, J = 7.5 and 1.4 Hz, H-3),
7.32 (dd, 1H, J = 7.8 and 1.2 Hz, H-6), 7.72 (dd, 1 H, J = 8.1
and 1.4 Hz, H-1), 7.79 (dd, 1H, J = 8.2 and 1.2 Hz, H-8), 9.56
(s, 1H, NH). 13C NMR(DMSO-d6) d:56.35 (OCH3), 112.41
(C- 6), 116.67 (C-1), 117.16 (C-8), 119.64 (C-3), 120.83 (C-
8a), 120.99 (C-7), 121.76 (C-9a), 121.78 (C-2), 130.71 (C-4a),
131.32 (C-10a), 133.64 (C-4), 147.80 (C-5), 176.75 (C-9).
(9) See: Claude, S.; Lehn, J.M.; Perez de Vega, M.J.; Vigneron,
J.P. New J. Chem. 1992, 16, 4.
O
O
ClCO(CH2)nCOCl
6 or 7
pyridine, reflux,
12 h
R1
H
N
12 a - f
O
12a R1 = OH; n = 3 (44%)
12b R1 = OH; n = 4 (52%)
6
7
Compound 7:1H NMR (DMSO-d6) d: 3.70 (t, 1H, J = 2.4 Hz
CH), 5.12 (d, 2H, J = 2.4 Hz, OCH2), 5.79 (s, 2H, NH2), 7.05
(t, 1H, J = 7.5 Hz, H-2), 7.08 (dd, 1H, J = 7.4 and 2.1 Hz, H-
3), 7.21 (t, 1H, J = 8.0 Hz, H-7), 7.43 (dd, 1H, J = 7.8 and 2.4
Hz, H-6), 7.57 (dd, 1H, J = 7.2 and 2.2 Hz, H-1), 7.83 (dd, 1H,
J = 8.2 and 1.1 Hz, H-8), 9.40 (s, 1H, NH).13C NMR (DMSO-
d6) d: 56.61 (OCH2), 78.88 (C), 79.22 (CH), 114.00 (C-6),
114.14 (C- 1), 117.42 (C-3), 118.06 (C-8), 120.43 (C-7),
120.99 (C-8a), 121.61 (C-9a), 121.98 (C-2), 129.82 (C-4a),
131.59 (C-10a), 137.35 (C-4), 145.50 (C-5), 176.86 (C-9).
(10) See reference 4. Compound 8:1H NMR (DMSO-d6) d: 4.04 (s,
3H, OCH3), 6.11 (s, 2H, NH2), 6.88 (dd, 1H, J = 7.2 and 1.3
Hz, H-3), 7.13 (dd, 1H, J = 7.5 and 0.9 Hz, H-6), 7.25 (dd, 1H,
J = 8.4 and 1.3 Hz, H-1), 7.34 (dd, 1H, J = 8.3 and 1.2 Hz, H-
2), 7.46 (dd, 1H, J = 8.5 and 1.0 Hz, H-7), 7.63 (dd, 1H, J = 8.5
and 0.8 Hz, H-8), 8.82 (s, 1H, H-9). 13C NMR(DMSO-d6) d:
55.81(OCH3), 106.66 (C-3), 106.86 (C-6), 113.77 (C-1),
119.77 (C-8), 125.91 (C-7), 127.04 (C-9a), 127.59 (C-8a),
127.65 (C- 2), 134.97 (C-9), 138.62 (C-4a), 139.03 (C-10a),
144.99 (C-4), 155.00 (C-5).
12c R1 = OH; n = 7 (61%)
12d R1
12e R1
12f R1
=
=
; n = 3 (47%)
; n = 4 (50%)
; n = 7 (51%)
OCH2C CH
OCH2C CH
OCH2C CH
=
Scheme 3
The last step was the oxidative coupling of the acetylenic
groups of the propargyloxy-9(10H)acridinones 12d-f,
with cupric acetate in pyridine according to the Lehn
procedure,9 in order to obtain intramolecular diacetylenic
coupling and bi-bridged acridanone macrocycles. Unfor-
tunately all our attempts of purification and characteriza-
tion of the recovered crude oil failed.
In conclusion, we reported the preparation of a new class
of mono- and bi-bridged acridines: the 4,4’-(diamino-a",
w"-acyl)-bis-(5-hydroxy, or propargyloxy-9(10H)-acridi-
nones), and the 4.4’-(diamino-a", w"-acyl) -5,5’-(dioxa-
a"', w"'-acyl) bisacridines; biological testing is now cur-
rently in progress to investigate their therapeutical activi-
ty.
Demethylation with 48% HBr led to the hydroxy derivative
9:1H NMR (DMSO-d6) d: 6.65 (s, 2H, NH2), 6.80 (dd, 1H,
J = 8.1 and 1.5 Hz, H-3), 7.03 (dd, 1H, J = 8.0 and 1.4 Hz, H-
6), 7.19 (dd, 1H, J = 7.9 and 1.5 Hz, H-1), 7.31 (t, 1H, J = 8.0
Hz, H- 2), 7.40 (t, 1H, J = 7.9 Hz, H-7), 7.51 (dd, 1H, J = 8.1
and 1.4 Hz, H-8), 8.79 (s, 1H, H-9), 9.97 (s, 1H, OH). 13
C
NMR d: 106.09 (C-3), 108.49 (C-6), 113.06 (C-1), 117.57 (C-
8), 126.79 (C-7), 127.11 (C-9a), 127.83 (C-2), 134.94 (C-9),
137.83 (C- 10a), 138.18 (C-4a), 145.60 (C-4), 153.08 (C-5).
Synlett 1999, No. 5, 641–643 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of New Mono- and Bi-bridged Acridine Dimers
643
(11) General acylation method: to a solution of 4-amino-5-
hydroxyacridine 9 (1 g, 4.76 mmol) dissolved in anhydrous
acetone (100 ml), was added dropwise at room temperature
the acyl dichloride (1.5 mmol). Then, the stirring was
continued for 3 hours, and the obtained precipitate was filtered
and washed with acetone, followed by hot ethanol. The
corresponding bisacridines 10a-c were obtained.
(C- 1), 131.68* (C-8), 131.68* (C-8a), 131.98* (C-7), 132.49
(C-6), 133.11 (C-3), 133.28 (C-9a), 135.24 (C-10a), 136.63
(C-4a), 143.17 (C-5), 152.90 (C-9), 178.09 (CH2a'), 179.47
(CH2a). Anal. Calcd. for C37H30N4O6: C, 70.93; H, 4.79; N,
8.95. Found: C, 71.07; H, 4.92; N, 9.21.
(15) Matzner, M.; Kurkjy, R.P.; Cotter, R.J. Chem. Rev. 1964, 64,
645.
Spectroscopic data of selected compound: 10b: 1H NMR
(DMSO- d6) d:1.85 (m, 4H, CH2ß), 2.83 (m, 4H, CH2a), 7.16
(d, 2H, J = 7.9 Hz, H-6), 7.49 (t, 2H, J = 7.9 Hz, H-7), 7.55 (t,
2H, J = 7.8 Hz, H-2), 7.59 (d, 2H, J = 7.9 Hz, H-8), 7.77 (d,
2H, J = 8.1 Hz, H-1), 8.82 (d, 2H, J = 8.0 Hz, H-3), 9.03 (s,
(16) General acylation method: to a solution of 6 or 7 (1 g, 4.42
mmol or 1g, 3.78 mmol) in freshly distilled pyridine (30 ml),
was added dropwise at room temperature the acyl dichloride
(2.4 mmol / 2.05 mmol). Stirring was continued for 12 hours
and the solution was poured on ice. The obtained precipitate
was filtered, washed with water, followed by hot ethanol, to
yield the corresponding 4,4’- (diamino-a",w"-acyl)-bis-(5-
hydroxy-9(10H)-acridinones) 12a-c or 4,4’-(diamino-a",w"-
acyl)-bis-(5-propargyloxy-9(10H)acridin- ones) 12d-f.
Spectroscopic data of selected compounds: 12b: 1H NMR
(DMSO-d6) d: 1.92 (m, 4H, CH2ß), 2.75 (m, 4H, CH2a), 7.12
(t, 2H, J = 7.8 Hz, H-7), 7.15 (d, 2H, J = 8.0 Hz, H-6), 7.25 (t,
2H, J = 7.9 Hz, H-2), 7.65 (d, 2H, J = 8.0 Hz, H-8), 7.68 (d,
2H, J = 8.1 Hz, H-3), 8.13 (d, 2H, J = 8.0 Hz, H-1), 10.31 (s,
2H, OH). 13C NMR(DMSO-d6) d:21.61 (CH2ß), 35.18
(CH2a), 116.03 (C-8), 115.87 (C-6), 120.41 (C-7), 121.16 (C-
8a), 121.69 (C-9a), 121.58 (C-2), 123.60 (C-1), 126.02 (C-4),
129.53 (C-3), 131.15 (C-10a), 134.78 (C-4a), 146.33 (C-5),
172.55 (CO), 176.77 (C-9). Anal. Calcd. for C32H26N4O6: C,
68.33; H, 4.63; N, 9.96. Found: C, 68.58; H, 4.86; N, 10.21.
12e:1H NMR (DMSO-d6) d: 1.90 (m, 4H, CH2ß), 2.62 (m, 4H,
CH2a), 3.67 (m, 2H, CH), 5.02 (sbr, 4H, OCH2), 7.22 (t, 2H,
J = 7.9 Hz, H-7), 7.30 (t, 2H, J = 7.8 Hz, H-2), 7.39 (d, 2H, J =
7.9 Hz, H-6), 7.70 (d, 2H, J = 7.5 Hz, H-3), 7.81 (d, 2H, J =
8.1 Hz, H-8), 8.15 (d, 2H, J = 8.0 Hz, H-1), 10.31 (s, 2H, H-
10). 13C NMR(DMSO-d6) d:25.26 (CH2ß), 35.85 (CH2a),
56.89 (OCH2), 78.66 (C), 79.32 (CH), 114.61 (C-6), 145.39
(C-4), 118.13 (C-8), 121.08 (C-7), 121.24 (C-8a and C-9a),
122.00 (C- 2), 123.82 (C-1), 126.33 (C-3), 130.01 (C-4),
131.39 (C-10a), 134.77 (C-4a), 145.39 (C-5), 172.77 (CO),
176.67 (C-9). Anal. Calcd. for C38H30N4O6: C, 71.47; H, 4.70;
N, 8.78. Found: C, 71.72; H, 4.85; N, 9.04.
2H, H-9), 10.68 (s, 2H, NH), 10.71 (s, 2H, OH). 13
C
NMR(DMSO-d6) d: 25.28 (CH2ß), 36.83 (CH2a), 110.56 (C-
6), 116.34 (C-3), 118.20 (C-8), 122.12 (C-1), 126.61 (C-9a),
126.66 (C-7), 127.53 (C-2), 127.34 (C-8a), 134.94 (C-4),
136.86 (C-9), 138.30 (C-10a), 138.73 (C-4a), 153.11 (C-5),
172.61 (CO). Anal. Calcd. for C32H26N4O4: C, 72.45; H, 4.91;
N, 10.57. Found: C, 72.70; H, 5.11; N, 10.83.
(12) Dhif, D.; Galy, J.P.; Barbe, J.; Elguero, J. Heterocycles 1990,
31, 1059.
(13) Taylor, E.C.; Hawaks, G.H.; McKillop, A. J. Am. Chem. Soc.
1968, 90, 9, 2421.
(14) Vidal, R.; Galy, J.P.; Vincent, E.J.; Barbe, J. Synthesis 1988,
2, 148. General acylation method to prepare 11a-d: the 4,4’-
(diamino-a", w"-acyl)-bis-(5-hydroxy acridines) 10a-c (1.94
mmol) were dissolved in hot absolute ethanol (250 ml). After
cooling, thallous ethoxide (3.88 mmol) was added with good
stirring and the mixture kept at room temperature for 2.5 h
more. The red salt obtained was filtered, washed with hot
ethanol and dried. After dissolution of this salt in anhydrous
pyridine (100 ml), the acyl dichloride, (1.3 eq.), was added
dropwise and the mixture kept at room temperature over 18 h.
The solution was filtered and evaporated in vacuo. The
obtained oil was precipitated in acetone, washed with hot
ethanol, filtered and dried. The 4,4’- (diamino-a",w"-acyl)-
5,5’-(dioxa-a"’, w"’-acyl) bis acridines were obtained in 16-
30% yields.
Spectroscopic data of selected compound:11a:1H NMR
(TFA) d:2.61 (m, 4H, CH2ß' and CH2g'), 2.83 (m, 2H, CH2ß),
3.39 (m, 4H, CH2a' and CH2d'), 3.63 (m, 4H, CH2a and CH2g),
8.30 (t, 2H, J = 8.1 Hz, H-7), 8.33 (t, 2H, J = 8.1 Hz, H-2),
8.43 (d, 2H, J = 7.6 Hz, H-6), 8.48 (d, 2H, J = 7.5 Hz, H-3),
8.67 (d, 2H, J = 8.0 Hz, H-8), 8.69 (d, 2H, J = 8.0 Hz, H-1),
10.12 (s, 2H, H-9). 13C NMR(TFA) d:22.42 (CH2g), 26.66
(CH2g'), 36.84 (CH2ß'), 38.50 (CH2ß), 130.34 (C-4), 130.68
* May be reversed
Article Identifier:
1437-2096,E;1999,0,05,0641,0643,ftx,en;G00899ST.pdf
Synlett 1999, No. 5, 641–643 ISSN 0936-5214 © Thieme Stuttgart · New York