Simple and convenient conversion of acridones into 9-unsubstituted acridines via acridanes using borane tetrahydrofuran complex

Article abstract of DOI:10.1016/j.tetlet.2009.09.141

A new method for the synthesis of 9-unsubstituted acridines from acridones using mild conditions is described. Various acridines bearing reduction-sensitive group(s) have been synthesized from the corresponding acridones using a two-step procedure that involved a commercially available borane complex reduction followed by an acridane oxidation.

Full text of DOI:10.1016/j.tetlet.2009.09.141

Tetrahedron Letters 50 (2009) 6894–6896
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Simple and convenient conversion of acridones into 9-unsubstituted
acridines via acridanes using borane tetrahydrofuran complex
Nicolas Desbois a, Anna Szollosi b, Aurélie Maisonial c,d, Valérie Weber c,d, Emmanuel Moreau c,d
,
Jean-Claude Teulade c,d, Olivier Chavignon c,d, Yves Blache e, Jean Michel Chezal c,d,
*
a CRI INSERM 866, F-21079 Dijon, France
b Laboratoire de Chimie Organique et Thérapeutique, EA 3660 Unité de Molécules d’Intérêt Biologique, Faculté de Pharmacie, 7 Boulevard Jeanne d’Arc, BP 89700, 21079 Dijon, France
c Clermont Université, Univ Clermont 1, EA 4231, Clermont-Ferrand F-63001, France
d Centre Jean-Perrin, Clermont-Ferrand F-63011, France
e Laboratoire MAPIEM EA 4323, UFR Sciences et Techniques, Université du Sud Toulon-Var, BP 20132, 83957 La Garde Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A new method for the synthesis of 9-unsubstituted acridines from acridones using mild conditions is
described. Various acridines bearing reduction-sensitive group(s) have been synthesized from the corre-
sponding acridones using a two-step procedure that involved a commercially available borane complex
reduction followed by an acridane oxidation.
Received 4 August 2009
Revised 22 September 2009
Accepted 23 September 2009
Available online 27 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Acridine
Acridone
Borane complex
Reduction
1. Introduction
tives.10 The final steps of all these methods require harsh
conditions such as strong acidic media, high temperatures and/
Acridine derivatives were primarily used as stains for dye man-
ufacturing (e.g., acridine orange) until their fluorescence and
chemiluminescence properties found numerous other applications
(e.g., acridinium salts, lucigenin).1,2 In addition to these optical
properties, this interesting heterocyclic family also displays a
broad range of biological properties including antibacterial,3 anti-
parasitic,4 and antitumor activities.5 Intensive research into this
last area has shown that the substitution on the heterocycle is cru-
cial to specific biological activity, especially in oncology. Depend-
ing on the substituted function introduced, the acridinic
antitumor derivatives include not only DNA-intercalating agents
but also hypoxia-specific drugs (e.g., nitacrine), topoisomerase I
and/or II (e.g., amsacrine, DACA), and telomerase inhibitors.6
Most routes to acridines and their derivatives proceed through
the corresponding acridones (Scheme 1) via a Jourdan–Ullman7 or
Buchwald–Hartwig8 amination reaction. Among the other acridine
synthesis methods that do not involve an acridone step, the most
widely used is the Bernthsen reaction9 between a diphenylamine
and a carboxylic acid in the presence of zinc chloride, and the intra-
molecular cyclization of diphenylamine-2-carboxaldehyde deriva-
or, drastic reductive agents. Consequently, the sensitive functional
groups are usually introduced later on, at specific and limited
positions.
As part of our ongoing research program to develop new target-
ing agents for radionuclide therapy11 of melanoma, we needed to
synthesize various iodoacridine-4-carboxylic acids. The literature
reports only a small number of 9-unsubsituted iodoacridines, all
essentially obtained by direct electrophilic iodination of acridines
bearing activated substituents12,13 or by diazotization and nucleo-
philic displacement with the iodide ion of the corresponding
aminoacridines.12 However, the most satisfactory route to access
to these derivatives appeared to be the two-step transformation
from acridones 1 to acridines 3 via the 9,10-dihydroacridines (or
‘acridanes’) 2 (Scheme 1). Unfortunately, this approach, which
required direct reduction of the corresponding acridone with alu-
minum,7 magnesium,14 phenylphosphine,15 or sodium16 amalgam
in alkali, appeared unsuitable for the synthesis of functionalized
acridines incorporating reduction-sensitive functional groups.
We observed that iodo-substituted acridones led to dehalogenated
derivatives, as previously noted by Atwell for the synthesis of
chloroacridine-4-carboxylic acids.7 To overcome this problem,
we developed an efficient protocol for the conversion of iodoacri-
dones to iodoacridines using borane tetrahydrofuran complex,11
* Corresponding author. Tel.: +33 473150822; fax: +33 47315080.
E-mail address: j-michel.chezal@u-clermont1.fr (J.M. Chezal).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.141

N. Desbois et al. / Tetrahedron Letters 50 (2009) 6894–6896
6895
O
reduction
oxidation
R1
R2
R2
R1
R1
R2
N
H
N
H
N
1
2
3
Scheme 1.
Table 1
Optimization of the reduction of acridone (1a) into acridane (2a) using different borane complexes
O
borane
complex
N
N
H
H
2a
1a
Entry
1a (M)
Borane complex (equiv)
Temperature (°C)
Time (h)
Yielda 2a (%)
1
2
3
4
5
6
7
8
9
0.51
0.51
0.51
0.51
0.51
0.51
0.51
0.10
0.80
0.51
BH3/SMe2 (1.2)
Reflux
Reflux
Reflux
Reflux
Reflux
40
3
18
48
5
1
1
12
1
1
61
BH3/diethyl aniline (1.2)
BH3/diethyl aniline (2.4)
BH3/diethyl aniline (3.2)
BH3/THF (1.2)
BH3/THF (1.2)
BH3/THF (1.2)
BH3/THF (1.2)
BH3/THF (1.2)
BH3/THF (2.4)
10b
21b
54
75
70
rtc
NRd
52
Reflux
Reflux
Reflux
58
71
10
1
a
b
c
Isolated yields after column chromatography (SiO2, CH2Cl2).
Predominantly start product.
rt = room temperature.
d
NR = no reaction.
Table 2
which is commonly used as regio-, chemo-, and stereoselective
reducing agents for a wide range of functional groups. Based on
this initial success, the protocol was tested on other acridone sub-
strates bearing sensitive functional groups, and the results are
reported here.
Reduction of acridones with borane tetrahydrofuran complex
O
8
5
1
4
8
1
4
1/BH3-THF, reflux
R2
R1
R1
R2
N
H
1
N
2/ FeCl3, EtOH/H2O
50 °C
5
2. Results and discussion
3
Producta
3a
R1
R2
Yieldb (%)
The reaction was first carried out with commercially available
acridone and with the three commercially available borane
complex solutions (Table 1, entries 1–5). Results clearly indicated
that borane tetrahydrofuran complex gave the fastest and high-
est-yield reaction. In this study, borane diethyl aniline complex
was the least reactive, requiring 3.2 equiv to complete the reaction
(Table 1, entries 2–4). Gradually decreasing the reaction tempera-
ture resulted in decreasing yields (Table 1, entries 6 and 7),
whereas changes in the concentrations of acridone (1a) or borane
tetrahydrofuran complex did not give better yields (Table 1, entries
8–10).
Entry
Substrate
1
2
3
4
5
6
7
8
9
1a
H
2-Cl
2-Br
2-I
1-NO2
2-NO2
1-CO2Et
3-CO2Et
4-CO2Me
4-CO2Et
4-CO2Et
H
H
H
H
H
H
H
H
59
47
48
83
50
1b18
1c20
1d22
1e24
1f26
1g27
1h27
1i29
1j11
1k11
1l11
3b19
3c21
3d23
3e25
3f25
3g
54
4428
73
3h
3i
7-Br
1-I
6-I
70
65
90
44
10
11
12
3j11
3k11
3l11
4-CONH(CH2)2NEt2
3-I
With the optimized conditions in hand, the reduction of various
acridone compounds was studied, and the results are summarized
in Table 2.17 Preparation of acridines 3a–l was performed by the
addition of a solution of BH3–THF to refluxing tetrahydrofuran
solution of compounds 1a–l. The reactions were maintained at re-
flux for 1 h and then hydrolyzed. The resulting unstable 9,10-dihy-
droacridines 2a–l were classically oxidized to acridines 3a–l with
FeCl3 in yields ranging from 44% to 90%. A quick column chroma-
tography for 9,10-dihydroacridines 2a–l compounds was necessary
to obtain pure acridines 3a–l. This method is compatible with var-
ious substituents such as iodo, chloro, nitro, and ester groups on
the acridone moiety. The high yields and fairly simple reaction
combined with the functional selectivity achieved with borane re-
a
All known compounds were characterized by 1H NMR and 13C NMR and their
spectroscopy profiles were identical to those reported in the literature. For the
others, see Ref. 17.
b
Isolated yields after two steps and column chromatography.
agents make the BH3–THF complex a promising reducing agent for
the conversion of acridones into synthetically and biologically po-
tent acridines. Moreover, this inexpensive and commercially avail-
able complex is environmentally friendly, whereas aluminum or
sodium amalgams are synthesized in the presence of mercuric
chloride, which is very toxic and an environmental hazard.

6896
N. Desbois et al. / Tetrahedron Letters 50 (2009) 6894–6896
without further purification (except for 3g: obtained by chromatographic
References and notes
purification over alumina (CH2Cl2–MeOH 98:2, v/v)). Spectroscopic data of the
final acridines 3: 2-iodoacridine (3d): mp 191–193 °C; IR (KBr) 2365,
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914 cmÀ1 1H NMR (CDCl3, 300 MHz) d 7.55 (t, 1H, J = 8 Hz), 7.84 (m, 1H),
;
7.96 (m, 3H), 8.22 (d, 1H, J = 9 Hz), 8.38 (s, 1H), 8.61 (s, 1H). Ethyl acridine-1-
carboxylate (3g): mp: 115–117 °C; IR (KBr) 1705, 1210 cmÀ1 1H NMR (CDCl3,
;
3. Wainwright, M. J. Antimicrob. Chemother. 2001, 47, 1.
300 MHz) d 1.51 (t, 3H, J = 7 Hz), 4.53 (q, 2H, J = 7 Hz), 7.58 (t, 1H, J = 8 Hz), 7.80
(m, 2H), 8.08 (d, 1H, J = 9 Hz), 8.23 (d, 1H, J = 9 Hz), 8.34 (d, 1H, J = 9 Hz), 8.43
(d, 1H, J = 9 Hz), 10.03 (s, 1H). Ethyl acridine-3-carboxylate (3h): mp: 109–
4. Guetzoyan, L.; Ramiandrasoa, F.; Dorizon, H.; Desprez, C.; Bridoux, A.; Rogier,
C.; Pradines, B.; Perree-Fauvet, M. Bioorg. Med. Chem. 2007, 15, 3278.
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;
J = 7 Hz), 4.46 (q, 2H, J = 7 Hz), 7.55 (t, 1H, J = 7.5 Hz), 7.79 (t, 1H, J = 7.5 Hz),
7.98 (m, 2H), 8.07 (d, 1H, J = 9 Hz), 8.23 (d, 1H, J = 9 Hz), 8.74 (s, 1H), 8.98 (s,
1H). Methyl 7-bromoacridine-4-carboxylate (3i): highly unstable compound;
1H NMR (300 MHz, (CD3)2CO) d 4.02 (s, 3H), 7.66 (m, 1H), 7.90 (d, 1H, J = 9 Hz),
8.06 (m, 2H), 8.26 (d, 1H, J = 9 Hz), 8.36 (s, 1H), 9.02 (s, 1H).
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17. General procedure for the synthesis of acridines 3. The appropriate 9,10-
dihydro-9-oxoacridine (acridone) 1 (0.69 mmol) was dissolved in anhydrous
tetrahydrofuran (2.6 mL) under a slowly flowing argon gas. A 1 M borane
tetrahydrofuran complex solution (0.83 mL, 0.83 mmol) was added dropwise
to the stirred reflux reaction. The mixture was refluxed for 1 h. After cooling to
room temperature, aqueous 3 N hydrochloric acid solution (5 mL) was added
dropwise and the reaction mixture was basified with an aqueous saturated
sodium carbonate solution (20 mL) before being extracted with
dichloromethane (3 Â 20 mL). The organic phases collected were dried
(MgSO4) and filtered, and the solvent was removed under reduced pressure.
The crude unstable product was quickly chromatographed (SiO2, CH2Cl2) to
give the corresponding 9,10-dihydroacridine (acridane) 2. This acridane
(0.38 mmol) was stirred in a mixture of ethanol (10 mL), water (2 mL), and
iron chloride hexahydrate (0.30 g) for 30 min at 50 °C. After cooling to room
temperature, an aqueous saturated sodium bicarbonate solution (20 mL) was
added and the mixture was extracted with dichloromethane (3 Â 30 mL). The
organic layers were dried (MgSO4) and filtered, and the solvent was removed
under reduced pressure to give the expected acridine 3 which could be used
26. Chen, J.; Zhang, J.; Zhuang, Q.; Chen, J.; Lin, X. Electroanalysis 2007, 19, 1765.
27. Stefanska, B.; Bontemps-Gracz, M. M.; Antonini, I.; Martelli, S.; Arciemiuk, M.;
Piwkowska, A.; Rogacka, D.; Borowski, E. Bioorg. Med. Chem. 2005, 13, 1969.
28. In addition to compound 3g, the following by-product was routinely observed:
R1 = CH2OH, R2 = H, 1-hydroxymethylacridine. Yield: 45%; mp: 169–171 °C; IR
(KBr) 3200–3000, 1136 cmÀ1 1H NMR (CDCl3, 300 MHz) d 5.26 (s, 2H), 7.55 (m,
;
2H), 7.67 (m, 1H), 7.79 (m, 1H), 8.02 (d, 1H, J = 8.5 Hz), 8.15 (d, 1H, J = 9 Hz),
8.21 (d, 1H, J = 9 Hz), 9.10 (s, 1H).
29. This compound was obtained from the acid 7-bromo-9,10-dihydro-9-
oxoacridine-4-carboxylic (Spicer, J. A.; Gamage, S. A.; Atwell, G J.; Finlay, G.
J.; Baguley, B. C.; Denny, W. A. J. Med. Chem. 1997, 40, 1919) according to the
procedure developed for the synthesis of methyl 9,10-dihydro-7-nitro-9-
oxoacridine-4-carboxylate described in Ref. 11a. Methyl 9,10-dihydro-7-
bromo-9-oxoacridine-4-carboxylate (1i): yield 60%; mp: 214–216 °C; IR (KBr)
3266, 1691, 1593, 1518, 1277, 1138, 1129 cmÀ1 1H NMR (CDCl3, 200 MHz) d
;
3.99 (s, 3H), 7.40 (t, 1H, J = 7.8 Hz), 7.90 (m, 2H), 8,27 (br s, 1H), 8.45 (dd, 1H,
J = 7.6, 1.6 Hz), 8.53 (d, 1H, J = 7.8 Hz), 11.67 (s, 1H).